EA040442B1 - USE OF THE COMPOUND IN THE TREATMENT OF DRY EYES OR EYE DISCOMFORT - Google Patents

Description

State of the art

Dry Eye Disease (DED) is a medical condition that affects millions of people worldwide. Approximately 40 million people in North America suffer from some form of dry eye, and many more millions worldwide. DED results from disruption of the natural tear film on the surface of the eye and can lead to eye discomfort, visual impairment, and reduced quality of life associated with vision. Patients with severe cases of DED are at risk of serious eye health problems such as corneal ulceration and may experience a deterioration in quality of life comparable to moderate to severe angina.

In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is administered as the free base. In some embodiments, (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine is administered as a pharmaceutically acceptable salt of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine. In some embodiments, the pharmaceutically acceptable salt is the galactate or citrate salt. In some embodiments, the pharmaceutically acceptable salt is the galactarate salt. In some embodiments, the pharmaceutically acceptable salt is the citrate salt. In some embodiments, the pharmaceutically acceptable salt is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine monocitrate salt.

In some embodiments, the dose of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is 500 μg to 10 mg per dose.

In some embodiments, said use further comprises local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or assist in the recovery of a peripheral nicotinic acetylcholine receptor from a desensitized state. In some embodiments, said one or more substances are selected from the group consisting of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, the calcineurin inhibitor is selected from the group consisting of cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered without any form of nicotine.

In some embodiments, 500 μg to 5 mg of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, less than 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, 1 to 3 mg of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, 500 μg to 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, 1 to 2 mg of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, about 1 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered. In some embodiments, about 1.5 mg of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, about 2 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof, is administered.

In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered as needed according to symptoms. In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least once a day. In some embodiments, (R)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least twice a day. In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least once a week.

In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, balm or nasal spray. In some embodiments, (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, device for spray powder, steam inhaler, patch, medicated stick, dropper, nasal spray bottle or liquid jet. In some variants of reality

(R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered as a nasal pharmaceutical formulation containing 5 to 200 mg/ml (R) -5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical dosage form for nasal administration contains from 10 to 75 mg/ml of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments, the nasal pharmaceutical formulation contains 10 to 50 mg/mL of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In some embodiments, the dose of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is 500 μg to 10 mg per dose.

Methods for treating the ophthalmic disorders described herein comprise local administration of a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) binds to the peripheral nicotinic acetylcholine receptor, providing a local effect. Although a small amount of a compound of formula (I), (II), (IIIa) or (IIIb) may enter the systemic circulation, this amount is not sufficient to cause a systemic pharmacological effect. In addition, the dose sizes of a compound of formula (I), (II), (IIIa) or (IIIb) required for the treatment of ophthalmic diseases in an individual in need thereof are significantly lower than the amounts required to produce a systemic pharmacological effect in such an individual. . Indeed, the amount of a compound of formula (I), (II), (IIIa) or (IIIb) that produces a systemic pharmacological effect in an individual will generally desensitize the peripheral nicotinic acetylcholine receptor in the individual's nasal cavity and therefore will not provide an effective treatment. ophthalmic diseases.

In some embodiments, the invention provides a method of increasing tear fluid production comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) binds to a peripheral nicotinic acetylcholine receptor, and a compound of formula (I) has a structure

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR3;

R1 is hydrogen, C ₁ . ₆ alkyl, halo, -OR4, -SR4 or -NR5R6;

R2 is hydrogen, C1. ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl) or cycloalkyl;

R3 is hydrogen, C ₁ . ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl), cycloalkyl, -OR ₇ , -SR ₇ , -NR8R9, -SOR7 or -SO2R7, wherein the C _1-6 alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from halogen, - CN, -NO2, -NH ₂ , -OH, -OR7, -CO ₂ H, -C(O)OR ₇ , -OC(O)R ₇ , -NR8R9, -NHC(O)R ₇ , -C( O)NR8R9, -SR7, -S(O)R7, -SO2R7, -NHSO2R7, -SO2NR8R9, -C(S)NR8R9, -NHC(S)R7 and -O-SO2R7;

R4, R5 and R ₆ are independently hydrogen or C _1-6 alkyl; And

R ₇ , R8 and R9 are hydrogen, C _1-6 alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), heterocycloalkyl, -C _1-6 alkyl(heterocycloalkyl) or cycloalkyl, wherein the C _1-6 alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10, -NR10R11, -CF3, -CN, -NO2, -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(O)NR _w Rii, -NRioC(= 0)R _w , -C(=0)Rio, -C(=O)OR _W , -(CH2)OR _w , -(CH2)2OR _w , -OC(=O)R _w , -OC(=O )NR _w R _n and -NR _W C(=O)OR _W ;

R ₁₀ and R 11 are independently hydrogen, C _1-6 alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R8 and R9 or _R10 and R11 together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4;

q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to

- 2 040442 the nasal cavity of an individual in need thereof, wherein X is N. In some embodiments, a method for increasing lacrimal fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein R2 is hydrogen. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein R1 is hydrogen, _C1 . ₆ αkyl, -OR ₄ or -NR5R6. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein R1 is hydrogen. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein q is 1. In some embodiments, a method of increasing tear fluid production is provided, comprising local administration a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein p is 2. In some embodiments, a method of increasing lacrimal fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need of in this, with the wavy line denoting the E geometry around the double bond. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is (R)-5-((E)- 2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of increasing tear fluid production is provided comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the nitrate salt of (R)-5-((E )-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the monocitrate salt of (R)-5-((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the HCl salt of (R)-5-((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is (R)-5-((E )-2-pyrrolidin3-ylvinyl)pyrimidine.

In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier. at the pharmacologically relevant concentration. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype, selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount which is not systemically bioavailable. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need of

- 3 040442 this, and the compound of formula (I) selectively binds to the peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In some embodiments, the invention further provides a method of treating dry eye, comprising topical administration of a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) binds to a peripheral nicotinic acetylcholine receptor, and a compound of formula (I) has the structure:

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR3;

R1 is hydrogen, C _1-6 alkyl, halo, -OR4, -SR4 or -NR5R6;

R2 is hydrogen, C _1-6 alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl) or cycloalkyl;

R3 is hydrogen, C _1-6 αkyl, aryl, -C1. ₆ alkyl(aryl), -aryl(C _{1 .6} alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl), cycloalkyl, -OR7, -SR7, -NR ₈ R ₉ , -SOR7 or -SO2R7, with C1. ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups optionally substituted with one or more substituents selected from halo, -CN, -NO2, -NH2, -OH, -OR7, -CO2H, -C(O)OR7, -OC(O) R7, -NR8R9, -NHC(O)R7, -C(O)NRsR9, -SR7, -S(O)R7, -SO2R7, -NHSO2R7, -SO2NR8R9, -C(S)NR8R9, -NHC(S) R7 and -O-SO2R7;

R ₄ , R5 and R ₆ are independently hydrogen or C1. ₆ alkyl; And

R7, _R8 and _R9 are hydrogen, C1. ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl) or cycloalkyl, with C ₁ . ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10, -NR10R11, -CF3, -CN, -NO2, -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(0)NRioRii, -NRioC(=0)Rio, -C(=O)R10, -C(=O)OR10, -(CH)ORio, -(CH^ ORio, -0C(=0)Rio, -0C(=0)NRioRii and -NRioC(=0)0Rio;

R ₁₀ and R11 are independently hydrogen, C1. ₆ alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R ₈ and R ₉ or R ₁₀ and R11 together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4 and q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein X is N. In some embodiments, a method of treating dry eye is provided, comprising topical administration of a therapeutically an effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein R ₂ is hydrogen. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein R ₁ is hydrogen, C1. ₆ alkyl, -OR4 or -NR5R6. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein R ₁ is hydrogen. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein q is 1. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective an amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein p is 2. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the wavy line represents the E geometry around the double bond. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is (R)-5-((E)-2 -pyrrolidin-3ylvinyl)pyrimidine. In some embodiments, a method for treating dry eye is provided, including

- 4 040442 local administration of a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the citrate salt of (R)-5-((E)-2-pyrrolidine-3- ilvinyl)pyrimidine. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the monocitrate salt of (R)-5-((E) -2-pyrrolidin-3ylvinyl)pyrimidine. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the HCl salt of (R)-5-((E) -2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the galactarate salt of (R)-5-((E) -2-pyrrolidin-3ylvinyl)pyrimidine.

In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier into pharmacologically relevant concentration. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount which is not systemically bioavailable. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that is not leads to unwanted psychoactive side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that is not leads to unwanted systemic side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes local effect.

In some embodiments, the invention also provides a method of alleviating eye discomfort comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) binds to a peripheral nicotinic acetylcholine receptor, and the compound formula (I) has the structure:

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR ₃ ;

R1 is hydrogen, C ₁ . ₆ alkyl, halogen, -OR ₄ , -SR ₄ or -NR ₅ R ₆ ;

R2 is hydrogen, C ₁ . ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl) or cycloalkyl;

R ₃ is hydrogen, C1. ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl), cycloalkyl, -OR ₇ , -SR7, -NR8R9, -SOR ₇ or -SO2R7, wherein C ₁ . ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups optionally substituted with one or more substituents selected from halo, -CN, -NO2, -NH2, -OH, -OR7, -CO2H, -C(O)OR7, -OC(O) R7, -NR8R9, -NHC(O)R7, -C(O)NR8R9,

- 5 040442

-SR7, -S(O)R7, -SO2R7, -NHSO2R7, -SO2NR8R9, -C(S)NR8R ₉ , -NHC(S)R7 and -O-SO2R7;

R4, R ₅ and R ₆ are independently hydrogen or C ₁ . ₆ alkyl; And

R7, _R8 and R9 are hydrogen, _C1-6alkyl , aryl, _{-C1_6alkyl} (aryl), -aryl( _{C1_6alkyl} ), heteroaryl, _{-C1_6alkyl} (heteroaryl), -heteroaryl( _{C1_6alkyl} ), heterocycloalkyl, _{-C1_6} alkyl(heterocycloalkyl) or cycloalkyl, wherein the _C1-6 alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10, -NR10R11, -CF3, -CN, -NO2, -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(O)NRioR _n , -NR _W C(=O)R _W , -C(= O)R ₁ o, -C(=O)OR _W , -(CH2)OR10, -(CH ₂ ) ₂ O^0, -OC(=O)R _w , -OC(=O) No. _p and - _NRW C(=O)OR _W ;

R ₁₀ and R 11 are independently hydrogen, C _1-6 alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R ₈ and R _g or R ₁₀ and R 11 together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4;

q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein X is N. In some embodiments, a method of alleviating eye discomfort is provided, comprising local administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein R2 is hydrogen. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein R1 is hydrogen, C _1-6 alkyl, -OR4, or -NR5R6. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein R ₁ is hydrogen. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein q is 1. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein p is 2. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need of in this, with the wavy line denoting the E geometry around the double bond. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is (R)-5-((E)- 2-pyrrolidin-3ylvinyl)pyrimidine. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the citrate salt of (R)-5-((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the monocitrate salt of (R)-5-((E )-2-pyrrolidin3-ylvinyl)pyrimidine. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is the HCl salt of (R)-5-((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) is (R)-5-((E )-2pyrrolidin-3-ylvinyl)pyrimidine.

In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier. at the pharmacologically relevant concentration. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype, selected from alpha3beta4, alpha4beta2 and alpha7.

- 6 040442

In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount which is not systemically bioavailable. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In some embodiments, the invention further provides a method of increasing tear fluid production, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein the compound of formula (II) binds to a peripheral nicotinic acetylcholine receptor, and the compound formula (II) has the structure:

Formula (11);

where R1 is C ₁ . ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₈ heterocycloalkyl, C ₃ _ ₈ cycloalkyl or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C 1_ ₆ alkyl, C ₂ balkenyl, C ₂ .balkynyl, C _3-8 heterocycloalkyl, C ₃ - ₈ cycloalkyl, heteroaryl, aryl, -C 1- ₆ alkyl (aryl), -aryl (C 1- ₆ alkyl), heteroaryl, -C 1- ₆ alkyl (heteroaryl), - heteroaryl( _C1-6 alkyl), halogen, -CN, -NO2, -Or ₃ , -NR4R5, -CF ₃ , -C2R ₃ , -SR ₃ , -N ₃ , -C(O)NR ₄ R ₅ , - NR ₄ C(O)R ₃ , -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R ₅ , -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R2 is Bond or -CH2-;

R ₃ is hydrogen, C ₁ . ₆ alkyl, C ₃ _ ₈ cycloalkyl, C ₃ _ ₈ heterocycloalkyl, aryl, -C1_ ₆ alkyl(aryl), -aryl(C1_ ₆ alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C ₁ . ₆ αalkyl, C ₃ _ ₈ cycloalkyl, C ₃ _ ₈ heterocycloalkyl, aryl, -C1_ ₆ alkyl(aryl), -aryl(C1_ ₆ alkyl) or heteroaryl; or R ₄ and R 5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of increasing tear fluid production is provided comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein R1 is heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C1- ₆ alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C1_ ₆ alkyl (aryl), -aryl (C1_ ₆ alkyl), heteroaryl, - C1_ ₆ alkyl (heteroaryl), -heteroaryl (C1_ ₆ alkyl), halogen, -CN, -OR ₃ , -NR4R5, -CF ₃ , -C(O)NR4R ₅ , -NR4C(O)R ₃ , -C( O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR4R ₅ , -NR ₄ C(O)OR ₃ , -SO2R ₃ , -NR4SO2R5 and -SO2NR4R5. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein R1 is 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl , 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5 -yl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl or 4-pyridinyl. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein R2 is a Bond. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein R ₂ is -CH ₂ -. In some embodiments, a method for increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound

- 7 040442 formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane.

In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier. at the pharmacologically relevant concentration. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype, selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount which is not systemically bioavailable. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In some embodiments, the invention further provides a method of treating dry eye, comprising topical administration of a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) binds to a peripheral nicotinic acetylcholine receptor, and a compound of formula (II) has a structure about

Formula (II);

where R1 is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _{1- 6} alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₈ heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl) , heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR ₄ R ₅ , -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N ₃ , -C(O)NR4R ₅ , -NR4C(O)R3, -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R3, -OC( O)NR4R ₅ , -NR4C(O)OR3, -SO2R3, -NR4SO2R5, -SO2NR4R5;

R ₂ is Bond or -CH ₂ -;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R ₄ and R ₅ are independently hydrogen, C _1-6 αkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl; or R4 and _R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein R1 is heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _{1 - 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl) , heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -OR ₃ , -NR4R5, -CF ₃ , -C(O)NR ₄ R ₅ , - NR ₄ C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR ₄ R ₅ , -NR ₄ C(O) OR ₃ , -SO ₂ R ₃ , -NR ₄ SO ₂ R ₅ and -SO ₂ NR4R ₅ . In some embodiments, a method for treating dry eye is provided, comprising topical administration of a therapeutically effective amount of a compound of the formula

- 8 040442 (II) into the nasal cavity of the individual in need thereof, wherein R ₁ is 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol5-yl or 4-pyridinyl. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein R2 is a Bond. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein R2 is -CH2-. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein the compound of formula (II) is N-(5-chlorofuran-2-ylcarbonyl)- 3,7-diazabicyclo[3.3.0]octane.

In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood brain barrier into pharmacologically relevant concentration. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount which is not systemically bioavailable. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that is not leads to unwanted psychoactive side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that is not leads to unwanted systemic side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes local effect.

In some embodiments, the invention further provides a method of alleviating eye discomfort, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein the compound of formula (II) binds to a peripheral nicotinic acetylcholine receptor, and the compound formula (II) has the structure:

O

Formula (II);

where Ri is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _{1- 6} alkyne, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl) , heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -Or ₃ , -NR ₄ R ₅ , -CF ₃ , -C2R3, -SR ₃ , -N ₃ , -C(O)NR ₄ R ₅ , -NR ₄ C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR ₄ R ₅ , -NR4C(O)OR ₃ , -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R2 is Bond or -CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

- 9 040442 or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein R1 is heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C C _1-6 alkyne, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -OR ₃ , -NR4R5, -CF ₃ , -C(O)NR ₄ R5, -NR4C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR ₄ R ₅ , -NR ₄ C(O)OR ₃ , -SO2R3, -NR ₄ SO ₂ R ₅ and -SO2NR4R5. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein R1 is 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl , 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl or 4-pyridinyl. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein R2 is a Bond. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein R2 is -CH2-. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein the compound of formula (II) is N-(5-chlorofuran-2ylcarbonyl)-3 ,7-diazabicyclo[3.3.0]octane.

In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier. at the pharmacologically relevant concentration. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) to the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype, selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount which is not systemically bioavailable. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In some embodiments, the invention further provides a method of increasing tear fluid production, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) binds with a peripheral nicotinic acetylcholine receptor, and the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O)n;

- 10 040442

Z is hydrogen, C^alkyl or C1-6haloalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R1 is -OR ₃ , -NR ₄ R ₅ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl is optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -nO ₂ , -OR ₃ , -NR4R5, -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N ₃ , -C(O)NR4R ₅ , -NR4C(O)R3, -C(O)R ₃ , -C(O)OR3, -OC(O)R ₃ , -OC(O)NR4R ₅ , -NR4C (O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R ₂ is -CH ₂ - or -CH2CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl (C _1-6 alkyl) or heteroaryl; And

R4 and _R5 are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl) , -aryl(C _1-6 alkyl) or heteroaryl; or R4 and _R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a method is provided for increasing tear fluid production, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein p is 1 and q is 0. In some embodiments, a method is provided. increasing tear fluid production, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein p is 0 and q is 1. In some embodiments, a method of increasing tear fluid production is provided, comprising local administration of a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein R ₂ is -CH ₂ -. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein R2 is -CH2CH2-. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein Z is hydrogen. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein Z is C _1-6 alkyl. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein X is C(O).

In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to at least at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa), or

- 11 040442 (IIIb) into the nasal cavity of the individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to undesirable systemic side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In some embodiments, the invention further provides a method of treating dry eye, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) binds to peripheral nicotinic acetylcholine receptor, and the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O) _n ;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R1 is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl is optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyne, C _2-6 alkenyl , C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO ₂ , -OR ₃ , -NR4R5, -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N ₃ , - C(O)NR4R5, -NR4C(O)R3, -C(O)R ₃ , -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4C0OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R ₂ is -CH ₂ - or -CH ₂ CH ₂ -;

R ₃ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl (C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein p is 1 and q is 0. In some embodiments, a method of treating dry eye, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein p is 0 and q is 1. In some embodiments, a method of treating dry eye is provided, comprising local administration of a therapeutically an effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein R ₂ is -CH2-. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein R ₂ is -CH ₂ CH ₂ -. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein Z is hydrogen. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein Z is C _1-6 alkyl. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein X is C(O).

In some embodiments, a method for treating dry eye is provided, comprising a local

- 12 040442 administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier into pharmacologically relevant concentration. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In some embodiments, the invention further provides a method of alleviating eye discomfort comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) binds with a peripheral nicotinic acetylcholine receptor, and the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O) _n ;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R1 is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl _{. _ _ _ _ _} , C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C1-6alkyl), halogen, -CN, -NO2, -OR3, -NR4R5, -CF3, -C2R3, -SR3, -N3, -C(O)NR4R5, -NR4C(O )R3, -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4COOR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R ₂ is -CH ₂ - or -CH2CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl (C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a method is provided for alleviating eye discomfort comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein p is 1 and q is 0. In some embodiments, a method is provided. relief of discomfort in the eyes, including local administration

- 13 040442 a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein p is 0 and q is 1. In some embodiments, a method for alleviating eye discomfort is provided, comprising local administration of a therapeutically effective amount compounds of formula (IIIa) or (IIIb) into the nasal cavity of the individual in need thereof, wherein R2 is -CH2-. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein R ₂ is -CH ₂ CH ₂ -. In some embodiments, a method for alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein Z is hydrogen. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein Z is C _1-6 alkyl. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein X is C(O).

In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at pharmacologically relevant concentrations. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to at least at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and in an amount that causes a local effect.

In a further embodiment of any of the aforementioned embodiments, said method further comprises locally administering one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In a further embodiment of any of the aforementioned embodiments, said method further comprises locally administering one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or assist in restoring the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, said one or more substances are selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, pAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus.

In another embodiment of any of the above embodiments, less than 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments, 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In a different

- 14 040442 embodiment of any of the above embodiments, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity.

In a further embodiment of any of the above embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is administered over at least two days.

In a further embodiment of any of the above embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered as needed. In another embodiment of any of the above embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is administered as needed, according to symptoms. In another embodiment of any of the above embodiments, the timing or frequency of administration of a compound of formula (I), (II), (IIIa) or (IIIb) is provided or adjusted to prevent desensitization of the nicotinic acetylcholine receptors.

In a further embodiment of any of the above embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion. or balm. In a further embodiment of any of the above embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette or liquid jet.

In a further embodiment of any of the above embodiments, activation of the trigeminal nerve occurs. In a further embodiment, activation of the anterior ethmoid nerve occurs.

In a further embodiment of any of the above embodiments, activation of the nasolacrimal reflex occurs.

In some embodiments, this document further provides a pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) has the structure:

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR3;

R1 is hydrogen, C _1-6 alkyl, halo, -OR4, -SR4 or -NR5R6;

R ₂ is hydrogen, C _1-6 alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), heterocycloalkyl, -C _1-6 alkyl(heterocycloalkyl) or cycloalkyl;

R3 is hydrogen, C _1-6 alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _{1 -6} alkyl), heterocycloalkyl, -C _1-6 alkyl (heterocycloalkyl), cycloalkyl, -OR7, -SR7, -NR8R9, -SOR7 or -SO2R7, wherein the C _1-6 alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from halo, -CN, -NO ₂ , -NH ₂ , -OH, -OR7, -CO ₂ H, -C(O)OR7, -OC(O)R7, -NR8R9, -NHC( O)R7, -C(O)NR ₈ R9, -SR7, -S(O)R7, -SO2R7, -NHSO2R7, -SO2NR ₈ R9, -C(S)NR ₈ R9, -NHC(S)R7 and -O-SO2R7;

R4, R5 and R6 are independently hydrogen or C _1-6 αkyl; And

R ₇ , R ₈ and R9 are hydrogen, C _1-6 alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl) , -heteroaryl(C _1-6 alkyl), heterocycloalkyl, -C _1-6 alkyl(heterocycloalkyl) or cycloalkyl, wherein the C _1-6 alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of from F, Cl, Br, I, R _w , -NR10R11, -CF3, -CN, -NO ₂ , -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(O)NR _W R11, - NR _w C(=O)R10, -C(=O)R _w , -C(=O)OR _w , -(CH ₂ )OR10, -(CH ₂ ) ₂ OR _w , -OC(=O)R _W , -OC(=O)NR _w R _n and -NR _W C(=O)OR _W ;

R ₁₀ and R 11 are independently hydrogen, C _1-6 alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or

- 15 040442 either R8 and R9 or Rjo and Rn together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4;

q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein X is N In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) for preventing desensitization of peripheral nicotinic acetylcholine receptors, wherein R ₂ is is hydrogen. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein R| is hydrogen, C _1-6 alkyl, -OR ₄ or -NR5R6. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) for preventing desensitization of peripheral nicotinic acetylcholine receptors, wherein R1 is hydrogen . In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein q is 1. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein p is 2. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, with the wavy line representing the E geometry around the double bond. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) ) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) ) is the citrate salt of (R)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) ) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate salt. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) ) is the HCl salt of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) ) is the galactarate salt of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine.

In some embodiments, this document further provides a pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at a dose that is not systemically bioavailable. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, containing

- 16 040442 squeezing the compound of formula (I) formulated in dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at a dose that does not lead to unwanted psychoactive side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at such a dose, which does not lead to unwanted systemic side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at such a dose, which has a local effect.

In some embodiments, this document further provides a pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (II) has the structure o

Formula (II);

where R1 is C _1-6 alkyl, C ₂ balkenyl, C ₂ balkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl , -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR ₄ R ₅ , -CF ₃ , -C2R ₃ , -SR ₃ , -N ₃ , -C(O)NR ₄ R ₅ , -NR ₄ C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , - OC(O)NR ₄ R ₅ , -NR4C(O)OR ₃ , -SO2R ₃ , -NR4SO2R5, -SO2NR4R5;

R2 is Bond or -CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein R ₁ is heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _{1 -6} alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), halogen, -CN, -OR3, -NR4R5, -CF3, -C(O)NR4R ₅ , -NR4C(O)R3, -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R ₅ , -NR4C( O)OR ₃ , -SO2R ₃ , -NR4SO2R5 and -SO2NR4R5. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein R1 is 2 -furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3 -yl, 1,2,4oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4thiadiazol-2-yl, 1,2 ,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl or 4-pyridinyl. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein R2 is a Bond . In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein R ₂ is -CH ₂ -. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors,

- 17 040442 wherein the compound of formula (II) is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane.

In some embodiments, this document further provides a pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at a dose that is not systemically bioavailable. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at such a dose, which does not lead to unwanted psychoactive side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at such a dose, which does not lead to unwanted systemic side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at such a dose, which has a local effect.

In some embodiments, this document further provides a pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O) _n ;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R1 is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl _{. _ _ _ _ _} , C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO ₂ , -OR ₃ , -NR ₄ R ₅ , -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N ₃ , -C(O)NR4R5, -NR4C(O)R3, -C(O)R ₃ , -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4C(O) OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R ₂ is -CH ₂ - or -CH ₂ CH ₂ -;

R ₃ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl (C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein p is 1; and q is 0. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) for preventing desensitization of peripheral nicotinic acetylcholine receptors, wherein p is 0 and q is 1. In some embodiments, a pharmaceutical dosage form is provided for topical administration to

- 18 040442 the nasal cavity of the individual, containing the compound of formula (IIIa) or (IIIb), formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and R2 represents -CH ₂ -. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein R ₂ is -CH ₂ CH ₂ -. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein Z is hydrogen. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein Z is C^alkyl. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein X is C(O). In some embodiments, this document further provides a pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at a dose that is not systemically bioavailable. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at a dose that does not lead to unwanted psychoactive side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and at a dose that does not lead to unwanted systemic side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, and in such a dose that causes a local effect.

In some embodiments, said pharmaceutical dosage form further comprises one or more of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus.

In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated into a dosage form (a) for nasal administration and (b) for prevention of desensitization of peripheral nicotinic acetylcholine receptors, wherein said pharmaceutical dosage form does not contain nicotine in any form. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated into a dosage form (a) for nasal administration and (b) for preventing desensitization of peripheral nicotinic acetylcholine receptors, wherein said pharmaceutical dosage form does not contain nicotine free base, nicotine salt, nicotine complex or nicotine solvate. In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated into a dosage form (a) for nasal administration and (b) for preventing desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2, and alpha7. In some embodiments, implementation pharmaceutical dosage form contains about 1 mg/ml of the compounds of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the pharmaceutical dosage form contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some variants of reality

- 19 040442 the pharmaceutical dosage form contains less than 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form contains 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form contains 1 mg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form contains about 1 mg of a compound of formula (I), (II), (IIIa), or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form contains about 1.5 mg of a compound of formula (I), (II), (IIIa), or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form contains about 1 mg of a compound of formula (I), (II), (IIIa), or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form contains about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the pharmaceutical dosage form is administered at least once a day. In some embodiments, the pharmaceutical dosage form is administered at least twice a day. In some embodiments, the pharmaceutical dosage form is administered over at least two days. In some embodiments, the pharmaceutical dosage form is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm. In some embodiments, the pharmaceutical dosage form is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette, or liquid jet.

It should also be understood that certain features of the present invention, which are described in the context of separate embodiments for clarity, may also be presented in combination in one embodiment. Conversely, various features of the present invention, which for brevity are described in the context of a single embodiment, may also be presented individually or in any suitable subcombination.

Additional embodiments, features and advantages of the present invention will become apparent from the following detailed description and from practice of the invention.

For brevity, the contents of publications cited in this specification, including patents, are incorporated herein by reference in their entirety.

Brief description of graphic materials

In FIG. 1 shows the toxicokinetic parameters of compound 1 after TID (three times a day) administration to rats on day 1 and day 7.

In FIG. 2 is a diagram of corneal surface separation for measuring fluorescein uptake.

In FIG. 3 shows an example of a questionnaire.

Detailed description of the invention

Methods for treating the ophthalmic disorders described herein comprise local administration of a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) binds to the peripheral nicotinic acetylcholine receptor, providing a local effect. Although a small amount of a compound of formula (I), (II), (IIIa) or (IIIb) may enter the systemic circulation, this amount is not sufficient to cause a systemic pharmacological effect. In addition, the dose sizes of a compound of formula (I), (II), (IIIa) or (IIIb) required for the treatment of ophthalmic diseases in an individual in need thereof are significantly lower than the amounts required to produce a systemic pharmacological effect in such an individual. . Indeed, the amount of a compound of formula (I), (II), (IIIa) or (IIIb) that produces a systemic pharmacological effect in an individual will generally desensitize the peripheral nicotinic acetylcholine receptor in the individual's nasal cavity and therefore will not provide an effective treatment. ophthalmic diseases. In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

The etiology of DED is becoming increasingly clear. DED is a progressive disease in nature, and is fundamentally caused by insufficient tear coating on the surface of the eye. Insufficient tear coating interferes with healthy gas exchange and nutrient transport to the surface of the eye, accelerates cellular dehydration, and creates an inadequate refractive surface for vision. Insufficient tear coverage is usually due to: 1) insufficient production of tear fluid in the lacrimal glands (eg, due to postmenopausal hormone deficiency, autoimmune disease, LASIK laser correction, etc.) and/or 2) excessive tear fluid evaporation due to dysfunction of the meibomian glands. The low volume of tears results in a hyperosmolar environment that causes an inflamed condition of the ocular surface. This inflammatory response induces apoptosis of surface cells, which in turn prevents proper distribution of the tear film over the surface of the eye, so that any

- 20 040442 this volume of tears becomes less effective. The result is a vicious circle in which more inflammation can cause more damage to surface cells, and so on. In addition, the neural control loop that controls reflex activation of tear fluid production is disrupted by damage to sensory neurons in the ocular surface. As a result, less tear fluid is produced, and a second vicious circle occurs, leading to further progression of the disease (less tear fluid causes loss of nerve cells, which leads to a decrease in tear fluid, etc.).

There are many drugs for the treatment of DED, however, none of them provides sufficient effectiveness for the treatment of this pathological condition. Treatment options include: artificial tear substitutes, ointments, gels, warm compresses, environmental modification, topical cyclosporine, omega-3 fatty acid supplements, punctal occluders, and wet-chamber goggles. Patients with severe disease can be further treated with punctal cauterization, administration of systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, PROSE scleral contact lenses, and tarsorrhaphy. Despite the availability of these treatment options, DED continues to be considered one of the most difficult to treat diseases in ophthalmology. Accordingly, it is desirable to have a more effective agent for the treatment of dry eye.

Nicotinic acetylcholine receptors are cholinergic receptors found in the central nervous system (CNS), peripheral nervous system (PNS), and skeletal muscle. These receptors are ligand-gated ion channels with binding sites for acetylcholine and other molecules. When a nicotinic acetylcholine receptor agonist binds to said receptor, it stabilizes the open state of the ion channel, allowing an influx of cations such as potassium, calcium and sodium ions.

Acting on the central nervous system, systemic nicotinic acetylcholine receptor agonists are gaining more attention as potential drugs for the treatment of many disorders such as Alzheimer's disease, Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder (ADHD) and nicotine dependence, but systemic effects of these agents acting on the central nervous system is associated with various unwanted psychoactive side effects, including anxiety, depression and irritability.

This document describes methods for the treatment of ophthalmic diseases and/or improvement of the surface of the eyes, comprising the local administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, wherein said agonist selectively binds to a peripheral nicotinic acetylcholine receptor, and wherein said agonist nicotinic acetylcholine receptor is a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) binds to a peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration, and is administered in an amount that is not systemically bioavailable. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration, and is administered in an amount that does not result in unwanted psychoactive effects. side effects. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration, and is administered in an amount that does not result in unwanted systemic effects. side effects. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration, and is administered in an amount that causes a local effect. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

Prolonged or repeated exposure to a stimulus often leads to a decrease in the sensitivity of the receptor to the stimulus, and this effect is called desensitization. After prolonged exposure of the nicotinic acetylcholine receptor to an agonist, the agonist itself has been described to cause an agonist-induced conformational change in the receptor, resulting in desensitization of the receptor.

This document describes methods for the treatment of ophthalmic diseases and/or improvement of the surface of the eyes, including the local introduction of a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need of it, when

- 21 040442 than the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor, and further comprising the local administration of one or more substances that prevent the transition or promote the recovery of the nicotinic acetylcholine receptor from the desensitized states. This document also describes methods for the treatment of ophthalmic diseases and/or improvement of the surface of the eyes, including local administration of a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, and the compound formulas (I), (II), (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor, and further comprising the local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or promote recovery nicotinic acetylcholine receptor from a desensitized state. In some embodiments, said one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state are selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA), or factors which activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

This document further describes pharmaceutical dosage forms for topical administration to the nasal cavity of an individual containing a compound of formula (I), (II), (IIIa) or (IIIb) formulated to prevent desensitization. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof. This document also describes pharmaceutical dosage forms for topical administration to the nasal cavity of an individual, additionally containing one or more substances that prevent the transition or help restore the nicotinic acetylcholine receptor from a desensitized state. This document also describes pharmaceutical dosage forms for topical administration to the nasal cavity of an individual, further containing one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state. This document also describes pharmaceutical dosage forms for topical administration to the nasal cavity of an individual, further containing one or more substances that prevent the transition or help restore the nicotinic acetylcholine receptor from a desensitized state, and the specified one or more substances are selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. Also described herein are pharmaceutical dosage forms for topical administration to the nasal cavity of an individual, further comprising one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state, wherein said one or more substances are selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors.

Increased production of tear fluid.

In some embodiments, provided herein is a method for increasing tear production in a subject. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa)

- 22 040442 or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of increasing tear fluid production is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that produces a local effect. In some embodiments, a method for increasing tear fluid production is provided, further comprising locally administering one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of increasing tear fluid production is provided, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state.

In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)2-pyrrolidine-3 -ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine in the form of a free base. In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the citrate salt of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidine- monocitrate salt 3-ylvinyl)pyrimidine. In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5((E)-2-pyrrolidine galactate salt -3-ylvinyl)pyrimidine. In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the hemigalactarate salt of (R)-5-((E)-2- pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the method for increasing tear fluid production described herein, said compound of formula (I), (II), (IIIa), or (IIIb) is

- 23 040442 is the monohydrate of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine hemigalactate salt. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate dihydrate (R)-5-((E)-2-pyrrolidin-3ylvinyl) pyrimidine.

In some embodiments, a method of increasing tear fluid production is provided, further comprising local administration of one or more substances that prevent the transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method of increasing tear fluid production is provided, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing tear fluid production is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for increasing tear fluid production is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for increasing tear fluid production is provided, further comprising topical administration of a calcineurin inhibitor. In some embodiments, a method for increasing tear fluid production is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for increasing tear fluid production is provided, further comprising topical administration of cyclosporine. In some embodiments, a method for increasing tear fluid production is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for increasing tear fluid production is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 5 μg to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 10 μg to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing tear fluid production into the nasal

- 24 040442 5 μg to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 5 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 5 μg to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 25 to 60 μg of the compound is administered into the nasal cavity.

- 25 040442 formulas (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production, 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear production, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above

1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 750 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above method embodiments increase the production of lacrimal fluid in the nasal cavity is administered from 1 to 100 μg of the compounds of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above embodiments of the method for increasing tear fluid production, 1 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb) In another embodiment, a pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical drug

- 27 040442 form for use in this method contains from about 10 to 50 mg/ml of the compounds of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered over at least two days. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, the compound

- 28 040442 formulas (I), (II), (IIIa) or (IIIb) are administered for at least twenty-one days. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a gel. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a lotion. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, devices for spraying powder, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments

A compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a patch. In another embodiment of any of the above embodiments of a method for increasing tear fluid production, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, activation of the trigeminal nerve occurs. In an additional embodiment of the method for increasing tear fluid production, the anterior ethmoid nerve is activated. In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the nasolacrimal reflex is activated. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing tear fluid production, the condition being alleviated by increasing tear fluid production is an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Dry eye treatment.

In some embodiments, provided herein is a method for treating dry eye in a subject. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method for treating dry eye is provided, comprising locally administering a therapeutically effective amount of

- 30 040442 unity of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need of it, and the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of treating dry eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that produces a local effect. In some embodiments, a method for treating dry eye is provided, further comprising topical administration of one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of treating dry eye is provided, further comprising topical administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3ylvinyl )pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutically acceptable salt. In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine in the form of a free base. In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the citrate salt of (R)-5-((E)-2pyrrolidine-3 -ylvinyl)pyrimidine. In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidine monocitrate salt -3-ylvinyl)pyrimidine. In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)-2-pyrrolidine -3ylvinyl)pyrimidine. In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidine galactarate salt -3-ylvinyl)pyrimidine. In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidine hemigalactate salt -3-ylvinyl)pyrimidine. In some embodiments of the method for treating dry eye described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate salt monohydrate (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate dihydrate (R)-5-((E)-2-pyrrolidine-3- ilvinyl)pyrimidine.

In some embodiments, a method of treating dry eye is provided, further comprising topical administration of one or more substances that prevent transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP -dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method of treating dry eye is provided, further comprising topical administration of one or more substances that prevent or reduce the transition of a nicotinic acetylcholine receptor to a desensitized state, or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In not

- 31 040442 which embodiments provide a method for treating dry eye, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for treating dry eye is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for treating dry eye is provided, further comprising topical administration of a calcineurin inhibitor. In some embodiments, a method for treating dry eye is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for treating dry eye is provided, further comprising topical administration of cyclosporine. In some embodiments, a method for treating dry eye is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for treating dry eye is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of a method for treating dry eye, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the dry eye treatment method, 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 5 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 10 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 5 to 50 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 100 to 750 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable thereof.

- 32 040442 wash the salt.

In another embodiment of any of the above embodiments of the dry eye treatment method, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the dry eye treatment method, 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 1 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 15 to 75 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 25 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 25 to 60 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity.

In another embodiment of any of the above embodiments of a method for treating dry eye, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 1 to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for treating dry eye, 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments, the

For the treatment of dry eyes, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 1 μg to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the dry eye treatment method, 1 μg to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for treating dry eye, 1 μg to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for

- 34 040442 changes in this method contains about 6 mg/ml of the compounds of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method of treatment

- 35 040442 dry eye compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered twice daily. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered over at least two days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least twenty one days. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream , paste, lotion or balm. In another embodiment of any of the above embodiments of a method for treating dry eye, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a gel. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of a method for treating dry eye, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of a method for treating dry eye, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a lotion. In another embodiment of any of the above method implementations

The compound of formula (I), (II), (IIIa) or (IIIb) is administered in the nasal cavity in the form of a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, device for powder spray, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the dry eye treatment method, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity using a patch. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of a method for treating dry eye, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, activation of the trigeminal nerve occurs. In a further embodiment of the dry eye treatment method, the anterior ethmoid nerve is activated. In another embodiment of any of the above embodiments of the dry eye treatment method, the nasolacrimal reflex is activated. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for treating dry eye, the condition ameliorated by treating dry eye is an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

Relief of discomfort in the eyes.

In some embodiments, provided herein is a method for alleviating eye discomfort in a subject. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method is provided for alleviating eye discomfort,

- 37 040442 comprising local administration of a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of alleviating eye discomfort is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that produces a local effect. In some embodiments, a method for alleviating ocular discomfort is provided, further comprising local administration of one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of alleviating eye discomfort is provided, further comprising locally administering one or more substances that prevent or reduce the transition of a nicotinic acetylcholine receptor to a desensitized state, or assist in restoring the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidine-3- ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidine-3- ylvinyl)pyrimidine in free base form. In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the citrate salt of (R)-5-((E)-2- pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the monocitrate salt of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some variants

- 38 040442 method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)-2- pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the galactarate salt of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidin- 3-ylvinyl)pyrimidine. In some embodiments of the method for alleviating eye discomfort described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2 hemigalactate salt monohydrate -pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5((E)-2-pyrrolidin-3-ylvinyl hemigalactarate dihydrate )pyrimidine.

In some embodiments, a method of alleviating ocular discomfort is provided, further comprising local administration of one or more substances that prevent transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC), or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method of alleviating eye discomfort is provided, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for alleviating ocular discomfort is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for alleviating eye discomfort is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for alleviating eye discomfort further comprising topical administration of a calcineurin inhibitor is provided. In some embodiments, a method for alleviating eye discomfort is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for alleviating eye discomfort further comprising topical administration of cyclosporine is provided. In some embodiments, a method for alleviating eye discomfort is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for alleviating eye discomfort is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with dry eye disease. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with symptoms of dry eye disease. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with symptoms of dry eye disease; wherein said symptoms are selected from itching, dryness, photophobia, blurring, pain, stickiness, burning, stinging, and foreign body sensation. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with blepharitis. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with dysfunction of the meibomian gland. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with allergic conjunctivitis. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with toxicity and irritation of the ocular surface. In another embodiment of any of the aforementioned embodiments of the method for alleviating eye discomfort, said eye discomfort is associated with impaired tear fluid outflow. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with eyelid disorders. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutical

- 39 040442 a ceutically acceptable salt.

In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, said eye discomfort is associated with an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 10 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 5 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 25 μg to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 50 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort in

100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity In another embodiment of any of the above embodiments of the method for alleviating discomfort in the eyes, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 75 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 5 to 75 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 25 to 60 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 mg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above

1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity in the third embodiment of the method for alleviating eye discomfort. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating discomfort in the eyes in the eyes, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, 1 to 50 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb).

- 42 040442

In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, pharmaceuticals

- 43 040442 tic dosage form for use in this method is about 10-150 µl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered over at least two days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least twenty one days. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In another embodiment of any of the aforementioned method implementations, it is easier

A compound of formula (I), (II), (IIIa) or (IIIb) is administered in the nasal cavity as a suspension to relieve discomfort in the eyes. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a gel. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a lotion. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, devices for spraying powder, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity using a patch. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for alleviating eye discomfort, activation of the trigeminal nerve occurs. In a further embodiment of the method for alleviating eye discomfort, the anterior ethmoid nerve is activated. In another embodiment of any of the above embodiments of the method for alleviating eye discomfort, the nasolacrimal reflex is activated. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

Improvement of the surface of the eye.

In some embodiments, provided herein is a method for healing the surface of the eyes in a subject. In some embodiments, a method for improving the surface of the eye is provided, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound is

Mules (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method of ocular surface health is provided comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) to the nasal cavity of an individual in need thereof, wherein the compound of formula (I), ( II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that produces a local effect. In some embodiments, a method of ocular surface health is provided, further comprising locally administering one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of ocular surface health is provided, further comprising local administration of one or more substances that prevent or reduce the transition of a nicotinic acetylcholine receptor to a desensitized state, or assist in restoring the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments of the method of improving the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidin-3-ylvinyl )pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of the method of improving the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidin-3-ylvinyl )pyrimidine in the form of a free base. In some embodiments of the method of improving the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a citrate salt of (R)-5-((E)-2-pyrrolidine -3

- 46 040442 ylvinyl)pyrimidine. In some embodiments of the method of improving the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a monocitrate salt of (R)-5-((E)-2-pyrrolidine -3-ylvinyl)pyrimidine. In some embodiments of the ocular surface health method described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)-2-pyrrolidine -3ylvinyl)pyrimidine. In some embodiments of the method of improving the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a galactarate salt of (R)-5-((E)-2-pyrrolidine -3-ylvinyl)pyrimidine. In some embodiments of the ocular surface treatment method described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidine hemigalactate salt -3ylvinyl)pyrimidine. In some embodiments of the method of improving the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate salt monohydrate (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate dihydrate (R)-5-((E)-2-pyrrolidine-3- ilvinyl)pyrimidine.

In some embodiments, a method of ocular surface health is provided, further comprising topical administration of one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC), or factors that activate or up-modulate PKC, cAMP -dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method of ocular surface health is provided, further comprising topical administration of one or more substances that prevent or reduce the transition of a nicotinic acetylcholine receptor to a desensitized state, or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for improving the surface of the eye is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method of ocular surface health is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for improving the surface of the eye is provided, further comprising local administration of a calcineurin inhibitor. In some embodiments, a method of ocular surface health is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for improving the surface of the eye is provided, further comprising topical administration of cyclosporine. In some embodiments, a method for improving the surface of the eye is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for improving the surface of the eye is provided, further comprising topical administration of tacrolimus. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the ocular surface health method, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface treatment method, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, at least 500 μg of a compound of formula (I), (II), (IIIa) is injected into the nasal cavity

- 47 040442 or (IIIb). In another embodiment of any of the above embodiments of the ocular surface treatment method, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eye, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 10 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 5 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. surface of the eyes in the nasal cavity enter from 25 to 1000 μg of the compounds of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the ocular surface health method, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eye, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eye, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eye, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 μg to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 μg to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 5 to 100 μg of a compound of formula

- 48 040442 (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 25 to 60 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 mg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eye, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the ocular surface health method, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 100 μg to 10

- 49,040,442 mg of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, from 1 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical

- 50 040442 dosage form for use in this method contains about 50 mg/ml of the compounds of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 µl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least two days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In a different

- 51 040442 embodiment of any of the above embodiments of the method of improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least twenty one days. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream , paste, lotion or balm. In another embodiment of any of the above embodiments of a method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In another embodiment of any of the above embodiments of the method for improving the surface of the eye, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a gel. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a cream. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a paste. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a lotion. In another embodiment of any of the above embodiments of a method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, device for powder spray, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a spray pump. In another variant

- 52 040442 implementation of any of the above embodiments of the method of improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a patch. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, activation of the trigeminal nerve occurs. In an additional embodiment of the method for improving the surface of the eyes, activation of the anterior ethmoid nerve occurs. In another embodiment of any of the above embodiments of the method for improving the surface of the eyes, the nasolacrimal reflex is activated. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the ocular surface remediation method, the condition being alleviated by ocular surface remediation is an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Protection of the eye surface under adverse environmental conditions.

In some embodiments, provided herein is a method for protecting the surface of an eye in a subject under adverse environmental conditions. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and binds selectively to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method for protecting the surface of the eye under adverse environmental conditions is provided, comprising locally administering a therapeutically effective amount of a compound.

- 53 040442 of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need of it, and the compound of formula (I), (II), (IIIa) or (IIIb) does not pass through the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that produces a local effect. In some embodiments, a method for protecting the surface of the eye under adverse environmental conditions is provided, further comprising local administration of one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments of the harsh environmental eye protection method described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)- 2-pyrrolidin-3-ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine in free base form. In some embodiments of the method for protecting the surface of the eyes under adverse environmental conditions described herein, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a citrate salt of (R)-5-((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for protecting the surface of the eye under adverse environmental conditions described herein, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a monocitrate salt of (R)-5-((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for protecting the surface of the eye under adverse environmental conditions described herein, the specified compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E )-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for protecting the surface of the eye under adverse environmental conditions described herein, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a galactarate salt of (R)-5-((E )-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for protecting the surface of the eye under adverse environmental conditions described herein, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a hemigalactarate salt of (R)-5-((E )-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for protecting the surface of the eye under adverse environmental conditions described herein, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a monohydrate of hemigalactarate salt (R)-5 ((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method described in

- 54 040442 of this document, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine hemigalactarate dihydrate.

In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of protecting the ocular surface under adverse environmental conditions is provided, further comprising local administration of one or more substances that prevent transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA), or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method is provided for protecting the surface of the eyes under adverse environmental conditions, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state, selected from a protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for protecting the ocular surface under adverse environmental conditions is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for protecting the ocular surface under adverse environmental conditions is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for protecting the surface of the eye under adverse environmental conditions is provided, further comprising local administration of a calcineurin inhibitor. In some embodiments, a method is provided for protecting the surface of the eye under adverse environmental conditions further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for protecting the surface of the eye under adverse environmental conditions is provided, further comprising local administration of cyclosporine. In some embodiments, a method for protecting the ocular surface under adverse environmental conditions is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for protecting the surface of the eyes under adverse environmental conditions is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions in the nose

- 55 040442 at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 10 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 5 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the ocular surface under adverse environmental conditions, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above options implementing a method for protecting the surface of the eyes under adverse environmental conditions, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

- 56 040442

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 25 to 60 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 mg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 mg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 mg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions in the nasal cavity

- 57 040442 about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment, any from the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment, any from the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, from 1 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4

- 58 040442 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb) In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II) , (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some variants

- 59 040442 In the embodiment, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least two days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least twenty-one days. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment , dry powder, cream, paste, lotion or balm. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In another implementation of any of the above options

A compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of an aerosol. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a gel. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a lotion. In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a balm. In some embodiments, the compound of formula (I) is (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder dispenser, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a patch. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes under adverse environmental conditions, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes, activation of the trigeminal nerve occurs under adverse environmental conditions. In an additional embodiment of the method for protecting the surface of the eyes, under adverse environmental conditions, activation of the anterior ethmoid nerve occurs. In another embodiment of any of the above embodiments of the method for protecting the surface of the eyes, under adverse environmental conditions, the nasolacrimal reflex is activated. IN

- 61 040442 In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Increased mucin content on the surface of the eyes.

In some embodiments, provided herein is a method for increasing the amount of mucin on the surface of the eyes in a subject. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not result in unwanted psychoactive side effects. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor, and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method is provided for increasing mucin on the surface of the eyes, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I ), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor, and is administered in an amount that produces a local effect. In some embodiments, a method for increasing mucin content on the surface of the eyes is provided, further comprising local administration of one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments of the method for increasing mucin content on the surface of the eyes described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or its pharmaceutically acceptable

- 62 040442 wash the salt. In some embodiments of the method for increasing mucin content on the surface of the eyes described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine in free base form. In some embodiments of the method for increasing mucin content on the surface of the eyes described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the nitrate salt of (R)-5-((E)- 2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for increasing the content of mucin on the surface of the eyes, described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a monocitrate salt of (R)-5-((E)- 2-pyrrolidin3-ylvinyl)pyrimidine. In some embodiments of the method for increasing mucin content on the surface of the eyes described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)- 2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for increasing the content of mucin on the surface of the eyes, described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a galactarate salt of (R)-5-((E)- 2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for increasing the content of mucin on the surface of the eyes, described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate salt (R)-5-((E)- 2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for increasing the content of mucin on the surface of the eyes described in this document, the specified compound of formula (I), (II), (IIIa) or (IIIb) is a monohydrate of hemigalactarate salt (R)-5-((E) -2-pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5((E)-2-pyrrolidin-3-ylvinyl hemigalactarate dihydrate )pyrimidine.

In some embodiments, a method of increasing mucin content on the surface of the eye is provided, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method for increasing mucin content on the surface of the eye is provided, further comprising local administration of one or more substances that prevent transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA), or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method of increasing mucin content on the surface of the eyes is provided, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C ( PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing ocular surface mucin content is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for increasing ocular surface mucin content is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for increasing mucin content on the surface of the eye is provided, further comprising local administration of a calcineurin inhibitor. In some embodiments, a method for increasing mucin content on the surface of the eye is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for increasing mucin content on the surface of the eye is provided, further comprising topical administration of cyclosporine. In some embodiments, a method for increasing mucin content on the surface of the eye is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for increasing mucin content on the surface of the eye is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method, the

At least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 10 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 5 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments

About 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 25 to 60 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity.

In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 1 mg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the mucin content on the surface of the eyes, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, about 3 mg of co

- 65 040442 units of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above embodiments of the method for increasing the mucin content on the surface of the eyes, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, from 1 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4

- 66040442 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some variants

- 67 040442 In the embodiment, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least two days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least twenty one days. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of Formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a liquid. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of Formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a suspension. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of an aerosol. In another embodiment of any of the above embodiments of the method for increasing the mucin content on the surface of the eyes of the formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a gel. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface

- 68 040442 eyes Formulas (I), (II), (IIIa) or (IIIb) are injected into the nasal cavity in the form of an ointment. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a dry powder. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a cream. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a paste. In another embodiment of any of the above embodiments of the method for increasing the mucin content on the surface of the eyes of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a lotion. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a patch. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, activation of the trigeminal nerve occurs. In an additional embodiment of the method for increasing the mucin content on the surface of the eyes, activation of the anterior ethmoid nerve occurs. In another embodiment of any of the above embodiments of the method for increasing the content of mucin on the surface of the eyes, the nasolacrimal reflex is activated. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing mucin content on the surface of the eyes, the content of mucin on the surface of the eyes is associated with an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation,

- 69 040442 surgical repair of a retinal detachment, surgical repair of a macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

An increase in the amount or concentration of one or more lacrimal proteins.

In some embodiments, provided herein is a method for increasing the amount or concentration of one or more lacrimal proteins in a subject. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formulas (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formulas (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formulas (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formulas (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formulas (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formulas (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor, and is administered in an amount that does not lead to unwanted psychoactive side effects. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa), or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor, and is administered in an amount that causes a local effect. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein said lacrimal protein is epithelial growth factor, lactoferrin, lacritin, prolactin,

- 70 040442 adrenocorticotropic protein, leucine-enkephalin, ALS2CL, ARHGEF19, KIAA1109, PLXNA1, POLG, WIPI1, ZMIZ2 or other tear fluid proteome proteins. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is an epithelial growth factor. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is lactoferrin. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is lacritin. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is prolactin. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is an adrenocorticotropic protein. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is leucine-enkephalin. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is ALS2CL. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is ARHGEF19. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is KIAA1109. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is PLXNA1. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is a POLG. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is WIPI1. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, wherein at least one lacrimal protein is ZMIZ2. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising locally administering one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising locally administering one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E) -2-pyrrolidin-3-ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E) -2-pyrrolidin-3ylvinyl)pyrimidine in free base form. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the nitrate salt of (R)-5((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5((E )-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (K)-5-(( E)-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-(( E)-2pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said

- 71 040442 the compound of formula (I), (II), (IIIa) or (IIIb) is a hemigalactarate salt of ^)-5-(^)-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-( hemigalactate salt monohydrate (E)-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate dihydrate (R)-5-((E)-2-pyrrolidine-3- ilvinyl)pyrimidine.

In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, further comprising locally administering one or more substances that prevent transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA), or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method is provided for increasing the amount or concentration of one or more lacrimal proteins, further comprising locally administering one or more substances that prevent or reduce the transition of a nicotinic acetylcholine receptor to a desensitized state, or help restore a nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising topical administration of a calcineurin inhibitor. In some embodiments, a method of increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising topical administration of cyclosporine. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for increasing the amount or concentration of one or more lacrimal proteins is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration

- 72 040442 of one or more lacrimal proteins, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 10 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 5 to 50 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 150 to 600 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or

- 73 040442 its pharmaceutically acceptable salt.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 75 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 25 to 60 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 mg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, 1 mg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above options

About 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity to implement a method for increasing the amount or concentration of one or more lacrimal proteins. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity. In another embodiment, of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 750 µg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, 1 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). IN

- 75 040442 in another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 4 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb) In another embodiment, a pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 μl. In another embodiment, the pharmaceutical dosage form

- 76 040442 ma for use in this method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered over at least two days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered over at least twenty one days. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm. In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacri

- 77 040442 small proteins the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a liquid. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a gel. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a lotion. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder dispenser, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a patch. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

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In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, activation of the trigeminal nerve occurs. In a further embodiment of the method for increasing the amount or concentration of one or more lacrimal proteins, activation of the anterior ethmoid nerve occurs. In another embodiment of any of the above embodiments of the method for increasing the amount or concentration of one or more lacrimal proteins, the nasolacrimal reflex is activated. In some embodiments, the compound of formula (I) is (R)5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of a method for increasing the amount or concentration of one or more lacrimal proteins, said amount or concentration of one or more lacrimal proteins is associated with an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

Increased outflow of tear fluid.

In some embodiments, provided herein is a method for enhancing tear flow in a subject. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor and does not cross the blood-brain barrier at a pharmacologically relevant concentration. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2 and alpha7. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration and selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that is not systemically bioavailable. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not result in unwanted psychoactive side effects.

- 79 040442 effects. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that does not lead to unwanted systemic side effects. In some embodiments, a method is provided for enhancing the outflow of lacrimal fluid, comprising locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I), (II), (IIIa) or (IIIb) binds selectively to the peripheral nicotinic acetylcholine receptor and is administered in an amount that produces a local effect. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising locally administering one or more substances that prevent or promote recovery of the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, a method of enhancing tear fluid outflow is provided, further comprising locally administering one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments of the method for enhancing tear fluid outflow described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidine-3- ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of the method for enhancing tear fluid outflow described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidine-3- ylvinyl)pyrimidine in free base form. In some embodiments of the method for enhancing the outflow of lacrimal fluid described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the citrate salt of (R)-5-((E)-2- pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the method for enhancing tear fluid outflow described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the monocitrate salt of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the lacrimal outflow enhancement method described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)-2- pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the method for enhancing the outflow of lacrimal fluid described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is the galactarate salt of (R)-5-((E)-2- pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments of the method for enhancing tear fluid outflow described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2pyrrolidin- 3-ylvinyl)pyrimidine. In some embodiments of the method for enhancing tear fluid outflow described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2 hemigalactate salt monohydrate -pyrrolidin-3ylvinyl)pyrimidine. In some embodiments of the process described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5((E)-2-pyrrolidin-3-ylvinyl hemigalactarate dihydrate )pyrimidine.

In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising local administration of one or more substances that prevent transition or promote recovery of the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method of enhancing tear fluid outflow is provided, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state, selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising local administration of protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising local administration of cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA.

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In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising local administration of a calcineurin inhibitor. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising topical administration of a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus, and tacrolimus. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising local administration of cyclosporine. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising topical administration of pimecrolimus. In some embodiments, a method for enhancing tear fluid outflow is provided, further comprising topical administration of tacrolimus.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, at least 250 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 1 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 10 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 5 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 50 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 100 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 100 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 150 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

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In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 1 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 5 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, 15 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 15 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 25 to 60 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 mg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid into

- 82 040442 about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 100 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 1 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 1 to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, from 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, 1 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method contains about 0.1 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 0.5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 1 mg/mL of a compound of formula

- 83 040442 (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 2 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 3 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 4 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 5 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 6 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 8 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 9 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 10 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 12 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 15 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 40 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, the pharmaceutical dosage form for use in said method contains from about 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment, a pharmaceutical dosage form for use in said method contains from about 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the pharmaceutical dosage form for use in said method is about 10-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-100 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 50-200 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 100-200 μl. IN

- 84 040442 in another embodiment, the pharmaceutical dosage form for use in said method is about 50-100 µl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10-150 μl. In another embodiment, the pharmaceutical dosage form for use in said method is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 µl. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered once a day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered twice a day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered three times a day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least three times a day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered within one day. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least two days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least three days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least four days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least five days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least seven days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least ten days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least fourteen days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least twenty one days. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nose.

- 85 040442 gel cavity. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a dry powder. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a lotion. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity in the form of a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, devices for spraying powder, steam inhaler, patch, medicated stick, pipette or liquid jet. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a spray pump. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a patch. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity using a pipette. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity in the form of a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, activation of the trigeminal nerve occurs. In an additional embodiment of the method for enhancing the outflow of lacrimal fluid, the anterior ethmoid nerve is activated. In another embodiment of any of the above embodiments of the method for enhancing the outflow of lacrimal fluid, the nasolacrimal reflex is activated.

In another embodiment of any of the above embodiments of the method for enhancing tear fluid outflow, the pathological condition alleviated by enhancing tear fluid outflow is an acute condition. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that

- 86 040442 reduce the function of the lacrimal gland. In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Urgent indications.

The ophthalmic diseases described herein may be acute conditions. An acute condition refers to a condition with a rapid onset of health effects that is considered to be rapid, of short duration. Acute conditions may result from ophthalmic surgery or other ophthalmic treatments. Provided herein is a method for treating an ophthalmic disorder comprising local administration of a therapeutically effective amount of a disclosed compound, said ophthalmic disorder being an acute condition. Also provided herein is a method for treating an ophthalmic disorder comprising locally administering a therapeutically effective amount of a disclosed compound, said ophthalmic disorder being the result of an ophthalmic surgery or ophthalmic treatment.

In some embodiments, the ophthalmic surgery is cataract surgery (cataract removal and lens replacement), refractive lens replacement, glaucoma surgery, LASIK (laser vision correction) surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy, or other treatments that reduce the function of the lacrimal gland.

In some embodiments, the ophthalmic treatment includes radiation therapy. In some embodiments, radiation therapy is directed to the orbital region, for example, in connection with the treatment of head and/or neck cancer.

Defined terminology.

Unless otherwise indicated, the following terms used in this invention, including the description and claims, have the definitions given below. It should be noted that in the text of this specification and the appended claims, the singular forms include reference to the plural, unless the context clearly dictates otherwise. In this application, the use of the words or or and means and/or, unless otherwise indicated. In addition, the use of the term including, as well as other forms such as include, includes, and included, is not limiting. The section headings used in this document are for organizational purposes only and should not be construed as limiting the described subject matter.

The terms co-administration or similar terms as used herein include the administration of selected therapeutic agents to a single patient, and include regimens in which said agents are administered by the same or different routes of administration, or at the same or different times.

The terms effective amount or therapeutically effective amount as used herein refer to a sufficient amount of an agent or compound administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. The result may be an alleviation and/or alleviation of the signs, symptoms or causes of a disease, or any other desired change in the biological system. For example, an effective amount for therapeutic use is that amount of a pharmaceutical dosage form containing a nicotinic acetylcholine receptor agonist compound of formula (I), (II), (IIIa) or (IIIb) described herein that is necessary to provide a clinically significant reducing the symptoms of the disease. The appropriate effective amount in any particular case can be determined using techniques such as a dose escalation study.

The terms individual, subject, and patient include mammals and non-mammals. Examples of mammals include, but are not limited to, any members of the mammalian class: humans, other primates such as chimpanzees, and other species of great apes and apes; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, and the like. In one embodiment, the mammal is a human.

The tissue contains two or more cells. Two or more cells may have the same function. The tissue may be connective tissue, epithelial tissue, muscle tissue or nervous tissue. Alternatively, the tissue is bone, tendon (both terms referred to as musculoskeletal tissue grafts), cornea, skin, heart valve, or vein.

An organ contains two or more tissues. Two or more tissues may perform a specific function or group of functions. In some cases, the organ is the lung, mouth, nose, parathyroid gland, pineal gland, pituitary gland, carotid gland, salivary gland, skin, gallbladder

- 87 040442 bladder, pancreas, small intestine, stomach, spleen, spinal cord, thymus, thyroid, trachea, uterus or appendix. Alternatively, the organ is an adrenal gland, appendix, brain, bladder, kidney, intestine, large intestine, small intestine, liver, heart, or muscle.

The term nicotinic acetylcholine receptor agonist includes full agonists or partial agonists of the nicotinic acetylcholine receptor. In some embodiments described herein, the nicotinic acetylcholine receptor agonist is a compound of formula (I), (II), (IIIa) or (IIIb).

The terms treat, treatment, or process of treatment as used herein include alleviating, alleviating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, preventing the progression of a disease condition, suppressing a disease or condition, e.g., arresting the development of a disease or condition, alleviating the disease or condition, initiating regression of the disease or condition, alleviating the condition caused by the disease or condition, or stopping the symptoms of the disease or condition. In one embodiment, said treatment is a prophylactic treatment. In another embodiment, the treatment refers to therapeutic treatment.

The term does not cross the blood-brain barrier at a pharmacologically relevant concentration as used herein refers to an insufficient amount of a nicotinic acetylcholine receptor agonist (i.e. a compound of formula (I), (II), (IIIa) or (IIIb)) described herein, which passes through the blood-brain barrier to produce a pharmacological response.

The term unwanted psychoactive side effects in this context refers to unintended effects in the brain, including, but not limited to, anxiety, depression, hallucinations, euphoria, addiction, sleep disturbance/disorder, insomnia, abnormal dreams, and nightmares.

The term unwanted systemic side effects in this context refers to non-intended effects in the body, including, but not limited to, abdominal pain, vomiting, nausea, constipation, diarrhea, bloating, dyspepsia, and dry mouth.

The term formulated to prevent desensitization as used herein refers to a dosage form that does not induce tolerance, dependence, withdrawal, or loss of sensitivity to the action of a nicotinic acetylcholine receptor agonist (i.e., compounds of formula (I), (II), ( IIIa) or (IIIb)).

The term produces a local effect in this context refers to the action of a nicotinic acetylcholine receptor agonist (i.e., a compound of formula (I), (II), (IIIa) or (IIIb)) on a peripheral nicotinic acetylcholine receptor, and the absence of a pharmacological response in the central nervous system.

The term adverse environmental conditions in this context refers to external conditions, including natural and artificial conditions. Natural adverse environmental conditions include, but are not limited to exposure to smoke, wind and dry climates. Man-made adverse environmental conditions include, but are not limited to, exposure to vehicle, industrial, and aircraft emissions, as well as home/office conditions with low humidity, high wind speeds, or poor air quality. In some embodiments, adverse environmental conditions refer to controlled adverse conditions commonly used for dry eye clinical trials.

The term eye discomfort includes, but is not limited to, symptoms of dry eye disease such as itching, dryness, photophobia, blurring, pain, sticky sensation, burning, stinging, and foreign body sensation. In some embodiments, eye discomfort is associated with blepharitis, meibomian gland dysfunction, allergic conjunctivitis, ocular surface toxicity and irritation, lacrimal drainage disorder, or eyelid disorders.

The term soft drug in this context refers to a drug substance that is rapidly metabolized to an inactive form immediately after reaching a therapeutic effect.

In this context, the dose of said agent can be calculated based on any form of the compound, including free acid, free base, or salt form (eg, pharmaceutically acceptable salt form). For example, in some embodiments, the dose or concentration is calculated based on the molecular weight of the free base. Similarly, in some embodiments, the dose or concentration is calculated based on the molecular weight of the salt form (eg, galactarate, hemigalactarate, citrate, monocitrate, etc.) as described herein.

Nicotinic acetylcholine receptor agonists.

The methods described herein comprise locally administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, said nicotinic acetylcholine receptor agonist

- 88 040442 is a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is a full agonist. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is a partial agonist. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine (or compound 1). In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine in the form of a free base. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is the nitrate salt of (R)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine . In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is the monocitrate salt of (R)-5((E)-2-pyrrolidin-3-ylvinyl) pyrimidine. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)2-pyrrolidin-3-ylvinyl) pyrimidine. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is the galactarate salt of (R)5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl hemigalactate salt )pyrimidine. In some embodiments of the methods described herein, said compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate monohydrate (R)-5-((E)-2-pyrrolidine-3- ilvinyl)pyrimidine. In some embodiments described herein, said compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl hemigalactarate dihydrate )pyrimidine. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3. 0]octane. In some embodiments of the methods described herein, nicotine is not administered. WO 2010/065443, the entire content of which is incorporated herein by reference, provides further description.

In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is a mild drug.

In some embodiments of the methods described herein, a compound of formula (I) is provided having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods described herein, a compound of formula (I) is provided having the structure:

in the form of hemigalactarate monohydrate or dihydrate.

In some embodiments of the methods described herein, a compound of formula (I) is provided having the structure:

But.

But

In some embodiments of the methods described herein, a compound of formula (I) is provided having the structure:

In some embodiments of the methods described herein, a compound of formula (I) is provided having the structure:

^N °n0 he .

In some embodiments of the methods described herein, a compound of formula (II) is provided having the structure:

- 89 040442 about

or a pharmaceutically acceptable salt thereof.

Polymorphs.

The compounds of this disclosure may crystallize in more than one form, a property known as polymorphism, and such polymorphic forms (polymorphs) are within the scope of this invention. Polymorphism, in general, may result from changes in temperature, pressure, or both. Polymorphism can also result from changes in the crystallization process. Polymorphs may differ in various physical characteristics known in the art, such as the XRD pattern, solubility in various solvents, and melting point.

This description includes various polymorphic forms of the salt forms of ^)-5-(^)-2pyrrolidin-3-ylvinyl)pyrimidine, including hydrates and solvates of these salts. Such polymorphs are characterized by X-ray powder diffraction (XRD) patterns.

One embodiment of this disclosure includes the crystalline form of (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate. Another embodiment of this disclosure includes the amorphous form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate. Another embodiment of this specification includes an amorphous form of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine monocitrate, the RPD pattern of which substantially corresponds to that shown in FIG. 1 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the Form I polymorph of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, which is characterized by an RPD pattern containing at least one of the following peaks:

Another embodiment of this disclosure includes the Form I polymorph of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, the RPD pattern of which substantially corresponds to that shown in FIG. 2 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the Form II polymorph of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, which is characterized by an X-ray powder diffraction pattern containing at least one of the following peaks:

Another embodiment of this disclosure includes the Form II polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, the RPD diagram of which essentially corresponds to

- 90 040442 diagram shown in FIG. 3 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the Form III polymorph of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, which is characterized by an RPD pattern containing at least one of the following peaks:

9.43

12.24

16.24

18.38

19.18

19.48

21.52

22.89

23.08

24.28

30.77

31.27

32.36

33.09

34.86

37.26

37.63

39.47

Another embodiment of this disclosure includes the Form III polymorph of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, the RPD pattern of which substantially corresponds to that shown in FIG. 4 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the Form IV polymorph of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, which is characterized by an RPD pattern containing at least one of the following peaks:

- 91 040442

Another embodiment of this disclosure includes the Form IV polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate, the RPD pattern of which substantially corresponds to that shown in FIG. 5 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the crystalline form of (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono-orotate.

One embodiment of this disclosure includes the Form I polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono-orotate, which is characterized by an RPD pattern containing at least one of the following peaks:

- 92 040442

Another embodiment of this specification includes the Form I polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine mono-orotate, the RPD pattern of which substantially corresponds to that shown in FIG. 6 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the crystalline form of (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monomaleate.

One embodiment of this disclosure includes the Form I polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monomaleate, which is characterized by an RPD diagram containing at least one of the following peaks:

Another embodiment of this specification includes the Form I polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monomaleate, the RPD pattern of which substantially corresponds to that shown in FIG. 7 in WO 2010/065443, the entire content of which is incorporated herein by reference.

One embodiment of this disclosure includes the Form II polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monomaleate, which is characterized by an RPD diagram containing at least one of the following peaks:

- 93 040442

Another embodiment of this disclosure includes the Form II polymorphic form of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monomaleate, the RPD pattern of which substantially corresponds to that shown in FIG. 8 in WO 2010/065443, the entire content of which is incorporated herein by reference.

As noted above, salt forms of (K)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine can exist in solvated, eg hydrated forms as well as in non-solvated forms. This invention includes all such forms.

This invention also includes isotopically labeled compounds in which one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O and ¹⁷ O. Such isotopically labeled compounds are useful as research or diagnostic tools.

Intranasal route of administration.

The methods described herein include local administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof. In some embodiments, the methods described herein comprise locally administering a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, wherein said nicotinic acetylcholine receptor agonist is a compound of formula (I), (II), (IIIa ) or (IIIb). In some embodiments, the methods described herein comprise locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a suspension. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an aerosol. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a gel. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as an ointment. In some embodiments of the methods described in this

- 94 040442 nom document, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a dry powder. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a cream. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a paste. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a lotion. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a balm. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the methods described herein comprise locally administering a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette or liquid jet. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is injected into the nasal cavity using a syringe. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a dropper. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray bottle. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a spray pump. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using an inhaler. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a powder spray device. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a steam inhaler. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity using a patch. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a medicated stick. In some embodiments of the methods described herein, the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity using a pipette. In some embodiments of the methods described herein, a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity as a liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nostrils in turn. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril after a certain time. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in both nostrils. For example, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine (or Compound 1). In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine in free base form. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine citrate salt. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate salt. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine galactate salt. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine hemigalactate salt. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine hemigalactate salt monohydrate. In some embodiments of the method described herein, said compound of formula (I), (II), (IIIa) or (IIIb)

- 95 040442 is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine hemigalactarate dihydrate.

Pharmaceutical dosage forms, methods of administration of doses and treatment regimens.

This document also provides pharmaceutical dosage forms of nicotinic acetylcholine receptor agonists for local administration in the nasal cavity of an individual. In some embodiments, provided herein is a pharmaceutical dosage form of a nicotinic acetylcholine receptor agonist for topical administration to the nasal cavity of an individual, wherein said nicotinic acetylcholine receptor agonist is a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, and further comprising one or more of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-activate PKA, and calcineurin inhibitors. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, said calcineurin inhibitor being selected from cyclosporine, pimecrolimus and tacrolimus. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, said calcineurin inhibitor being cyclosporine. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, said calcineurin inhibitor being pimecrolimus. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, said calcineurin inhibitor being tacrolimus.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is the citrate salt of (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine . In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is provided, comprising:

- 96 040442 a unit of formula (I), (II), (IIIa) or (IIIb), formulated to prevent desensitization, and at a dose that is not systemically bioavailable, additionally containing a calcineurin inhibitor, and the compound of formula (I ), (II), (IIIa) or (IIIb) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monopitrate salt. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is the HCl salt of (R)-5-((E)-2-pyrrolidin-3-ylvinyl) pyrimidine. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is a galactarate salt of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is N5-chlorofurai-2ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, and the specified pharmaceutical dosage form does not contain nicotine in any form. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, wherein said pharmaceutical dosage form does not contain free base nicotine, nicotine salt, nicotine complex or nicotine solvate.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not systemically bioavailable, wherein the compound of formula (I), (II), (IIIa), or (IIIb) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2, and alpha7. In some embodiments, a pharmaceutical drug is provided. a form for local administration to the nasal cavity of an individual, containing a compound of formula (I), (II), (IIIa) or (IIIb), formulated to prevent desensitization, and at a dose that is not systemically bioavailable, and the compound of formula ( I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not systemically bioavailable, and the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not systemically bioavailable, and the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not is systemically bioavailable, additionally containing a calcineurin inhibitor, and the compound of formula (I), (II), (IIIa) or (IIIb) is a mild drug. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that is not systemically bioavailable, wherein the compound of formula (I) has the structure :

- 97 040442

or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that is not systemically bioavailable, wherein the compound of formula (I) has the structure :

in the form of hemigalactarate monohydrate or dihydrate; or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that is not systemically bioavailable, wherein the compound of formula (I) has the structure :

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that is not systemically bioavailable, wherein the compound of formula (I) has the structure :

hnO _ _ns| \=N

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (II) formulated to prevent desensitization and at a dose that is not systemically bioavailable, wherein the compound of formula (II) has the structure :

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (II) formulated to prevent desensitization and at a dose that is not systemically bioavailable, wherein the compound of formula (II) has the structure :

or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is further described, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not lead to unwanted psychoactive side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not results in an undesirable psychoactive side effect, and further comprising one or more of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-activate PKA, and calcineurin inhibitors. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted psychoactive side effects, additionally containing protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted psychoactive side effects,

- 98 040442 additionally containing cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted psychoactive side effects, additionally containing a calcineurin inhibitor. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted psychoactive side effects, additionally containing a calcineurin inhibitor, and the specified calcineurin inhibitor is selected from cyclosporine, pimecrolimus and tacrolimus. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable psychoactive side effects, further comprising a calcineurin inhibitor, said calcineurin inhibitor being cyclosporine. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted psychoactive side effects, additionally containing a calcineurin inhibitor, and the specified calcineurin inhibitor is pimecrolimus. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted psychoactive side effects, further comprising a calcineurin inhibitor, said calcineurin inhibitor being tacrolimus.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable psychoactive side effects, additionally containing a calcineurin inhibitor, and the compound of formula (I), (II), (IIIa) or (IIIb) is a mild drug. In some embodiments, the compound of formula (I) is (R)-5((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted psychoactive side effects, wherein the compound of formula (I ) has the structure:

\=N _; or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted psychoactive side effects, wherein the compound of formula (I ) has the structure: hC^'V^ \=N , in the form of hemigalactarate monohydrate or dihydrate; or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted psychoactive side effects, wherein the compound of formula (I ) has the structure:

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted psychoactive side effects, wherein the compound of formula (I ) has the structure:

- 99 040442

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted psychoactive side effects, wherein the compound of formula (I ) has the structure:

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated to prevent desensitization and at a dose that does not result in unwanted psychoactive side effects, wherein the compound of formula (II ) has the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not result in to unwanted psychoactive side effects, wherein the compound of formula (I), (II), (IIIa), or (IIIb) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2, and alpha7. In some embodiments, proposed pharmaceutical dosage form for local administration in the nasal cavity of an individual, containing a compound of formula (I), (II), (IIIa) or (IIIb), formulated to prevent desensitization, and at a dose that does not lead to unwanted psychoactive side effects effects, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to peripheral eskim nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not result in to unwanted psychoactive side effects, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not result in to unwanted psychoactive side effects, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form for topical administration to the nasal cavity of an individual is further described, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not lead to unwanted systemic side effects. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not results in an undesirable systemic side effect, and further comprising one or more of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-activate PKA, and calcineurin inhibitors. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to unwanted systemic side effects, additionally containing protein kinase C (PKC) or factors that activate or up-modulate PKC. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, additionally

- 100 040442 containing cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, additionally containing a calcineurin inhibitor. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, additionally containing a calcineurin inhibitor, and the specified calcineurin inhibitor is selected from cyclosporine, pimecrolimus and tacrolimus. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, further comprising a calcineurin inhibitor, said calcineurin inhibitor being cyclosporine. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, additionally containing a calcineurin inhibitor, and the specified calcineurin inhibitor is pimecrolimus. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, additionally containing a calcineurin inhibitor, and the specified calcineurin inhibitor is tacrolimus.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that is not leads to undesirable systemic side effects, additionally containing a calcineurin inhibitor, and the compound of formula (I), (II), (IIIa) or (IIIb) is a mild drug.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted systemic side effects, wherein the compound of formula (I ) has the structure:

=N · or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted systemic side effects, wherein the compound of formula (I ) has the structure:

in the form of hemigalactarate monohydrate or dihydrate; or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted systemic side effects, wherein the compound of formula (I ) has the structure:

OH he

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted systemic side effects, wherein the compound of formula (I ) has the structure:

- 101 040442

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I) formulated to prevent desensitization and at a dose that does not result in unwanted systemic side effects, wherein the compound of formula (I ) has the structure:

BUT OH Q °H0 he

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated to prevent desensitization and at a dose that does not result in unwanted systemic side effects, wherein the compound of formula (II ) has the structure:

NH.

or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not result in to unwanted systemic side effects, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to at least one peripheral nicotinic acetylcholine receptor subtype selected from alpha3beta4, alpha4beta2, and alpha7. In some embodiments, proposed pharmaceutical dosage form for local administration in the nasal cavity of an individual, containing a compound of formula (I), (II), (IIIa) or (IIIb), formulated to prevent desensitization, and at a dose that does not lead to unwanted psychoactive systemic effects, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to peripheral nicotinic acetylcholine receptor subtype alpha3beta4. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I), (II), (IIIa), or (IIIb) formulated to prevent desensitization, and at a dose that does not result in to undesirable systemic side effects, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha4beta2. In some embodiments, a pharmaceutical dosage form is provided for topical administration to the nasal cavity of an individual comprising a compound of formula (I), (II), (IIIa) or (IIIb) formulated to prevent desensitization and at a dose that does not result in to undesirable psychoactive systemic effects, and the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to the peripheral nicotinic acetylcholine receptor subtype alpha7. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 0.1 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 0.2 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 0.5 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 1 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 2 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 3 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 4 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 5 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 6 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the aforementioned embodiments of the pharmaceutical dosage form, the pharmaceutical formulation

- 102 040442 This dosage form contains about 7 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 8 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 9 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 10 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 12 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 15 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 20 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 40 mg/mL of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 200 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 100 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 30 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 25 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 20 to 50 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb). In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 30 to 75 mg/ml of a compound of formula (I), (II), (IIIa) or (IIIb).

In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 1 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the aforementioned pharmaceutical dosage form embodiments, said

- 103 040442 pharmaceutical dosage form contains at least 5 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 250 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 500 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains at least 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 50 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 25 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 50 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 100 to 1000 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 150 to 1000 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 100 to 750 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 150 to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 150 to 600 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains less than 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains less than 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per

- 104 040442 dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains less than 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains less than 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains less than 15 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above embodiments of the method for enhancing the outflow of tear fluid, about 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered to the nasal cavity. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 25 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 10 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 15 to 100 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 15 to 75 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 25 to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 25 to 75 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 25 to 60 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 500 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 500 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 500 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another variant,

- 105 040442 lysing any of the above embodiments of the pharmaceutical dosage form, said pharmaceutical dosage form contains from 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 500 µg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 2.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains about 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 5 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 10 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 25 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 50 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 100 µg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 150 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 10 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 4 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 3 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 750 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another implementation of any

- 106 040442 of the above embodiments of the pharmaceutical dosage form, said pharmaceutical dosage form contains from 1 μg to 600 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 100 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form contains 1 μg to 50 μg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered once a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least once a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered twice a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least twice a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered three times a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least three times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered four times a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least four times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered five times a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least five times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered six times a day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least six times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered seven times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least seven times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered eight times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least eight times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered nine times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least nine times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered ten times per day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered at least ten times per day.

In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered within one day. In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered over at least two days. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least three days. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least four days. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least five days. In another variant

- 107 040442 implementation of any of the above embodiments of the pharmaceutical dosage form, the specified pharmaceutical dosage form is administered for at least seven days. In another embodiment of any of the aforementioned pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least ten days. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least fourteen days. In another embodiment of any of the aforementioned pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least twenty one days. In another embodiment of any of the above pharmaceutical dosage form embodiments, said pharmaceutical dosage form is administered for at least thirty days. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In another embodiment of any of the aforementioned pharmaceutical dosage forms, said pharmaceutical dosage form is administered to the nostrils in turn. For example, the specified pharmaceutical dosage form is administered in one nostril and then in the other nostril after a certain time. In another embodiment, said pharmaceutical dosage form is administered to both nostrils. For example, said pharmaceutical dosage form is administered in one nostril and then in the other nostril at the same time or just after the first nostril. In another embodiment, said pharmaceutical dosage form is administered in one nostril. In some embodiments, the compound of formula (I) is (R)-5-((E)2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical dosage forms described herein are administered for prophylactic and/or therapeutic treatment. In some therapeutic applications, pharmaceutical dosage forms are administered to a patient already suffering from a disease or condition in an amount sufficient to treat or at least partially arrest at least one symptom of the disease or condition. The amount effective for this purpose will depend upon the severity and course of the disease or condition, prior therapy, the patient's health status, weight and response to drugs, and the judgment of the attending physician. A therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation clinical trial. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In prophylactic use, the pharmaceutical dosage forms described herein are administered to a patient who is susceptible to or otherwise at risk for a particular disease, disorder, or condition. Such an amount is defined as a prophylactically effective amount or dose. For such an application, the exact amount also depends on the state of health, the weight of the patient, and the like. When used in a patient, the effective amount for such use also depends on the severity and course of the disease, disorder or condition, prior therapy, the patient's medical condition and drug response, and the judgment of the attending physician.

In some embodiments, if the patient's condition does not improve, then at the discretion of the physician, the administration of pharmaceutical dosage forms is carried out continuously, that is, for an extended period of time, including administration throughout the life of the patient, in order to alleviate or otherwise halt the development, or limit the symptoms of the disease. or pathological condition of the patient.

In some embodiments, if the patient's condition improves, then the dosage of the pharmaceutical dosage form administered may be temporarily reduced, or the administration may be temporarily suspended for a certain period of time (ie, drug rest). In specific embodiments, drug rest periods range from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days or more than 28 days. Dose reduction during drug rest is, by way of example only, a reduction of 10-100%, including, by way of example only, a reduction of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100%.

In some embodiments, the dosage of the pharmaceutical dosage form administered may be temporarily reduced, or the administration may be temporarily suspended for a certain period of time (i.e., withdrawal of the drug). In specific embodiments, the duration of drug withdrawal is from 2 days to 1 year, including, by way of example only, 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, or more than 28 days. Dose reduction during drug withdrawal is, by way of example only, a reduction of 10-100%, including, by way of example only, a reduction of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 , 65, 70, 75, 80, 85, 90, 95 and 100%. After an appropriate period of time, the usual dosing regimen is optionally resumed.

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In some embodiments, after improvement in the patient's condition, a maintenance dose is administered as needed. Then, in certain embodiments, reduce the dose or frequency of administration, or both, depending on the symptoms, to a level at which improvement in the disease, disorder, or pathological condition is maintained. However, in some embodiments, the patient is in need of intermittent treatment on a long-term basis for any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount varies depending on factors such as the particular pharmaceutical dosage form, the disease state and its severity, the identity (e.g., weight, sex) of the subject or recipient in need of treatment, but, nevertheless, may be defined according to the specific circumstances relevant to the case, including, for example, the specific nicotinic acetylcholine receptor agonist administered (i.e., a compound of formula (I), (II), (IIIa) or (IIIb)), the condition to be treated and the subject to be treated.

In this context, a pharmaceutical dosage form refers to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) described herein with other chemical components (i.e., pharmaceutically acceptable inactive ingredients), such as carriers , excipients, binders, fillers, suspending agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, humectants, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives or one or more combinations thereof. In some embodiments, the pharmaceutical dosage forms described herein are mixed with other active ingredients as part of a combination therapy. In some embodiments, these pharmaceutical dosage forms contain other therapeutically valuable substances. In other embodiments, the pharmaceutical dosage forms contain other medical or pharmaceutical agents, carriers, adjuvants, preservatives, stabilizers, wetting or emulsifying agents, dissolution accelerators, salts for regulating osmotic pressure and/or buffers. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a buffer. In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a phosphate buffer. In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a phosphate buffer, the pH of the phosphate buffer being about 7.0. In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a phosphate citrate buffer. In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a phosphate citrate buffer, the pH of the phosphate citrate buffer being about 6.0. In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a phosphate-citrate buffer. In some embodiments, the pharmaceutical dosage forms described herein refer to a mixture of a compound of formula (I), (II), (IIIa) or (IIIb) and a phosphate/citrate buffer, the pH of the phosphate/citrate buffer being about 5.0. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Said pharmaceutical dosage form facilitates administration of the compound to the body. In the practice of the methods provided herein, a therapeutically effective amount of a compound of formula (I), (II), (IIIa) or (IIIb) described herein is administered in pharmaceutical dosage form to a mammal suffering from a disease, disorder, or pathological condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound of formula (I), (II), (IIIa) or (IIIb) can be used alone or in combination with one or more therapeutic agents as components of various mixtures. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

The pharmaceutical dosage forms described herein are administered to the nasal cavity of a subject. Pharmaceutical dosage forms described herein include, but are not limited to, liquids, suspensions, aerosols, gels, ointments, dry powders, creams, pastes, salves

- 109 040442 onas or balms. In some embodiments, the compound of formula (I) is (R)5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

Pharmaceutical dosage forms containing a compound of formula (I), (II), (IIIa) or (IIIb) described herein are manufactured in a standard manner. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

These pharmaceutical dosage forms contain the compound of formula (I), (II), (IIIa) or (IIIb) described herein as the active ingredient in free acid or free base form, or in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is in free base form. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is in free base form. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is an HCl salt. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is a citrate salt. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is a monocitrate salt. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is a galactarate salt. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is a hemigalactarate salt. In some embodiments, the compound of formula (I), (II), (IIIa) or (IIIb) is hemigalactarate monohydrate. In addition, the methods and pharmaceutical dosage forms described herein include the use of N-oxides (if appropriate), crystalline forms, amorphous phases, as well as active metabolites of these compounds of Formula (I), (II), (IIIa) or (IIIb) having the same type of activity. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) described herein may exist in unsolvated form or in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. . Solvated forms of the compounds of Formula (I), (II), (IIIa) or (IIIb) provided herein are also considered to be described herein. In some embodiments, these compounds may exist as tautomers. All tautomers are included within the scope of the description of the compounds of Formula (I), (II), (IIIa) or (IIIb) as provided herein. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (I), (II), (IIIa) or (IIIb) exist in the form of enantiomers, diastereomers, or other stereoisomeric forms. The compounds of formula (I), (II), (IIIa) or (IIIb) described herein include all enantiomeric, diastereomeric and epimeric forms, as well as mixtures thereof. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In some embodiments, pharmaceutical dosage forms provided herein contain one or more preservatives to inhibit the action of microbes. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

In some embodiments, the pharmaceutical dosage forms described herein are enhanced with antioxidants, metal chelating agents, thiol-containing compounds, and other general stabilizing agents. Examples of such stabilizing agents include, but are not limited to: (a) from about 0.5 to about 2% wt./about. glycerol, (b) from about 0.1 to about 1% wt./about. methionine, (c) from about 0.1 to about 2% wt./about. monothioglycerol, (d) from about 1 mm to about 10 mm EDTA, (e) from about 0.01 to about 2% wt./about. ascorbic acid, (f) from 0.003 to about 0.02% wt./about. polysorbate 80, (g) from 0.001 to about 0.05% wt./about. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (p) combinations thereof.

Pharmaceutical dosage forms described herein that contain a compound of formula (I), (II), (IIIa) or (IIIb) are formulated into any suitable dosage form, including, but not limited to, liquids, suspensions, aerosols, gels , ointments, dry powders, creams, pastes, lotions or balms. Pharmaceutical dosage forms described herein, which contain a compound of formula (I), (II), (IIIa) or (IIIb), are formulated into any suitable dosage form and administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder dispenser, steam inhaler, patch, medicated stick, pipette or liquid jet. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

Combined therapy.

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In some cases, it is appropriate to administer a compound of formula (I), (II), (IIIa) or (IIIb) in combination with another therapeutic agent. In some embodiments, the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof.

In one embodiment, the compositions and methods described herein are also suitable in combination with other therapeutic agents selected according to their particular suitability for use against the condition being treated. In general, the compositions described herein and other agents in those embodiments that use combination therapy do not necessarily need to be administered as a single pharmaceutical dosage form or composition, and due to their different physical and chemical characteristics, they are administered in different ways. In one embodiment, the initial administration is carried out in accordance with established protocols, and then, based on the observed effect, the dose, routes of administration, and time of administration are further modified.

In various embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same therapeutic protocol) or sequentially with other therapeutic agents that are selected according to their particular suitability for use against the pathological condition to be treated. In some embodiments, the determination of the order of administration, the number of repeated administrations of each therapeutic agent within a single therapeutic protocol is based on an assessment of the disease being treated and the condition of the patient.

In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered concurrently (e.g., simultaneously, substantially simultaneously, or within the same therapeutic protocol) or sequentially with another dry eye therapeutic agent. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is administered concurrently (eg, simultaneously, substantially simultaneously, or within the same therapeutic protocol) or sequentially with Restasis® eye drops. In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is administered concurrently (eg, simultaneously, substantially simultaneously, or within the same therapeutic protocol) or sequentially with artificial tears. In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered concurrently (eg, simultaneously, substantially simultaneously, or within the same therapeutic protocol) or sequentially with ophthalmic steroids.

For the combination therapy described herein, the doses of the co-administered compounds will vary depending on the type of drug being co-administered, the particular drug being used, the disease or condition being treated, and so on.

Individual compounds of such combinations are administered either sequentially or simultaneously as separate or combined pharmaceutical dosage forms. In one embodiment, the individual compounds are administered simultaneously as a combined pharmaceutical dosage form. Appropriate doses of known therapeutic agents are known to those skilled in the art.

The combinations mentioned herein are for convenience of use presented in the form of pharmaceutical compositions together with a pharmaceutically acceptable diluent(s) or carrier(s).

The introduction of a combination of agents in this context includes the introduction of the described agents in the form of a single composition or in the form of combination therapy, when one or more agents are administered separately from at least one other agent.

In some embodiments, a compound of formula (I), (II), (IIIa), or (IIIb) is administered in combination using a medical device. In some embodiments, a compound of formula (I), (II), (IIIa) or (IIIb) is administered in combination with the use of punctal occluders.

Illustrative embodiments of the invention.

Implementation variant I-1. A method for increasing lacrimal fluid production, comprising local administration of a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) binds to a peripheral nicotinic acetylcholine receptor, and the compound of formula (I) has the structure:

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR3;

R ₁ is hydrogen, C _1-6 alkyl, halo, -OR4, -SR4 or -NR ₅ R ₆ ;

R ₂ is hydrogen, C _1-6 alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl,

- 111 040442

-C1.6alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1.6alkyl(heterocycloalkyl) or cycloalkyl;

R ₃ is hydrogen, C1.6alkyl, aryl, -C1.6alkyl(aryl), -aryl(C1.6alkyl), heteroaryl, -C1.6alkyl(heteroaryl), -heteroaryl(C1.6alkyl), heterocycloalkyl, -C1 .6alkyl(heterocycloalkyl), cycloalkyl, -OR ₇ , -SR ₇ , -NR ₈ R ₉ , -SOR7 or -SO ₂ R ₇ , wherein the C _1-6 αalkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents , selected from halogen, -CN, -NO ₂ , -NH ₂ , -OH, -OR ₇ , -CO ₂ H, -C(O)OR ₇ , -OC(O)R ₇ , -NR ₈ R ₉ , -NHC(O)R ₇ , -C(O)NR ₈ R ₉ , -SR7, -S(O)R7, -SO2R7, -NHSO2R7, -SO2NR8R9, -C(S)NR8R9, -NHC(S)R7 and -O-SO2R7;

R4, R5 and R ₆ are independently hydrogen or C ₁ . ₆ alkyl; And

R ₇ , R ₈ and R ₉ are hydrogen, C1. ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C ₁ . ₆ alkyl(heterocycloalkyl) or cycloalkyl, with C ₁ . ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10, -NR10R11, -CF3, -CN, -NO ₂ , -C2R10, -N3 , -SO2CH3, -OR10, -SR10, -C(0)NRioRii, -NRioC(=0)Rio, -C(=O)R10, -C(=O)OR10, -(CH2)ORio, -(CH2 )20Rio, -OC(=O)R _w , -0C(=0)NRioR _u and -NR _w C(=O)OR _w ;

R ₁₀ and R 11 are independently hydrogen, C _1-6 alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R ₈ and R ₉ or R ₁₀ and R _u together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4;

q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

Implementation option I-2. A method of treating dry eye, comprising local administration of a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) binds to a peripheral nicotinic acetylcholine receptor and the compound of formula (I) has the structure:

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR ₃ ;

R1 is hydrogen, C ₁ . ₆ alkyl, halo, -OR4, -SR4 or -NR5R6;

R2 is hydrogen, C ₁ . ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl (heteroaryl), -heteroaryl (C ₁ . ₆ alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl) or cycloalkyl;

R ₃ is hydrogen, C ₁ . ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl (heteroaryl), -heteroaryl (C ₁ . ₆ alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl), cycloalkyl, -OR ₇ , -SR ₇ , -NR ₈ R ₉ , -SOR ₇ or -SO ₂ R ₇ , wherein C ₁ . ₆ αalkyl, heterocycloalkyl, heteroaryl and aryl groups optionally substituted with one or more substituents selected from halo, -CN, -NO2, -NH2, -OH, -OR7, -CO2H, -C(O)OR7, -OC(O) R7, -NR8R9, -NHC(O)R7, -C(O)NR8R9, -SR ₇ , -S(O)R ₇ , -SO ₂ R ₇ , -NHSO2R7, -SO ₂ NR ₈ R ₉ , -C (S)NR ₈ R ₉ , -NHC(S)R ₇ and -O-SO2R7;

R4, R5 and R ₆ are independently hydrogen or C ₁ . ₆ alkyl; And

R ₇ , R ₈ and R ₉ are hydrogen, C1. ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _C1.6 alkyl), heterocycloalkyl, -C1. ₆ alkyl(heterocycloalkyl) or cycloalkyl, with C ₁ . ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10, -NR10R11, -CF3, -CN, -NO2, -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(0)NRioR _u , -NR _w C(=0)Rio, -C(=O)R10, -C(=0)0Rio, -(CH2)0Rio, - (CH2)20Rio, -0C(=0)Rio, -0C(=0)NRioR _u and -NR _w C(=O)OR _w ;

R ₁₀ and R 11 are independently hydrogen, C _1-6 alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R ₈ and R ₉ or R 10 and R 11 together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4 and q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

Implementation variant I-3. A method of alleviating eye discomfort comprising locally administering a therapeutically effective amount of a compound of formula (I) into the nasal cavity of an individual in need thereof, wherein the compound of formula (I) binds to a peripheral nicotinic acetylcholine receptor and the compound of formula (I) has the structure:

- 112 040442

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR3;

R1 is hydrogen, C1-6alkyl, halo, -OR4, -SR4 or -NR5R6;

R2 is hydrogen, C ₁ . ₆ alkyl, aryl, _{-C1_6} alkyl(aryl), -aryl( _{C1_6} alkyl), heteroaryl, -C1. ₆ alkyl(heteroaryl), -heteroaryl( _{C1_6} alkyl), heterocycloalkyl, _{-C1_6} alkyl(heterocycloalkyl) or cycloalkyl;

R3 is hydrogen, C ₁ . ₆ alkyl, aryl, -C1. ₆ alkyl(aryl), -aryl( _C1.6 alkyl), heteroaryl, _{-C1_6} alkyl(heteroaryl), -heteroaryl( _{C1_6} alkyl), heterocycloalkyl, _{-C1_6} alkyl(heterocycloalkyl), cycloalkyl, -OR ₇ , - SR ₇ , -NR8R9, -SOR7 or -SO ₂ R ₇ , wherein the C1_ ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -NH2, -OH, - OR7, -CO2H, -C(O)OR7, -OC(O)R7, -NR8R9, -NHC(O)R7, -C(O)NR ₈ R9, -SR7, -S(O)R7, -SO2R7 , -NHSO2R7, -SO2NR8R9, -C(S)NR8R9, -NHC(S)R7 and -O-SO2R7;

R ₄ , R5 and R ₆ are independently hydrogen or C ₁ _ ₆ alkyl; And

R ₇ , R ₈ and R9 are hydrogen, C _1-6 alkyl, aryl, -C1_ ₆ alkyl(aryl), -aryl(C1_ ₆ alkyl), heteroaryl, -C1_ ₆ alkyl(heteroaryl), -heteroaryl(C1_ ₆ alkyl), heterocycloalkyl, _{-C1_6} alkyl(heterocycloalkyl), or cycloalkyl, wherein the _{C1_6} alkyl, _{heterocycloalkyl} , heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10 , -NR10R11, -CF3, -CN, -NO2, -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(O)NR10R _n , -NRioC(=0)Rio, -C(=0) Rio, -C(=O)OR10, -(CH2)ORio, -(CH^OR^, -OC(=O)R _w , -OC(=0)NRioRii and -NR _W C(=O)OR _W ;

R ₁₀ and R11 are independently hydrogen, _{C1_6} alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R ₈ and R 9 or R ₁₀ and R 11 together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4 and q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

Implementation variant I-4. The method according to any of the embodiments I-1-I-3, wherein X is N.

Embodiment I-5. The method according to any one of embodiments I-1-I-4, wherein R2 is hydrogen.

Implementation variant I-6. The method according to any one of embodiments I-1-I-5, wherein R1 is hydrogen, C1-6alkyl, -OR4 or -NR5R6.

Implementation variant I-7. The method according to any one of embodiments I-1-I-5, wherein R1 is hydrogen.

Embodiment I-8. The method according to any of the embodiments I-1-I-7, characterized in that q is equal to 1.

Embodiment I-9. The method according to any of the embodiments I-1-I-7, characterized in that p is equal to 2.

Embodiment I-10. The method according to any one of embodiments I-1-I-9, wherein the wavy line represents E geometry around the double bond.

Embodiment I-11. The method according to any one of embodiments I-1-I-10, wherein the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine.

Embodiment I-12. The method according to any one of embodiments I-1-I-10, wherein the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine monocitrate salt.

Embodiment I-13. A method for increasing lacrimal fluid production, comprising local administration of a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) binds to a peripheral nicotinic acetylcholine receptor, and the compound of formula (II) has the structure:

O

Formula (II);

where R1 is C ₁ _ ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₃ _ ₈ heterocycloalkyl, C3-8 cycloalkyl or heteroaryl optionally substituted with one to three non-hydrogen and substituent

- 113 040442 mi, independently selected from and from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl ( aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR ₄ R ₅ , -CF ₃ , -C2R ₃ , -SR ₃ , -N ₃ , -C(O)NR4R ₅ , -NR4C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR4R ₅ , -NR ₄ C(O)OR ₃ , -SO ₂ R ₃ , -NR ₄ SO ₂ R ₅ , -SO ₂ NR ₄ R ₅ ;

R2 is Bond or -CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 αkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Embodiment I-14. A method of treating dry eye, comprising local administration of a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) binds to a peripheral nicotinic acetylcholine receptor and the compound of formula (II) has the structure:

O

Formula (II);

where R1 is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C3-8 cycloalkyl, or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl , -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO ₂ , -OR ₃ , -NR4R5, -CF ₃ , -C2R ₃ , -SR ₃ , - N ₃ , -C(O)NR4R ₅ , -NR4C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR ₄ R ₅ , -NR4C(O)OR ₃ , -SO ₂ R ₃ , -NR ₄ SO ₂ R ₅ and -SO ₂ NR ₄ R ₅ ;

R ₂ is Bond or -CH ₂ -;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 αkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Embodiment I-15. A method for alleviating eye discomfort, comprising locally administering a therapeutically effective amount of a compound of formula (II) into the nasal cavity of an individual in need thereof, wherein the compound of formula (II) binds to a peripheral nicotinic acetylcholine receptor and the compound of formula (II) has the structure:

O

Formula (II);

where R1 is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C3-8 cycloalkyl, or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl , -C1-6alkyl(heteroaryl), -heteroaryl(C1-6alkyl), halogen, -CN, -NO2, -OR3, -NR4R5, -CF3, -C2R3, -SR3, -N3, -C(O)NR4R5, -NR4C(O)R3, -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5 ;

R ₂ is Bond or -CH ₂ -;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R4 and _R5 are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl ; or R ₄ and R ₅ together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Embodiment I-16. The method according to any one of embodiments I-13-I-15 wherein R1 is heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C ₃ .

- 114 040442 ₈ cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl,

-C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -OR ₃ , -NR4R5, -CF ₃ , -C(O)NR ₄ R5, -NR4C(O) R3, -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR4R5, -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5.

Embodiment I-17. Method according to any one of claims 13-16, characterized in that R1 is 2-furanyl, 3-furanyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5isoxazolyl, 1.3 ,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4 -isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl or 4-pyridinyl.

Embodiment I-18. The method according to any one of embodiments I-13 -I-17, wherein R2 is a Link.

Embodiment I-19. The method according to any one of embodiments I-13 -I-17, wherein R2 is -CH ₂ -.

Implementation option I-20. The method according to any one of embodiments I-13 - I-17, wherein the compound of formula (II) is N-(5-chlorofuran-2-ylcarbonyl)-3,7diazabicyclo[3.3.0]octane.

Embodiment I-21. A method for increasing lacrimal fluid production, comprising local administration of a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) binds to a peripheral nicotinic acetylcholine receptor, and the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O) _n ;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R1 is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl _{. _ _ _ _ _} , C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR4R5, -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N ₃ , -C (O)NR4R5, -NR4C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R ₃ , -OC(O)NR4R5, -NR4C(O)OR ₃ , -SO ₂ R ₃ , -NR4SO2R5 and -SO2NR4R5;

R2 is -CH2- or -CH2CH2-;

R3 is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, _C3-8 heterocycloalkyl, aryl, _-C1-6alkyl (aryl), -aryl( _C1-6alkyl ) or heteroaryl ; And

R ₄ and R ₅ are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl ), -aryl(C _1-6 alkyl) or heteroaryl; or R4 and _R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Implementation option I-22. A method for treating dry eye, comprising local administration of a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) binds to a peripheral nicotinic acetylcholine receptor, and the compound of formula ( IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O)n;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;

n is 1 or 2;

p is 0 or 1;

- 115 040442 q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R ₁ is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, with C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _{1- 6} alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR4R5, -CF ₃ , -C2R ₃ , -SR ₃ , -N3, -C(O )NR4R5, -NR4C(O)R3, -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R2 is -CH ₂ - or -CH2CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl (C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Implementation option I-23. A method for alleviating eye discomfort, comprising local administration of a therapeutically effective amount of a compound of formula (IIIa) or (IIIb) into the nasal cavity of an individual in need thereof, wherein the compound of formula (IIIa) or (IIIb) binds to a peripheral nicotinic acetylcholine receptor, and the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O) _n ;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R ₁ is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl is optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _{1- 6} alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR4R5, -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N3, -C (O)NR4R5, -NR4C(O)R3, -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R2 is -CH2- or -CH2CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl (C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; or R4 and _R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Implementation option I-24. The method according to any of the embodiments of I-21-I-23, characterized in that p is equal to 1 and q is equal to 0.

Implementation option I-25. The method according to any of the embodiments I-21-I-23, wherein p is 0 and q is 1.

Implementation option I-26. The method according to any of the embodiments of I-21-I-25, wherein R ₂ is -CH ₂ -.

Implementation option I-27. The method according to any of the embodiments of I-21-I-25, wherein R2 is -CH2CH2-.

Implementation option I-28. The method according to any of the embodiments of I-21-I-27, wherein Z is hydrogen.

Implementation option I-29. The method according to any of the embodiments of I-21-I-27, characterized in that

- 116 040442 that Z is _C1-6 alkyl.

Implementation option I-30. The method according to any of the embodiments of I-21-I-29, wherein X is C(O).

Implementation variant I-31. The method according to any one of embodiments I-1-I-30, wherein the compound of formula (I), (II), (IIIa) or (IIIb) does not cross the blood-brain barrier at a pharmacologically relevant concentration.

Implementation option I-32. The method according to any one of embodiments I-1-I-31, wherein the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2 and alpha7.

Implementation option I-33. The method according to any one of embodiments I-1-I-32, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is administered in an amount that is not systemically bioavailable.

Implementation option I-34. The method according to any of the embodiments of I-1-I-33, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor in an amount that does not lead to undesirable psychoactive side effects.

Implementation option I-35. The method according to any of the embodiments of I-1-I-34, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to a peripheral nicotinic acetylcholine receptor in an amount that does not lead to undesirable systemic side effects.

Implementation option I-36. The method according to any one of embodiments I-1-I-35, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the nicotinic acetylcholine receptor from a desensitized state.

Implementation option I-37. The method of embodiment I-36, wherein said one or more substances are selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA , and calcineurin inhibitors.

Implementation option I-38. The method of embodiment I-37 wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus and tacrolimus.

Implementation option I-39. The method according to any one of embodiments I-1-I-38, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is administered without any form of nicotine.

Implementation option I-40. The method according to any of the embodiments of I-1-I-39, characterized in that less than 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity.

Implementation option I-41. The method according to any of the embodiments of I-1-I-39, characterized in that from 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity.

Implementation option I-42. The method according to any of the embodiments of I-1-I-39, characterized in that 1 mg to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity.

Implementation option I-43. The method according to any of the embodiments of I-1-I-39, characterized in that about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity.

Implementation option I-44. The method according to any one of embodiments I-1-I-39, characterized in that about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity.

Implementation option I-45. The method according to any of the embodiments of I-1-I-39, characterized in that about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity.

Implementation option I-46. The method according to any one of embodiments I-1-I-45, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a day.

Implementation option I-47. The method according to any one of embodiments I-1-I-45, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least twice a day.

Implementation option I-48. The method according to any one of embodiments I-1-I-45, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is administered at least once a week.

Implementation option I-49. The method according to any of the embodiments of I-1-I-48, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) is introduced into the nasal cavity in the form of a liquid, suspension, aerosol, gel, ointment , dry powder, cream, paste, lotion or balm.

Implementation option I-50. The method according to any of the embodiments of I-1-I-49, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder dispenser, steam inhaler, patch, medicated stick, pipette or liquid jet.

Implementation option I-51. The method according to any of the embodiments of I-1-I-50, characterized in that the activation of the trigeminal nerve occurs.

Implementation option I-52. The method of embodiment I-51, wherein what happens is

- 117 040442 activation of the anterior ethmoid nerve.

Implementation option I-53. The method according to any of the implementation options 1-1-1-52, characterized in that the nasolacrimal reflex is activated.

Implementation option I-54. A pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (I) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (I) has the structure x= \ //—<0n-r, ^R ~(\ H

Formula (I);

where the wavy line represents the E or Z geometry around the double bond;

X is N or CR ₃ ;

Ri is hydrogen, C ₁ _ ₆ alkyl, halogen, -OR4, -SR4 or -NR5R6;

R ₂ is hydrogen, C ₁ _ ₆ alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), heterocycloalkyl, -C _1-6 alkyl(heterocycloalkyl) or cycloalkyl;

R ₃ is hydrogen, C ₁ _ ₆ alkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), heterocycloalkyl, -C _1-6 alkyl (heterocycloalkyl), cycloalkyl, -OR7, -SR7, -NR8R9, -SOR7 or -SO2R7, wherein the C _1-6 alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted one or more substituents selected from halogen, -CN, -NO2, -NH2, -OH, -OR7, -CO2H, -C(O)OR7, -OC(O)R7, -NR8R9, -NHC(O)R7 , -C(O)NR ₈ R9, -SR7, -S(O)R7, -SO2R7, -NHSO2R7, -SO2NR8R9, -C(S)NR8R9, -NHC(S)R7 and -O-SO2R7;

R 4 , R ₅ and R ₆ are independently hydrogen or C ₁ _ ₆ alkyl; And

R7, _R8 and _R9 are hydrogen, _{C1-6alkyl ,} aryl, _-C1-6alkyl (aryl), -aryl( _C1-6alkyl ), heteroaryl, _-C1-6alkyl ( _heteroaryl ), -heteroaryl (C ₁ - ₆ alkyl), heterocycloalkyl, -C ₁ - ₆ alkyl (heterocycloalkyl) or cycloalkyl, wherein the C ₁ _ ₆ alkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, R10, -NR10R11, -CF3, -CN, -NO ₂ , -C2R10, -N3, -SO2CH3, -OR10, -SR10, -C(O)NR1oR11, -NR1oC(=O )R1o, -C(=O)R1o, -C(=O)OR _w , -(CH2)OR _w , -(CH ₂ ) ₂ OR10, -OC(=O)R _w , -OC(=O) NR10R11 and _-NRW C(=O)OR10;

R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl, pyridyl, quinolinyl, pyrimidinyl, pyrimidinyl, phenyl or benzyl; or either R ₈ and R 9 or R ₁₀ and R _n together with the nitrogen atom to which they are attached optionally form a heterocycloalkyl ring;

p is 1, 2, 3 or 4 and q is 1, 2 or 3;

or its enantiomer, diastereomer, tautomer or pharmaceutically acceptable salt.

Implementation option I-55. The pharmaceutical dosage form of embodiment I-54, wherein X is N.

Implementation option I-56. The pharmaceutical dosage form of Embodiment I-54 or Embodiment I-55, wherein R ₂ is hydrogen.

Implementation option I-57. A pharmaceutical dosage form according to any one of embodiments I-54 - I-56, characterized in that R ₁ is hydrogen, C _1-6 alkyl, -OR4 or -NR ₅ R ₆ .

Implementation option I-58. Pharmaceutical dosage form according to any of the options for implementing I-54 - I-56, characterized in that R ₁ represents hydrogen.

Implementation option I-59. Pharmaceutical dosage form according to any of the embodiments of I-54 -I-58, characterized in that q is equal to 1.

Implementation option I-60. Pharmaceutical dosage form according to any of the embodiments of I-54 -I-59, characterized in that p is equal to 2.

Implementation option I-61. Pharmaceutical dosage form according to any one of the options for implementing I-54 - I-60, characterized in that the wavy line indicates the E geometry around the double bond.

Implementation option I-62. A pharmaceutical dosage form according to any of the embodiments of I-54-I-61, characterized in that the compound of formula (I) is (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine.

Implementation option I-63. A pharmaceutical dosage form according to any one of the embodiments of I-54-I-61, characterized in that the compound of formula (I) is a monocitrate salt of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine.

Implementation option I-64. A pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (II) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (II) has the structure:

- 118 040442 about

Formula (II);

where R ₁ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, or heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl ), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C 1-6 alkyl), halogen, -CN, -NO2, -OR3, -NR4R5, -CF ₃ , -C2R3, -SR3, -N3, - CONR4R5, -NR4COR3, -C(O)R3, -C(O)OR3, -OC(O)R3, -OC(O)NR4R5, -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5;

R2 is Bond or -CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl) or heteroaryl; And

R4 and R5 are independently hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), or heteroaryl;

or R4 and R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Implementation option I-65. The pharmaceutical dosage form of embodiment I-64 wherein R1 is heteroaryl optionally substituted with one to three non-hydrogen substituents independently selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -8} heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl(aryl), -aryl(C _1-6 alkyl), heteroaryl, -C _1-6 alkyl(heteroaryl), -heteroaryl(C _1-6 alkyl), halogen, -CN, -OR ₃ , -NR4R5, -CF3, C(O)NR4R5, -NR4C(O)R3, -C(O)R3, -C(O)OR3, -OC (O)R3, -OC(O)NR4R5, -NR4C(O)OR3, -SO2R3, -NR4SO2R5 and -SO2NR4R5.

Implementation option I-66. The pharmaceutical dosage form of Embodiment I-64 or Embodiment I-65, wherein R1 is 2-furanyl, 3-furanyl, 2oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1,3,4-thiadiazol-2-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl or 4-pyridinyl.

Implementation option I-67. A pharmaceutical dosage form according to any of the embodiments of I-64-I-66, characterized in that R2 is a Bond.

Implementation option I-68. A pharmaceutical dosage form according to any of the embodiments of I-64-I-66, characterized in that R2 is -CH2-.

Implementation option I-69. A pharmaceutical dosage form according to any of the embodiments of I-64-I-66, characterized in that the compound of formula (II) is N-(5-chlorofuran-2ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane.

Implementation option I-70. A pharmaceutical dosage form for topical administration to the nasal cavity of an individual, comprising a compound of formula (IIIa) or (IIIb) formulated into a dosage form (a) for nasal administration and (b) to prevent desensitization of peripheral nicotinic acetylcholine receptors, wherein the compound of formula (IIIa) or (IIIb) has the structure:

Formula (Sha) Formula (SH);

where X represents C(O), C(S) or S(O) _n ;

Z is hydrogen, C _1-6 alkyl or C _1-6 haloαalkyl;

n is 1 or 2;

p is 0 or 1;

q is 0 or 1;

if p is 1, then q is 0;

if q is 1, then p is 0;

R1 is -OR ₃ , -NR4R5, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, aryl or heteroaryl, wherein C _1-6 alkyl _{. _ _ _ _ _} , C _2-6 alkynyl, C _3-8 heterocycloalkyl, C _3-8 cycloalkyl, heteroaryl, aryl, -C _1-6 alkyl (aryl), -aryl (C _1-6 alkyl), heteroaryl, -C _1-6 alkyl (heteroaryl), -heteroaryl (C _1-6 alkyl), halogen, -CN, -NO2, -OR ₃ , -NR4R5, -CF ₃ , -C ₂ R ₃ , -SR ₃ , -N3,

- 119 040442

-C(O)NR4R ₅ , -NR4C(O)R ₃ , -C(O)R ₃ , -C(O)OR ₃ , -OC(O)R3, -OC(O)NR4R ₅ , -NR4C( O)OR ₃ , -SO2R ₃ , -NR4SO2R5 AND -SO2NR4R5;

R2 is -CH ₂ - or -CH2CH2-;

R ₃ is hydrogen, C _1-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C _3-8 cycloalkyl, C ₃ _ ₈ heterocycloalkyl, aryl, -C1_ ₆ alkyl(aryl), -aryl(C1_ ₆ alkyl) or heteroaryl; And

R4 and _R5 independently represent hydrogen, C _1-6 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₈ cycloalkyl, C _3-8 heterocycloalkyl, aryl, -C _1-6 alkyl(aryl) , -aryl(C _{1 .6} alkyl) or heteroaryl; or R4 and _R5 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring;

or a pharmaceutically acceptable salt thereof.

Implementation option I-71. The pharmaceutical dosage form of embodiment I-70, wherein p is 1 and q is 0.

Implementation option I-72. The pharmaceutical dosage form of Embodiment I-70, wherein p is 0 and q is 1.

Implementation option I-73. A pharmaceutical dosage form according to any of the embodiments of I-70-I-72, characterized in that R ₂ is -CH ₂ -.

Implementation option I-74. A pharmaceutical dosage form according to any one of the embodiments of I-70-I-72, characterized in that R ₂ is -CH ₂ CH ₂ -.

Implementation option I-75. A pharmaceutical dosage form according to any of the embodiments of I-70-I-74, wherein Z is hydrogen.

Implementation option I-76. A pharmaceutical dosage form according to any of the embodiments of I-70-I-74, wherein Z is C _1-6 alkyl.

Implementation option I-77. A pharmaceutical dosage form according to any of the embodiments of I-70-I-76, wherein X is C(O).

Implementation option I-78. A pharmaceutical dosage form according to any one of the embodiments of I-54-I-77, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) is formulated at a dose that does not result in unwanted psychoactive side effects.

Implementation option I-79. A pharmaceutical dosage form according to any one of embodiments I-54-I-78, wherein the compound of formula (I), (II), (IIIa) or (IIIb) is formulated at a dose that is not systemically bioavailable.

Implementation option I-80. A pharmaceutical dosage form according to any one of the embodiments of I-54-I-79, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) is formulated in a dosage form that does not lead to undesirable systemic side effects.

Implementation option I-81. A pharmaceutical dosage form according to any one of the embodiments of I-54-I-80, further comprising one or more substances selected from protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors, which activate or up-modulate PKA, and calcineurin inhibitors.

Implementation option I-82. The pharmaceutical dosage form of embodiment I-81, wherein the calcineurin inhibitor is selected from cyclosporine, pimecrolimus, and tacrolimus.

Implementation option I-83. Pharmaceutical dosage form according to any of the embodiments of I-54-I-82, which does not contain nicotine in any form.

Implementation option I-84. A pharmaceutical dosage form according to any one of embodiments I-54-I-83, characterized in that the compound of formula (I), (II), (IIIa) or (IIIb) selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2 and alpha7.

Implementation option I-85. A pharmaceutical dosage form according to any one of embodiments I-54-I-84, wherein the compound of formula (I), (II), (IIIa) or (IIIb) contains about 5 mg/ml of a nicotinic acetylcholine receptor agonist.

Implementation option I-86. A pharmaceutical dosage form according to any one of embodiments I-54-I-84, wherein the compound of formula (I), (II), (IIIa) or (IIIb) contains about 10 mg/ml of a nicotinic acetylcholine receptor agonist.

Implementation option I-87. A pharmaceutical dosage form according to any one of embodiments I-54-I-84 containing less than 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose.

Implementation option I-88. A pharmaceutical dosage form according to any one of embodiments I-54-I-84 containing 500 μg to 5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose.

Implementation option I-89. A pharmaceutical dosage form according to any one of embodiments I-54-I-84 containing 1 to 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose.

Implementation option I-90. A pharmaceutical dosage form according to any one of embodiments I-54-I-84 containing about 1 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose.

Implementation option I-91. A pharmaceutical dosage form according to any one of embodiments I-54-I-84 containing about 1.5 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose.

Implementation option I-92. Pharmaceutical dosage form according to any of the real options

- 120 040442 entry I-54-I-84 containing about 2 mg of a compound of formula (I), (II), (IIIa) or (IIIb) per dose.

Implementation option I-93. A pharmaceutical dosage form according to any of the embodiments of I-54-I-92, which is administered at least once a day.

Implementation option I-94. A pharmaceutical dosage form according to any of the embodiments of I-54-I-92, which is administered at least twice a day.

Implementation option I-95. A pharmaceutical dosage form according to any of the embodiments of I-54-I-92, which is administered at least once a week.

Implementation option I-96. A pharmaceutical dosage form according to any of the embodiments of I-50-I-92, which is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm.

Implementation option I-97. A pharmaceutical dosage form according to any one of the embodiments of I-54-I-96, which is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette, or in the form of a liquid jet.

Implementation variant II-1. A method for increasing lacrimal fluid production, comprising local administration of a therapeutically effective amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof into the nasal cavity of an individual in need thereof.

Implementation variant II-2. A method for treating dry eye, comprising local administration of a therapeutically effective amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof, into the nasal cavity of an individual in need thereof.

Implementation variant II-3. A method for alleviating eye discomfort, comprising locally administering a therapeutically effective amount of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof, into the nasal cavity of an individual in need thereof.

Embodiment II-4. The method according to any one of embodiments II-1-II-3, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is administered in free base form.

Embodiment II-5. The method according to any of the embodiments of II-1-II-3, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is administered in the form of a pharmaceutically acceptable salt of (R)-5- ((E)-2-pyrrolidin-3-ylvinyl)pyrimidine.

Embodiment II-6. The method of embodiment II-5 wherein the pharmaceutically acceptable salt is the galactarate or citrate salt.

Embodiment II-7. The method of embodiment II-6 wherein the pharmaceutically acceptable salt is the galactarate salt.

Embodiment II-8. The method of embodiment II-6 wherein the pharmaceutically acceptable salt is the citrate salt.

Embodiment II-9. The method of embodiment II-8 wherein the pharmaceutically acceptable salt is (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine monocitrate salt.

Embodiment II-10. The method according to any of the embodiments of II-1-II-3, characterized in that the dose of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 500 μg to 10 mg per dose.

Embodiment II-11. The method according to any of the embodiments of II-1-II-10, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in an amount that is not systemically bioavailable.

Embodiment II-12. The method according to any of the embodiments of II-1-II-10, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof selectively binds to peripheral nicotinic acetylcholine receptors in an amount that does not lead to unwanted systemic side effects.

Embodiment II-13. The method according to any of the embodiments II-1-I-12, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof selectively binds to peripheral nicotinic acetylcholine receptors in an amount that does not lead to unwanted psychoactive side effects.

Embodiment II-14. The method according to any one of embodiments II-1-II-13, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the peripheral nicotinic acetylcholine receptor from a desensitized state.

Embodiment II-15. The method of embodiment II-14, wherein said one or more substances are selected from the group consisting of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors.

Embodiment II-16. The method of embodiment II-15 wherein the calcineurin inhibitor is selected from the group consisting of cyclosporine, pimecrolimus and tacrolimus.

- 121 040442

Embodiment II-17. The method according to any one of embodiments II-1-II-16, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered without any form of nicotine .

Embodiment II-18. The method according to any of the embodiments of II-1-II-17, characterized in that 500 μg to 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered .

Embodiment II-19. The method of embodiment II-18 wherein less than 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-20. The method of embodiment II-18, wherein 1 mg to 3 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-21. The method of embodiment II-18, wherein 500 μg to 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-22. The method of embodiment II-18, wherein 1 mg to 2 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-23. The method of embodiment II-18, wherein about 1 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-24. The method of embodiment II-18, wherein about 1.5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-25. The method of embodiment II-18, wherein about 2 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered.

Embodiment II-26. The method according to any one of embodiments II-1-II-25, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered as needed in accordance with symptoms.

Embodiment II-27. The method according to any of the embodiments of II-1-II-26, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least once per day.

Embodiment II-28. The method according to any of the embodiments of II-1-II-26, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least twice per day.

Embodiment II-29. The method according to any of the embodiments of II-1-II-26, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least once per week.

Embodiment II-30. The method according to any of the embodiments of II-1-II-29, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is introduced into the nasal cavity as a liquid , suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion or balm.

Embodiment II-31. The method according to any of the embodiments of II-1-II-30, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is injected into the nasal cavity using a syringe , dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette or liquid jet.

Embodiment II-32. The method according to any of the implementation options II-1-II-31, characterized in that the activation of the trigeminal nerve occurs.

Embodiment II-33. The method of embodiment II-32, wherein the anterior ethmoid nerve is activated.

Embodiment II-34. The method according to any of the implementation options II-1-II-33, characterized in that the activation of the nasolacrimal reflex occurs.

Embodiment II-35. The method according to any of the embodiments of II-1-II-34, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical dosage form for nasal administration containing 5 to 200 mg/ml of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment II-36. The method of embodiment II-35, wherein the pharmaceutical dosage form for nasal administration contains 10 to 75 mg/mL of N)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment II-37. The method of embodiment II-36, wherein the nasal pharmaceutical dosage form contains 10 to 50 mg/mL of (R)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment II-38. A pharmaceutical dosage form for topical administration to the nasal cavity of an individual, containing (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof, formulated for nasal administration.

- 122 040442

Embodiment II-39. The pharmaceutical dosage form of embodiment II-38, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is formulated as a free base.

Embodiment II-40. The pharmaceutical dosage form of embodiment II-38, wherein the pharmaceutically acceptable salt is the galactarate or citrate salt.

Embodiment II-41. The pharmaceutical dosage form of embodiment II-40, wherein the pharmaceutically acceptable salt is the galactarate salt.

Embodiment II-42. The pharmaceutical dosage form of Embodiment II-40, wherein the pharmaceutically acceptable salt is the citrate salt.

Embodiment II-43. Pharmaceutical dosage form according to embodiment II-42, characterized in that the nitrate salt is a monocitrate salt of N)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine.

Embodiment II-44. A pharmaceutical dosage form according to any of the embodiments of II-38-II-43, formulated to administer a dose of 500 μg to 10 mg per dose.

Embodiment II-45. A pharmaceutical dosage form according to any of the embodiments of II-38-II-44, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is formulated in such a dose, which is not systemically bioavailable.

Embodiment II-46. A pharmaceutical dosage form according to any of the embodiments of II-38-II-44, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is formulated in such a dose, which does not lead to unwanted systemic side effects.

Embodiment II-47. A pharmaceutical dosage form according to any one of embodiments II-38-II-46, further comprising one or more substances selected from the group consisting of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA ) or factors that activate or up-modulate PKA, and calcineurin inhibitors.

Embodiment II-48. The pharmaceutical dosage form of embodiment II-47, wherein the calcineurin inhibitor is selected from the group consisting of cyclosporine, pimecrolimus, and tacrolimus.

Embodiment II-49. Pharmaceutical dosage form according to any of the options for implementing II-38-II-48, not containing nicotine in any form.

Embodiment II-50. A pharmaceutical dosage form according to any one of the embodiments of I-38-I-49, containing from 5 to 200 mg/ml of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment II-51. The pharmaceutical dosage form of embodiment II-50 containing 10 to 75 mg/mL of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment II-52. The pharmaceutical dosage form of Embodiment II-51 containing 10 to 50 mg/mL of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment II-53. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-52, containing from 500 μg to 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutically acceptable salt per one dose.

Embodiment II-54. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-52 containing less than 5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof per dose.

Embodiment II-55. Pharmaceutical dosage form according to any of the embodiments of II-38-II-52, containing from 1 to 3 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutically acceptable salt per dose .

Embodiment II-56. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-52, containing from 1 mg to 2 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutically acceptable salt per one dose.

Embodiment II-57. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-52 containing about 1 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof per dose.

Embodiment II-58. A pharmaceutical dosage form according to any of the embodiments of II-38-II-52 containing about 1.5 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof per dose .

Embodiment II-59. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-52 containing about 2 mg of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof per dose.

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Embodiment II-60. A pharmaceutical dosage form according to any of the embodiments of II-38-II-59, formulated to be administered as needed according to symptoms.

Embodiment II-61. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-59, formulated for administration at least once a day.

Embodiment II-62. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-59, formulated for administration at least twice a day.

Embodiment II-63. A pharmaceutical dosage form according to any one of the embodiments of II-38-II-59, formulated for administration at least once a week.

Embodiment II-64. A pharmaceutical dosage form according to any of the embodiments of II-38-II-63 formulated as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm.

Embodiment II-65. Pharmaceutical dosage form according to any of the embodiments of II-38-II-64, formulated for local delivery to the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick , pipette or in the form of a jet of liquid.

Embodiment II-66. A method for treating an ophthalmic pathological condition, comprising local administration of a therapeutically effective amount of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof into the nasal cavity of an individual in need thereof, said ophthalmic pathological condition being acute condition.

Embodiment II-67. A method for treating an ophthalmic pathological condition, comprising local administration of a therapeutically effective amount of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof into the nasal cavity of an individual in need thereof, said ophthalmic pathological condition being result of ophthalmic surgery or ophthalmic treatment.

Embodiment III-1. The compound (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof, for use in the treatment of dry eyes or eye discomfort, which is administered to the nasal cavity of an individual in need thereof.

Embodiment III-2. The compound (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine, or a pharmaceutically acceptable salt thereof, for use in the treatment of dry eye or eye discomfort, which is administered to the nasal cavity of an individual in need thereof, and when This ophthalmic disease is the result of ophthalmic surgery or ophthalmic treatment.

Embodiment III-3. A compound for use according to any one of embodiments III-1 or III-2, wherein the dose of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 500 μg up to 10 mg per dose.

Embodiment III-4. A compound for use according to any of the preceding embodiments, wherein (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is administered as the free base.

Embodiment III-5. A compound for use according to any of the preceding embodiments, wherein the pharmaceutically acceptable salt is the galactarate or citrate salt.

Embodiment III-6. A compound for use according to embodiment III-5, wherein the pharmaceutically acceptable salt is (R)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine monocitrate salt.

Embodiment III-7. A compound for use according to any of the embodiments III-1III-6, which is administered together with one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state, or help restore the peripheral nicotinic acetylcholine receptor from a desensitized state.

Embodiment III-8. A compound for use according to embodiment III-7, wherein said one or more substances are selected from the group consisting of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors which activate or up-modulate PKA, and calcineurin inhibitors.

Embodiment III-9. The compound for use according to embodiment III-8, wherein the calcineurin inhibitor is selected from the group consisting of cyclosporine, pimecrolimus, and tacrolimus.

Embodiment III-10. A compound for use according to any of the embodiments of III-1III-9, which is administered without any form of nicotine.

Embodiment III-11. The compound for use according to any of the embodiments III-1III-10, which is administered in an amount of 500 μg to 5 mg.

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Implementation option Sh-12. A compound for use according to any of the embodiments of W-1III-11, which is administered in an amount of less than 5 mg.

Embodiment III-13. The compound to be used according to any of the embodiments of III-1III-11, which is administered in an amount of 1 to 3 mg.

Embodiment III-14. The compound to be used according to any of the embodiments of III-1III-11, which is administered in an amount of 500 μg to 5 mg.

Embodiment III-15. The compound for use according to any of the embodiments of III-1 III-11, which is administered in an amount of from 1 to 2 mg.

Embodiment III-16. The compound to be used according to any of the embodiments III-1III-11, which is administered in an amount of about 1 mg.

Embodiment III-17. The compound to be used according to any of the embodiments III-1III-11, which is administered in an amount of about 1.5 mg.

Embodiment III-18. The compound to be used according to any of the embodiments of III-1III-11, which is administered in an amount of about 2 mg.

Embodiment III-19. A compound for use according to any one of the embodiments of III-1III-18, which is administered at least once a day.

Embodiment III-20. A compound for use according to any one of the embodiments of III-1III-18, which is administered at least twice a day.

Embodiment III-21. A compound for use according to any one of the embodiments of III-1III-18, which is administered at least once a week.

Embodiment III-22. A compound for use according to any one of embodiments III-1III-21, which is administered to the nasal cavity as a liquid, suspension, aerosol, gel, ointment, dry powder, cream, paste, lotion, or balm.

Embodiment III-23. A compound for use according to any one of embodiments III-1III-21, which is administered into the nasal cavity using a syringe, dropper, spray bottle, spray pump, inhaler, powder spray device, steam inhaler, patch, medicated stick, pipette, or in the form of a liquid jet.

Embodiment III-24. A compound for use according to any one of embodiments III-1III-23, which is administered in a nasal pharmaceutical dosage form containing 5 to 200 mg/mL of (R)-5-((E)-2-pyrrolidin-3-ylvinyl )pyrimidine or a pharmaceutically acceptable salt thereof.

Embodiment III-25. A compound for use according to embodiment III-24, wherein the pharmaceutical dosage form for nasal administration contains 10 to 75 mg/ml of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutically acceptable salt.

Embodiment III-26. A compound for use according to embodiment III-24, wherein the pharmaceutical dosage form for nasal administration contains 10 to 50 mg/ml of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or its pharmaceutically acceptable salt.

Embodiment III-27. Pharmaceutical dosage form containing W)-5-((E)-2pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof, for use in the treatment of dry eyes or eye discomfort.

Embodiment III-28. A pharmaceutical dosage form for use according to embodiment III-27 containing a compound as defined in any of embodiments III-1-III-25.

Examples

The following specific examples are to be understood as illustrative only and not in any way limiting the remainder of this description.

Example 1 Clinical trial to evaluate the safety and efficacy of nasal administration of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine (compound 1) for the treatment of dry eye disease (DED).

Target. This study evaluated the use of compound 1 in the form of a 0.1% nasal spray (OC-01) for the treatment of moderate and severe DED in adult patients. This study examined the safety and efficacy of OS-01 in initiating tear production and reducing symptoms of DED.

Patients. Overall, the study included 30 patients with moderate to severe dry eye who met the following inclusion and exclusion criteria.

Criteria.

Inclusions:

men and women >18 years of age;

voluntarily signed informed consent and presumably able to comply with the study protocol;

at 1 screening visit, the Schirmer tear test (with local anesthesia) was < 10 mm/5 min. for at least one eye;

- 125 040442 at 1 screening visit, the Schirmer test results (with local anesthesia and nasal cotton swab stimulation) were at least 7 mm greater than the value without stimulation for at least one eye;

the baseline ocular surface lesion index score was at least 23, and there were no more than 3 responses not applicable at the first screening visit;

normal anatomy of the eyelids / eyelashes, the function of blinking and closing.

Exceptions:

chronic or recurrent nosebleeds;

use of tobacco or nicotine products (cigarettes, cigars, electronic cigarettes) within the last 1 year;

clotting disorders that can lead to increased bleeding, such as hemophilia and thrombocytopenia;

neoplasia or significant trauma to the lacrimal gland, nose, or sinus; previous surgery or ablation of the lacrimal gland, in the nose or in the nasal sinus, causing denervation of the gland or nasal passages, as evidenced by the lack of response to nasal stimulation with a cotton swab;

severe nasal airway obstruction (eg, severe deviated septum or inferior turbinate hypertrophy);

ophthalmic surgery (such as refractive surgery or cataract surgery) on either eye within 3 months prior to the first screening visit;

an unstabilized systemic disease state or disease, or a disease that, in the opinion of the Investigator, is incompatible with participation in the study (eg, existing systemic infection, uncontrolled autoimmune disease, uncontrolled immunodeficiency disease, history of myocardial infarction, uncontrolled hypertension, etc.) or with the frequency of assessments that is necessary for this study;

a history or presence of any ophthalmic disorder or disease in any eye that is likely to interfere with the interpretation of test results or compromise patient safety, such as significant corneal or conjunctival scarring, pterygium, or pinguecula nodosum; existing eye infection or inflammation not associated with dry eyes clinically significant anterior (epithelial) basement membrane corneal dystrophy or other clinically significant corneal dystrophy or degeneration; clinically significant blepharitis; herpetic eye infection, etc.;

known hypersensitivity to any of the procedural agents or materials in the study preparation that come into contact with the nasal mucosa;

active or uncontrolled severe systemic allergies, chronic seasonal allergies, rhinitis or sinusitis requiring treatment (ie, antihistamines, decongestants, oral or aerosol steroids) at the time of initial screening;

current use of any drugs known to cause dry eyes (eg, cyclosporine, antihistamines, tricyclic antidepressants, anxiolytics, antimuscarinics, beta-blocking agents, diuretics, phenothiazines, steroids, etc.) that have not previously been used on a stable schedule for 30 days prior to the first screening visit;

the presence of dissolvable punctal occluders (participants with silicone occluders or permanent occluded puncta are eligible for the study);

active use of contact lenses, with the exception of stopping their use at least 7 days before the first screening visit and throughout the study;

participation in any clinical trial with a new active substance or new device within the last 3 months;

women who are pregnant, planning pregnancy, or breastfeeding at the time of enrollment Women of childbearing age should have a urine pregnancy test;

known allergic or adverse reactions to Compound 1;

any unstable or uncontrolled cardiac, pulmonary, renal, oncological, neurological, metabolic, or other systemic condition that, in the opinion of the Investigator, may result in a patient being treated as a medical emergency during this study. Such conditions include, but are not limited to, cardiac arrhythmia, hypertension, coagulopathy, renal failure, and diabetes mellitus.

Special cases of inclusion/exclusion.

The investigator has the right to exclude any patient from participation in the study if, in his/her opinion, this is in the best interests of the patient.

Minor exceptions to the inclusion/exclusion criteria must be submitted to the sponsor for review and then routinely approved in consultation with the medical supervisor, if necessary.

Substantial exceptions affecting the safety/rights of the patient or the reliability of the data should be immediately sent by the investigator to the ESMU/EC.

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primary result. The design of this study allows for the following measurements in relation to OS-01 and tear fluid production:

change in the production of tear fluid associated with the introduction of a single dose of OS-01.

secondary result. The design of this study allows for the following measurements in relation to OS-01 and tear fluid production:

change in the production of lacrimal fluid associated with the introduction of a single dose of the carrier;

change in symptoms associated with the administration of a single dose of OS-01;

the duration of symptomatic relief associated with the administration of a single dose of OS-01; change in symptoms associated with the introduction of a single dose of the carrier;

duration of symptomatic relief associated with administration of a single dose of vehicle.

The pooled results of these comparisons will provide valuable information on the safety and efficacy of OS-01 in increasing tear production in patients with dry eye disease.

The primary safety endpoint in this study is the incidence and association of adverse events (AEs) with the study drug. Descriptive statistics of adverse events and a textual description of any severe, unexpected, or drug-related AEs will be provided. During the study, an appropriately qualified specialist will monitor the integrity of the nasal passages for the safety of the patient.

Study design. This study is a prospective non-comparative crossover study to evaluate the safety and efficacy of compound 1 0.1% nasal spray in participants with moderate to severe dry eye. The study included up to 30 participants and observed them for seven days. 0.1% nasal spray refers to the concentration in the container from which the dose is administered.

At the first screening visit, all eligible participants must waive their current artificial tears or lubricating drops for the duration of the study and are given a single dose of unpreserved artificial tears to use if dry eye symptoms become intolerable. Empty single dose vials are collected at each study visit and counted. Patients are instructed not to use artificial tears for 30 minutes after administration of the nasal medication or for 2 hours after the study visit.

At the second screening visit/Day 0 of the study, all eligible participants are screened for their response to two nasal dosage forms: OS-01 and vehicle control. The production of tears in each eye is assessed immediately before and immediately after the delivery of each intranasal dose using the Jones Schirmer test. The order in which the OS-01 and vehicle dosage forms are administered to the patient is randomized and neither the patient nor the investigator knows the composition of the nasal dosage form. At least 90 minutes after the assessment of lacrimal fluid production, an assessment is made of the change in symptoms in response to the administration of each of the two nasal dosage forms. Symptom scores are performed using a commonly accepted environmental model, the ClimaTears goggle system manufactured by Biocentric Developments, LLC.

After the day 0 trial, all patients are given a vial of OS-01, which they keep at home and self-administer once a day, from day 1 to day 6. On Day 7, patients return to the clinic where they are again assessed for tear production and symptoms associated with the administration of each nasal dosage form.

Evaluation of the production of tear fluid.

The following assessments of the ocular surface and tear film were performed in this order:

Ocular surface staining - staining of the cornea with fluorescein.

The staining of the ocular surface of each eye with fluorescein and lyssamine green was assessed and recorded in a schematic form consisting of 5 corneal and 6 conjunctival areas in an individual patient record card using the National Eye Institute scoring system. A graphical and descriptive score (from 0 to 3 points) was included in the individual patient registration card (CRF).

1. Corneal staining was assessed using 1.0 mg sodium fluorescein strips.

2. After wetting the end of the strip with one drop of buffered saline solution, shake off the excess into the trash can by tapping it sharply with your finger.

3. The lower eyelid was then pulled down and the flat edge of the nozzle was carefully inserted into the inferior tarsal conjunctiva to instill a very small amount of dye and not cause reflex lacrimation.

4. The patient was instructed to blink freely several times without excessive closure of the eyelids to distribute the fluorescein.

5. After the fluorescein remained in the eye for at least 1 min, 5 corneal regions were assessed using a yellow (Wratten No. 12) barrier filter along with a cobalt (blue) filter to maximize visible fluorescence. The upper eyelid was slightly raised to assess the surface of the entire cornea. A yellow barrier filter was added to enhance contrast.

- 127 040442 fall on the reverse path of the light (and not on the path of the incident light).

Tear film break time (TFBUT).

TFBUT was evaluated using slit lamp biomicroscopy according to the following steps.

1. The slit lamp was set to a magnification of about 10X.

2. After proper administration of fluorescein (preferably with DET strips), the subject was asked to look straight ahead without blinking until instructed otherwise. The test should be carried out indoors, with no wind towards the patient's face.

3. A stopwatch was used to record the time between the last full blink and the first appearance of a growing micelle indicating tear film rupture.

Note: If the patient blinks before the spot breaks, the examiner should try again to take the reading.

4. After recording TFBUT, the patient was allowed to blink freely. This test was then repeated a second time for the same eye.

5. If the difference between the first and second value was more than two seconds, then a third measurement was also taken and the results recorded.

6. Then the indicated procedure was carried out for the other eye.

7. It is recommended to measure TFBUT in a room with a temperature of about 18°C and a humidity of about 50%.

Staining of the ocular surface - staining of the conjunctiva using lyssamine green.

Ocular surface staining was assessed by staining the conjunctiva with lissamine green.

1. A lyssamine green ophthalmic strip was soaked in buffered saline and inserted into the inferior tarsal conjunctiva. Care must be taken to instill a sufficient amount of dye.

2. After lyssamine green remained in the eye for 1 min, six nasal and temporal conjunctival regions were assessed.

3. To assess the temporal zone, the subject was asked to look towards the nose; to assess the nasal zone, the subject was asked to look towards the temple.

4. Then the indicated procedure was carried out for the other eye. Schirmer test.

Screening Visit #1 performed one baseline Jones Schirmer test followed by a Schirmer test using nasal cotton swab stimulation. The Jones Schirmer test with local anesthesia was used to assess tear production according to the following stages:

1. A local anesthetic drop such as 0.5% proparacaine hydrochloride or equivalent (Akorn, Lake Forest, IL) was instilled into both eyes of the patient.

2. The patient was asked not to open his eyes for 1 min.

3. After opening the eyes and allowing the eyes to recover for about another 1 minute, excess moisture in the inferior fornix was carefully removed with a cotton-tipped applicator.

4. Schirmer strips (35 mm x 5 mm filter paper strips) were placed in each eye at a position between the middle and lateral thirds of the lower eyelid.

5. Under natural light, the patient was asked to look straight ahead and blink normally throughout the test. The test must be carried out indoors, without wind towards the patient's face.

6. After 5 minutes, the strips were removed from both eyes and the degree of wetting was recorded. The strips were sutured to the CRF. Note: If the Schirmer score reaches its maximum value before the end of the 5 minute evaluation period, then the strip can be removed and the time elapsed until the maximum is recorded. However, the strip from the other eye should not be removed if it also did not reach the maximum score before the end of the 5-minute evaluation period.

7. When performing several Schirmer tests, new anesthetic drops should be administered as needed.

Schirmer test using nasal stimulation with a cotton swab.

1. At screening visit #1, a Schirmer test was performed using nasal stimulation with a cotton swab. After inserting new strips, the examiner should simultaneously insert cotton swabs into both nostrils of the patient and gently touch both middle turbinates for about 30 seconds. After that, the examiner can simply hold the sticks in one place, applying slight pressure, and periodically repeat the touch, as needed.

2. Alternatively, the researcher may be asked to hold the cotton swabs on their own and gently touch both turbinates at the same time, resting periodically before touching again. The investigator must continuously instruct the research participant on how to properly conduct this test.

3. Schirmer strips must remain in place until the end of the five-minute period or until

- 128 040442 moments when they reach the maximum score.

Both Schirmer scores should be recorded and verified as meeting the inclusion criteria. When performing several Schirmer tests, new anesthetic drops should be instilled as necessary.

Schirmer test using each of two nasal sprays.

For each of the two nasal applications, the Jones Schirmer test with local anesthesia was used to assess lacrimal fluid production according to the following steps.

1. Local anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent were instilled into both eyes of the study participant for each application.

2. The study participant was asked not to open their eyes for 1 min.

3. After opening the eyes and allowing the eyes to recover for about another 1 min, excess moisture in the lower fornix was carefully removed with a tupfer.

4. Schirmer strips (35 mm x 5 mm filter paper strips) were placed in each eye at a position between the middle and lateral thirds of the lower eyelid.

5. Under natural light, the subject was asked to look straight ahead and blink normally throughout the test. The test should be carried out indoors, with no wind towards the subject's face.

6. After 5 minutes, the strips were removed from both eyes and the degree of wetting was recorded. The strips must be sewn to the CRF.

Dry eye provocation and evaluation of symptoms.

The ClimaTears goggle system (Biocentric Developments, LLC) was used to reduce periocular moisture and trigger dry eye symptoms in patients. This system was developed to standardize experimental conditions for clinical trials of patients with dry eye.

Patients wore the ClimaTears glasses continuously for up to 90 minutes and during the experimental period their symptoms were recorded on a visual analogue scale (VAS) every 5 minutes. The subject was asked to rate the symptoms of dryness (for both eyes at the same time) using a vertical mark on a horizontal line indicating the degree of discomfort. 0 corresponds to no dryness and 5 corresponds to maximum dryness. The length of the line on the evaluation scale is 100 mm.

There are many symptoms of dry eyes, including dryness, sticky feeling, burning sensation, foreign body sensation, itching, blurred vision, sensitivity to light, and pain. Patients were asked to rate the severity of their current symptoms of dryness (and nothing more) using a vertical stroke on the line below:

© ©

1 2 3 4 5

Absence Severe

On day 0, patients began wearing spectacles and were observed until a symptom score of 45 mm or more was achieved for two consecutive measurements, at which time they were randomly administered either a dose of OS-01 nasal spray or a dose of a control nasal spray (placebo (nasal spray carrier for OS-01)), which were injected 2.5 minutes after two consecutive measurements of 45 mm. Symptoms continued to be observed until the patient again reached a score of 45 mm or more for two consecutive measurements, at which point the patient was administered a second nasal dose of the experimental drug that had not been administered the first time. After the second nasal dose, symptoms were again controlled until the patient reached a score of 45 mm or more for two consecutive measurements. At this time, it was possible to take off the glasses, and the test ended. If continued, the test should be terminated after 90 minutes of wearing goggles. At the end of this period, each patient was asked to rate which of the nasal sprays provided the most relief from dry eye symptoms.

On day 7, patients started wearing glasses and were observed until they reached a symptom score of 45 mm or more for two consecutive measurements, at which time they were dosed with OS-01 nasal spray. Symptoms continued to be monitored until the patient again reached a score of 45 mm or more for two consecutive measurements, at which time the glasses could be removed and the test ended. If continued, the test should be terminated after 90 minutes of wearing goggles.

Patients entering the study with a baseline symptom score greater than 45 mm should have a treatment threshold equal to the specified baseline score and will therefore be treated after two consecutive symptom measurements are greater than or equal to the specified value.

The instructions (in bold above) should be given to the patient prior to the start of the test,

- 129 040442 as well as before reading the symptom values immediately after the administration of any nasal spray.

Example 2 Dosage form OS-01.

OS-01 contained 0.1% w/v. Compounds 1 in sterile phosphate buffered saline (PBS) consisting of 137 mM sodium chloride, 2.7 mM potassium chloride and 10 mM phosphate buffer pH 7.4, without preservatives. The dosage form was packaged in a 20 ml opaque polyethylene nasal spray bottle delivering a single dose of 50 μl. The vehicle control was presented in the same package. OS-01 and the carrier had a label with a code indicating the contents of the package, which was not known to either the participants in the study or the specialists conducting the blind study.

Example 3. Additional pharmaceutical dosage forms.

To obtain pharmaceutical dosage forms suitable for intranasal administration, 50 mg of a compound of formula (I), (II), (IIIa) or (IIIb) was dissolved in 10 ml of the indicated carrier. 1 ml of the resulting solution was diluted in 9 ml of the carrier to obtain a dosage form with a dilution of 0.1X. After a first dilution, 1 ml of the 0.1X dilution dosage form was diluted in 9 ml of vehicle to give a 0.01X dilution dosage form. The resulting three dosage forms with different concentrations of the nicotinic acetylcholine receptor agonist were stored at 4°C.

Example 4 Compound 1: Orally effective and selective alpha4beta2 neuronal nicotinic receptor agonist with anti-allodynic activity.

The results described herein summarize the in vitro and in vivo profile of a new selective NNR agonist alpha4beta2, Compound 1, which demonstrates a promising general preclinical drug profile for the control of neuropathic pain in humans. Compound 1 has a high binding affinity for alpha4beta2 (Ki=27 nM) and exhibits significantly less activity for NNR alpha7 or nAChR alpha3beta2 or alpha3beta4 compared to nicotine. Compound 1 was functionally shown to be an alpha4beta2 receptor agonist (120%) as well as in a DA release model (E _max = 114% of nicotine). In addition, electrophysiological studies have shown that Compound 1 has agonist activity in both high and low sensitivity alpha4beta2 containing NNR subtypes. It is easily absorbed after oral administration and has favorable pharmacokinetics. Compound 1 is active in promoting anti-allodynic action after bolus and repeat administration, demonstrating efficacy in animal models of neuropathic pain. In particular, compound 1 significantly reversed tactile allodynia in a model of diabetic neuropathy (STZ-induced) with bolus administration (0.1 and 1 mg/kg; po) and with repeated administration (0.1-10 mg/kg p.o.). .O.). Compound 1 was also effective in reversing tactile allodynia in a chemotherapy-induced neuropathy model (paclitaxel-induced; 0.01-1 mg/kg po). Compound 1 shows a faster onset of action (ie 30 minutes) and comparable potency and duration of action compared to gabapentin. This compound demonstrates a favorable margin of safety in non-clinical safety studies, including in vitro and in vivo cardiovascular studies, bolus and 14-day reintroduction studies, 90-day summary studies, and a full set of genotoxicity studies. Overall, the results of the preliminary studies conducted with Compound 1 provide evidence for the use of a neuronal nicotinic modulator with potential efficacy in controlling neuropathic pain and an excellent cumulative profile compared to previously described analgesic compounds acting via a nicotinic or other neuronal mechanism.

Example 5: Connection properties 1.

Compound 1: α4β2.

Compound 1 binds to human a4b2-containing nAChR receptors with Ki = 17 nM.

Compound 1 is a full agonist at the human a4b2-containing nAChR and is more potent than nicotine (Emax = 120% compared to nicotine; EC ₅₀ = 600 nM).

There are two types of a4b2-containing nAChRs, depending on which subunit occupies the fifth subunit of the pentameric complex. There is a high sensitivity subtype, (α4β2)2β2 and a low sensitivity subtype, (α4β2)2α4. Targacept uses elemental analysis to drive the expression of one subtype over another based on incubation temperature. The database summary states that Compound 1 is a full agonist (Emax = 120%) for both high sensitivity (HS) and low sensitivity (LS) subtypes with similar potency (EC ₅₀ = 3300 for HS and EC ₅₀ = 5300 for LS) . According to the database summary, Compound 1 completely inhibits the high and low susceptibility subtypes with similar potency (IC ₅₀ = 430 for HS and IC ₅₀ = 450 for LS). These data indicate that Compound 1 acts similarly on both high and low sensitivity α4β2 nAChRs.

Compound 1: α3β4.

Compound 1 binds to human a3b4-containing nicotinic acetylcholinergics

- 130 040442 receptors (nAChR) with Ki = 600 nM.

Compound 1 is an agonist at the human a3b4-containing nAChR and is less potent than nicotine (Emax = 60% compared to nicotine and _EC50 = 18,000 nM in SHSY5Y cells; Emax = 79% compared to nicotine and _EC50 = 22,000 nM in IMR-32 cells).

Compound 1: α7.

Compound 1 binds to human nAChR α7 with Ki = 15,000 nM.

Example 6 Testing a panel of compounds with different receptor binding profiles.

A panel of twenty compounds with different receptor binding profiles was tested, including other nicotinic acetylcholine receptor (nAchR) agonists. At the start of the experiment, 50 μl of the 0.01 mg/ml formulation of the compound was administered intranasally to three subjects. The dose of each compound was increased logarithmically until a lacrimation and/or discomfort response was achieved, up to a maximum compound concentration of 10 mg/mL. The effect on lacrimation response and discomfort was recorded for each compound as shown in the following table. Compound 1 showed the desired combination of efficacy and tolerability.

Compound Target receptor Causes lacrimation Reaction in the form of discomfort Varenicillin nAchR α7, α3β4 (partial), α4β2 (partial), α6β2 (partial) Yes No Nicotine nAchR: wide spectrum Yes strong Compound 1 nAchR α4β2, α3β4, α3β2 (partial) Yes No TS-6987 nAchRα7 No No

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cytisine nAchRα3β4, a7 and α4β2 (partial) Partially Moderate AVT-418 nAchR α4β2, α3β4, α2β2, α7 Yes Moderate RHA-543613 nAchRα7 No No GTS-21 nAchR α7, α4β2 (partial) Yes strong denatonius T2R No No Eucalyptol TrpM8 No No Geraniol TrpM8 No No Pulegon TrpM8 No No Menthol TrpM8/V3 No No capsaicin TrpVl Yes strong Benzaldehyde TrpVl/Al No No Camphor TrpVl/V2/Al No No Eugenol TrpVl/V3/Al/M8 No No Carvacrol TrpV2/Al/M7 Yes strong Ethylvanillin TrpV3 No No Betahistine Hl No No

nAchR - nicotinic acetylcholine receptor; T2R - taste receptor type 2; TrpAl - cation channel of the transient receptor potential, subfamily A, member 1; TrpM7 - cation channel of the transient receptor potential, subfamily M, member 7; TrpM8 - cation channel of the transient receptor potential, subfamily M, member 8; TrpV1 - cation channel of the transient receptor potential, subfamily V, member 1; TrpV2 - cation channel of the transient receptor potential, subfamily V, member 2; TrpV3 - cation channel of the transient receptor potential, subfamily V, member 3; H1 - H1 histamine receptor.

Example 7 Pharmacological overview and pharmacodynamics of Compound 1.

The following tables present the pharmacological and pharmacodynamic data of Compound 1.

Primary pharmacodynamics

Study Type Views/line Method of administration Notable observations RECEPTOR BINDING -α4β2 receptor binding [inhibition of [^H]-(S)nicotine binding to nicotinic acetylcholine Rats / brain membrane preparations in vitro dissolution Binding to a4p2 (rats) Effectively inhibits the binding of [^H]-Snicotine to α4β2 in

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by the α4β2ποΛ receptor by the action of the Compound 1 rat brain cortical membranes (Ki = 27 nM). Nicotine displaces [^H]-S-hhkothh in rat cortical membranes with cKi = 2 nM. Receptor binding -α4β2 Human/ recombinant receptors - cells in vitro not dissolved Binding to α4β2 (human) Effectively inhibits the binding of [^H]-Snicotine to human α4β2 expressed in SH-EP1 cells (Ki = 17 nM). Receptor binding - α3β2 Human/ recombinant receptors - cells in vitro not dissolved Binding to α3β2 (human) Effectively inhibits the binding of [^H]-Snicotine to human α3β2 expressed in HEK cells (Ki = 27 nM). Receptor binding - a7 [inhibition of [^H]methyl lycaconitin binding Rats / brain membrane preparations in vitro not dissolved Bonding with a 7 (rats) Weak inhibitor of [3h]-MLA binding to a7 in preparations

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([ ³ H]MLA) with nicotinic acetylcholine receptor a7 under the action of Compound 1 brain hippocampal membrane of the rat brain (Ki = 5500nM). Nicotine displaces [ ³ H]MLA in rat cortical membranes with cKi = 1000 nM. Binding receptor - a7 Human/ recombinant receptors - cells in vitro dissolution Binding to a 7 (human) Weak inhibitor of [ ³ H]epibatidine binding to human a7 expressed in HEK cells (Ki = 15,000 nM) Binding receptor muscle receptor (αϊβίδγ) Human / native human receptors - cells in vitro dissolution Binding to αϊβΐ δγ (human) Inhibits binding of [ ³ H]-epibatidine to receptors in TE-671 membranes with Ki 3bmkM Binding receptor ganglionic Human / native human in vitro dissolved Binding to α3β4 (human)

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receptor (α3β4) cell receptor Not Inhibits binding of [3n]-epibatidine to receptors in 8H-8V5¥ membranes with Ki 620nM RECEPTOR FUNCTION Receptor function -α4β2 Human/recombinant human receptor - cells in vitro not dissolved Function of α4β2 (human) in SH-EP1 cells expressing human α4β2, Compound 1 induces Ca++ influx with an Emax of 120% relative to nicotine and an EC50 of 5300nM. Receptor function release of dopamine Membranes of the striatum of the brain of rats in vitro not dissolved Function α4β2 (rats) - Compound 1 induces the release of [3h]-DA from rat striatal synaptosomes with an Emax of 114% relative to nicotine and an EC50 of 3932 nM. Compound 1 is a full agonist for the a4p2 subtype. Receptor function - human / recombinant in vitro Function α3β4 (rats) - Activity at

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ganglionic receptor (rat) th human receptor - cells dissolution rat ganglion receptors in PC-12 cells was low (19%). Receptor function of ganglionic receptor (human) human ganglion cells in vitro dissolution Function of α3β4 (Human) In human ganglion cells (SH-SY5Y cells) activity was low (mean Emax = 60% relative to nicotine and EC50 was 18 mM). In human ganglion cells (IMR-32 cells) the activity was higher (mean Emax = 79% relative to nicotine), but the efficacy was also low, with an EC50 of 22mM. Receptor function - muscle receptor (αίβίδγ) Human / recombinant human receptor in vitro dissolution Muscle receptor function (αίβίδγ) Compound 1 caused minimal activation of human muscle - cells receptors in TE671 cells (Emax=42% relative to nicotine and EC50=15 µM). The reduced efficacy in muscle and ganglionic NOs suggests a lower likelihood of side effects for Compound 1 compared to nicotine.

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Secondary pharmacodynamics

Type research Species/whether NIA Method of administration Doses (mg/kg) Gender and number of o in the group Notable observations IN VITRO BINDING (NON-TARGERED RECEPTORS) In hygobinding e different e / 10 µM Solution 10 2 M in DMSO then diluted n/a n/a In addition to high affinity for neuronal nicotinic receptors (100%), the only vH2O Another binding affinity exhibited by Compound 1 (hemigalactarate salt) was affinity for muscarinic (non-selective) sites (51%). In a subsequent analysis (CEREP No. 9920133), a dose-response study for these interactions showed that the Kx for muscarinic M4 was 5.8 μM. Ki values for the rest

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muscarinic subtypes were >10 μM. IN VIVO Pain relief effect Compounds 1 (hot plate test) MbinimN MRI r.o. (single doses) 0.01 0.1 1.0 mg/kg YUM Compound 1 (hemigalactarate salt) (0.01, 0.1 and 1 mg/kg.d.) had no effect on paw licking delay compared to vehicle control. Morphine (64 mg/kg, po) significantly increased (+57%) paw lick delay compared to vehicle controls. Compound 1

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(hemigalactarate salt) showed no analgesic effect in the tested dose levels. Analgesic effect Compound 1 (formalin test) Mouse: C D-1 r.o. (doses were administered once a day for 7 days) 0.1 1.0 10.0 YUM On day 1, Compound 1 (hemigalactate salt) (0.1, 1 and 10 mg/kg) and aspirin at 100 mg/kg did not produce any significant analgesic effect within 35 minutes of formalin injection. Morphine (30 mg/kg, po) showed a significant analgesic effect on

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compared with the vehicle control group during the early phase (05 minutes) and late phase (15-25 minutes) after formalin injection 1 hour post-dose. On day 7, Compound 1 (0.1, 1 and 10 mg/kg), aspirin (100 mg/kg) showed no analgesic effect. The analgesic effect of morphine (30 mg/kg) was maintained on day 7.

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Reversed no symptoms neuropathy induced paclitaxele m Rats: Sp raga- Dawley r.o. Once a day during 28 days 0.01, od, 1.0mg/kg Gabapent in 100 mg/kg (1r) YUM Allodynia at 3 and 4 weeks post-dose of paclitaxel was significantly reduced from baseline levels in the vehicle group, indicating the onset of neuropathic pain. Two-way analysis of variance of all data showed treatment effect, time effect, and cross-effect (all p<0.001). Gabapentin at a dose of 100 mg/kg was effective in reversing allodynia,

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observed in the vehicle-administered groups when administered 90 minutes prior to trial (p<0.001; Bonferroni retrospective analysis) at weeks 3 and 4. Chronically administered Compound 1 at all doses significantly reduced allodynia compared to the vehicle group at 4 weeks post-dose of paclitaxel, but at 3 weeks post-dose significantly

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a difference compared to vehicle was only observed for the 0.1 mg/kg dose. Effect of Compound 1 on mechanical allodynia (rat model STZ diabetic neuropathy) Rats: Si raga- Cowley r.o. Bolus 0.01, 0.1, 1 mg/kg Gabapent in 100 mg/kg (ip) Once a day for 6 weeks 0.1, 1, 10 mg/kg 12 M Bolus dose Compound 1 reversed allodynia at 0.5 and 2 hours post-dose in the 0.1 and 1 mg/kg bolus dose groups. Gabapentin (100 mg/kg) was also effective in reducing allodynia at 0.5 and 2 hours post-dose compared to the vehicle group. Compound 1 provided

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almost the same levels of allodynia and duration of action as effective as gabapentin. Re-dosing Chronically administered Compound 1 at all doses caused a significant reduction in allodynia compared to the vehicle group at 6 weeks post STZ dosing, but none at 4 weeks post STZ dosing.

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the dose of said compound did not result in reversal of mechanical allodynia. There were no changes in blood glucose levels in animals treated with Compound 1. In the insulin treated group, reduced blood glucose levels were observed, but no significant improvement in pain perception was observed.

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Pharmacological safety

Proven Organ Systems Views/Lines Method of administration Doses (mg/kg) Gender and number of people in the group Notable observations cns Rats: Spr aga-Dawley r.o. 15 50 150 5M Compound 1 had no effect on overall behavior (Irwin profile) with a maximum inactive dose (MND) greater than 150 mg/kg. cns Rats: Spr aga-Dawley r.o. 10 thirty 100 8M Compound 1 had no effect on overall behavior (Irwin profile) at doses up to and including 100 mg/kg. cns Rats: Spr aga-Dawley r.o. 3 10 thirty 8M Compound 1 at all doses tested was not associated with behavioral sensitization as measured by motor activity in rats. Nicotine administration resulted in marked behavioral sensitization.

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Bolus nicotine challenge in rats treated with Compound 1 for 15 days and treated with Compound 1 at 30 mg/kg after being dosed daily with nicotine for 15 days showed no interaction between Compound 1 and nicotine with respect to behavioral sensitization. cns Rats : Spr aha-dawley r.o. 10 thirty 100 8M Compound 1 in combination with a subconvulsive dose of pentylenetetrazole did not cause convulsions. Damphetamine sulfate in combination with pentylenetetrazole

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caused convulsions in 6 out of 8 rats. Compound 1, which was administered orally at doses of 10, 30 or 100 mg/kg in combination with pentylenetetrazole, did not cause convulsions. The MND value was 100 mg/kg. cns Rats: Sir aga-Dawley r.o. 10 thirty 100 8M Compound 1 had no effect on body temperature at doses up to and including 100 mg/kg. Cardiovascular hERG channel in vitro 30 µM 100 µM 300 µM n/a Compound 1 produced a marked dose dependent inhibition of hERG with an IC50 value of 285 μM. Cardiovascular rabbit fiber in vitro 3 µM N/A Compound 1 caused dependent on

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Purkinje 10 µM 30 µM 100 µM concentration increased the duration of the action potential directly at 30 and 100 μM, but had no effect on the resting membrane potential, the amplitude of the action potential and Vmax at all concentrations. Cardiovascular Purkinje fiber rabbits in vitro 3 µM 10 µM 30 µM 100 µM N/A Compound 1 caused a concentration-dependent increase in the duration of the action potential at 30 and 100 μm (and had no effect at 3 and 10 μm). There was no marked effect on resting membrane potential, action potential amplitude, or maximal

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the frequency of the action potential rise at any tested concentration. Cardiovascular Guinea pigs i.v. 0.1 0.3 1 3 10 4M At doses of 0.1 and 0.3 mg/kg, blood pressure and heart rate remained unchanged. At doses of 1, 3, and 10 mg/kg, the peak increase in diastolic blood pressure was 41 mmHg; the peak increase in systolic blood pressure was 58 mmHg; and the peak increase in heart rate was 41 beats per minute. At a dose of 1 and 3 mg/kg, the effect ended

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in 3 minutes. A dose of 10 mg/kg was lethal. Compound 1 had no effect on ECG at doses up to 0.3 mg/kg, had a moderate and reversible effect on QTc at 1 mg/kg, and had a severe effect at 3 and 10 mg/kg. An intravenous dose of 0.3 mg/kg is the maximum tolerated dose (MTD). heart sucker distal Dogs: big l r.o. 5 10 20 2Mh2F Compound 1 caused a temporary and slight increase in blood pressure and bursts of sinus tachycardia in

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all dogs. • The 5 mg/kg dose did not cause other effects. • The 10 mg/kg dose was associated with 1 ventricular premature beat 10-25 minutes post-dose. • The 20 mg/kg dose was associated with 1 ventricular premature beat 10-25 minutes post-dose. In addition, at a dose of 20 mg/kg, a slight increase in the QT interval and vomiting were observed. The definition of TC revealed a terminal half-life of 1.3 to 4.2 hours,

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variable absorption and low impact at the maximum dose of 20 mg/kg. Dista heart sucker Dogs: big l r.o. 2.5 5 10 Once per day in bleeding 5 days 3 MiZ F PD: Oral administration of Compound 1 has been associated with elevated arterial blood pressure (mainly diastolic), marked tachycardia and a reduced PQ interval. These effects were similar after a single dose and after 5 days of dosing and were not dose dependent. There were no changes in QRS duration, QT interval, or

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body temperature. TC: There was no proportional increase in Cmax and AUC on any day of sampling. There were no differences between the sexes. No cumulation was observed after repeated doses. heart sucker distal Monkeys: I'm Van Monkey r.o. 3 10 thirty 3 MiZ F Single oral doses (3, 10, and 30mg/kg) of TC6499 given to conscious monkeys measured by telemetry had no significant effect on blood pressure,

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heart rate, ECG parameters and body temperature. Respiratory Rats: Spr aga-Dawley r.o. 10 thirty 100 9M Doses of 10 and 30 mg/kg did not cause changes in respiratory parameters. A dose of 100 mg/kg caused a moderate and short-term increase in respiratory rate, minute volume and maximum inspiratory rate, as well as a decrease in inspiratory time. There were no changes in tidal volume and airway resistance index during the 5 hour observation period. MND value was ZOmg/kg.

Example 8 In vitro data and summary report for Compound 1.

The following table presents the in vitro data and summary report for Compound 1.

Kinds Subtype Ki (nM) Analysis type Fabric type Human a4b2 17 [ ^Zn ] Nicotine SH-EP1 cells transfected with α4β2 Rats a4b2 34 Rats a4b2 27 gn] Nicotine Cortical membranes of rats Human a3b2 27 [ ³ N] Nicotine HEK cells transfected with α3β2 Human a6/a3b2b3 240 Human a4b4 680 Human a6b3b4a5 1100

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Human a7 15000 [ ³ H] MLA HEK cells transfected with a7 Rats a7 3500 Rats a7 5533 [ ³ H] MLA Rat hippocampal membranes Human Anglionic type (a34*) 620 [ ^JH ] Epibatidine SHSY5Y cell line membranes Human Anglionic type (a34*) 8800 Human Muscular type 36000 [ ³ H] Epibatidine TE671 cell line membranes Kinds Subtype EU50 Emax Analysis type Fabric type Rats a4b2*/a6b2* 3900 BY Release [ ³ H] DA Synaptosomes rat striatum 3932 114 Rats a4b2*/a6b2* Release ratio 0.55 DA Release [ ³ H] DA Synaptosomes rat striatum Human a4b2 600 120 Influx of Ca++ SH-EP1 cells transfected

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s α4β2 Human a4b2 5300 120 Influx of Ca++ Human a4b2 HS 29°C 3300 120 Influx of Ca++ Human a4b2 LS 37°C 5300 120 Influx of Ca++ (IC50) (I'm ah) Human a4b2 HS 29°C 430 98 Influx of Ca++ (DC50) (Dm ah) Human a4b2 LS 37°C 450 98 Influx of Ca++ Human a3b2 8700 66 Influx of Ca++ Human a6/a3b2b3 470 92 Influx of Ca++ (IC50) (im ah) Human a6/a3b2b3 2800 49

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(DC50 ) (Dm ah) Human a6/a3b2b3 31 99 Influx of Ca++ Human a4b4 4300 98 Influx of Ca++ Human ganglionic type (a3b4*) 13000 150 Influx of Ca++ Human ganglionic type (a3b4*) 18000 60 Rb+ inflow SHSY5Y cells Human ganglionic type (a3b4*) 22000 79 Rb+ inflow IMR cells Rats ganglionic type (a3b4*) 53000 35 Influx of Ca++ Rats ganglionic type (a3b4*) 19 Rb+ inflow, one point Human Muscular type 15000 42 Influx of Ca++ Human Muscular type 12 Rb+ inflow, one point

Example 9 Preclinical data for compound 1 (5-2-[(R)-pyrrolidin-3-yl]vinyl)pyrimidine, hemigalactarate, dihydrate).

Preclinical data for compound 1 (5-2-[(K)-pyrrolidin-3-yl]vinyl)pyrimidine, hemigalactarate, dihydrate) are presented below.

Chemical name and structure.

Name 5-2-[(K)-Pyrrolidin-3-yl]vinyl)pyrimidine, hemigalactarate, dihydrate (Compound 1) Structural formula He Ν o=< HE Ν BUT'< X 0.5 / ^OH x2 H.0 BUT-\ MO but Molecular formula C10H13N3 -0.5 C6HIOO8 2 H2O Molecular mass 175.24 (free base) 316.34 (hemigalactarate salt)

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Dosage form, route of administration and dosage regimen.

Dosage form nasal spray Method of administration intranasal Dosing schedule For the phase 2 clinical study, subjects were administered a low dose, medium dose, or high dose (not exceeding 3.3%, i.e. 33.2 μg/μl Compound 1 free base) of Compound 1, nasal dosage form (5-

2-[(K)-pyrrolidin-3-yl]vinyl)pyrimidine, hemigalactarate, dehydrate) at the 2nd scheduled visit.

Chemical production and control summary.

A batch of drug substance was manufactured under current Good Manufacturing Practice and a 36-month shelf life was established based on ICH stability analysis performed on previously received batches of drug substance. This batch was used to provide supplies to the clinic for a clinical study. This batch was stored under controlled environmental conditions from the time of manufacture until the expiration of the 36-month shelf life. It was then tested for material compliance with the original quality requirements at product release and then tested for stability under real ICH conditions to verify stability over the proposed study. An intranasal formulation of the drug was formulated and used for several weeks, so long-term loss of drug stability posed minimal risk.

medicinal substance.

Compound 1 nasal spray drug has previously been used in clinical studies as an oral dosage form. Compound 1 was considered safe in clinical studies but did not meet endpoints of efficacy. The dosage form of compound 1 was changed to obtain a nasal spray.

The following are the general properties and stability of Compound 1.

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General properties.

Property Result Physical form Off-white to yellow powder Solubility The solubility of Compound 1 was tested in several aqueous solutions. The results are presented below. Solvent Solubility (mg/ml in terms of base equivalents) 0.1 i. HC1 >10 0.1 M citrate buffer (pH 4.0) >10 Water (pH 5.9) >10 0.1 M phosphate buffer (pH 6.8) >10 Polymorphism Four morphological forms were identified and designated A, B, C and D. Form A is the dihydrate form and is physically unchanged at 50-85% RH. Forms B, C and D are the anhydrous forms of the product. Anhydrous forms are converted to Form A when exposed to more than 50% RH. Form A is converted to Forms B and C when exposed to strong dehydrating conditions; but reverts to Form A when exposed to more than 50% RH. Using X-ray powder diffraction (XRD) to determine and verify the preferred morphological form (Form A) drug substance, a differential scanning calorimetry (DSC) chart was obtained that is specific to Form A of the drug substance. A DSC test was performed as a flow control at the last stage of the synthesis to confirm the receipt of Form A. Optical isomerism The free base of Compound 1 contains one chiral center. Chiral centers are formed during the synthesis. The chirality of the compound was controlled at the isolation/purification step during the synthesis.

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Optical rotation [a] _D ²⁰ = -7.5 ± 0.5 (c = 0.5, water) pKa value pKa(1): 1.73 pKa(2): 10.3 Split ratio log P (calculated): 0.29 Distribution coefficient Log D (pH 7.4): < 1 Melting temperature 180-183°C

Description of the production process.

A clinical batch of the proposed medicinal substance was prepared. The manufacturing process is described in WO 2010/065443, the entire content of which is incorporated herein by reference.

Specifications.

The medicinal substance was released from production according to the technical characteristics described in Table. 1. Specified characteristics refer to a reanalysis of the lot on which the stability tests were carried out: appearance, assay, related substances, chiral purity and water content. These stability tests and specifications were also used to monitor the stability of the drug substance during the proposed study.

Table 1

Connection 1 Specifications

Trial Validity criteria Analytical method Appearance ¹ Off-white to yellow solid Visually Identification Fourier IR HPLC The spectrum of the sample corresponds to the spectrum of the reference standard obtained in a similar way. Fourier IR The retention time of the main peak corresponds to the time HPLC - UV

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holding main peak reference standard. Quantitative analysis ¹ Bulk analysis percentage showed 98-102% relative to the reference standard, in terms of a substance that does not contain volatile compounds and moisture. HPLC - UV Related substances ¹ Individual impurities not identified Amide ² rhss-Isomer ³ Set level > 0.05% no more than 1% (а/а) no more than 1% (а/а) no more than 1% (а/а) HPLC - UV Total content of identified and unidentified impurities no more than 2% (а/а) Chiral purity ¹ not more than 2% (a / a) (S) enantiomer Chiral HPLC -UV

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Residual solvents and process volatile impurities (Methods A and B) ethanol not more than 5000 ppm GC-FID ethyl acetate not more than 3000 ppm Heptane not more than 5000 ppm MTBE not more than 5000 ppm 2-propanol (IPA) not more than 5000 ppm Chloroform not more than 5000 ppm Dimethoxyethane not more than 600 ppm Dimethylacetamide not more than 1090 ppm N-methylpyrro lidone not more than 530 ppm T tetrahydrofuran not more than 720 ppm Toluene not more than 890 ppm Residue from incineration not more than 0.5% (w/w) cUSP<281> Heavy metals not more than 20 ppm cUSP<231> Palladium not more than 20 ppm ICP-OES Content of galactic acid 35.5%-39.5% Titrimetric analysis Water content ¹ Report results by Karl Fischer cUSP<921>

Stability Analysis

The amide is 2,3,4,5-tetrahydroxy-6-oxo-6-[(3K)-(2pyrimidin-5-ylvinyl)pyrrolidin-1-yl]hexanoic acid g/s-Isomer is 5-{( 7)-2-[3-pyrrolidin-3yl] vinyl } pyrimidine

Party release.

The batch was tested and released in accordance with the specifications described in this document, and received the following results, presented in table. 2.

table 2

Compound 1 drug batch analysis

Trial Validity criteria Result Appearance Off-white to yellow solid off-white solid Identification

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Fourier IR HPLC The spectrum of the sample corresponds to the spectrum of the reference standard obtained in a similar way. The retention time of the main peak corresponds to the retention time of the main peak of the reference standard. Corresponds to Corresponds to Quantitative Mass percentage analysis 100.1% analysis content showed 98-102% relative to the reference standard, in terms of a substance that does not contain volatile compounds and moisture. (May/May) Related Substances Set level > 0.05% Not no more than 1% (а/а) NZ ³ identified no more than 1% (а/а) BUT ⁴ individual substances Amide ¹ gshs-Isomer ² no more than 1% (а/а) BUT ⁴ Total content of identified and unidentified impurities no more than 2% (а/а) NZ ³ Chiral purity not more than 2% (a/a) (8)-enantiomer BUT ⁴

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Trial Validity criteria Result Residual solvents and process volatile impurities ethanol not more than 5000 ppm 461 ppm ethyl acetate not more than 3000 ppm BUT ⁴ Heptane not more than 5000 ppm BUT ⁴ MTBE not more than 5000 ppm BUT ⁴ 2-propanol (IPA) not more than 5000 ppm BUT ⁴ Chloroform not more than 5000 ppm BUT ⁴ Dimethoxyethane not more than 600 ppm BUT ⁴ Dimethylacetamide not more than 1090 ppm 100 ppm N-methylpyrro lidone not more than 530 ppm BUT ⁴ T tetrahydrofuran not more than 720 ppm BUT ⁴ Toluene not more than 890 ppm BUT ⁴ Residue from incineration not more than 0.5% (w/w) 0.0% Heavy metals not more than 20 ppm < 20 ppm Palladium not more than 20 ppm < 20 ppm The content of the galactar 35.5%-39.5% 38.3% acids wt./wt. Water content Report results 11.4% w/w 1 Amide is 2,3,4,5-tetrahydroxy-6-oxo-6-[(3K)-2pyrimidin-5-ylvinyl)pyrrolidin-1-yl]hexanoic acid The 2 z/wc isomer is 5-{(7)-2-[3-pyrrolidin-3yl]vinyl}pyrimidine (an impurity formed during synthesis and the main product of UV degradation). 3 Not recorded 4 Undefined

Stability.

A previous batch of Compound 1 was prepared under current Good Manufacturing Practice conditions. 3.

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Table 3

Compound Stability Test Protocol 1

venous substances, water content, chiral purity, X-ray powder diffraction.

B = analyses: appearance, assay, related substances, water content.

Stability data obtained at 25°C/60% RH after 36 months indicate that the drug substance undergoes minimal change and is stable over the studied time period. There is a slight decrease in the quantitation parameter to below 98% after 6 months at 40°C/75% RH and after 9 months at 30°C/65% RH. However, based on minimal change under accelerated conditions and the stability of real-time data, the drug substance is currently considered to be stable for at least 36 months. These data are summarized in table. 4.

Table 4

Compound 1 stability test results at 25°C/60% RH

Options Method Specifications Initial 1M gp 6M 9M 12M 18M 24M 36M External view visual Solid off-white BEFORE yellow Gryaznova is a white solid about palen Yellow solid thing Pale yellow solid Pale yellow solid palen Yellow solid thing Pale yellow solid Pale yellow solid palen Yellow solid thing Pale yellow solid Quantities value 98 - 102% 100.9 102.4 100.2 98.9 99.7 101.2 100.4 100.0 99.7

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enny analysis X- UV Chiral purity (% ee) chiral VESH X- UV no more than 2% (а/а) 100 ND ND ND ND 100 ND 100 100 Related Substances (% w/w)* HPLC - UV Each individually no more than 1% RRT= 0.18 BUT But But But But 0.10 But BUT BUT RRT= 0.26 0.05 0.09 0.09 But 0.09 BUT 0.07 0.05 0.04 RRT= 0.88 BUT But BUT But BUT 0.05 BUT BUT BUT Total content of related substances VESH ! X- UV no more than 2% (а/а) 0.05 0.09 0.09 0.05 0.12 0.16 0.07 0.05 0.04 Water content (% w/w) By Charles At Fish eru Report results 11.36 12.10 12.25 12.04 11.52 11.52 11.50 11.42 11.53

medicinal product.

Previous formulations of Compound 1 drug product used for other clinical indications contained admixture with excipients in a two-part hard shell capsule for oral administration. For clinical studies, an aqueous dosage form containing the drug was made in glass vials and closed with a rubber stopper. The clinic used a filter needle to extract the required amount of solution from the vial for delivery to the nasal cavity through a nebulizer.

The release of clinical material was carried out in accordance with the technical characteristics presented in table. 5.

During the development of the dosage form, a short-term stability test (about 2 weeks) was performed to show that the quantitative analysis, the content of achiral impurities and the pH of the solution remained within specifications during the time interval necessary for the release and administration of the dose of the drug.

Table 5

Compound 1 Solution Specifications

Trial Validity criteria Method Description of the external kind Clear colorless solution visual inspection Identification The retention time of the active peak in the sample should correspond to the retention time of the active peak in the standard preparation. HPLC - UV Quantitative Analysis 90-110% of the declared content HPLC - UV Decomposition products Amide no more than 1% (а/а) HPLC - UV

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cis isomer Unidentified individual impurities The total content of identified and not identified impurities no more than 1% (а/а) no more than 1% (а/а) no more than 2% (а/а)

Preclinical studies.

Conducted non-clinical studies of the oral dosage form of compound 1, and they included studies of pharmacology, pharmacological safety, pharmacokinetics/drug metabolism, toxicokinetics (TK), toxicology and genotoxicity. To date, no carcinogenicity or reproductive toxicity studies have been conducted for Compound 1. The baseline studies regarding the systemic safety of Compound 1 are briefly summarized below.

primary pharmacology.

nAChRs are a class of neurotransmitter receptors that respond to the natural product nicotine, which is derived from tobacco. They are a large family of receptors consisting of combinations of α and β subunits. Compound 1 has been shown to be a full α4β2 and α3β4 nicotinic receptor subtype agonist and a partial α3β2 subtype agonist. A nicotinic pharmacological effect mediated by α4β2 receptors has been described in neurons that originate from the dorsal motor nuclei of the vagus nerve; The α3β4 receptor subtype is present at the ganglionic synapses of the autonomic nervous system.

pharmacological safety.

In accordance with the recommendations of ICH S7, Safety Pharmacology Studies for Human Pharmaceuticals, the effect of compound 1 on the cardiovascular, respiratory systems and CNS was evaluated. Compound 1 did not show marked changes in behavioral sensitization, locomotor activity, general behavior, body temperature, or pro-convulsive properties in a series of pharmacological safety studies conducted in rats. Temporary adverse events with respect to respiratory rate were noted at 100 mg/kg.

The results of in vitro studies showed IC ₅₀ hERG 285 μm; and in a study of rabbit Purkinje fibers, an increase in action potential duration at concentrations of 30 and 100 μM (by 7 and 20%, respectively) was observed, but no effect was observed on the resting membrane potential and action potential amplitude at any concentration.

Results from a telemetric study in conscious dogs showed dose-independent increases in systolic and diastolic blood pressure and heart rate at oral doses up to 10 mg/kg. Similar observations were made at the 20 mg/kg dose, except that a slight increase in QT interval duration was observed for this dose. Dogs exhibited vomiting at all doses shortly after their administration, concurrently with maximal cardiovascular changes. Previous general toxicology studies have shown that dogs are the most susceptible species to Compound 1 (as well as to other nicotinic agonists), showing severe gastric upset/vomiting upon dosing.

In a telemetry study conducted on monkeys, no significant changes were observed with oral doses up to 30 mg/kg.

Pharmacokinetics and metabolism of the product in animals.

Studies to evaluate the pharmacokinetics of Compound 1 were performed in mice, rats and monkeys. Compound 1 has also been investigated in several in vitro and in vivo assays designed to determine tissue distribution, drug metabolism, excretion pathways, and plasma protein binding. The results of the conducted studies are summarized below. Of particular note is one study that assessed the absorption of compound 1 by nasal route of administration and the results of which are presented in this document.

Absorption.

Oral administration.

In single dose pharmacokinetic studies, Compound 1 was rapidly absorbed into the general circulation and time to peak concentration (T _max ) ranged from 0.167 to 2.25 hours in mice, rats and monkeys. When administered orally to mice at a dose of 1 mg/kg, the terminal half-life

- 168 040442 excretion was about 0.5 h, and the effect on the brain was about 30% of the effect on plasma. In a study using male Sprague-Dawley rats orally administered 0.3 or 3 mg/kg of the indicated compound, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from zero to 24 h (AUC _{0- 24} ) in the 3 mg/kg group were higher than for the proportional dose. Plasma and brain concentrations declined rapidly with a half-life of 1.4 hours; the effect on the brain was about 15% of the effect on plasma. In a monkey study, [ ¹⁴ C]-compound 1 was administered at a dose of 10 mg/kg orally or 5 mg/kg by intravenous infusion. Oral bioavailability in this study was about 30%. For unchanged parent compound, Cmax and AUC _inf were 254 ng/mL and 969 ng h/mL, respectively, in the oral dosing group; the half-life was 1.9 hours. In the intravenous infusion group, Cmax and AUC _inf were 2032 ng/ml and 1532 ng^h/ml, respectively.

Pharmacokinetic parameters of compound 1 after oral or intravenous administration to mice, rats or monkeys are summarized in table. 6.

Table 6 Pharmacokinetic parameters after oral and intravenous administration of compound 1 in mice, rats and monkeys

View Dose (mg/kg) Smax (ng / ml) Ttah (Ch.) tv2 (h) AU Co. _t (ng*h/ml) ^Fe (%) Oral administration Swiss Russian mice 1.0 ^a 15 0.167 0.5 10.1 ^e Rats SpragueDawley oh w ^a 6.51 0.5 1.4 13.5 ^e Rats Sprague- Dowley s ^a 169 0.167 1.4 211 ^e Rats Sprague- Dowley 30 ^b 1707 0.25 1.2 ^3307d Yavansk ie 10 ^b 254 2.25 1.9 ^942d 31.1 macaques 20-minute intravenous administration Javanese macaque 5 ^b 2032 0.333 2.1 ^1530d

a dose = compound 1.

^b dose = [ ¹⁴ C]-compound 1.

^c t = 24 h.

^dt = 168 hours

^e F = oral bioavailability.

In the 2-week and 13-week repeated-dose TK studies in rats, animals were orally administered 30, 100, or 200 mg/kg/day (2-week study) or 30, 100, or 300 mg/kg/day (13-week study) of the drug. In both studies, Compound 1 was rapidly absorbed with a _Tmax of 0.5 to 2 hours. Exposure parameters (Cmax and AUC _0.24 ) increased approximately in proportion to dose on days 1 and 15 in the 2- _week study and on days 1, 29, and 91 in a 13 week study. In a 2-week study, a 1.2-2.2-fold increase in exposure from day 1 to day 15 was observed. In a 13-week study, an overall increase from day 1 to day 29 was observed and approximately the same

- 169 040442 action from 29 days to 91 days. Exposure in females was much higher than in males in both studies, especially in the 200 mg/kg/day dose group in the 2-week study.

In the 2-week and 13-week repeated-dose TA studies in monkeys, animals were orally administered 10, 30, or 100 mg/kg/day (2-week study) or 10, 30, or 60 mg/kg/day (13-week study) of the drug. In both studies, Compound 1 was rapidly absorbed with a T _max of 0.5 to 6 hours and was rapidly eliminated from the body. In the 2-week study, exposure increased almost proportionally with dose from 10 to 30 mg/kg/day on days 1 and 14, and less than proportionally with dose increases from 30 to 100 mg/kg/day on days 1 and 14; this may have been facilitated by vomiting in the 100 mg/kg/day group, in 6/6 animals on day 1 and in 5/6 animals on day 14. Slight cumulation was observed across all dose groups from day 1 to day 14. In the 13-week study, exposure increased less than proportionally with dose increases from 10 to 30 mg/kg/day and substantially did not increase with dose increases from 30 to 60 mg/kg/day. Little or no cumulation was observed in each study and no influence of gender was observed in each study.

Intranasal administration.

The following is the uptake of Compound 1 by nasal route in a 7-day trial study of intranasal toxicity and toxicokinetics in rats.

Distribution.

Binding assays for Compound 1 and [ ¹⁴ C] Compound 1 showed low (<13%) plasma protein binding in mice, rats, guinea pigs, dogs, monkeys and humans at concentrations up to about 113 μM. Binding of Compound 1 to red blood cells was 28-54% immediately after injection and 41-63% 0.5 and 1 hour after injection. The blood/plasma ratio ranged from 0.78 to 1.26 and was independent of animal species and concentration.

Distribution studies performed on male Long Evans rats (1 mg/kg, po) and female Sprague-Dawley rats (30 mg/kg, po) showed that [ ¹⁴ C]-compound 1 is rapidly absorbed from the GI tract and distributed throughout the body, with peak radioactivity concentrations typically observed after 0.5-1 h. and 168 hours in all tissues, most of which showed radioactivity above the lower limit of quantitation (LQQ) (9 ng-Eq/g) at 168 hours. The adrenal medulla showed the highest concentration of radioactivity at the time of the last sampling, at 168 hours; other tissues with relatively high AUC values included the uveal tract, corticomedullary junction of the kidneys, spleen, liver, prostate, renal pelvis, kidneys in general, and the walls of the small intestine. In male and female Sprague-Dawley rats, tissue distribution was similar to that in Long Evans rats. Tissues with relatively high AUC values included excretory organs, salivary submandibular gland, adrenal medulla, and prostate (in males); the adrenal medulla showed the highest concentration of radioactivity at the last moment of sampling, after 24 hours.

Metabolism.

Metabolism in vitro.

Studies were carried out in human liver microsomes. Heat-treated human liver microsomes and human S9 fraction showed that compound 1 is relatively stable in all experimental systems, suggesting that cytochromes P450, flavin-containing monooxygenases and monoamine oxidases do not play a major role in the metabolism of this compound. After a 24-hour incubation, [ ¹⁴ C]-compound 1 was weakly or moderately metabolized in cryopreserved hepatocytes obtained from rats, dogs, monkeys and humans, depending on the animal species, according to the following order: rats > monkeys > human > dogs. In humans and monkeys, the main metabolic pathway was the oxidation of the pyrrolidine ring (M02 metabolite) followed by metabolism via dioxidation to M1 or M3. In humans, the parent compound accounted for 37% of extracellular radioactivity, M02 accounted for 13.9%, M1 4.1%, and M3 1.1%. In monkeys, the parent compound accounted for 14.2%, M02 5.0%, M1 5.8%, and M3 29.4%. In rats, the main metabolite was a pyrimidine N-oxide derivative (M9); it accounted for 71.9% of extracellular radioactivity, while the parent compound accounted for only 1.4%.

Metabolism in vivo.

After r.o. administration of a single dose of [ ¹⁴ C]-compound 1 to rats (30 mg/kg), the parent compound was extensively metabolized. The main metabolite in plasma and urine was M9; in plasma collected 6-24 hours post-dose, a significant proportion of the radioactivity was due to an unknown polar metabolite (M13). Plasma parent compound accounted for 11.7% of total AUC0-24 radioactivity, M9 20.9%, and M13 15.9%. Over a 24-hour period, the parent compound in urine (the major route of elimination) accounted for 17.8% of the total radioactivity, M9 37.7%, and M13 0.7%.

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Excretion.

The mode and extent of excretion of radioactive [ ¹⁴ C]-compound 1 was studied in Sprague-Dawley rats after p.o. administration of a single dose of 30 mg/kg, as well as in monkeys after p.o. a single dose of 10 mg/kg and a single iv infusion of 5 mg/kg. In rats, almost all the radioactivity isolated in the excreta was eliminated within 24 hours. On average, 91.2% of the administered dose was recovered during the 168-hour post-dose period (77.6% in urine, 10.9% in faeces, 2.2% in exhaled CO ₂ ). In monkeys, in 24 hours (iv) or 48 hours (p.o.) almost all the radioactivity isolated in the excreta was eliminated. For oral dosing, an average of 90.3% of the administered radioactive dose was recovered during the 168 hour post-dose period (60.7% in urine, 12.8% in faeces, 10.2% in cell wash water, and 6.6 % in food fragments). For intravenous dosing, an average of 93.0% of the administered radioactive dose was recovered during the 168-hour post-dose period (70.7% in urine, 7.6% in faeces, 7.6% in cell wash water, and 6 .9% in food fragments).

Toxicology.

The non-clinical toxicology program for Compound 1 contained the following elements: single dose general toxicity studies in rats, dogs and monkeys; repeated dose general toxicity studies in rats and monkeys up to 13 weeks; and genotoxicity studies, which included the Ames test, micronucleus text, and chromosomal aberration analysis. The following are results from 13-week repeat dose studies and genetic toxicology studies.

13-week repeated dose toxicity in rats.

Compound 1 was administered to rats once a day for at least 13 weeks via oral gavage at doses of 30, 100 or 300 mg/kg/day. Two out of 15 females administered 300 mg/kg/day died. Clinical signs in males and females in this high dose group included reduced food intake, anogenital staining, lacrimation, chromodacryorrhea, and tremor. Laboratory findings included significantly lower red blood cell mass, which correlated with elevated reticulocyte counts, with normalization; elevated levels of liver enzymes and bilirubin throughout the dosing period, with signs of recovery upon normalization; urinary changes, including increased urine volume, increased urinary proteins, and higher bilirubin and urobilinogen, with recovery in the process of normalization. Rats receiving doses of 100 mg/kg/day or more had clinical signs that included excessive salivation, brown muzzle, closed or partially closed eyelids, and reduced body weight. Laboratory findings included elevated levels of white blood cells (lymphocytes and neutrophils), with normalization; elevated bilirubin; and a slight decrease in total serum proteins (globulins and albumin). Macroscopic and histological examination of the tissues showed a significantly increased mass of the liver. At doses > 100 mg/kg/day, microscopic findings are evidence of centrolobular hepatocellular hypertrophy, medullary adrenal cell hypertrophy, small intestinal mucosal epithelial cell hyperplasia, and increased extramedullary hematopoiesis and hemosiderin deposits in the red pulp of the spleen. At a dose of 300 mg/kg/day, macroscopic and histological tissue studies revealed an increased mass of the spleen with hemosiderin deposits in the red pulp of the spleen and in the Kupffer cells of the liver. The low dose, 30 mg/kg/day, was well tolerated, with the exception of minimal hepatocellular hypertrophy, which was observed in 7 out of 10 males, but was not observed in females. Accordingly, the maximum non-toxic dose (MNTD) was considered to be 30 mg/kg/day. Compound 1 was rapidly absorbed with a T _{max of} 0.5-2 hours post-dose and was detectable in plasma up to 24 hours post-dose. AUC and C _max increased from 1 to 29 days. The AUC remained constant between days 29 and 91, suggesting that a state of equilibrium was reached on day 29. With MINTD, C _max values ranged from 2570 ng/ml for males to 3150 ng/ml for females. AUC values ranged from 12100 vpch/ml for males to 10200 vpch/ml for females.

13-week repeated dose toxicity in monkeys.

Compound 1 was administered to cynomolgus monkeys once daily for at least 13 weeks via oral gavage at doses of 10, 30, or 60 mg/kg/day. At the end of the dosing period, 2 monkeys of each sex in the high dose group and in the control group were selected for normalization within 4 weeks. One monkey, administered 60 mg/kg/day, was euthanized during the fourth week due to marked malnutrition, including weight loss (-22% from day 1), reduced locomotor activity, hyporeactivity, hypothermia, and significant changes in clinical chemistry (elevated urinary nitrogen and creatinine, low sodium and potassium, and reduced chloride) suggestive of impaired renal function, combined with microscopic evidence of mild tubulointerstitial nephritis characterized by nephrophilic and mononuclear interstitial inflammation, intratubular neutrophilic inflammation, degeneration, and regeneration of the tubular epithelium, as well as the presence of cylinders, mineralization and expansion of the tubules. In surviving monkeys at a dose of 60 mg/kg/day, clinical observations included vomiting, reduced locomotor activity, weight loss, no

- 171 040442 a large increase in QT intervals (up to +16%), QTcB (up to +9.2%) and QTcF (up to +11%), associated with a slight decrease in heart rate. These parameters were restored by the end of the 4-week normalization period. Importantly, no significant changes in ECG measurements have been found to date in clinical studies of compound 1. Microscopic measurements in the 60 mg/kg group revealed moderate interstitial vacuolization in the heart in 1 of 2 males and 2 of 3 females. At a dose of 30 mg/kg, all animals experienced vomiting, but the number of emetic episodes was less than in animals at a dose of 60 mg/kg. The 30 mg/kg dose was well tolerated and was considered MRTD. C _max and AUC increased less than proportionally at doses between 10 and 30 mg/kg. No dose effect was observed at doses between 30 and 60 mg/kg, suggesting absorption saturation; inter-individual variability in plasma concentrations was high. With MINTD, C _max values ranged from 382 ng/ml for males to 696 ng/ml for females. AUC values ranged from 1670 ng-h/ml for males to 2440 ng-h/ml for females.

Genotoxicity studies.

Compound 1 was negative for mutagenicity in in vitro bioassays including the Ames test, micronucleus test in murine lymphoma cells, and chromosome aberration assay using cultured human peripheral blood lymphocytes, as well as in vivo micronucleus test in rat bone marrow.

Intranasal toxicity studies.

Intranasal toxicity studies can be performed in rodents (rats and mice), rabbits, and larger animal species, including dogs and primates, although experimental technologies (eg, single nostril dose volume, delivery device) for administering an experimental drug may differ between species. . The use of rats and dogs or monkeys is the most common way to evaluate intranasal drugs in rodents and non-rodent animals, respectively. However, rabbits are also used, and methods for histopathological evaluation in the rabbit nasal cavity in safety evaluation studies have been developed by Pereira et al. (Pereira ME, Macri NP, Creasy DM. Evaluation of the rabbit nasal cavity in inhalation studies and a comparison with other common laboratory species and man Toxicologic Pathology 2011 39:893-900).

Although systemic toxicity has previously been evaluated in rats and monkeys in oral administration studies conducted in accordance with good laboratory practice for up to 13 weeks, rats and rabbits (New Zealand) were chosen to evaluate compound 1 in intranasal toxicity studies. The main objective of intranasal toxicity studies in rats and rabbits was to evaluate local toxicity using clinically relevant dose concentrations of Compound 1, up to 6% (calculated as hemigalactarate salt). Since rabbits have not previously been tested in systemic toxicity studies with Compound 1, a full systemic evaluation will also be performed in the ongoing 28-day study, which is conducted in accordance with good laboratory practice.

Completed toxicological studies.

7-day trial study of compound 1 intranasally in rats.

The potential toxicity and TC of compound 1 was evaluated in a 7-day intranasal study in rats. Below is the study design.

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Table 7

Experimental design of a 7-day trial study of compound 1-A in intranasal administration to rats

No. groups Pepa tyvae drug Dose volume (µL/animal/dose) ^a Dose volume (µL/animal/duck) ^a Dose concentration (%) ^s Number of animals Main study Toxicokinetic study Sam tsy Sam ki Males females 1 Control ^drug 60 180 0 5 5 - - 2 Connect singing 1 60 180 0.5 5 5 9 9 3 Connection 1 60 180 2 5 5 9 9 4 Connect knowledge 60 180 6 5 5 9 9

- Not applicable.

^a The indicated dose volume was administered to each animal, with the total volume administered equally divided between both nostrils (30 µl per nostril per dose), 3 times daily.

^b Phosphate buffered saline (PBS).

^c In terms of hemigalactarate salt.

In this study, the following parameters and expected outcomes were assessed: clinical signs, body weight, body weight gain, food intake, ophthalmic, toxicokinetic parameters, autopsy results, organ weights, and histopathological examination of selected tissues, including the nasal cavity at levels I-IV and detailed ocular histopathology for all dose groups; histopathology of the brain, pharynx, larynx, trachea, lung, and selected target tissues (i.e., adrenal, liver, and spleen) as determined in the 13-week oral toxicity study in rats (DSE 2004-0356) conducted according to good laboratory practice, in a group of 1 and 4 animals; and macroscopic lesions.

The toxicokinetics of systemic exposure to compound 1 is presented below (in Fig. 1 and in Table 8). Blood samples were taken to analyze the plasma concentration of compound 1 in 3 rats/sex/group/time point before dosing and at 0.083, 2, 5, 6.083 (5 min after the second daily dose), 8, 11, 12.083 (at 5 minutes after the third daily dose) and 24 hours after the first daily dose on days 1 and 7.

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Table 8

Toxicokinetic parameters of compound 1 after

TID administration in rats on day 1 and day 7

Floor Day Dose level ^a (mg/day) AU Co. _t (ng*h/m l) DN AUCo b -t C ^s (ng/m l) t _max ^with O ) Cl ^d (ng/m l) C2 ^d (ng/m l) ^C3d (ng/ml) Sam ts 1 0.9 BUT BUT 54.2 12.08 3 51.9 36.3 54.2 3.6 829 230 343 6.083 86.4 343 134 10.8 1700 157 924 12.08 3 208 332 924 Females 1 0.9 138 154 34.9 12.08 3 26.1 34.8 34.9 3.6 626 174 278 12.08 3 50.2 119 278 10.8 4170 386 481 6.083 326 481 329 Sam ts 7 0.9 BUT BUT 33.7 12.08 3 12.4 28.0 33.7 3.6 298 82.7 BY 0.083 BY 53.8 25.5 10.8 878 81.3 225 12.08 3 166 209 225 Females 7 0.9 148 164 37.5 12.08 3 20.3 16.3 37.5 3.6 336 93.5 79.9 6.083 68.0 79.9 76.0 10.8 1480 137 224 6.083 218 224 210

a Dose concentrations of 0.5, 2, and 6% are equivalent to 0.9, 3.6, and 10.8 mg/day of hemigalactate salt, respectively.

^b Units of dose-normalized (DN) AUCo-t are (ng*h/mL)/(mg).

^c C _max is the maximum concentration, and T _max is the time to reach the peak concentration during the entire time interval of blood collection. ^d C1, C2 and C3 are the peak concentrations after the 1st, 2nd and 3rd installation.

NA = not reportable because < 3 consecutive concentrations were used to determine AUC0-t.

Compound 1 was rapidly absorbed after intranasal administration and showed an increase in systemic exposure in males and females with increasing dose. Peak systemic exposure to compound 1 after each instillation was observed 5 minutes after the time of dosing. T _max , correlating with the maximum observed exposure, C _max , usually occurred after the second or third instillation, with one exception (group 3, males, day 7). Based on TK data from a limited number of samples that show rapid absorption and a half-life of 1.4 h, it is not possible to accurately determine if there is a systemic accumulation of Compound 1 or onset of clearance within 7 days when Compound 1 is administered to rats on a TID schedule.

As a result of intranasal administration to rats of 60 μl of compound 1 at dose concentrations of 0, 0.5, 2 and 6% 3 times a day for 7 days, all animals survived until the planned euthanasia. statistics

- 174 040442 a clinical difference was observed for net body weight, food intake and organ weight compared to corresponding controls; however, there is no principle, trend or correlation data to suggest that these values were toxicologically relevant. Clinical observations, obtained ophthalmological, macroscopic and microscopic data were considered random, which are usually observed in rats of this line and age, and/or they had the same frequency of occurrence in control and experimental animals and, therefore, they were considered not related to the administration of compound 1-A . Thus, the maximum non-toxic dose (MNTD) was considered equal to 180 μl of 6% compound 1 per animal per day.

Single dose tolerance and PK in rabbits.

The possible toxicity and TC of Compound 1 nasal spray was assessed after a single injection (100 μl) of 2% or 5% Compound 1 into the right nostril of male New Zealand white rabbits (N=36). As a control, phosphate-buffered saline (PBS) was used, which was injected as a spray (100 μl) into the left nostril. Bioanalytical and histopathological analyzes were performed at 1, 3, 6, 9 and 24 hours post-dose. Prior to euthanasia, the intranasal/nasal area of each animal was assessed using the Draize classification system for assessing skin irritation.

No clinical signs were observed in the animals during the entire study, and no signs of redness, swelling, formation or separation of ulcers were observed during intranasal/nasal evaluation. Histopathologically, no macroscopic or microscopic signs were observed associated with the use of the experimental drug, 2 or 5% Compound 1, in the nasal cavity.

Ongoing toxicological studies.

Studies to evaluate the toxicity of Compound 1 Nasal Spray need to be conducted, which will be ongoing and follow-up studies:

28-day repeated-dose intranasal toxicity study in rats;

7-Day Repeat Dose Tolerance and PK Study in Rabbits;

A 28-day repeated-dose intranasal toxicity study in rabbits.

Baseline toxicity studies intended to support clinical trials are conducted in full compliance with the requirements of Good Laboratory Practice (GLP). Below is a summary of the protocol for each study.

28 day GLP toxicology study of repeated doses of Compound 1 administered intranasally to rats with a 4 week normalization period

Target Assess the possible toxicity and toxicokinetics of Compound 1-A administered intranasally GLP In accordance with GLP 21, CFR Section 58 Experimental drug Compound 1-A Experimental system Sprague-Dawley rats, 80/sex, 160 total Experiment Design 28 days of dosing and 4 weeks of normalization Group Grade Normalization Toxicokinetic

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security I A Males Female and Males Female and Males females Carrier 10 10 5 5 3 3 Compound 1 0.5% 10 10 9 9 connect 1 2% 10 10 9 9 connect 1 6% 10 10 5 5 9 9 Method / hour that introduction DOS Intranasal instillation with a micropipette, 30 ml per nostril, 3x per day. Security Endpoints • Observations at the cage: 2x per day; doom/agony • Clinical observations: once a week • Battery of standard tests: before examination and at 14 day (30 minutes after dosing) • Massatela: pre-study, for 1 day (before the introduction doses), then once a week and before ending at the end

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dosing and normalization periods • Food intake: once a week; quantitative grade • Ophthalmological testing (with slit lamp and indirect): before the study, on the first day of dosing (day 1), in the middle of the dosing period (day 15), and at the end of the treatment and normalization periods. Clinical Clinical chemistry, hematology and parameters and I coagulation: before treatment and at the end of treatment periods and pathology normalization. Toxicocci Blood samples are taken from all animals before and after administration of the first netika and last study dose. Necropsy Perform with full tissue collection and measure organ weights (liver, lungs, heart, kidneys, brain, adrenals, testicles, thyroid, pituitary, spleen, and thymus). Histopatol Histopathology in the control group and in the group with high ogiya dose (6% of Compound 1), including complete histopathology of the eyes and respiratory tract, as well as histopathology of selected target tissues of rats (adrenals, liver, spleen) and brain. In addition, in all groups, it is necessary to conduct a detailed histopathology of the nose. I also study macroscopic lesions.

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7-Day Repeated Dose Tolerance and PK Study in Rabbits.

Target Evaluate possible toxicity and toxicokinetics Compound 1-A administered intranasally GLP No Experimental drug Compound 1-A Experimental system New Zealand white rabbits, total 24 (male) Experiment Design 7 day dosing Group Dosing frequency Number of animals Carrier (PBS) 2x per day 6 Compound eleven% 1x per day 6 Compound! 2.5% 1x per day 6 Compound! 2.5% 2x per day 6

Method of administration Intranasal instillation with a micropipette, 100 µl per nostril Security Endpoints • Clinical observations • Intranasal assessment: Intranasal assessment irritations are carried out using the Draize rating scale • Body mass Toksikok inetika Blood samples are taken from all animals after the first dose (1 hour post-dose) and at the end (24 hours post-dose).

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Necropsy i Perform with full tissue collection and measure organ weights (liver, lungs, heart, kidneys, brain, adrenals, testicles, thyroid, pituitary, spleen, and thymus). Histopathology Histopathological assessment of the nasal cavity (right and left nostrils) and respiratory tissues (pharynx, larynx, mediastinal lymph nodes and trachea with lung lobes) is performed in 3 animals per group. In the remaining 3 animals in each group, the mucosa of the right nasal passage and the anterior lobe of the brain are analyzed for analysis of FC in tissues.

A 28-day GLP repeated-dose toxicity study of Compound 1 administered as an intranasal spray to New Zealand white rabbits, with a 4-week normalization period.

Target Evaluate the potential toxicity of the toxicokinetics of the nasal spray Compound 1 GLP In accordance with GLP 21, CFR Section 58 Experimental drug Nasal spray Compounds 1 Experimental system New Zealand White Rabbits, 18/g, 36 total Experiment Design 28 days of dosing and 4 weeks of normalization Group At the end of the study Normalization males females males females Carrier 3 3 3 3 Compound 1 0.5% 3 3 Compound 12% 3 3 Compound 16% 3 3 3 3 Method / hour that introduction DOS Intranasal spray, 100 µl per nostril, 2 times a day. Security endpoints • Observations at the cage: 2x per day; doom/agony

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And • Clinical observations: once a week • Body weight: before the study, once a week (up to doses) and before the end • Food intake: once a week; quality grade • Intranasal/nasal assessment: before examination and at the end of periods of treatment and normalization; assessment is performed using an otoscope, and assessment of intranasal irritation is performed using the Draize rating scale • Ophthalmological examinations (with slit lamp and indirect): before the study, on the first day of dosing (day 1), in the middle of the dosing period (day 15) and at the end of the treatment and normalization periods. • Test to determine the production of tear fluid Schirmer: on the first day of dosing (Day 1), in the middle of the dosing period (Day 15) and at the end of the treatment and normalization periods. Clinical pathology Clinical chemistry, hematology and coagulation parameters: before treatment; mid-dose period (day 15); and at the end of periods of treatment and normalization. Toxicoki netica Blood samples are taken from all animals before and after administration of the first and last dose of the study. Necropsia Perform with a complete collection of tissues and measure the mass of organs (liver, heart, kidneys, brain, adrenal glands, testicles, thyroid gland, pituitary gland, spleen and thymus). Histopathology Complete histoptology in the control group and in the high dose group (6% Compound 1). In addition, detailed nasal histopathology is performed in all groups. Macroscopic lesions are also assessed.

Preclinical generalization.

Conducted studies of oral toxicity of repeated doses of compound 1 in rats and monkeys for up to 13 weeks. Compound 1 was well tolerated in both species at a dose of 30 mg/kg. Significant signs of toxicity in a 13-week study in rats included death at the high dose of 300 mg/kg and histopathological observations (adrenal, liver, small intestine, and spleen) at >100 mg/kg. In a 13-week study in monkeys, renal toxicity was observed in one monkey at 60 mg/kg, which was euthanized in a state of agony for 4 weeks, and moderate interstitial vacuolization was observed in the heart of 3 monkeys at 60 mg/kg. The MINTD in the 13 week study in rats and monkeys was considered to be 30 mg/kg for both studies.

Rats and rabbits were chosen to evaluate Compound 1 in intranasal toxicity studies. Since systemic toxicity was previously assessed in two species as described above, the main goal of intranasal toxicity studies in rats and rabbits was to evaluate local toxicity using clinically relevant dose concentrations of Compound 1-A, up to 6%. Dose levels for baseline GLP studies were chosen to estimate expected clinical dose concentrations in the range of 0.5% to 6%. In addition, the frequency of dosing (ie three times a day in rats and twice a day in rabbits) was planned to exceed the maximum planned clinical frequency of dosing in the proposed clinical study.

Compound 1 doses for an ongoing 28 day GLP intranasal toxicity study

- 180 040442 features in rats and rabbits are presented in table. 9 are expressed in mg/day, mg/kg/day and in mg/cm ² . Table 9 Doses of Compound 1 in an ongoing 28-day GLP intranasal toxicology study in rats and rabbits

GROUP ^PA Dose volume (µl/animal/day) Dose concentration (%) ^{a, b} mg/day ^b mg/kg/ ^day μ / cm ² (b, d) 28-Day Rat Toxicology Study 2 180 0.5 0.9 3.6 0.06 3 180 2 3.6 14.4 0.26 4 180 6 10.8 43.2 0.77 28-Day Rabbit Toxicology Study 2 400 0.5 2 0.8 0.03 3 400 2 8 3.2 0.13 4 400 6 24 9.6 0.39

^a 0.5% = 5 µg/µl; 2% = 20 µg/µl; 6% = 60 µg/µl. b

In terms of hemigalactarate salt.

^c Approximate weight: 0.25 kg for rats; 2.5 kg for rabbits.

^d Approximate nasal area: 14 cm ² (both nostrils), rats; 61 cm ² (both nostrils), rabbits; 180 cm ² (both nostrils), people.

Table 10

Compound 1 free base equivalent doses in an ongoing 28-day GLP intranasal toxicology study in rats and rabbits

Group Dose volume (µl/animal/day) Dose concentration (%) ^{a, b} mg/day ^b mg/kg/day and ^bc μ / s m ^{2 (hell} 28-Day Rat Toxicology Study 2 180 0.28 0.5 2 0.04 3 180 1.1 2 8 0.14 4 180 3.3 6 24 0.43 28-Day Rabbit Toxicology Study 2 400 0.28 1.1 0.4 0.02 3 400 1.1 4.4 1.8 0.07 4 400 3.3 13.3 5.3 0.22

^a 0.28% = 2.8 µg/µl; 1.1% = 11.1 µg/µl; 3.3% = 33.2 µg/µl.

^b Free base; conversion factor from hemigalactate salt to free base = 0.554.

^c Approximate weight: 0.25 kg for rats; 2.5 kg for rabbits.

^d Approximate nasal area: 14 cm ² (both nostrils), rats; 61 cm ² (both nostrils), rabbits; 180 cm ² (both nostrils), people.

Intranasal doses for humans are usually 50-100 microliters per spray. For example, before

- 181 040442 assuming two sprays (100 µl per spray per nostril, total 200 µl; equivalent to 6.6 mg/day or 0.11 mg/kg for a 60 kg patient) 3.3% (33.2 µg/ µl) Compound 1 nasal spray (free base) in the proposed clinical study, on an animal-to-human basis, the exposure limit at high dose in 28-day repeat dose studies in rats and rabbits would be 10.8-fold and 5.5-fold higher, respectively . On a mg/m ² basis, the safety margins would be much higher, 218 and 48.2 times higher for rats and rabbits, respectively. Ongoing pivotal studies in rats and rabbits are designed to determine a sufficient margin of safety (at least 2-3 times mg/cm ² ) for the maximum clinical dose (to be determined) in the proposed clinical study.

Clinical researches.

The oral form of Compound 1-A, Compound 1, was investigated in several clinical trials. In total, 108 people took compound 1: 69 healthy volunteers in the phase 1 studies, 23 subjects in the gastroparesis phase 1b study, and 16 subjects with irritable bowel syndrome with predominant constipation (IBS-C) in the phase 2a study. Subjects were administered doses of Compound 1 from 5 mg to (and including) 200 mg. No noticeable clinical changes have been established on physical examination, laboratory measurements of blood or urine, or ECG measurements. Adverse events reported in all studies were generally associated with the GI tract and included nausea, abdominal pain, vomiting, and diarrhea.

Example 10 Proposed Phase 2 Clinical Study for Compound 1 (5-(2-[(R)pyrrolidin-3-yl]vinyl)pyrimidine, hemigalactarate, dihydrate).

Below is a summary of the proposed phase 2 study.

Protocol name: Multicentre, Randomized, Controlled, Double-Blind Clinical Trial Evaluating Compound 1 Nasal Spray for Signs and Symptoms of Dry Eye Disease Investigational drug: Nasal spray Compounds 1 Purpose of the study: The purpose of this study is to evaluate the safety and efficacy of Compound 1 nasal spray versus placebo in relation to signs and symptoms of dry eye disease. General Study Design Structure: Multicenter, randomized, controlled, double-blind phase 2 study Duration: Two study visits within approximately two weeks Control: Placebo (carrier nasal spray for Connections 1)

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Dosing schedule: Dosing at 1st visit and at 2nd visit Generalization of the scheme of visits: Visit 1 = 1 day, selection and dosing (assessed using the Schirmer test) Visit 2 = Day 15 + 4 Dose (Dry eye assessment) Measures taken to reduce the standard error: Randomized, double-blind study Characteristics of the experimental group Number of subjects: About 200 (50 per group) Condition/disease: Dry eye disease Inclusion Criteria: Subjects must meet the following conditions: 1. Age at the selection visit at least at least 22 years old 2. Application and/or desire for application artificial tears to treat dry eye symptoms for 6 months up to 1 visit 3. OSDI® score > 23 with number of responses "N/A" < 3 at the qualifying visit 4. At the selection visit, ALL have the following characteristics in the examined eye: • Assessment of fluorescein staining

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corneas > 2 in at least one corneal area OR sum > 4 for all corneal areas • Baseline Schirmer score (with local anesthesia) <10 mm/5 min. with nasal stimulation with a cotton swab. Schirmer test score of at least 7 mm greater in the same eye • The eye being examined should be defined as an eye that meets all inclusion criteria; if both eyes match, then choose the eye with the highest increase in tear production with cotton swab stimulation at the screening visit, or, if there is no difference in stimulated tear production, the eye with the lower baseline Schirmer score at the screening visit. If there is no difference for both parameters, the right eye is used as the test eye. 5. Visual acuity with maximum correction (BCVA) of 0.7 logMAR or better (logMAR < 0.7; equivalent to a Snellen score of 20/100 or better) for each eye at the screening visit 6. Normal eyelid/eyelash anatomy, function blinking and closing, as determined by the investigator

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7. Lack of information (for example, information about the investigational tear-stimulating drug being used) or no previous use of the experimental drug 8. Literacy, the ability to speak English and the ability to independently complete the questionnaire 9. Opportunity to participate in research for about four consecutive hours on day 15 10. Ability and willingness to use an investigational drug and participate in all experimental evaluations and visits 11. Availability of oral and written informed consent 12. For women of childbearing potential, the presence of a negative urine test for pregnancy on day 1 Exclusion Criteria: Subjects must not: 1. Have clinically significant defects corneal epithelium on the 1st day of the study before the Schirmer test 2. Have chronic or recurrent bleeding from the nose, coagulation disorders or other pathological conditions that, according to

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in the opinion of the investigator, may lead to a clinically significant risk of increased bleeding 3. Have experienced nose surgery or sinuses (including a history of nasal cauterization) or significant trauma to these areas 4. Have a polyp on a vascular pedicle, significant deviated nasal septum, chronic and recurrent nosebleeds, or severe nasal airway obstruction confirmed by intranasal examination performed up to day 1 5. Currently undergoing treatment with continuous positive airway pressure (CPAP) 6. Have experienced intraocular surgery (such as cataract surgery), extra-ocular surgery (such as blepharoplasty) in either eye within the past three months, or refractive surgery (such as LASIK, LASEK, PRK, or corneal implant) within the past twelve months up to 1 visit 7. Have a corneal graft in any eye or both eyes 8. Use contact lenses for 7 days to 1 visit or suggest use

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contact lenses during the experimental period 9. Have a punctal occluder or intratubular occluder in any eyelid (participants with permanent occlusion of the lacrimal tubules are eligible) 10. Have a history of or currently experience any ophthalmic disorder or condition in any eye that, in the opinion of the Investigator, may interfere with the interpretation of study results or compromise participant safety, such as significant corneal or conjunctival scarring; pterygium or knotty pinguecula; existing eye infection, conjunctivitis, or inflammation not associated with dry eyes corneal dystrophy of the anterior (epithelial) basement membrane or other clinically significant dystrophy or degeneration of the cornea; herpetic eye infection; signs of keratoconus; etc. Let's say untreated blepharitis and mild meibomian gland disease, which are usually associated with dry eye disease. 11. Have an unstabilized systemic condition or disease that, in the opinion of the Investigator, is incompatible with participation in the study or with longer trials required

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for investigation (eg, current systemic infection, uncontrolled autoimmune disease, uncontrolled immunodeficiency disease, history of myocardial infarction, or heart disease). 12. Have a known hypersensitivity to any procedural agent or to the components of the experimental drug 13. Use snuff at the same time tobacco, chewing tobacco, or cigarettes/cigars during the entire study or within the previous 30 days 14. Concomitant use of nicotinic acetylcholine receptor agonists [Nicoderm®, Nicorette®, Nicotrol NS® (nicotine), Tabex®, Desmoxan® (cytisine), and Chantix® (varenicillin)] or within the previous 30 days 15. Have an active or uncontrolled severe form: • Systemic allergies • Chronic seasonal allergies at risk started during the study • Rhinitis or sinusitis requiring treatment, for example, antihistamines, decongestants, oral or aerosol

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steroids, at the qualifying visit • An untreated nasal infection at 1 visit 16. Have any condition or history of disease that, in the opinion of the Investigator, may interfere with adherence to study design, assessment of outcomes, safety parameters, and/or worsen the general medical condition of the subject 17. Be pregnant, nursing or planning a pregnancy at 1 visit 18. Currently participating in a study of an experimental drug or device or taking an experimental drug or using an experimental device for 30 days prior to the 1st visit Experimental dosage forms: • Nasal spray Compounds 1 • Placebo (carrier nasal spray for Connections 1) Criteria for evaluation Efficiency parameters: Primary performance parameters: • Schirmer test at 1 visit • Dry eye assessment (EDS) at 2nd visit

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Security options: • Questionnaire on unfavorable phenomena (AE) Other options: • Ora Calibra™ Eye Discomfort Scale • Urine pregnancy test General statistical methods and types of analyzes Group analysis: • Group of patients according to the prescribed treatment - Group patients according to the prescribed intent-to-treat treatment (intent-to-treat ITT) includes all randomized subjects. Subjects in the ITT group were analyzed according to randomization. • Protocol group - protocol group (per protocol, PP) includes subjects in the ITT arm who did not have significant protocol deviations and who completed the study. Protocol deviations are evaluated before database access is closed and unmasked. Subjects in the PP group were analyzed according to the treatment given. randomly. • Safety Assessment Group - Safety Assessment Group includes all subjects who received at least one dose of the experimental drug. Subjects in the safety group were analyzed according to treatment. Sample size: The sample size for this study is not based on considerations of study power. It is envisaged that each of the four experimental groups will involve about 50 subjects, for a total of about 200 randomized subjects. Assuming an exclusion rate of 5%, it is assumed that about 47

- 190,040,442 subjects in each group will complete the study.

Repeatability considerations:

For this early phase study, no corrections for multiple trials will be used.

Primary performance analysis:

Schirmer test scores and dry eye scores will be summarized by visit number, by time point (if applicable) and by treatment using descriptive statistics (n, mean, median, standard deviation, minimum and maximum).

An analysis of covariance model will be used to compare the results of the Schirmer test, conducted in parallel with treatment, between experimental groups with each dose of Compound 1 nasal spray and a placebo control group. The analysis of covariance model will include baseline Schirmer score (obtained at screening), treatment, and site of clinical trial as covariates. Based on this model of covariance analysis, weighted means (root mean square means) for each treatment, corresponding 95% confidence intervals (CI) and estimated treatment difference between each dose of Compound 1 nasal spray and placebo will be calculated. In addition, in a separate model, the influence of the study site on treatment will be examined to assess how the effect of treatment may differ for different study centers.

The change in dry eye score (EDS) from pre-treatment to post-treatment will be analyzed using an analysis of covariance model using pre-treatment EDS as covariate and treatment and time as fixed effects (taking into account repeated measurements). Based on the indicated covariance model

- 191 040442 analysis will calculate the weighted means for each treatment, the corresponding 95% confidence intervals and the estimated treatment difference between each dose of Compound 1 nasal spray and placebo. In a separate model, the effect of the study center on treatment will also be examined to assess how the treatment effect may differ for different study centers.

Primary analysis will be done in the ITT group using observed data. Two-sample t-tests and non-parametric Wilcoxon rank-sum tests will be used as unadjusted sensitivity analyzes to compare treatment options. Sensitivity analyzes will also be performed on the ITT group with multiple substitutions (M1) to recover missing data, as well as on the PP group for observed data only.

Other efficacy analyses:

The change in EDS from pre-treatment to post-treatment at each individual time point will also be analyzed, in the same manner as the primary analysis of the Schirmer test. The specified analysis of covariance models will include pre-treatment EDS, treatment, and study site as covariates.

The change in score on the Ora Calibra Eye Discomfort Scale from pre-treatment to post-treatment will be summarized by visit number, by time point (if relevant) and by treatment using quantitative descriptive statistics, and will be analyzed at each individual time point in the same way. way like EDS.

These analyzes will only be performed on observed data in the ITT and PP groups.

Security Variables:

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Adverse events will be coded using the Medical Dictionary of Regulatory Vocabulary. For each treatment group, the frequency and percentage of subjects with treatment-related adverse events (AEs), severe AEs, and AEs leading to early withdrawal from the study will be determined. An AE is treatment-related if it occurs or worsens after the first dose of the experimental drug. In addition, the frequency of occurrence will be presented for subjects with AELV by organ system class, by organ system class and preferred term, by organ system class, by preferred term and highest severity, by organ system class, preferred term and most closely related, and by organ system class, preferred term, maximum severity, and most closely related. Separate analyzes will be performed for eye-specific AEs and for all AEs (including systemic).

Other safety endpoints, including visual acuity, slit lamp biomicroscopy, and intranasal endoscopy, will be summarized by treatment group and visit number using descriptive statistics. Changes or shifts from the original value will also be summarized, if appropriate. For a per-eye assessment, the observations for the experimental eye and the other eye should be summarized separately. In addition, changes from baseline to the worst value during treatment will be summarized to assess ophthalmic safety.

Summarizing known and possible risks and benefits for humans

There are no known risks associated with the instillation of Compound 1 nasal spray.

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List of abbreviations

nya adverse event BCVA Visual acuity with maximum correction CAE ^-SM Controlled adverse environmental conditions CFR Code of Federal Regulations CI Confidence interval DED Dry eye disease CRF Patient registration card FDA Food and Drug Administration GCP Good Clinical Practice HIPAA U.S. Health Insurance Preservation and Personalized Health Care Account Act ICF Informed Consent Form ICH International Conference on Harmonization IRB Institutional/Independent Control commission logMAR logarithm of minimum resolution angle MM Millimeter OSDI® Eye Surface Damage Index® OTC OTC SAE Serious adverse event TENS transcutaneous electrical nerve stimulation USA USA

1. Introduction.

Dry eye is a multifactorial age-related disorder of the ocular surface resulting in severe pain, visual disturbances, tear film hyperosmolarity and instability, inflammation and corneal damage. Although the prevalence of dry eye cases is difficult to describe due to different criteria for definition and diagnosis, worldwide it is believed that between 5% and 35% of people over the age of 50 suffer from this condition. In the United States, an estimated 3.2 million women and 1.7 million men over age 50 suffer from dry eye, with an estimated 40% increase by 2030.

Compound 1 nasal spray is designed to treat dry eye by targeting the nasolacrimal reflex cascade. The nasolacrimal reflex is a well-studied cascade by which nasal stimuli accelerate basal resting tear secretion and bolus tearing. This reflex plays a functional role in the expulsion of foreign bodies or irritants from the nose through the secretion of lacrimal fluid into the nasal cavity along the nasolacrimal duct when stimulated by the stimulus. Activation of the lacrimal gland reflex is also one of the main compensatory mechanisms of the body to eliminate dryness of the ocular surface. Unfortunately, over time, dry environmental conditions and the resulting inflammation lead to damage to the afferent nerves that innervate the cornea, which impairs the reflex response and ultimately causes an even drier surface.

- 194 040442 Eyes.

Compound 1 serves as a nasal irritant through activation of nicotinic acetylcholine receptors (nAchR). It is well known that nAchRs can mediate afferent signals in the trigeminal nerve, including response to nicotinic nasal stimuli. These afferent signals form the basis for the nasolacrimal reflex, which leads to the production of tear fluid. Indeed, nicotine-containing nasal sprays designed for smoking cessation are known to increase tear production as a side effect of treatment. Therefore, nAchRs are a logical target for activating the tear reflex to treat dry eye.

This study used a controlled adverse environmental conditions (CAE ^SM ) model to assess symptoms of dry eye. The CAE is a room in which environmental conditions are standardized by adjusting humidity, temperature, air velocity, lighting conditions and visual objectives. Patients with dry eyes are subjected to CAE conditions for up to 2 hours during which subjective and objective parameters can be assessed before, during and after exposure. The CAUs mimic the everyday situations faced by dry eye patients, such as forced air heating systems, air travel, and computer work, and provide the ability to standardize these influencing factors.

2. Research objectives.

The purpose of this study is to evaluate the safety and efficacy of Compound 1 Nasal Spray versus placebo for signs and symptoms of dry eye disease (DED).

3. Clinical hypothesis.

The clinical hypothesis for this study is that Compound 1 nasal spray is superior to placebo in treating the signs and symptoms of DED.

4. General study design.

This study is a phase 2, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of Compound 1 nasal spray in adult participants with DED. Approximately 200 subjects aged at least 22 years with a history of dry eye described by the subject who met all other study eligibility criteria were randomized to receive compound 1 or placebo at visit 1 and visit 2.

Selection and treatment (Schirmer score) 1 Visit (1 day) Selection Informed Consent Demographics, medical care/medical and ophthalmic drug history Inclusion Criteria Questionnaires about dry eyes Visual acuity with maximum correction Biomicroscopy with slit lamp Cornea staining with fluorescein

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Schirmer test Schirmer test with nasal stimulation (cotton swab) Examination of the nasal cavity Urine pregnancy test (if applicable) Concomitant medicinal products Adverse events Treatment (assessment with a test Schirmer) Randomization Treatment and concurrent Schirmer test Visual acuity with maximum correction Biomicroscopy with slit lamp Inspection of the nasal cavity with an endoscope Concomitant medicinal products Adverse events Appointment of time for 2 visits of participants

I

2 Visit (15 + 4 days) Updated medical care/medical and StrAU ophthalmic preparations Symptoms before SAE SAE exposure, symptom assessment and treatment Visual acuity with maximum correction Biomicroscopy with slit lamp Inspection of the nasal cavity with an endoscope Concomitant medicinal products Adverse events End of study

Participants who prematurely discontinued participation in the study during the dosing period were asked to complete the safety assessment (with the consent of the participants) prior to withdrawal from the study. Participants who terminated early participation in the study were not replaced by others.

5. Experimental group.

5.1. Number of subjects.

Approximately 200 subjects (approximately 50 per treatment group) were estimated to have enrolled in the study at up to 3 study centers in the United States.

- 196 040442 doses (not exceeding 3.3%, i.e. 33.2 μg/μl of the free base of Compound 1) or placebo.

5.2. Characteristics of the experimental group.

All subjects must be at least 22 years of age, may be of any gender or race, and must meet all inclusion criteria and none of the exclusion criteria.

5.3. Inclusion Criteria.

Subjects must meet the following conditions.

1. Age at the selection visit is at least 22 years old.

2. Use and/or desire to use artificial tears to treat dry eye symptoms for 6 months up to 1 visit.

3. OSDIkk score > 23 with N/A < 3 responses at screening visit.

4. At the screening visit, have ALL of the following characteristics in the examined eye:

corneal fluorescein stain score >2 in at least one corneal area or sum >4 for all corneal areas;

baseline Schirmer test score (with local anesthesia) < 10 mm/5 min. with nasal stimulation with a cotton swab. Schirmer score at least 7 mm higher in the same eye;

the eye of interest should be defined as an eye that meets all of the inclusion criteria; if both eyes match, then choose the eye with the highest increase in tear production with cotton swab stimulation at the screening visit, or, if there is no difference in stimulated tear production, the eye with the lower baseline Schirmer score at the screening visit. If there is no difference for both parameters, the right eye is used as the test eye.

5. A maximally corrected visual acuity (BCVA) of 0.7 logMAR or better (logMAR < 0.7; equivalent to a Snellen score of 20/100 or better) for each eye at the screening visit.

6. Normal eyelid/lashes anatomy, blink function and closure, as determined by the investigator.

7. Lack of information (for example, information about the investigational tear stimulant being used) or no previous use of the investigational drug.

8. Literacy, the ability to speak English and the ability to complete the questionnaire independently.

9. Opportunity to participate in the study for approximately four consecutive hours on Day 15.

10. Ability and willingness to use an experimental drug and participate in all experimental evaluations and visits.

11. Availability of oral and written informed consent.

12. For women of childbearing potential, the presence of a negative urine test for pregnancy on day 1.

5.4. exclusion criteria.

Subjects must not:

1. Have clinically significant corneal epithelial defects on study day 1 prior to the Schirmer test.

2. Have chronic or recurrent nosebleeds, coagulation disorders, or other pathological conditions that, in the opinion of the investigator, may lead to a clinically significant risk of increased bleeding.

3. Have experienced nasal or paranasal sinus surgery (including a history of nasal cauterization) or significant trauma to these areas.

4. Have a vascular pedicled polyp, significant deviated septum, chronic and recurrent nosebleeds, or severe nasal airway obstruction confirmed by intranasal examination performed up to day 1.

5. Currently being treated with continuous positive airway pressure (CPAP).

6. Have experienced intraocular surgery (such as cataract surgery), extraocular surgery (such as blepharoplasty) on either eye within the past three months, or refractive surgery (such as LASIK, LASEK, PRK or corneal implant) within the past twelve months up to 1 visit.

7. Have a corneal graft in either eye or both eyes.

8. Use contact lenses for 7 days prior to 1 visit or consider using contact lenses during the trial period.

9. Have a punctal occluder or intratubular occluder in any eyelid (Participants with permanent occlusion of the lacrimal ducts are eligible).

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10. Have a history of or currently experience any ophthalmic disorder or condition in any eye that, in the opinion of the Investigator, may interfere with the interpretation of study results or compromise participant safety, such as significant corneal or conjunctival scarring; pterygium or knotty pinguecula; existing eye infection, conjunctivitis, or inflammation not associated with dry eyes corneal dystrophy of the anterior (epithelial) basement membrane or other clinically significant dystrophy or degeneration of the cornea; herpetic eye infection; signs of keratoconus; etc. Let's say untreated blepharitis and mild meibomian gland disease, which are usually associated with dry eye disease.

11. Have an unstabilized systemic disease condition or disease that, in the opinion of the Investigator, is incompatible with participation in the study or longer trials required for the study (e.g., current systemic infection, uncontrolled autoimmune disease, uncontrolled immunodeficiency disease, history of myocardial infarction, or heart disease).

12. Have a known hypersensitivity to any procedural agent or to the components of the experimental drug.

13. Concomitant use of snuff, chewing tobacco, or cigarettes/cigars during the entire study or within the previous 30 days.

14. Concomitant use of nicotinic acetylcholine receptor agonists [Nicoderm®, Nicorette®, Nicotrol NS® (nicotine), Tabex, Desmoxan (cytisine), and Chantix (varenicillin)] or within the previous 30 days.

15. Have an active or uncontrolled severe form:

systemic allergies;

chronic seasonal allergies with a risk of onset during the study;

rhinitis or sinusitis requiring treatment, such as antihistamines, decongestants, oral or aerosol steroids, at the screening visit;

untreated nasal infection at 1 visit.

16. Have any condition or history of disease that, in the opinion of the Investigator, may interfere with adherence to study design, assessment of outcomes, safety parameters, and/or worsen the general medical condition of the subject.

17. Be pregnant, breastfeeding or planning a pregnancy at 1st visit.

18. Currently participating in an investigational drug or device study or taking an experimental drug or using an experimental device for 30 days prior to the 1st visit.

5.5. Criteria for suspension (if applicable).

If, at any time during the study, the investigator determines that the subject's safety is at risk, the subject may be removed from participation in the study.

Subjects may revoke consent to participate in the study at any time.

The sponsor and/or investigator may exclude any subject for non-adherence or for any reasonable medical reason during the study (see Section 8.6.2).

6. Research parameters.

6.1. Efficiency parameters.

6.1.1. Primary parameters of efficiency.

The following primary evaluation criteria are subject to testing:

Schirmer test at 1 visit;

dry eye assessment (EDS) at visit 2.

6.2. Security settings.

Adverse events.

6.3 Other parameters.

Ora Calibra™ Eye Discomfort Scale.

Urine pregnancy test (1 day).

7. Research materials.

Experimental drug(s).

medicinal forms.

Compound nasal spray 1.

Placebo (vehicle nasal spray for Compound 1).

Introduction scheme.

At visit 1, enrolled subjects are randomized and given the first dose of the experimental drug on an outpatient basis.

At Visit 2, subjects will receive a second dose of experimental drug during CAE™ exposure.

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Instructions for use.

Compound 1 (and placebo) is formulated at the required concentration, depending on the prescribed dose for this group, in phosphate-buffered saline as a sterile aqueous solution and presented in disposable glass ampoules closed with a rubber stopper.

The product does not contain a preservative and is intended for intranasal use only. The product must not be used if it is cloudy or contains particulate matter.

Compound 1 solution is administered without dilution.

The drug solution is removed from the glass ampoule using a 5 micron filter needle.

The 5 micron filter needle is then removed and discarded, and Compound 1 is administered using the supplied disposable syringe and disposable intranasal nebulizer.

Other supporting research materials.

Urine pregnancy test kits.

Sodium fluorescein solution or fluorescein strips.

Schirmer test strips.

Proparacaine.

8. Methods and techniques of research.

Procedures for enrolling participants in the study.

General information.

This study includes participants defined by the criteria specified in sections 5.2, 5.3 and 5.4.

informed consent.

Prior to participation of participants in the trial (i.e., prior to the commencement of study-related procedures), the progress of the study must be discussed with each potential participant, and participants wishing to participate must obtain and sign an informed consent form using the Informed Consent Form (ICF) approved by the IRB. The ICF shall be the most up-to-date version approved by the appropriately appointed Institutional Review Board.

washout periods.

Prohibited medicines, treatments, and active substances are listed in the exclusion criteria (section 5.4).

Procedures for final inclusion in the study.

Subjects must meet all inclusion criteria and none of the exclusion criteria.

Methods of division into experimental groups.

Each subject included in the study must be assigned a selection number. All selection numbers are assigned in the research center in a strict numerical sequence, and you cannot jump over numbers or skip them. If all inclusion and exclusion criteria are met at visit 1, then each subject accepted into the study is then assigned a randomization number.

A randomization scheme is sent to each research center. The randomization design should be stratified by study site so that each of the four treatment groups at each study center has an approximately equal number of subjects. Research facility staff should provide the patient with an experimental kit labeled with the appropriate randomization number. The randomization number is recorded in the patient entry document and in the electronic medical record (eCRF). The sponsor, investigators, and staff involved in the study should not have information during the randomization process and the entire study.

concomitant therapy.

The use of any concomitant medicinal products, whether prescription or non-prescription, must be recorded in the patient entry document and in the corresponding electronic medical record (eCRF) indicating the reason for the use of the medicinal product.

Simultaneous participation in the study of another experimental drug or device is not allowed.

Prohibited drugs/treatment.

Drugs/treatments prohibited during the study are listed in the exclusion criteria (section 5.4).

Additional analgesia.

No additional analgesia is required for this study.

Special diet or exercise.

No special diet or exercise is required for this study.

Inspection procedure.

Procedures to be carried out at each visit scheduled for this study

- 199 040442 with regard to the purpose(s) of the study.

It is necessary to carry out the following procedures:

1. Visit (1 day): selection and evaluation according to the Schirmer test.

Selection.

Informed Consent/Consent to the U.S. Health Insurance Preservation and Personalized Health Account Act (HIPAA).

Demographics, health care/medical and ophthalmic drug history.

Inclusion Criteria.

OSDI®.

EDS (visual analogue scale).

Ora Calibra™ Eye Discomfort Scale.

Visual acuity with maximum correction.

Biomicroscopy with a slit lamp.

Corneal staining with fluorescein.

Schirmer test.

Schirmer test with nasal stimulation (cotton swab).

Inspection of the nasal cavity.

Urine pregnancy test (if applicable).

Concomitant medications.

Adverse events.

Treatment (assessment using the Schirmer test).

procedures prior to treatment.

Randomization: Participants included in the study will be treated with low dose, medium dose or high dose (not exceeding 3.3%, i.e. 33.2 µg/µL Compound 1 free base) or placebo.

procedures during treatment.

Instructing subjects to administer the experimental drug/placebo.

Treatment and concurrent Schirmer test.

Administration of the experimental drug/placebo.

Procedures after treatment.

Maximum corrected visual acuity (BCVA).

Biomicroscopy with a slit lamp.

Inspection of the nasal cavity with an endoscope.

Concomitant medications.

Adverse events.

Appointment of time 2 visits of the participant.

2. Visit (15 + 4 days): StrAU.

Updated medical care/medical and ophthalmic drug history.

Dry eye score (EDS, visual analogue scale).

Ora Calibra™ Eye Discomfort Scale.

Approximately 120 min exposure to CAE conditions.

EDS data is obtained at the start of CAE ^SM exposure, and every 5 minutes thereafter.

Score on the Ora Calibra™ Eye Discomfort Scale at the start of CAE ^SM exposure, and every 5 minutes thereafter.

Participants included in the study are treated with low dose, medium dose or high dose (not exceeding 3.3%, i.e. 33.2 μg/μl Compound 1 free base) or placebo.

Experimental drug/placebo doses are administered if the participant has an eye discomfort score > 3 at two or more consecutive time points in at least one eye during CAE exposure (if the participant has an eye discomfort score of 3 at time = 0 for one eye then he/she must have an eye discomfort score of 4 for two consecutive measurements for that eye) as measured by the Ora Calibra™ scale. The participant should recap the symptom score 1 min after the end of the dose, every 5 min.

Visual acuity with maximum correction.

Biomicroscopy with a slit lamp.

Inspection of the nasal cavity with an endoscope.

Urine pregnancy test (if applicable).

Concomitant medications.

Adverse events.

End of research.

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Schedule of visits, measurements and doses.

Scheduled visits.

This section of this document presents a schedule of visits and measurements.

Unscheduled visits.

Such visits may be undertaken to ensure the safety of the subject.

Assessments that can be done at an unscheduled visit include:

biomicroscopy with a slit lamp;

visual acuity;

examination of the nasal cavity using an endoscope;

those st urine for pregnancy;

assessment of adverse events;

evaluation of concomitant medicinal products and/or treatment; and any other assessments deemed necessary by the investigator.

Protocol compliance.

Subjects are instructed on how to administer the experimental drug at Visits 1 and 2, with detailed written instructions for review.

Compliance with the dosing regimen is based on used/unused experimental drug at visits 1 and 2.

Distribution of study participants.

Participants who completed the study.

A subject who completes a study is a subject not withdrawn from the study.

Subjects who discontinued participation in the study.

Subjects may be excluded from the study at any time prior to completion for the following reasons:

not favorable phenomena;

unmasking in case of medical necessity;

protocol violations;

reasons of an administrative nature (eg, inability to continue, loss of contact with the subject for follow-up);

termination of the study by the sponsor;

choice of the subject (for example, withdrawal of his consent); And so on.

Note: In addition, any subject may be excluded for any apparent medical reason, at the discretion of the investigator (after consultation with the sponsor) or the sponsor.

Recording the exclusion of a subject from the study and the reason for exclusion should be clearly documented.

Subjects who interrupt the study cannot be replaced.

Termination of the study.

The study can be stopped at any time with appropriate notice.

Study duration.

Individual subject participation includes 2 visits over a period of about 2 weeks (14 days).

Monitoring and quality control.

During the course of a study, a clinical investigator or designee will make regular visits to the study site to check adherence to the protocol, assess treatment of the experimental drug, subject safety, and verify that the study is being conducted in accordance with current regulatory requirements. Subjects' medical records are reviewed in a manner that maintains confidential information about the subject. Additional details regarding study monitoring are described in the monitoring plan.

9. Adverse events/adverse event.

An adverse event is defined as any adverse medical event associated with the use of a drug in humans, whether or not the event is thought to be drug related. Therefore, an adverse event can be any undesirable and unintended sign (e.g., an abnormal laboratory value), symptom, or disease that occurs after a subject has started dosing an experimental drug, without any belief as to its relationship to the investigational drug. Any pre-existing medical condition that worsens after administration of an experimental drug is also considered a new adverse event.

An experimental drug includes an investigational drug being evaluated and a placebo.

The adverse event should be documented with its nature, date of onset, end date, severity, association with the experimental product, action taken, severity, and outcome for any sign or symptom observed or reported by the investigator.

- 201 040442 to my subject in an indirect survey.

Heaviness.

The severity of an adverse event is defined as a qualitative assessment of the degree of intensity of an adverse event as determined by the investigator or reported to him/her by the patient/subject. Severity is rated regardless of the relationship to the experimental drug or the severity of the event, and such a rating is carried out in accordance with the following scale.

Mild: The phenomenon is noticeable to the subject, but is easily tolerated and does not affect the subject's daily activities.

Moderate: The event is distressing, possibly requiring additional therapeutic intervention, and interferes with the subject's daily activities.

Severe: The event is intolerable, necessarily requiring additional therapeutic intervention or treatment modification, and interferes with the subject's daily activities.

Relationship with the experimental drug.

The relationship of each AE to the experimental product is determined by the investigator (blindly) using the following explanations.

Definite: if there is a good reason and sufficient documented evidence to demonstrate a direct causal relationship between the experimental product and the AE.

Conjectural: When there are good reasons and enough documented evidence to suggest a causal relationship in the sense of probable, possible, plausible, but not necessarily very obvious.

Possible: When there is sufficient information to accept the possibility of a causal relationship in meaning, it is neither impossible nor implausible, although such a relationship is not definitely known or doubtful, for example, due to loss of data or insufficient data.

Absence: if there is enough information to accept the absence of a causal relationship in the sense of impossible and implausible.

Not classified: When a causal relationship cannot be assessed for any reason, due to insufficient data, inconsistent data, or poor documentation.

Expectancy.

The expected adverse event is determined on the basis of existing information on the safety of the experimental drug, using the following explanations:

Not Expected: An adverse event that is not listed in the Investigator's Brochure or is not listed in the observed specificity or severity.

Expected: An adverse event that is listed in the Investigator's Brochure in the observed specificity and severity.

Not applicable: Any adverse event not related to the experimental drug.

Adverse events listed in the Investigator Brochure as occurring with a particular class of drug or as expected based on the pharmacological properties of the drug, but not specifically listed as occurring with a particular drug under investigation, should be considered unanticipated.

The investigator should initially rate the expected adverse event, but the final rating should be established by the medical observer.

Serious adverse events.

An adverse event is considered serious if, in the opinion of the investigator or sponsor, it leads to any of the following outcomes:

death;

undesirable event that threatens life.

Note: An adverse event is considered life-threatening if, in the opinion of the investigator or sponsor, its occurrence would immediately endanger the life of the patient or subject. This group does not include an adverse event that, if it occurred in a more severe form, could cause death.

Hospitalization or an increase in the duration of the current hospitalization.

Note: The term hospitalization refers to any hospital admission (even if less than 24 hours). For chronic or long-term hospitalization, hospitalization includes transfer within the hospital to an inpatient emergency/intensive care unit. Hospitalization does not include: visits to emergency rooms; outpatient/day-to-day/outpatient procedures; departments for examination/preoperative preparation; rehabilitation institutions; hospices; homes for the chronically ill; or Clinical Research Unit/Phase 1.

Note: The term increase in the duration of current hospitalization refers to any increase in the duration of hospitalization beyond the duration anticipated or required.

- 202 040442 because of the initial intake, which is determined by the investigator or the attending physician.

Permanent or significant inability or significant impairment of the ability to carry out normal life functions;

Note: A serious adverse event, in particular one involving a risk to vision, should be interpreted as any possible impairment or impairment of the subject's eyes (eg, hemorrhage, retinal detachment, central corneal ulcer, or optic nerve injury).

Congenital anomaly / pathology of childbirth.

Any medical event that may not be fatal, life-threatening or not requiring hospitalization may be considered serious if, from a medical point of view, it may endanger the patient or subject and may require medical or surgical intervention to prevent one of the outcomes, listed in this definition.

Procedure for reporting adverse events.

All adverse events and their outcomes should be noted and recorded.

Reporting of a suspected unexpected adverse reaction.

It is necessary to record all adverse events that are expected and unforeseen.

Reporting a serious adverse event.

To ensure the safety of the subject, all adverse events should be recorded immediately, regardless of their relationship to the experimental drug. All information related to a serious adverse event should be recorded on the appropriate patient records. All subjects experiencing a serious adverse event should be observed and the outcome recorded.

In the event of a serious adverse event, the investigator must notify the sponsor immediately; obtain and maintain in his/her files all relevant medical records, information and medical opinions of colleagues assisting in the treatment and follow-up of the subject; provide the sponsor with a full description of the specific case.

9.1. Procedures for unmasking an experimental drug.

All subjects, investigators and investigators who participate in the conduct of the trial should not be aware of the allocation to treatment groups. In the event of medical necessity, the investigator may need to determine which treatment group the subject is assigned to. The unmasked subject is excluded from the study.

9.2. Type and duration of follow-up of subjects after adverse events.

The investigator should observe unresolved AEs until normalization, loss of contact with the subject for follow-up, or reclassification of AEs. Normalization means that the subject has returned to the original state of health, or the researcher does not expect any further improvement or worsening of the AE. In the event of loss of contact with the patient for follow-up, the investigator must make 3 available attempts to contact the patient by phone, mail, or registered mail. Follow-up information should be documented in the subject's input document.

If the investigator learns any new information regarding an existing SAE (ie, normalization, change of condition, or new treatment), then the New SAE/Unforeseen AE Report Form must be completed. The original form of the SAE is not subject to change. The report should describe the fact of normalization or persistence of this phenomenon, as well as the method of treatment of this phenomenon.

10. Statistical hypotheses and methods of analysis.

Group analysis.

The following analysis groups are considered.

Intent-to-treat (ITT) patient group - The intent-to-treat (ITT) patient group includes all randomized subjects. Subjects in the ITT group were analyzed according to randomization.

Protocol group - the protocol group (per protocol, PP) includes subjects in the ITT group who have no significant deviations from the protocol and have completed the study. Protocol deviations are evaluated before database access is closed and unmasked. Subjects in the RR group were analyzed according to treatment.

Safety Evaluation Group - The safety evaluation group includes all subjects who received at least one dose of the experimental drug. Subjects in the safety group were analyzed according to treatment.

Statistical analysis of the safety data is carried out for the safety evaluation group. Analysis of baseline and efficacy data is performed for the ITT group. Efficacy analysis is also carried out for the PP group as a sensitivity analysis.

statistical hypotheses.

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But1: No difference between Compound 1 nasal spray (low dose, medium dose, or high dose) and placebo in terms of change in Schirmer test results from baseline.

H11: There is a difference between Compound 1 nasal spray (low dose, medium dose, or high dose) and placebo in terms of change in Schirmer test results from baseline.

H ₀₂ : No difference between Compound 1 nasal spray (low dose, medium dose, or high dose) and placebo in terms of EDS change before and after treatment.

H ₁₂ : There is a difference between Compound 1 nasal spray (low dose, medium dose, or high dose) and placebo in terms of EDS change before and after treatment.

A successful outcome is an outcome that rejects both null hypotheses (H ₀₁ and H ₀₂ ).

Sample size.

The sample size for this study is not based on considerations of study power. It is envisaged that each of the four experimental groups will involve about 50 subjects, for a total of about 200 randomized subjects. Assuming an exclusion rate of 5%, approximately 47 subjects in each group are expected to complete the study.

Statistical analysis.

General considerations.

Quantitative variables should be summarized using the number of subjects (n), mean, median, standard deviation, minimum and maximum. Qualitative variables should be summarized using numbers and percentages.

All summaries must be presented by experimental group. Generalizations should be made on demographics, medical history, concomitant treatment, and distribution of study participants.

For summary purposes, medical history, concomitant medications, and adverse events are coded according to the Medical Regulatory Dictionary and the WHO Medicines Glossary, if appropriate.

Baseline measurements are defined as the last measurements before the start of the experimental treatment, usually at visit 1 sampling.

Unit of analysis.

Security endpoints are analyzed for both eyes. For efficacy endpoints, the unit of analysis is the eye of interest, defined as follows.

An eye of interest is defined as an eye that meets all of the inclusion/exclusion criteria; if both eyes match, then choose the eye with the highest increase in tear production with cotton swab stimulation at the screening visit, or, if there is no difference in stimulated tear production, the eye with the lower baseline Schirmer score at the screening visit. If there is no difference for both parameters, the right eye is used as the test eye.

Missing data.

The primary analysis is carried out using the observed data (without introducing missing data). Sensitivity analysis for the primary efficacy analysis is performed using a Monte Carlo multiple substitution method using Markov chains (MSMC) to recover missing data. The frequency of missing data is presumably low; however, if the missing data rate is greater than 5%, then additional missing data imputation methods (such as critical point analysis) should be used to understand the possible impact of missing data on the primary results.

Other efficacy analyzes are performed using observed data only.

Repeatability considerations.

For this early phase study, no corrections for multiple trials will be used.

Primary efficiency analysis.

Primary performance analysis is carried out on the following final evaluation criteria.

Schirmer test at 1 visit.

Evaluation of dry eye during CAE exposure at visit 2.

Schirmer test scores and dry eye scores are summarized by visit number, by time point (if applicable) and by treatment using quantitative descriptive statistics (n, mean, median, standard deviation, minimum and maximum).

An analysis of covariance model was used to compare the results of the Schirmer test, conducted in parallel with treatment, between experimental groups with each dose of Compound 1 nasal spray and a placebo control group. The analysis of covariance model includes baseline Schirmer score (obtained at screening), treatment, and site of clinical trial as covariates. Based on this model of analysis of covariance, weighted means (root mean square means) are calculated for each treatment, corresponding to 95% confidence

- 204 040442 Intervals (CI) and Estimated Treatment Difference Between Each Dose of Compound 1 Nasal Spray and Placebo. In addition, in a separate model, the effect of the study center on treatment is examined to assess how the effect of treatment may differ for different study centers.

The change in dry eye score (EDS) from pre-treatment to post-treatment was analyzed by an analysis of covariance model using pre-treatment EDS as covariate and treatment and time as fixed effects (taking into account repeated measurements). Based on this model of analysis of covariance, the weighted means for each treatment, the corresponding 95% confidence intervals, and the estimated treatment difference between each dose of Compound 1 nasal spray and placebo are calculated. In a separate model, the effect of the study center on treatment is also examined to assess how the treatment effect may differ for different study centers.

Primary analysis is performed in the ITT group using observed data. Two-sample t-tests and non-parametric Wilcoxon rank-sum tests are used as unadjusted sensitivity analyzes to compare treatment options. Sensitivity analyzes are also performed on the ITT group with multiple substitutions (M1) to recover missing data, and also on the PP group for observed data only.

Other efficacy analyses.

The change in EDS from pre-treatment to post-treatment at each individual time point is also analyzed, in the same manner as the primary analysis of the Schirmer test. The specified analysis covariance models include pre-treatment EDS, treatment, and study center as covariates.

The change in score on the Ora Calibra Eye Discomfort Scale from pre-treatment to post-treatment is aggregated by visit number, by time point (if appropriate) and by treatment using quantitative descriptive statistics, and analyzed at each individual time point in the same manner like EDS.

These analyzes are performed only for the observed data in the ITT and PP groups.

Security variables.

Adverse events are coded using the Medical Dictionary of Legal Vocabulary. For each experimental group, the frequency and percentage of subjects with treatment-related adverse events (AELI), severe AELI, and AELI that caused early termination of participation in the study are determined. An AE is treatment-related if it occurs or worsens after the first dose of the experimental drug. In addition, the frequency of occurrence is reported for subjects with AELV by organ system class, by organ system class and preferred term, by organ system class, by preferred term and greatest severity, by organ system class, preferred term and most closely related, and by organ system class, preferred term, maximum severity, and most closely related. A separate analysis is performed for eye-specific AEs and for all AEs (including systemic).

Other safety endpoints, including visual acuity, slit lamp biomicroscopy, and intranasal endoscopy, are summarized by treatment group and visit number using descriptive statistics. Changes or shifts from the original value are also summarized, if appropriate. For the assessment carried out for each eye separately, the observations for the experimental eye and the other eye are summarized separately. In addition, changes from baseline to the worst value during treatment are summarized to assess ophthalmic safety.

intermediate analyses.

No interim analyzes are scheduled for this study.

11. Compliance with good clinical practice, ethical considerations and administrative issues.

This study will be conducted in accordance with the protocol, good clinical practice (GCP), including the International Conference on Harmonization (ICH) guidelines and, in general, in accordance with the Declaration of Helsinki. In addition, all applicable local, state, and federal requirements relating to the use of experimental drugs in various countries will be met.

Protection of people who are the subject of research.

Informed consent of the subject.

Informed consent/statement of will must be obtained prior to any study procedures. Signed and dated written informed consent must be obtained from each subject and/or the subject's parent or legal guardian prior to enrollment in the study. If the subject is under the age of sexual majority, then the consent form must be signed by a legal guardian or as required by state and/or local laws and regulations.

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All forms of informed consent/statements of will must be approved for use by the sponsor and must be approved/favorable by the IRB/IEC before they can be used. If the consent form requires revision (for example, due to a change in the protocol or the emergence of significant new safety information), then it is the responsibility of the investigator to review the modified informed consent and approve it by Ora before submission to the IRB/IEC steering committee, as well as to read it, sign and dating all subjects later included in the study as well as subjects already included in the study.

Institutional Review Board (IRB) approval.

This study is carried out in accordance with the requirements.

Institutional Review Board (US CFR 21, section 56.103). The investigator must obtain the appropriate IRB approval before starting the study and must obtain re-approval at least once a year.

Only the IRB/ERC approved version of the informed consent form should be used.

Research ethics.

This research is conducted in accordance with the ethical principles set forth in the Declaration of Helsinki on Subject Confidentiality.

All personal data about subjects taking part in a study that are collected and processed in accordance with the purposes of this study are kept by the investigator and his/her staff with precautions to maintain data confidentiality in accordance with local, state and federal laws and regulations.

A report on the results of this study may be published or sent to the appropriate public health authorities in any country where the investigational drug will eventually be marketed, but these documents do not disclose information about the identity of the subject.

Documentation.

Source documents may include medical records, hospital records, subject clinical records, investigator files on study subjects, and diagnostic test results such as x-rays, laboratory tests, and ECGs. A copy of the patient's registration card, available to the investigator, serves him for recording the data foreseen by the study about the subjects.

Saving documentation.

All study correspondence, subject data, consent forms, grouping and use records of all experimental drugs, and copies of the subject's registration card must be archived for at least two years after the last approval of the marketing authorization application in the region ICH and prior to the expected or proposed approval of an application for a trade license in the ICH region; or until at least two years have passed since the formal termination of clinical development of the experimental drug. These documents are subject to longer retention if required by applicable regulations or as agreed with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution of the timeframe for the end of the need to keep these records.

If the responsible researcher changes place of work, place of residence, or for other reasons ceases to be responsible for the preservation of documents related to the study, then the responsibility for storage should be shifted to the person accepting such responsibility. The sponsor must be notified in writing with the name and address of the new responsible person.

Labeling, packaging, storage, accountability, and return or disposal of an experimental drug.

Labeling/packaging.

The experimental drug is supplied in disposable vials and administered prior to each dose at Visit 1 and Visit 2.

Storage of experimental drug/placebo.

The experimental drug/placebo must be stored in a secure place accessible only to the investigator and his/her authorized person(s). The experimental drug(s) must be stored in a refrigerator (2-8°C, no freezing) in a dark place, in a closed container at the research center.

Accountability of the experimental drug.

The experimental drug/placebo is prescribed only by the principal investigator or his/her designated junior investigator(s) and is used only in accordance with this protocol. Experimental drugs should only be given to subjects who have been appropriately selected in accordance with this protocol to receive the experimental drug. The investigator should keep a careful record of investigational products by completing a detailed record. It contains information on the number of experimental drugs received by each study site, the amount dispensed to subjects, the amount returned to the experiment

- 206 040442 mental center by the subjects, and the amount returned to the sponsor at the end of the study.

Return or disposal of an experimental drug.

All investigational products must be returned to the sponsor or authorized person for destruction.

Recording data in entry documents and in electronic medical record forms (eCRFs).

All data about the subject is obtained from the primary documentation of the subject and transferred to the eCRF. The investigator is responsible for the completeness and accuracy of the recording of study data in the eCRF of each subject, all input documents, and all study-related materials. All experimental data must also be substantive, clear, relevant and original. Recorded data may only be corrected in such a way that the previous record is not erased, corrupted, or rendered unreadable (for example, by crossing out an incorrect value with a single line and recording the correct value after correction). The person who made the change to the data element must indicate who made the change and when, completing the change with his/her initials, as well as the date the change was made.

All subjects randomized to the study are entered using software that complies with CFR 21, Section 11, and data entry is performed only by personnel who have been trained on and have access to the system. Data on subjects that did not pass the selection are not subject to entry. There must be an audit trail in the electronic system to keep track of all changes made to the eCRF database. At the end of the study and access to the database is closed, CDs containing copies of all eCRFs of eligible subjects are sent to each study site for storage in the investigator's archive.

Working with biological samples.

Not applicable.

Publications.

This study is documented in the final report, which contains the relevant statistical analysis and medical report.

12. Links.

1. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye Workshop (2007). The ocular surface 5, 93-107 (2007).

2. Schaumberg, D. A., Dana, R., Buring, J. E. & Sullivan, D. A. Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. Archives of ophthalmology 127, 763-768, doi:10.1001/archophthalmol.2009.103 (2009).

3. Schaumberg, D. A., Sullivan, D. A., Buring, J. E. & Dana, M. R. Prevalence of dry eye syndrome among US women. American journal of ophthalmology 136, 318326 (2003).

4. Schaumberg, D. A., Sullivan, D. A. & Dana, M. R. Epidemiology of dry eye syndrome. Advances in experimental medicine and biology 506, 989-998 (2002).

5. Albrecht J, Kopietz R, Linn J, Sakar V, Anzinger A, Schreder T, et al. Activation of olfactory and trigeminal cortical areas following stimulation of the nasal mucosa with low concentrations of S(-)-nicotine vapor-An fMRI study on chemosensory perception. Hum. brain mapping. Wiley Subscription Services, Inc., a Wiley Company; 2009 Mar;30(3):699-710.

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8. Prescribing Information - NicotiolNS (nicotine nasal spray). Pfizer, Inc.; 2010.

9. DEWS. Design and conduct of clinical trials: report of the Clinical Trials Subcommittee of the International Dry Eye Workshop Ocul Surf 2007;5:158.

10. Abelson R, Lane KJ, Rodriguez J, et al. A single-center study evaluating the effect of the controlled adverse environment (CAE(SM)) model on tear film stability. Clin Ophthalmol 2012;6:1865-72.

11. Meerovitch K, Torkildsen G, Lonsdale J, et al. Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol 2013;7:1275-85.

12. Mundorf T, Wilcox KA, Ousler GW, 3rd, Welch D, Abelson MB. Evaluation of the comfort of Alphagan P compared with Alphagan in irritated eyes. Advances in therapy 2003;20:329-36.

13. Ousler GW, 3rd, Abelson MB, Nally LA, Welch D, Casavant JS. Evaluation of the time to natural compensation in normal and dry eye subject populations during exposure to a controlled adverse environment. Advances in experimental medicine and biology 2002;506:1057-63.

14. Patane MA, Cohen A, From S, Torkildsen G, Welch D, Ousler GW, 3rd. Ocular iontophoresis of EGP-437 (dexamethasone phosphate) in dry eye patients: results of a randomized clinical trial. Clin Ophthalmol 2011;5:633-43.

15. Petrov A, Perekhvatova N, Skulachev M, Stein L, Ousler G. SkQl Ophthalmic Solution for Dry Eye Treatment: Results of a Phase 2 Safety and Efficacy Clinical Study in the Environment and During Challenge in the Controlled Adverse Environment Model. Advances in therapy 2016;33:96-115.

16. Semba CP, Torkildsen GL, Lonsdale JD, et al. A phase 2 randomized, doublemasked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye. Am J Ophthalmol 2012;153:1050-60 el.

17. Sosne G, Ousler GW. Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo-controlled, Phase II clinical trial conducted using the controlled adverse environment (CAE) model. Clin Ophthalmol 2015;9:877-84.

18. Ousler GW, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocul Surf 2005;3:143-54.

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Schedule of visits and measurements

Procedure 1 Visit (1 day) 2 Visit (15 + 4 days) Selection Score by Schirmer's test Before exposure to CAE ^SM After exposure to CAE ^SM Informed Consent/HIPAA X Demographics X History and updated history of receiving medical care/medical and ophthalmic drugs X X Inclusion Criteria X Urine pregnancy test xs xs Poll LIS! OSDI® X Dry Eye Assessment (EDS) X X4 X4 Ora Calibra™ Eye Discomfort Scale X X4 X4 Visual acuity with maximum correction X X1 x5 Biomicroscopy with slit lamp X X1 x5 Cornea staining with fluorescein X Schirmer test X X Schirmer test with cotton swab stimulation X Nasal examination cavities X X1 X

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Concomitant medicinal products X X1 X Randomization X Introduction experimental drug / placebo X2 X Poll about adverse events X X1 X X exit from research X Xi = after medical procedures; X ₂ = simultaneously with the Schirmer test; X3 = for women of childbearing potential; X4 = procedure started at time 0 and then performed every 5 minutes for 120 minutes of exposure to CAE ^SM conditions; X5 = the procedure can be performed after the end of CAE ^SM exposure, at the discretion of the investigator, if necessary

Inspection procedure, testing, equipment and technologies

This section describes the procedure for inspection, testing, equipment and technology.

Procedure for checking visual acuity.

Visual acuity LogMAR is determined using the table ETDRS.

The procedure used should be in accordance with the guidelines suggested for the use of the ETDRS Visual Acuity Chart. Visual acuity is assessed at the beginning of each study visit (i.e. prior to the slit lamp study). Participants must use the most current corrective lens to achieve corrected distance visual acuity (CDVA); if they have forgotten their glasses, the trial frame can be fitted with a prescribed lens.

Equipment.

The visual acuity table to be used is the ETDRS table. When using a smaller (18" x 18" (46 x 46 cm) wall-mounted chart, such as from Prevent Blindness), the participant must be exactly 10 feet (3m) from the chart (or manufacturer's specification). In ALL cases, in order to standardize test conditions during the study, all experimental centers should use only Table. 1 and 2 of the ETDRS 2000 series, and the right eye should be checked first. Due to the reflectivity of (wall) tables, the tables should be placed frontally and well lit.

Measurement technology.

The table should be set at a comfortable viewing angle.

The right eye should be checked first. The competitor must try to read each letter, line by line, from left to right, starting from line 1 at the top of the chart. The participant must be informed that the table contains only letters and does not contain numbers. If the participant says a number, he/she should be reminded that the table does not contain a number, and then the researcher should ask for a letter instead of a number. The participant should be asked to read slowly to best identify each letter. He/she does not move on to the next letter until he/she gives a clear answer.

If the competitor changes the answer (for example, it was a C, not an O) before he/she has spoken the next letter, then the change must be accepted. If the participant changes the answer after reading the next letter, then such an amendment will not be accepted. During the test, the researcher should not point to the table or specific letters on the table.

Every effort must be made to identify each letter in the table. If a competitor says that he/she cannot read a letter, then he/she must make a guess. If the participant recognizes one letter as one of two letters, then he/she is asked to choose one letter and, if necessary, make a guess. When it becomes clear that the next reading will not be effective despite attempts to read or guess, the researcher should stop testing that eye. However, it is necessary to try to read all the letters in the last line, since the complexity of the letters varies, and the last one may be the only one that is read correctly. It is necessary to record the number of missing letters or letters read incorrectly.

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Calculation of visual acuity LogMAR.

The last line in which the letter was correctly read is taken as the base logMAR value. Added to this value is N x 0.02, where N is the total number of letters skipped up to and including the last line read. The sum indicated is the logMAR visual acuity for that eye.

Example: The participant correctly read 4 out of 5 letters on line 0.2 and 2 out of 5 letters on line 0.1.

base value of logMAR = 0.1 N (total number of incorrect letters on line 0.2 and line 0.1) = 4 N x T (T=0.02) = 0.08 Base logMAR + (N x T) = 0.1 + 0.08 Visual acuity logMAR = 0.18

Repeat the procedure on the left eye.

To ensure standardized and well-controlled visual acuity assessments during a study, all visual acuity assessments at one study center should be performed using the same lighting conditions and the same correction, if possible, throughout the study. If the same correction cannot be used (i.e. if the competitor has broken his/her glasses), then the reason for changing the correction must be documented.

Note: A clinically significant decrease in visual acuity (defined as an increase in logMAR score of 0.22 or more) since the screening visit (1 visit) should be considered by the investigator as a potential AE.

Biomicroscopy with a slit lamp.

In the process of research, biomicroscopy with a slit lamp is carried out. Observations are classified as normal or pathological.

Pathological parameters that are clinically significant are described. At each visit, check the following:

cornea, conjunctiva, anterior chamber, eyelids, corneal staining with fluorescein.

The examiner should instill 5 µl of a preservative-free 2% sodium fluorescein solution into the inferior conjunctival cecum of each eye. Alternatively, corneal staining can be assessed using a 1.0 mg sodium fluorescein strip. After wetting the tip of the strip with sterile buffered saline, the excess is shaken off into the trash can by tapping sharply with the finger. The lower eyelid is then pulled down and the flat edge of the tip is carefully inserted into the inferior tarsal conjunctiva to instill a very small amount of dye and not cause reflex lacrimation.

The study participant is asked to blink freely several times without excessive closure of the eyelids to distribute the fluorescein. To achieve maximum fluorescence, the examiner waits at least 2 minutes after instillation before assessing corneal fluorescein staining. To improve the ability to classify fluorescein staining, a Wratten No. 12 yellow filter is used. Staining is classified according to the NEI scale. The upper eyelid is slightly lifted to classify the surface of the entire cornea. For digital analysis, digital photographs of fluorescein staining can be taken.

NEI/industrial operating scale.

The score for each of the five corneal regions in each eye using the scoring system is shown in FIG. 2. In FIG. 2 shows a diagram of corneal surface separation for measuring fluorescein uptake. Use a standardized scoring system from 0 to 3 for each of the five areas of each cornea. Score 0 put in the absence of staining. The maximum score is 15.

Inspection of the nasal cavity.

Participants admitted to the study must undergo a nasal examination to determine final eligibility for the study (for example, the presence of severe obstruction of the nasal airways, severe deviated septum, or hypertrophy of the lower

- 211 040442 turbinate or pedunculated polyp are reasons for exclusion from the study). To control the integrity of the nasal mucosa during the study, to ensure the safety of the participant, examination of the nasal cavity using a camera with an endoscope is carried out at the selection visit (after completion of all other selection procedures). This examination is carried out by a specialist otorhinolaryngologist (ENT), otolaryngologist or other appropriately qualified medical specialist (i.e. a specialist who has been trained to perform nasal endoscopy). You can take pictures or record videos. Participants are instructed not to provide nasal stimulation on the day of the nasal endoscopy.

Schirmer test with local anesthesia.

At the screening visit, one baseline Schirmer test is performed, followed by a Schirmer test using nasal cotton swab stimulation. The Schirmer test with local anesthesia is used to assess tear production according to the following steps.

1. Local anesthetic drops such as 0.5% proparacaine hydrochloride or equivalent are instilled into both eyes of the study participant.

2. The study participant is asked not to open their eyes for 1 minute.

3. After opening the eyes and allowing the eyes to recover for about another 1 minute, excess moisture in the lower fornix is carefully removed with a tupfer.

4. Schirmer strips (35 mm x 5 mm filter paper strips) are placed in each eye at a position between the middle and lateral thirds of the lower eyelid.

5. In natural light, the subject is asked to look straight ahead and blink normally throughout the test. The test should be carried out indoors, with no wind towards the subject's face.

6. Schirmer strips must remain in place until the end of the five minute period or until both strips reach the maximum score.

7. After 5 minutes, the strips are removed from both eyes and the degree of wetting is recorded. The strips must be sewn to the CRF.

Schirmer test using nasal stimulation with a cotton swab.

At the screening visit, a Schirmer test is performed using nasal stimulation with a cotton swab. It is necessary to instill anesthetic drops again, and then carry out the same procedure as described above in stages 1-3.

1. After inserting new strips, the examiner should simultaneously insert cotton swabs into the patient's two nostrils and gently touch both middle turbinates for about 30 seconds. After that, the examiner can simply hold the sticks in one place, applying slight pressure, and periodically repeat the touch, as needed.

2. Alternatively, the researcher may be asked to hold the cotton swabs on their own and gently touch both turbinates at the same time, resting periodically before touching again. The investigator must continuously instruct the research participant on how to properly conduct this test.

3. The Schirmer strips must remain in place until the end of the five minute period or until both strips reach the maximum score.

Both Schirmer scores should be recorded and verified as meeting the inclusion criteria.

Eye Surface Damage Index© (OSDI©).

To minimize error, participants are asked to complete the OSDI questionnaire at home after receiving instructions from the research center staff.

The OSDI is a 12-item questionnaire developed by the Treatment Outcomes Research Group at Allergan (Irvine, CA) that asks participants to describe the severity and nature of irritation symptoms. The participant must answer 12 questions by circling the value that best represents each answer: 4 (always), 3 (almost all the time), 2 (half the time), 1 (sometimes), or 0 (never). The final score of the questionnaire is calculated as follows:

Summation of intermediate results from sections I, II and III = A.

Determining the total number of questions answered from sections I, II and III (not including n/a) = c.

Final ODSI score = Ax25 divided by B.

An example of a questionnaire is shown in Fig. 3.

Dry Eye Assessment (EDS) using the Visual Analogue Scale (VAS).

Participants were asked the following question regarding dry eyes every 5 min during exposure to the CAE ^SM condition.

Participants were asked to rate symptoms in the eye (for both eyes at the same time) associated with dry eye, using a vertical mark on a horizontal line indicating the degree of discomfort.

- 212 040442 that; 0 corresponds to no discomfort and 100 corresponds to maximum discomfort. The length of the line on the evaluation scale is 100 mm.

Please rate the momentary dryness of the eyes by making a vertical mark on the following line:

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Absence Maximum discomfort Discomfort

EDS is a tool used in other studies ^23,24 .

Ora Calibra™ Eye Discomfort Scale.

The assessment of discomfort in the eyes of the participants in the study is subjectively classified in accordance with the following scale, separately for each eye.

= no discomfort.

= occasional restlessness.

= constant anxiety.

= occasional discomfort.

= constant discomfort.

Although preferred embodiments of the present invention are presented and described herein, those skilled in the art will appreciate that such embodiments are provided by way of example only. Numerous variations, modifications and substitutions will be apparent to those skilled in the art without departing from the present invention. It should be understood that various alternative forms of the embodiments of the invention described herein may be used in the practice of this invention. It is provided that the following claims define the scope of this invention, and that the methods and structures included in the scope of the specified claims, as well as their equivalents, are included in it.

Claims (36)

CLAIM 1. The use of (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof in the treatment of dry eye or eye discomfort, comprising local administration of a therapeutically effective amount of (K)-5-( (E)-2-pyrrolidin-3-ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof into the nasal cavity of an individual in need thereof. 2. The use according to claim 1, characterized in that (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine is administered in the form of a pharmaceutically acceptable salt of (R)-5-((E)-2 -pyrrolidin-3-ylvinyl)pyrimidine. 3. Use according to claim 2, characterized in that the pharmaceutically acceptable salt is the galactarate salt or the citrate salt. 4. Use according to claim 3, characterized in that the citrate salt is a monocitrate salt and the galactarate salt is a hemigalactarate salt. 5. The use according to any one of claims 1 to 4, characterized in that the pharmaceutically acceptable salt is hemigalactarate dihydrate (R)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine or hemigalactarate monohydrate (R)- 5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine. 6. Use according to any one of claims 1 to 4, characterized in that the pharmaceutically acceptable salt is (K)-5-((E)-2-pyrrolidin-3-ylvinyl)pyrimidine monocitrate. 7. Use according to any one of claims 1 to 6, characterized in that the dose of (K)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 1 μg to 10 mg. 8. Use according to any one of claims 1 to 6, characterized in that the dose of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 1 μg to 2 mg. 9. The use according to any one of claims 1 to 6, characterized in that the dose of (K)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 1 μg to 3 mg. 10. The use according to any one of claims 1 to 6, characterized in that the dose of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 1 μg to 5 mg. 11. The use according to any one of claims 1 to 6, characterized in that the dose of (K)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is from 100 to 1000 μg. 12. Use according to any one of claims 1 to 6, characterized in that the dose of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is less than 5 mg. 13. The use according to any one of claims 1 to 12, further comprising local administration of one or more substances that prevent or reduce the transition of the nicotinic acetylcholine receptor to a desensitized state or help restore the peripheral nicotinic acetylcholine receptor from a desensitized state. 14. Use according to claim 13, characterized in that said one or more substances are selected from - 213 040442 group consisting of protein kinase C (PKC) or factors that activate or up-modulate PKC, cAMP-dependent protein kinase (PKA) or factors that activate or up-modulate PKA, and calcineurin inhibitors. 15. Use according to claim 14, wherein said calcineurin inhibitor is selected from the group consisting of cyclosporine, pimecrolimus and tacrolimus. 16. Use according to any one of claims 1 to 15, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered without any form of nicotine. 17. The use according to any one of claims 1 to 16, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered at least once a day or at least at least twice a day. 18. Use according to any one of claims 1 to 17, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered into the nasal cavity in the form of a liquid, suspension, aerosol , gel, ointment, dry powder, cream, paste, lotion, balm or nasal spray. 19. Use according to any one of claims 1-18, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is injected into the nasal cavity using a syringe, dropper, vial - nebulizer, nebulizer pump, inhaler, powder dispenser, steam inhaler, patch, medicated stick, dropper, nasal spray bottle or liquid jet. 20. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing 5 to 200 mg/ml of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 21. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing 5 to 50 mg/ml of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 22. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing 10 to 25 mg/ml of (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 23. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing about 1 mg/ml (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 24. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing about 2 mg/ml (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 25. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing about 5 mg/ml (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 26. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing about 10 mg/ml (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 27. The use according to any one of claims 1 to 19, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered in the form of a nasal pharmaceutical dosage form containing about 20 mg/ml (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 28. Use according to any one of claims 1 to 27, characterized in that the dryness of the eyes or discomfort in the eyes is the result of an ophthalmic surgery or ophthalmic treatment. 29. Use according to any one of claims 1 to 28, characterized in that (R)-5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof is administered before or after LASIK ophthalmic surgery. 30. Use according to any one of claims 1 to 29, characterized in that the individual in need of it has one or more symptoms, including itching, dryness, photophobia, blurring, pain, stickiness, burning, stinging and foreign body sensation. 31. The use according to any one of claims 1 to 30, characterized in that the individual in need of it has undergone or will undergo an ophthalmic surgery or ophthalmic - 214 040442 for treatment. 32. Use according to claim 31, wherein the ophthalmic surgery is cataract surgery, refractive lens replacement, glaucoma surgery, LASIK surgery, vitrectomy, retinal photocoagulation, surgical repair of retinal detachment, surgical repair of a macular hole, removal of a tumor or mass behind the iris, posterior sclerotomy, optic neurotomy; and characterized in that the ophthalmic treatment includes radiation therapy. 33. The use according to any one of claims 1 to 32, characterized in that the discomfort in the eyes is associated with dry eye disease, blepharitis, meibomian gland dysfunction, allergic conjunctivitis, toxicity and irritation of the surface of the eyes, a violation of the outflow of lacrimal fluid or disorders of the eyelids. 34. Use according to any one of claims 1 to 33, characterized in that the individual in need of it has one or more signs and/or symptoms of dry eye disease. 35. The use according to any one of claims 1 to 34, characterized in that in an individual in need of it, the assessment of the production of lacrimal fluid according to the Schirmer test is < 10 mm / 5 min in at least one eye before the administration of a therapeutically effective amount (R) - 5-((E)-2-pyrrolidin-3ylvinyl)pyrimidine or a pharmaceutically acceptable salt thereof. 36. The use according to claim 35, characterized in that the Schirmer test for determining the production of lacrimal fluid is carried out with local anesthesia.