Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/88—Oxygen atoms
  • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present disclosure relates to crystalline forms of 4-(7-Hydroxy-2-isopropyl-4- oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) processes and methods for their
• the invention also relates to formulations of compound I and methods for treating ocular surface disorders using same.
• ocular surface pain particularly chronic ocular surface pain have a significant decline in quality of life, and many develop depression, moderate-to- severe angina, dialysis, disabling hip fracture and in some cases become suicidal.
• the ocular surface pain remains unresolved despite treatment of the underlying pathology (e.g., recent trauma or surgery, infection, or inflammation) and other known treatments cannot be used for long term therapy.
• TRPV1 Transient Receptor Potential Vanilloid 1
• Formulating hydrophobic ophthalmic drugs can be particularly troublesome, because they are particularly prone to agglomeration within aqueous topical ophthalmic compositions. Agglomeration may cause stability and potentially other quality issues for the compositions, and may arise from other interactions of drugs and excipients. Accordingly, there is a need for identification of different polymorphic forms that may be formulated in ophthalmic formulations for delivery to the ocular surface.
• the invention relates to a crystal form A of 4-(7 -Hydroxy -2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the present disclosure relates to a method of preparing a crystal form A of compound I, comprising cooling a hot solution of the free base of compound I in methanol and cooling to about 0°C, to crystallize compound I as crystal form A.
• the invention relates to a crystal form C of 4-(7-Hydroxy-2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the invention relates to a method of preparing a crystal form C of compound I, comprising heating compound I in crystal form A to a temperature of at least about 250 °C, or at least about 270 °C, or about 280 °C.
• the invention relates to a crystal form E of 4-(7-Hydroxy-2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the crystal form E of compound I is characterized by an X ray diffraction pattern having three or more peaks at 2Q values selected from 12.7, 16.7, 22.6 ⁇ 0.2 °2Q.
• the crystal form E of compound I is characterized by an X ray diffraction pattern having three or more peaks at 2Q values selected from 12.7, 15.1, 16.7, 22.6, 27.1, 27.7, 28.5 ⁇ 0.2 °20.
• the invention relates to a method of preparing a crystal form E of compound I, comprising heating a hydrate form of compound I to temperatures greater than about 250 °C or about 260 °C to provide compound I as crystal form E.
• the invention relates to a crystalline hydrate of 4-(7-Hydroxy- 2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the crystalline hydrate of compound I is characterized by an X ray diffraction pattern having three or more peaks at 20 values selected from 6.6, 14.4, 18.3 ⁇ 0.2 °20. In some embodiments, the crystalline hydrate of compound I is characterized by an X ray diffraction pattern having three or more peaks at 20 values selected from 6.6, 11.9,
• the invention relates to a method of preparing the crystalline hydrate of compound I, comprising equilibrating a slurry of compound I in a mixture of water and a water miscible solvent, to crystallize compound I as the crystalline hydrate.
• the water miscible solvent is acetone.
• the equilibration is carried out for about 12 hours, about 18 hours, or about 24 hours, or about 48 hours.
• the invention relates to a crystalline methanol solvate of 4-(7- Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the crystalline methanol solvate of compound I is
• the invention relates to a method of preparing a crystalline methanol solvate of compound I, comprising equilibrating a slurry of compound I in methanol, to obtain compound I as polymorphic form G to provide compound I as the crystalline methanol solvate.
• the equilibration is carried out for at least about 24 hours at room temperature.
• the invention relates to a crystalline acetonitrile solvate (form J) of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the crystalline acetonitrile solvate of compound I is characterized by an X ray diffraction pattern having three or more peaks at 2Q values selected from 8.2, 17.0, 23.8 ⁇ 0.2 °20. In some embodiments, the crystalline acetonitrile solvate of compound I is characterized by an X ray diffraction pattern having three or more peaks at 20 values selected from 8.2, 11.8, 17.0, 22.8, 23.8, 27.6 ⁇ 0.2 °20.
• the invention relates to a method of preparing crystalline acetonitrile solvate of compound I, comprising equilibrating a slurry of compound I in acetonitrile to provide compound I as the crystalline acetonitrile solvate.
• the equilibration is carried out for at least about 24 hours at room temperature.
• the invention relates to a crystal form K of 4-(7 -Hydroxy -2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the crystal form K of compound I is characterized by an X ray diffraction pattern having three or more peaks at 2Q values selected from 5.3, 12.3, 22.4 ⁇ 0.2 °2Q.
• the crystal form K of compound I is characterized by an X ray diffraction pattern having three or more peaks at 2Q values selected from 5.3, 6.5, 10.5, 12.3, 17.2, 19.3, 22.4 ⁇ 0.2 °20.
• the invention relates to a method of preparing a crystal form K of compound I, comprising crystallizing by evaporation a solution of compound I in actone to provide compound I as crystal form K.
• the invention relates to a crystal form L of 4-(7-Hydroxy-2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) having structure
• the invention relates to a method of preparing a crystal form L of compound I, comprising adding a hydrocarbon solvent to a solution of compound I in acetone to provide compound I as crystal form L.
• the hydrocarbon solvent is hexane.
• the present disclosure provides a pharmaceutical formulation, comprising an effective amount of a crystal form of compound I according to any crystal forms selected from the group consisting of: crystal form A, crystal form C, crystal form D, crystal form E, crystal form F, crystal form L, crystal form K, and combinations thereof, and a pharmaceutically acceptable excipient.
• the present disclosure provides a pharmaceutical formulation for ocular use (e.g., topical application to the ocular surface), comprising an effective amount of compound I in crystal form B, and an additional crystal form selected from the group consisting of: crystal form A, crystal form C, crystal form D, crystal form E, crystal form F, crystal form L, crystal form K, and combinations thereof, and a pharmaceutically acceptable excipient.
• a pharmaceutical formulation for ocular use e.g., topical application to the ocular surface
• an additional crystal form selected from the group consisting of: crystal form A, crystal form C, crystal form D, crystal form E, crystal form F, crystal form L, crystal form K, and combinations thereof, and a pharmaceutically acceptable excipient.
• the disclosure provides a pharmaceutical formulation, comprising the crystal form A in substantially pure form. In some embodiments, the disclosure provides a pharmaceutical formulation, comprising the crystal form C in substantially pure form.
• the disclosure provides a pharmaceutical formulation, comprising the crystal form E in substantially pure form.
• the disclosure provides a pharmaceutical formulation, comprising the crystal form F in substantially pure form.
• the disclosure provides a pharmaceutical formulation, comprising the crystal form K in substantially pure form.
• the disclosure provides a pharmaceutical formulation, comprising the crystal form L in substantially pure form.
• the disclosure provides a pharmaceutical formulation, comprising a mixture of two or more crystal forms of compound I.
• the disclosure provides a pharmaceutical formulation, comprising a mixture of mixture of crystal forms B and E, crystal forms B and F, crystal forms B and C, crystal forms A and C, crystal forms A and F, in ratios of from about 1 : 99 to about 99: 1.
• the pharmaceutical formulation comprising any of the crystal forms disclosed herein is formulated for ocular use (e.g., topical application to the ocular surface).
• aqueous formulation that includes:
• a surfactant selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative.
• the 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)- benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof is present in the formulation as a suspension.
• the 4-(7-Hydroxy-2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof is present in the formulation in an amount of about 0.5% w/v to about 3.5% w/v.
• an aqueous formulation that includes: 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v, present as a suspension in the formulation,
• a tonicity agent a buffer, a preservative, a salt, and a preservative.
• the invention described herein is a formulation that includes: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v,
• a preservative optionally, a preservative
• the present disclosure relates to a formulation, comprising: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v,
• a surfactant selected from the group consisting of non-ionic, anionic, cationic surfactants, and combinations thereof;
• the formulation includes a non-ionic surfactant.
• the non-ionic surfactant is selected from the group consisting of a polysorbate surfactant, a block copolymer of ethylene oxide, propylene oxide surfactant, poloxamer, tyloxapol, and combinations thereof.
• the non-ionic surfactant is tyloxapol, which is present in an amount of at least about 0.001% w/v, at least about 0.01% w/v, at least about 0.02% w/v, least about 0.03% w/v, or at least about 0.04% w/v, and no more than about 1% w/v, no more than about 0.5% w/v, no more than about 0.3% w/v, or no more than about 0.2% w/v, no more than about 0.1% w/v, or no more than about 0.08% w/v.
• the tyloxapol is present in an amount of about 0.03% w/v to 0.08% w/v, or about 0.05% w/v.
• the non-ionic surfactant is poloxamer in an amount of about 15 to about 20% w/v of the formulation.
• the suspending agent is selected from the group consisting of carbomer, hydroxypropyl methyl cellulose
• the suspending agent is carbomer, present in the formulation in an amount of at least about 0.05% w/v, at least about 0.1% w/v, or at least about 0.2% w/v, and no greater than about 1.0% w/v, no greater than about 0.6% w/v, or no greater than about 0.5%.
• the carbomer is present in the formulation in an amount of 0.1% w/v to about 0.3% w/v, or about 0.2% w/v.
• the suspending agent is hydroxypropyl methyl cellulose present in the formulation in an amount of at least about 0.05% w/v, at least about 0.1% w/v, or at least about 0.25% w/v, and less than about 1.8% w/v, less than about 1.0% w/v, less than about 0.8% w/v, or less than about 0.6% w/v.
• the suspending agent is a polyethylene glycol (PEG) having molecular weight of from about 200 to about 20,000 Da.
• the suspending agent is PEG400, at a concentration of from about 4% w/v to about 9% w/v, about 5% w/v to about 8% w/v, or about 7% w/v, or PEG6000 at a concentration of from about 1% w/v to about 4% w/v, about 1% w/v to about 3% w/v, or about 2% w/v.
• the suspending agent is substantially all carbomer homopolymer Type B.
• the tonicity agent is selected from the group consisting of polyols.
• the polyol is selected from the group selected from mannitol, glycerin, xylitol, sorbitol and propylene glycol, and combinations thereof. In some embodiments, the polyol is present in an amount from about 0.05% w/v to about 10% w/v, from about 0.1% to about 8% w/v, from about 0.1% to about 7% w/v, from about 0.1% to about 5% w/v.
• the polyol is mannitol or glycerin, present in the formulation in an amount of from 0.1% w/v to about 5% w/v, or about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 2.5% w/v, about 3.0% w/v, about 3.5% w/v, about 4.0% w/v, about 4.5% w/v, or about 5% w/v.
• the buffer is selected from the group consisting of acetate, ascorbate, borate, hydrogen carbonate, carbonate, citrate, edetate (EDTA) gluconate, lactate, phosphate, propionate and TRIS (tromethamine).
• the buffer is phosphate or TRIS.
• the salt is sodium chloride or potassium chloride.
• the suspending agent is carbopol (carbomer homopolymer Type B) and amount of sodium chloride is adjusted to an amount to provide a viscosity of the formulation of about 20 cP to about 200 cP, when using spindle CP-42 at 60 rpm at about 25 °C.
• the sodium chloride is present in an amount from about 0.01 % w/v to about 0.5% w/v, from about 0.02% w/v to about 0.4% w/v, from about 0.03% w/v to about 0.3% w/v, from about 0.04% w/v to about 0.2% w/v, from about 0.05% w/v to about 0.1% w/v, or about 0.05% w/v.
• the pH of the formulation is about 5.5 to about 8.0. In some embodiments, the pH of the formulation is from about 6.0 to about 8.0, about 6.0, or about 7.4.
• the formulations described herein further include an additional agent selected from the group consisting of cyclodextrins in an amount of at least about 1.5 w/v%, at least about 3.0 w/v%, at least about 3.5 w/v% or at least about 4.5 w/v, but no greater than about 10.0 w/v%, no greater than about 8.0% w/v, no greater than about 6.5 w/v%, or no greater than about 5.5 w/v.
• the cyclodextrin is hydroxypropyl b-cyclodextrin or sulfoalkylether b-cyclodextrin in an amount of about 5% w/v of the formulation.
• the present disclosure is related to a formulation, comprising: the compound I or a salt, co-crystal, or polymorph thereof, is in an amount of about 0.5% w/v to about 2.5% w/v,
• the a non-ionic surfactant is tyloxapol, poloxamer, or combinations thereof, in an amount of from about 0.01 to 0.2% w/v;
• the a suspending agent is hydroxypropyl methyl cellulose, polyethylene glycol or carbomer homopolymer Type B;
• the a tonicity agent is at least one polyol in an amount of from about 0.05% w/v to about 10% w/v;
• the buffer is edetate, phosphate, borate, or combinations thereof
• the pH is in the range of from about 5.5 to about 8.0.
• the present disclosure is related to a formulation, comprising: compound I or a salt, co-crystal, or polymorph thereof, is present in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• non-ionic surfactant which is tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v, poloxamer in an amount of about 0.005-0.12% w/v, or combinations thereof
• a suspending agent which is hydroxypropyl methyl cellulose in an amount of from about 0.1% w/v to about 0.8 w/v %, polyethylene glycol in an amount of from about 2% w/v to about 8% w/v, carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.5% w/v, or combinations thereof;
• a tonicity agent which is mannitol or glycerin in an amount of from about 0.1% w/v to about 5% w/v;
• a buffer which is edetate, phosphate, borate, tromethamine, or combinations thereof; sodium chloride in an amount of from 0.01% w/v to about 1% w/v; and water qs to 100%; and
• having a pH is in the range of from about 5.5 to about 8.0.
• the present disclosure is related to a formulation, comprising: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v;
• carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.4% w/v;
• glycerin in an amount of from about 0.5% w/v to about 5% w/v;
• a buffer selected from the group consisting of edetate, phosphate, borate, tomethamine, and combinations thereof;
• sodium chloride in an amount of from 0.01% w/v to about 1% w/v;
• the formulation has a pH in the range of from about 5.5 to about 8.0.
• compound I is in polymorphic form B.
• the present disclosure is related to a formulation, comprising: a suspension of polymorphic form B of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H- quinazolin-3-yl)-benzonitrile (compound I), in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v;
• carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.4% w/v;
• glycerin in an amount of from about 0.5% w/v to about 5% w/v;
• a buffer selected from edetate, phosphate, borate, tomethamine, or combinations thereof;
• sodium chloride in an amount of from 0.01% w/v to about 1% w/v;
• the formulation has a pH in the range of from about 5.5 to about 8.0.
• the formulation comprises:
• compound I in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• hydrochloric acid to adjust pH to about 6.4 to about 8.4;
• the polymorphic form B of compound I is is characterized by an X-ray diffraction pattern having three or more peaks at 20 values selected from 9.3, 10.6 and 14.4.+-.0.2 °20.
• the formulations described herein have a viscosity of about 20 cP to about 200 cP.
• the formulations described herein have an osmolality of about 200 to about 450 milliosmoles per kilogram (mOsm/kg).
• the D90 of compound I (diameter at which 90% of compound I is comprised of smaller particles) is below about 10 pm, below about 8 pm, below about 6 pm, below about 4 pm, below about 3 pm, or about 2 pm. In some embodiments, the D50 of compound I in the formulation (diameter at which 50% of compound I is comprised of smaller particles) is below about 10 pm, below about 8 pm, below about 6 pm, below about 4 pm, below about 3 pm, below about 2 pm, or about 1 pm.
• the Dio of compound I in the formulation is below about 5 pm, below about 4 pm, below about 3 pm, below about 2 pm, below about 1 pm, or about 0.3 pm.
• the formulation exhibits settling of less than about 10%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% after storage at room temperature for six months.
• the amount of compound I in the formulation is at least 90% of the initial amount after about 6 months, after about 8 months, about 10 months, about 12 months, about 15 months, or about 18 months of storage under refrigeration.
• the amount of compound I in the formulation at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least about 97% or at least about 98% of the initial amount after about 18 months of storage under refrigeration.
• the formulation comprises no more than about 10% of a degradation product after 6 months under refrigeration, wherein the degradation product has a relative retention time of 1.23, compared to compound I, when analyzed by HPMC using a gradient 0.1 % trifluoroacetic acid (TFA) water/acetonitrile mobile phase.
• TFA trifluoroacetic acid
• no more than about 10% of compound I in the formulation degrades upon storage for 12 weeks at 40 °C.
• the compound I is in a crystal form selected from the group consisting of crystal form A, crystal form B, crystal form C, crystal form E, crystal form F, crystal form G, crystal form J, crystal form K, crystal form L, and combinations thereof.
• compound I is in a crystal form selected from the group consisting of crystal form A, crystal form B, crystal form C, crystal form E, crystal form F, crystal form K, crystal form L, and combinations thereof.
• the present disclosure is related to a method of making a formulation, comprising
• a salt optionally, a preservative
• adjusting the pH to a range of from about 5.5 to about 8.0.
• the method of making the formulations disclosed herein include the addition of compound I as a stock suspension.
• the stock suspension is milled to achieve a desired particle size of compound I.
• the D90 of compound I in the formulation is below about 10 pm, below about 8 pm, below about 6 pm, below about 4 pm, below about 3 pm, or about 2 pm.
• the D50 of compound I in the formulation is below about 10 pm, below about 8 pm, below about 6 pm, below about 4 pm, below about 3 pm, below about 2 pm, or about 1 pm.
• the Dio of compound I in the formulation is below about 5 pm, below about 4 pm, below about 3 pm, below about 2 pm, below about 1 pm, or about 0.3 pm.
• the present disclosure is related to a method of treating ocular surface pain in a subject in need thereof, comprising ocularly administering an effective amount of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound of formula I) having structure:
• the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is chronic ocular surface pain lasting for at least 1 month, at least 2 months, or at least 3 months. In some embodiments, the compound of Formula I is administered to the cornea of the subject.
• the COSP is associated with dry eye disease.
• the administration results in a decrease in the symptoms of dry eye disease.
• the administration results in a decrease in the pain associated with dry eye disease.
• the administration results in reduced incidence of at least about 10% in one or more of ocular dryness, ocular discomfort, ocular hyperemia, ocular burning or stinging, grittiness or foreign body sensation, or photophobia.
• the subject suffers from one or more of dry eye disease, Sjogren’s Syndrome, conjunctivitis (including keratoconjuctivitis, vernal
• keratoconjunctivitis keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis,
• corneal epitheliopathies corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), crizis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia,
• xerophthalmia patients recovering from neurotrophic keratitis, or ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.
• PRK photorefractive keratectomy
• LASIK laser-assisted in situ keratomileusis
• the method comprises administering an additional therapeutic agent to the subject.
• the administration results in a reduction in a pain score on the visual acuity scale (VAS) of at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9 or at least about 10, compared to a placebo.
• VAS visual acuity scale
• the reduction in VAS score arises from the difference in VAS scores prior to and after administration of compound I to the subject.
• the administration of compound I results in a reduction in hyperemia in the subject of at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5, on the McMonnies scale. In some embodiments, the administration does not result in a change in one or more of best corrected visual acuity, intraocular pressure, slit-lamp biomicroscopy, dilated eye exam, blink rate, tear production, corneal staining, compared to a placebo.
• the compound of formula I is administered in the form of a formulation as described herein. In some embodiments, the formulation is administered for at least about one, about two, or about three months. In some embodiments, the formulation is administered one to four times daily.
• the disclosure provides a formulation as described herein, for use in the treatment of ocular surface pain.
• the ocular surface pain is episodic (e.g., acute) ocular surface pain or chronic ocular surface pain lasting for at least 1 month, at least 2 months, or at least 3 months.
• the disclosure provides a method of reducing ocular surface pain in a subject in need thereof, comprising ocularly administering 4-(7-Hydroxy-2- isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having structure:
• the ocular surface pain is episodic (e.g., acute) ocular surface pain the ocular surface pain is chronic ocular surface pain (COSP).
• COSP chronic ocular surface pain
• the COSP is associated with dry eye disease.
• the administration results in a decrease in the symptoms of dry eye disease. In some embodiments, the administration results in a decrease in the pain associated with dry eye disease. In some embodiments, the administration results in reduced incidence of at least about 10% in one or more of ocular dryness, ocular discomfort, ocular hyperemia, ocular burning or stinging, grittiness or foreign body sensation, or photophobia.
• the subject suffers from one or more of dry eye disease, Sjogren’s Syndrome, conjunctivitis (including keratoconjuctivitis, vernal
• keratoconjunctivitis keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven- Johnson’s syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous ker
• the subject suffers from ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.
• PRK photorefractive keratectomy
• LASIK laser-assisted in situ keratomileusis
• the method comprises administering an additional therapeutic agent to the subject.
• the administration results in a reduction in a pain score on the visual acuity scale (VAS) of at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9 or at least about 10, compared to a placebo.
• VAS visual acuity scale
• the administration results in a reduction in a VAS pain score of at least about 6, at least about 7, at least about 8, at least about 9 or at least about 10, compared to a placebo.
• the reduction in the pain score arises from the difference in pain scores prior to and after administration of compound I to the subject.
• the reduction in pain score occurs after about 7 days of administration of compound I to the subject.
• the reduction in pain score occurs after about 14 days of administration of compound I to the subject.
• the administration results in a reduction in hyperemia in the subject of least about 1, at least about 2, at least about 3, at least about 4, or at least about 5, on the McMonnies scale.
• the administration results in a reduction in a pain score on the visual acuity scale (VAS) of at least about 3 as compared to a VAS score prior to
• the compound of formula I is administered in the form of a formulation as described herein.
• the present disclosure relates to a method of treating or reducing ocular surface pain in a subject in need thereof, comprising administering to the subject a formulation comprising a compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H- quinazolin-3-yl)-benzonitrile (compound I) having structure:
• the formulation results in a rabbit corneal Cmax compound I of about 1.5 to about 3 times conjunctival Cmax, wherein Cmax is the maximum concentration of compound I in the specified tissue after administration of a single dose.
• the compound I is administered as a formulation as described herein.
• the present disclosure relates to a method of treating or reducing ocular surface pain in a subject in need thereof, comprising administering to the subject a formulation comprising a compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H- quinazolin-3-yl)-benzonitrile (compound I) having structure:
• the formulation results in a Cmax of compound I in a rabbit cornea of about 500 times the Cmax of compound I in plasma, wherein Cmax is the maximum concentration of compound I in the specified tissue after administration of a single dose.
• the compound I is administered as a formulation as described herein.
• Figure 1 provides a superposition of experimental and calculated XRPD patterns of crystal form A of compound I.
• Figure 2 provides the X-ray powder diffraction pattern of crystal form A of compound I.
• Figure 3 provides a superposition of experimental and calculated XRPD patterns of crystal form C of compound I.
• Figure 4 provides the X-ray powder diffraction pattern of crystal form C of compound I.
• Figure 5 provides a superposition of experimental and calculated XRPD patterns of crystal form E of compound I.
• Figure 6 provides the X-ray powder diffraction pattern of crystal form E of compound I.
• Figure 7 provides the X-ray powder diffraction pattern of Crystal form F (Hydrate HA) of compound I.
• Figure 8 provides a superposition of experimental and calculated XRPD patterns of crystal form G (methanol solvate SB) of compound I.
• Figure 9 provides the X-ray powder diffraction pattern of crystal form G (methanol solvate SB) of compound I.
• Figure 10 provides the X-ray powder diffraction pattern of crystal form J (acetonitrile solvate SA) of compound I.
• Figure 11 provides the X-ray powder diffraction pattern of crystal form K of compound I.
• Figure 12 provides the X-ray powder diffraction pattern of crystal form L of compound I.
• Figure 13 demonstrates the relationship of polymorphic and solvated/hydrated forms of compound I free base and exemplary methods for their conversion.
• Figure 14A shows the percent of compound I in the exploratory formulations described in Table 13 through 12 weeks at room temperature.
• the formulation with percent of compound I at about 75% of original at 12 weeks is the formulation of compound I as a solution.
• Figure IB shows the percent of compound I in the exploratory formulations after 12 weeks at 40 °C.
• the formulation with percent of compound I at about 20% of original at 12 weeks is the formulation of compound I as a solution.
• Figure 15 shows the X-ray Powder Diffraction Patterns of compound I Recovered from 12-Week Stability Samples versus Control.
• TRPV1 receptor refers to the Transient Receptor Potential Vanilloid 1 that has been characterized through molecular cloning and pharmacology. See e.g., Caterina MJ, el al., . Nature 1997; 389:816-824. TRPVl receptor activity is measured as described in
• an effective amount of the compounds described herein refers to that amount of a therapeutic compound necessary or sufficient to perform its intended function within a mammal.
• An effective amount of the therapeutic compound can vary according to factors such as the amount of the causative agent already present in the mammal, the age, sex, and weight of the mammal, and the ability of the therapeutic compounds of the present disclosure to treat the ocular surface disorder and/or symptoms thereof in the mammal.
• ophthalmically compatible refers to formulations, polymers and other materials and/or dosage forms which are suitable for use in contact with the ocular tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• the term“treat”,“treating” or“treatment” in connection to a disease or disorder refers in some embodiments, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
• “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
• “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g, stabilization of a physical parameter), or both.
• “treat”,“treating” or“treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder or symptom thereof.
• the term“subject” or“patient” refers to human and non-human mammals, including but, not limited to, primates, rabbits, pigs, horses, dogs, cats, sheep, and cows.
• a subject or patient is a human.
• the term“patient” or“subject” refers to a human being who is diseased with the condition (i.e., disease or disorder) described herein and who would benefit from the treatment.
• a subject is“in need of’ a treatment if such subject (patient) would benefit
• the subject is an adult human of at least about 18 years of age. In some embodiments, the subject is an adult human from about 18 years of age to about 75 years of age. In some embodiments, the subject is a child of up to about 18 years of age.
• “ocular surface” refers to the outer surface of the eye, which anatomically comprises the cornea (with epithelium, bowman layer, stroma, descement membrane, endothelium), conjunctiva, cul de sac, and the corneo-scleral junction, i.e. limbus.
• Pain refers to constant or intermittent sensation of actual pain described as but not limited to stabbing, dull, sharp, or ache. Pain may also refer to similar related descriptors such as but not limited to burning, stinging, grittiness, foreign body sensation, dryness, sandy, tired, itchy, irritated, sensitivity to light.
• ocular administration includes administration to all parts of the eye including all parts of the ocular surface such as the cornea, conjunctiva, the cul de sac and the corneo-scleral junction, i.e., limbus.
• Ocular surface pain refers to pain on the surface of the eye, e.g., cornea.
• Ocular pain may be nociceptic pain, which is generally caused by external physical or chemical damaging stimuli such as corneal surgery, inflammation, or other damage to the corneal surface.
• Ocular pain may also result from neuropathic pain, which may occur due to direct damage to the neurons of the body, resulting in messages of pain being sent to the central nervous system and brain regardless of the presence of noxious stimuli.
• ocular surface pain includes both nociceptic pain and neuropathic pain.
• VAS visual analog scale
• NRS numerical rating scale
• the number scale may be from 1-10, or 1-100.
• the Wong-Baker FACES Pain Scale combines pictures and numbers for pain ratings. It can be used in children over the age of 3 and in adults. Six faces depict different expressions, ranging from happy to extremely upset. Each is assigned a numerical rating between 0 (smiling) and 10 (crying).
• the Verbal Pain Intensity Scale uses wordings on a scale to rate pain intensity: No Pain / Mild Pain / Moderate Pain / Severe Pain Very Severe Pain / Worst Possible Pain.
• the Eye Sensation Scale is a specific pain scale was developed to measure ophthalmic pain severity. See Caudle L.E. el al. , Optom Vis Sci. 2007 Aug; 84(8):752-62. In this scale, pain, discomfort or light sensitivity is typically measured by 5 category labels of “extreme,”“severe,”“moderate,”“mild,” or“none.”
• Ocular Pain Assessment Survey is a quantitative, multidimensional questionnaire, specifically designed for assessment of corneal and ocular surface pain and Quality of Life (QoL) changes.
• QoL Quality of Life
• the OPAS assesses pain intensity, frequency of eye and non eye pain, QoL changes, aggravating factors, associated factors, and symptomatic relief quantitative, allowing for monitoring of treatment responses. See Qazi et al., Ophthalmology July 123(7): 1458-1468 (2016).
• Visual Tasking Questionnaire refers to a questionnaire that asks the subject to subjectively rate how much difficulty they have conducting certain activities that require a fixed or prolonged stare that may exacerbate ocular pain. The questionnaire also asks about coping mechanisms associated with the difficulties they experience during visual tasking activities.
• ocular hyperemia refers to redness of the ocular surface.
• Ocular hyperemia may be a clinical marker for inflammation and/or ocular irritation.
• Ocular hyperemia is typically measured using the McMonnies scale, at values from 0 to 5, based on standard photographs.
• placebo refers to an ophthalmic formulation that includes all the components of the administered drug composition without the drug.
• the term“about” refers to a range of values + 10% of a specified value.
• polymorph refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
• solvate refers to a crystalline form of a molecule, atom, and/or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure.
• the solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement.
• the solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
• a solvate with a nonstoichiometric amount of solvent molecules may result from partial loss of solvent from the solvate.
• Solvates may occur as dimers or oligomers comprising more than one molecule of compound I within the crystalline lattice structure.
• amorphous refers to a solid form of a molecule, atom, and/or ions that is not crystalline. An amorphous solid does not display a definitive X-ray diffraction pattern.
• substantially pure when used in reference to a form, means a compound having a purity greater than 90 weight %, including greater than 90 , 91 , 92, 93, 94, 95, 96, 97, 98, and 99 weight %, and also including equal to about 100 weight % of compound I, based on the weight of the compound.
• the remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation.
• a crystalline form of compound I may be deemed substantially pure in that it has a purity greater than 90 weight %, as measured by means that are at this time known and generally accepted in the art, where the remaining less than 10 weight % of material comprises other form(s) of compound I and/or reaction impurities and/or processing impurities.
• “Compound of formula I,”“Compound I,”“Formula I,” and “compound I” are used interchangeably and mean a compound that has the name 4-(7- hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, the structure shown below, and can be synthesized using procedures known in the art and described in W02005/120510 and U.S. Patent No. 8,349,852 (“Quinazolinone derivatives useful as vanilloid antagonists”) to Chen et al., both of which are hereby incorporated by reference in their entireties.
• “crystal form,”“crystalline form,”“modification,” or“polymorph,” or“polymorphic form” in upper or lower case are used interchangeably and refer to the crystalline or polymorphic form of compound I.
• Compound I may be used in amorphous or crystalline forms. Additionally or alternatively, various crystalline and polymorphic forms of Compound (I) may be used.
• “polymorphic forms” or“polymorphs” of compound (I) is intended to encompass crystalline hydrates or other crystalline solvates of compound (I).
• any chemical formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
• Isotopically labeled compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
• Isotopes that can be incorporated into compounds of the disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 3 H, U C, 13 C, 14 C, and 15 N.
• methods of the present invention can or may involve compounds that incorporate one or more of any of the aforementioned isotopes, including for example, radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
• isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
• Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, e.g., using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
• the present invention encompasses embodiments that include all pharmaceutically acceptable salts of the compounds useful according to the invention provided herein.
• pharmaceutically acceptable salt refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
• pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• the pharmaceutically acceptable salts include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
• the pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
• such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences , 17 th ed., Mack Publishing Company, Easton, Pa.,
• preferred pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines.
• the salt can be a hydrochloride salt.
• suitable salts can be found in U.S. Patent No. 8,349,852, the content of which is hereby incorporated by its entirety.
• phrases“pharmaceutically acceptable” as employed herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• % w/v % weight/volume
• % w/v value refers to the amount of the particular component or ingredient in the formulation. It is commonly understood that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1% w/v can also be expressed as a 1 mg/ml solution.
• the weight or dosage referred to herein for the compound of formula I is the weight or dosage of the compound itself, not that of a salt or prodrug thereof, which can be different to achieve the intended therapeutic effect.
• the weight or dosage of a corresponding salt of a compound suitable for the methods, compositions, or combinations disclosed herein may be calculated based on the ratio of the molecular weights of the salt and compound itself.
• Crystal form B of compound I is described in U.S. Patent No. 8,349,852, incorporated by reference herein.
• Polymorph B is characterized by an X-ray diffraction pattern having three or more peaks at 2Q values selected from 9.3, 10.6 and 14.4.+-.0.2 °20.
• polymorph B is characterized by an X-ray diffraction pattern having three or more peaks at 20 values selected from 9.3, 10.6, 14.4, 15.5, 17.9, 19.9, 23.4 ⁇ 0.2 °20.
• the present invention relates to crystal form A of compound I, characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 7.2, 12.7, and 21.4 ⁇ 0.2 °20.
• crystal form A is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 7.2, 12.7, 13.9, 18.1, 21.4, 25.1, and 26.8 ⁇ 0.2 °20.
• crystal form A is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 20 values selected from 7.2, 12.7, 13.3, 13.9, 14.5, 15.6, 18.1, 19.9, 21.4, 22.8, 25.1, 26.8, 27.8, 29.0 ⁇ 0.2 °20.
• Crystal form A may be prepared by cooling a hot solution of the free base of compound I in methanol and cooling to about 0°C, to crystallize compound I as crystal form A.
• a crystal form A of compound I is provided in substantially pure form.
• This crystal form A of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I in crystal form A.
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as crystal form A.
• the present invention relates to crystal form C of compound I, characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 7.4, 14.9, 19.1 ⁇ 0.2 °2Q.
• crystal form C is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 7.4, 14.1, 14.9, 16.4, 19.1, 26.1, 31.2 ⁇ 0.2 °20.
• crystal form C is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 20 values selected from 7.4, 14.1, 14.9, 16.4, 19.1, 24.8, 26.1, 28.4, 31.2 ⁇ 0.2 °20.
• Crystal form C may be prepared by heating crystal form A.
• a crystal form C of compound I is provided in substantially pure form.
• This crystal form C of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I in crystal form C.
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as crystal form C.
• the present invention relates to crystal form E of compound I, characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 12.7, 16.7, 22.6 ⁇ 0.2 °20.
• crystal form E is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 12.7, 15.1, 16.7, 22.6, 27.1, 27.7, 28.5 ⁇ 0.2 °20.
• polymorph E of compound I has a melting onset temperature of about 281 °C.
• crystal form E is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 20 values selected from 9.1, 11.9, 12.7, 13.8, 15.1, 16.7, 18.3, 21.3, 22.6, 24.4, 27.1, 27.7, 28.5, 37.8 ⁇ 0.2 °20.
• Crystal form E may be prepared by heating a hydrate form of compound I to temperatures greater than about 250 °C or about 260 °C to provide compound I as crystal form E. In some embodiments, the heating is carried out in an oven.
• a crystal form E of compound I is provided in substantially pure form.
• This crystal form E of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I in crystal form E.
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as crystal form E.
• the present invention relates to a crystalline hydrate of compound I (polymorph F).
• the crystalline hydrate of compound I is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 6.6, 14.4, 18.3 ⁇ 0.2 °20.
• the crystalline hydrate is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 6.6, 11.9, 14.4, 18.3, 23.9, 26.5, 29.2 ⁇ 0.2 °20.
• the crystalline hydrate is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 20 values selected from 6.7, 11.9, 12.8, 14.4, 15.6, 16.3, 18.3, 19.5, 22.7, 23.9, 24.7, 25.6, 26.5, 29.2 ⁇ 0.2 °20.
• Crystal form F may be prepared by equilibration of a slurry of compound I in a mixture of water and a water miscible solvent, to crystallize compound I as crystal form F.
• the water miscible solvent is acetone.
• the equilibration is carried out for about 12 hours, about 18 hours, or about 24 hours, or about 48 hours. In some embodiments, the equilibration is carried out at room temperature, i.e., about 25 °C.
• a crystal form F of compound I is provided in substantially pure form.
• This crystal form F of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I as the crystalline hydrate form (polymorph F).
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as the crystalline hydrate (polymorph F).
• the present invention relates to a crystalline methanol solvate form (polymorph G) of compound I.
• the crystalline methanol solvate of compound I is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 6.1, 14.5, 22.7 ⁇ 0.2 °20.
• the crystalline methanol solvate is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 6.1, 12.2, 14.5, 18.0, 22.7, 24.6 ⁇ 0.2 °20.
• Polymorphc form G may be prepared by equilibrating a slurry of compound I inmethanol, to obtain compound I as crystal form G.
• the equilibration is carried out for about 12 hours, about 18 hours, or about 24 hours, or about 48 hours.
• the equilibration is carried out at room temperature, i.e., about 25 °C.
• a crystal form G of compound I is provided in substantially pure form.
• This crystal form G of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I as the crystalline methanol form (polymorph G).
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as the crystalline methanol solvate (polymorph G).
• the present invention relates to a crystalline acetonitrile solvate (crystal form J).
• the crystalline acetonitrile solvate of compound I is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 8.2, 17.0, 23.8 ⁇ 0.2 °20.
• the crystalline acetonitrile solvate is characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 8.2, 11.8, 17.0, 22.8, 23.8, 27.6 ⁇ 0.2 °20.
• the crystalline acetonitrile solvate is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 20 values selected from 8.2, 11.8, 17.0, 22.8, 23.8, 27.6, 31.4 ⁇ 0.2 °20.
• the crystalline acetonitrile solvate may be prepared by equilibrating a slurry of compound I in acetonitrile.
• the compound I n the slurry is in crystal form A.
• the equilibration is carried out for about 12 hours, about 18 hours, or about 24 hours, or about 48 hours. In some embodiments, the equilibration is carried out at room temperature, i.e., about 25 °C.
• the crystalline acetonitrile solvate of compound I is provided in substantially pure form.
• This crystalline acetonitrile solvate of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I as the crystalline acetonitrile solvate (polymorph J).
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as the crystalline acetonitrile solvate (polymorph J).
• the present invention relates to crystal form K of compound I, characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 5.3, 12.3, 22.4 ⁇ 0.2 °20.
• crystal form K is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, or 6 or more peaks at 20 values selected from 5.3, 6.5, 10.5, 12.3, 17.2, 19.3, 22.4 ⁇ 0.2 °20.
• Crystal form K may be prepared by evaporation crystallization of compound I in acetone, to crystallize compound I as crystal form K.
• a crystal form K of compound I is provided in substantially pure form.
• This crystal form K of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I as the polymorph K.
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as the polymorph K.
• the present invention relates to crystal form L of compound I, characterized by an X-ray diffraction pattern having 3 or more peaks at 20 values selected from 7.1, 8.7, 10.6 ⁇ 0.2 °2Q.
• crystal form L is characterized by an X- ray diffraction pattern having 3 or more peaks at 20 values selected from 3.5, 7.1, 8.7, 10.6, 12.2, 19.1, 22.4 ⁇ 0.2 °20.
• crystal form L is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 20 values selected from 3.5, 7.1, 8.7, 10.6, 11.1, 12.2, 19.1, 21.1, 22.4, 23.4 ⁇ 0.2 °20.
• Crystal form L may be prepared by precipitation of a solution of compound I in acetone by the adding a hydrocarbon solvent, to crystallize compound I as crystal form L.
• the hydrocarbon solvent is pentane, hexane, or heptane.
• the hydrocarbon solvent is hexane.
• a crystal form L of compound I is provided in substantially pure form.
• This crystal form L of compound I in substantially pure form may be employed in pharmaceutical compositions, e.g., ophthalmic formulations as described herein.
• the disclosure provides for pharmaceutical formulations including compound I as the polymorph L.
• the present disclosure provides ophthalmic suspensions of compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of compound I is present as the polymorph L.
• the present invention provides formulations of the compound of formula I.
• the formulations are aqueous suspensions of a compound of formula I.
• the suspension includes the compound of formula I at a concentration of from about 0.5% to about 1.5 % w/v, about 0.5% to about 2.5 % w/v, about 0.5% to about 3.5% w/v, about 0.5% to about 3.0% w/v, about 1.0% to about 2.5% w/v, about 1.5% to about 3.0% w/v, about 0.5% to about 2.5% w/v.
• the concentration of the compound of formula I in a formulation for topical ocular use is at least about 0.5% w/v, at least about 1.0% w/v, at least about 1.5% w/v, at least about 2.0% w/v, or at least about 2.5% w/v. In some embodiments, the concentration of the compound of formula I in a formulation for topical use is no more than about 5.0% w/v, no more than about 4.5% w/v, no more than about 4.0% w/v, no more than about 3.5% w/v, or no more than about 3.0 %w/v.
• the concentration of the compound of formula I in a formulation for topical use is about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, about 2.5% w/v, about 3.0% w/v, or about 3.5% w/v.
• compound of formula I is administered to the subject at a concentration of about 5 mg/ml to about 35 mg/ml, about 5 mg/ml to about 25 mg/ml, or about 5 mg/ml to about 15 mg/ml, about 5 mg/ml to about 30 mg/ml, about 10 mg/ml to about 25 mg/ml, about 15 mg/ml to about 30 mg/ml, or about 5 mg/ml to about 25 mg/ml.
• the concentration of the compound of formula I in a formulation for topical use is at least about 5 mg/ml, at least about 10 mg/ml, at least about 15 mg/ml, at least about 20 mg/ml, or at least about 25 mg/ml. In some embodiments, the concentration of the compound of formula I in a formulation for topical use is no more than about 50 mg/ml, no more than about 45 mg/ml, no more than about 40 mg/ml, no more than about 35 mg/ml, or no more than about 30 mg/ml.
• the compound of formula I is administered at a concentration of about 5 mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, or about 35 mg/ml.
• the compound of formula I is present in the form of polymorph A, polymorph B, polymorph C, polymorph E, polymorph F (hydrate HA), polymorph J (acetonitrile solvate SA), polymorph G (methanol solvate SB), polymorph K, polymorph L, or combinations thereof.
• compound I is present as polymorph B in substantially pure form in the ophthalmic formulations described herein.
• compound I is present as polymorph A in substantially pure form in the ophthalmic formulations described herein. In some embodiments, compound I is present as substantially pure form as polymorph C in the ophthalmic formulations described herein. In some embodiments, compound I is present as polymorph E in substantially pure form in the ophthalmic formulations described herein. In some embodiments, compound I is present as polymorph F in substantially pure form in the ophthalmic formulations described herein. In some embodiments, compound I is present as polymorph K in substantially pure form in the ophthalmic formulations described herein. In some embodiments, compound I is present as polymorph L in substantially pure form in the ophthalmic formulations described herein.
• compound I is present in the formulation as a mixture of two or more polymorphic forms in different ratios.
• compound I is present as a mixture of polymorphs B and E, polymorphs B and F, polymorphs B and C, polymorphs A and C, polymorphs A and F, in ratios of from about 1 : 99 to about 99: 1.
• the formulation further includes at least one opthalmically acceptable excipient.
• the formulations include an ophthalmically acceptable surfactant.
• the surfactant is an anionic surfactant.
• the anionic surfactant is selected from C10-C22 alkylsulfates, C10- C22alkyl(oligooxyalkylene)sulfates, C4-C22 alkyl sulfosuccinate esters, C10- C22acylsarcosinatesand C10-C22 alkylcarboxylates; wherein oligooxyalkylene moieties have from one to five oxy-Ci-C6 alkylene moieties, e.g., oxyethylene moieties.
• the anionic surfactants may have a countercation is selected from alkali metal, e.g., sodium, Ci- C3 alkylammonium, tri(Ci-C3 alkanol)ammonium, e.g., triethanolammonium, di(Ci- C3 alkanol)ammonium and ammonium cations.
• concentration of anionic surfactant in the formulation is from about 0.005 to 0.1 g/L, or 0.005 to 0.05 g/L.
• the surfactant is a cationic surfactant.
• Non-limiting examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, acyl aminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl
• imidazolines 1-acyl aminoethyl - 2-alkyl imidazoline, 1 -hydroxy ethyl-2-alkyl imidazoline, include chi orhexi dine or the like salts thereof, chi orhexi dine or a salt thereof, e.g., chlorhexidine gluconate.
• the cationic surfactant is present in the formulation in an amount of from about 0.001 to about 5 % w/v, or about 0.001 to about 1% w/v, or about 0.001 to about 0.1% w/v, or about 0.001 to about 0.01% w/v, or about 0.001 to about 0.005% w/v.
• the surfactant is a non-ionic surfactant.
• the non-ionic surfactant is a polysorbate surfactant, a block copolymer of ethylene oxide and propylene oxide surfactant (e.g., a pluronic or tetronic surfactant), poloxamer, tyloxapol, or combinations thereof.
• Tyloxapol is a nonionic liquid polymer of the alkyl aryl polyether alcohol type. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)).
• the non-ionic surfactant is tyloxapol.
• the tyloxapol is present in an amount at least about 0.001% w/v, at least about 0.01% w/v, at least about 0.02% w/v, at least about 0.03% w/v, at least about 0.04% w/v, and no more than about 1% w/v, no more than about 0.5% w/v, no more than about 0.3% w/v, or no more than about 0.2% w/v, no more than about 0.1% w/v, or no more than about 0.08% w/v.
• the non-ionic surfactant is tyloxapol, present in an amount of about 0.03% w/v to 0.08% w/v, or about 0.05% w/v.
• the formulations include about 15-20% w/v of a poloxamer surfactant. In some embodiments, the formulations include about 15, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, or about 20% w/v of poloxamer. In particular embodiments, the formulations include about 17.5% w/v poloxamer. In yet particular embodiments, the poloxamer is Poloxamer 407. In particular embodiments, the surfactant is substantially all tyloxapol.
• the formulations include a suspending agent.
• the suspending agent is a carbomer, hydroxypropyl methyl cellulose
• Carbomers are carboxyvinyl polymers that have a network of cross-linked polymer chains. The polymers are often characterized as having carboxylic acid functional groups and may contain from 2 to 7 carbon atoms per functional group.
• Carbomers i.e. synthetic high-molecular-weight polymers of acrylic acid that are crosslinked e.g. with allyl sucrose or allyl ethers of pentaerythritol, particularly water-soluble and water-swellable carbomers.
• Carbomers are available under the trade name CARBOPOL ® from various suppliers In particular embodiments, the carbomer is carbomer homopolymer Type B.
• the carbomer is CARBOPOL ® 934P (Carbomer 934P), 940 or 974P.
• the suspending agent is carbomer and is present in the formulation in an amount of at least about 0.05% w/v, at least about 0.1% w/v, or at least about 0.2% w/v, and no greater than about 1.0% w/v, no greater than about 0.6% w/v, or no greater than about 0.5%.
• the suspending agent is carbomer, and is present in the formulation in an amount of 0.1% w/v to about 0.3% w/v, or about 0.2% w/v.
• the suspending agent is hydroxypropyl methyl cellulose.
• the hydroxypropyl methyl cellulose is present in the formulation in an amount of at least about 0.05% w/v, at least about 0.1% w/v, or at least about 0.25% w/v, and less than about 1.8% w/v, less than about 1.0% w/v, less than about 0.8% w/v, or less than about 0.6% w/v.
• the hydroxypropyl methyl cellulose is present in the formulation in an amount of from about 0.1% w/v to about 0.8 w/v %; from about 0.1% w/v to about 0.6% w/v; from about 0.25% w/v to about 0.8% w/v; from about 0.4% w/v to about 0.6% w/v.
• the suspending agent is a polyethylene glycol (PEG) having molecular weight of at least about 200 Da. In some embodiments, the PEG has a molecular weight of at least about 400, 1,000, 2,000, 3,000, 4,000, 6,000, or about 10,000 Da. In some embodiments, the suspending agent is a polyethylene glycol (PEG) having molecular weight of from about 200 to about 20,000 Da. In some embodiments, the PEG has a molecular weight of about 400, 1,000, 2,000, 3,000, 4,000, 6,000, or about 10,000 Da.
• the PEG is present in the formulation in an amount of at least 1% w/v, at least about 2% w/v, at least about 3% w/v, and less than about 10% w/v, less than about 9% w/v, or less than about 8% w/v.
• the suspending agent is PEG400 at a concentration of from about 4% w/v to about 9% w/v, about 5% w/v to about 8% w/v, or about 7% w/v.
• the suspending agent is PEG6000 at a
• concentration of from about 1% w/v to about 4% w/v, about 1% w/v to about 3% w/v, or about 2% w/v.
• the suspending agent is a combination of more than one suspending agent. In other embodiments, the suspending agent is substantially all carbomer.
• the suspending agent can provide the desired viscosity of the formulation. Without being bound by theory, it is believed that the appropriate viscosity is beneficial in maintaining compound I in a suspended state in the formulation without settling and caking.
• the formulation viscosity is from about 10 to about 200 cP (centipoise), from about 20 cP to about 200 cP, or from about 20 cP to about 150 cP. In some embodiments, the formulation viscosity is at least about 10 cP, 20 cP, 50 cP, 100 cP, or at least about 150 cP. Viscosity measurements for the formulations are measured using a Brookfield viscometer using spindle CP-42 at either 3 rpm or 60 rpm. Viscosity is typically measured at room temperature, i.e., 25 °C.
• the formulation includes a tonicity agent. In some embodiments, the formulation includes a tonicity agent.
• the tonicity agent is a polyol.
• polyol includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in trans configuration relative to each other.
• the polyols can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, so long as the resultant complex is water soluble and pharmaceutically acceptable. Examples of such compounds include: sugars, sugar alcohols, sugar acids and uronic acids.
• the tonicity agent is a polyol such as sugars, sugar alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol, sorbitol and propylene glycol, or combinations thereof.
• the composition includes mannitol, glycerin or a combination thereof.
• the amount of polyol in the formulation is from about 0.05% w/v to about 10% w/v, from about 0.1% to about 8% w/v, from about 0.1% to about 7% w/v, from about 0.1% to about 5% w/v.
• the tonicity agent is mannitol or glycerin, which is present in the formulation in an amount of from 0.1% w/v to about 5% w/v, or about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 1% w/v, about 2% w/v, about 2.5% w/v, about 3.0% w/v, about 3.5% w/v, about 4.0% w/v, about 4.5% w/v, or about 5% w/v.
• the tonicity agent is mannitol.
• the tonicity agent is glycerin.
• the formulation includes a buffer.
• buffer substances include acetate, ascorbate, borate, hydrogen carbonate, carbonate, citrate, edetate (EDTA) gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffers.
• the buffer is a phosphate buffering system.
• the buffer is a tromethamine buffer.
• the amount of buffer substance added is, typically, that necessary to ensure and maintain a physiologically tolerable pH range.
• the pH range is in the range of from about 4 to about 9, from about 4.5 to about 8.5, from about 5.0 to about 8.0, from about 5.5 to about 8.0, from about 6.4 to about
• the pH is about 6.0. In particular embodiments, the pH is about
• the formulation includes a salt.
• salt is sodium chloride, potassium chloride, calcium chloride, or magnesium chloride.
• the salt is sodium chloride.
• the salt is present in an amount of at least about 0.01% w/v, at least about 0.02% w/v, at least about 0.03% w/v, at least about 0.04% w/v, and no more than about 0.5% w/v, no more than about 0.4% w/v, no more than about 0.3% w/v, no more than about 0.2% w/v, or no more than about 0.1% w/v.
• the salt is present in an amount of from about 0.01 % w/v to about 0.5% w/v, from about 0.02% w/v to about 0.4% w/v, from about 0.03% w/v to about 0.3% w/v, from about 0.04% w/v to about 0.2% w/v, from about 0.05% w/v to about 0.1% w/v.
• the salt is sodium chloride and is present in the formulation in an amount of about 0.02% to about 0.07% w/v, or about 0.05% w/v.
• the formulations described herein have an osmolality of about 200 to about 450 milliosmoles per kilogram (mOsm/kg), about 200 to about 400 mOsm/kg, about 200 to about 300 mOsm/kg, or about 240 to about 360 mOsm/kg.
• the formulation may also be self-preserved and does not include a preservative.
• the formulation includes a preservative.
• the preservative includes, without limitation, polyhexylmethylene biguanidine (PHMB), polymeric quaternary ammonium compound (e.g., polyquaternium-1), chlorine containing preservatives such as benzalkonium chloride (BAK), chlorite
• the preservative is polymeric quaternary ammonium
• polymeric ammonium compound is polyquatemium 1, otherwise known as POLYQUAD® or
• ONAMERM® with a number average molecular weight between 2,000 to 30,000.
• the number average molecular weight is between 3,000 to 14,000.
• the polymeric quaternary ammonium compound When used, the polymeric quaternary ammonium compound is generally used in an amount that is greater than about 0.00001 w/v %, greater than about 0.0003 w/v %, or greater than about 0.0007 w/v % of the formulation. Moreover, the polymeric quaternary ammonium compound, when used in the formulation, is generally used at a concentration that is less than about 0.03 w/v %, less than about 0.003 w/v %, or less than about 0.0015 w/v % of the formulation.
• the concentration of polymeric quaternary ammonium compound in the formulation are as follows: greater than about 0.0003 w/v% but less than about 0.003 w/v %; greater than about 0.0003 w/v % but less than about 0.0015 w/v %; greater than about 0.0007 w/v % but less than about 0.003 w/v %; and greater than about 0.0007 w/v % but less than about 0.0015 w/v %.
• the formulation includes polyquartemium 1 at a concentration of about 0.001% w/v.
• the formulation includes BAK at a concentration that is at least about 0.0005 w/v%, about 0.001 w/v %, or greater than about 0.007 w/v % of the
• any of the lower limits on the concentration of BAK may be used in conjunction with any of the upper limits on the concentrations of BAK.
• the concentration of BAK in the composition are as follows: greater than about 0.001 w/v% but less than about 0.02 w/v %; greater than about 0.001 w/v % but less than about 0.0035 w/v %; greater than about 0.007 w/v % but less than about 0.02 w/v %; and greater than about 0.007 w/v % but less than about 0.0035 w/v %.
• an aqueous formulation that includes: 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v, and one or more excipients selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative.
• an aqueous formulation that includes: 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, present as a suspension in the formulation, in an amount of about 0.5% w/v to about 3.5% w/v,
• a surfactant selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative.
• aqueous formulation that includes: 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, present as a suspension in the formulation,
• a surfactant selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative.
• aqueous formulation that includes: a suspension of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof,
• aqueous formulation that includes: 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v, present as a suspension in the formulation
• a tonicity agent a buffer, a preservative, a salt, and a preservative.
• the invention described herein is a formulation that includes: 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v, present as a suspension in the formulation,
• a preservative optionally, a preservative
• the invention described herein is a formulation that includes: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 3.5% w/v,
• the invention described herein is a formulation that includes: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v to about 2.5% w/v,
• non-ionic surfactant selected from tyloxapol, poloxamer, or combinations thereof in an amount of from about 0.01 to 0.2% w/v;
• a suspending agent selected from hydroxypropyl methyl cellulose, polyethylene glycol or carbomer homopolymer Type B;
• a tonicity agent selected from polyols in an amount of from about 0.05% w/v to about 10% w/v;
• a buffer selected from edetate, phosphate, borate, or combinations thereof;
• the invention described herein is a formulation that includes: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• non-ionic surfactant selected from tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v, poloxamer in an amount of about 0.005-0.12% w/v, or combinations thereof;
• a suspending agent selected from hydroxypropyl methyl cellulose in an amount of from about 0.1% w/v to about 0.8 w/v %, polyethylene glycol in an amount of from about 2% w/v to about 8% w/v, carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.5% w/v, or combinations thereof;
• a tonicity agent selected from mannitol or glycerin in an amount of from about 0.1% w/v to about 5% w/v;
• a buffer selected from edetate, phosphate, borate, tromethamine, or combinations thereof;
• sodium chloride in an amount of from 0.01% w/v to about 1% w/v;
• the invention described herein is a formulation that includes: a suspension of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof, in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v;
• carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.4% w/v;
• glycerin in an amount of from about 0.5% w/v to about 5% w/v;
• a buffer selected from edetate, phosphate, borate, tomethamine, or combinations thereof;
• sodium chloride in an amount of from 0.01% w/v to about 1% w/v;
• the invention described herein is a formulation that includes: a suspension of polymorphic form B of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H- quinazolin-3-yl)-benzonitrile (compound I), in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• tyloxapol in an amount of about 0.04 w/v to about 0.06% w/v;
• carbomer homopolymer Type B in an amount from about 0.05% w/v to about 0.4% w/v;
• glycerin in an amount of from about 0.5% w/v to about 5% w/v;
• a buffer selected from edetate, phosphate, borate, tomethamine, or combinations thereof;
• sodium chloride in an amount of from 0.01% w/v to about 1% w/v;
• the invention described herein is a formulation that includes: a suspension of polymorphic form B of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H- quinazolin-3-yl)-benzonitrile (compound I), in an amount of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, or about 2.5% w/v,
• acids or bases such as hydrochloric acid, sodium hydroxide, or combinations thereof are used to adjust pH of the formulation.
• hydrochloric acid is used to adjust pH to about 6.0, or about 7.4.
• the formulations described herein are aqueous, that is, they include at least about 90%, at least about 92%, or at least about 95% water.
• the present inventors also found that inclusion of a surfactant in the formulation acts as a wetting agent for the compound of formula I, thereby providing adequate wetting of the particles of compound I while decreasing the potential for irritation and foaming and aiding in redispersibility of the suspension.
• the formulations described herein further include additional components.
• the formulation includes a cyclodextrin derivative, for example, b-cyclodextrin derivative, g-cyclodextrin derivative or a combination thereof.
• the cyclodextrin is a hydroxypropyl b-cyclodextrin or
• the cyclodextrin derivative may be present in an amount of at least about 1.5 w/v%, at least about 3.0 w/v%, at least about 3.5 w/v% or at least about 4.5 w/v, but no greater than about 10.0 w/v%, no greater than about 8.0% w/v, no greater than about 6.5 w/v%, or no greater than about 5.5 w/v.
• the formulation includes about 5% w/v of either hydroxypropyl b-cyclodextrin or
• the formulations of the invention may include an additional therapeutic agent in addition to compound I.
• Further therapeutic agents may include, for instance, other compounds and antibodies useful for treating ocular surface disorders.
• a non limiting list of such agents incudes nonsteroidal anti-inflammatory drugs such as ketorolac, nepafenac, bromfenac, corticosteroids; drugs for dry eye disease such as cyclosprine, lifitegrast, or other TRPV1 inhibitors.
• the additional therapeutic agent is an ophthalmic steroid such as dexamethasone, fluocinolone, loteprednol,
• difluprednate difluprednate, fluorometholone, prednisolone, prednisone, medrysone, triamcinolone, betamethasone, rimexolone, or pharmaceutically acceptable salts thereof.
• additional therapeutic agents that may be included in the pharmaceutical composition include Xiidra® (lifitegrast), Restasis® (cyclosporine), minocycline, doxycycline, or other tetracycline antibiotics.
• Other examples include keratolytic agents such as selenium disulfide, salicylic acid, glycolic acid etc., or
• the formulation is stored at refrigerated temperatures (e.g., 4°C). In some embodiments, the formulation is warmed to room temperature prior to administration.
• the suspension is packaged in a single dose container. In some embodiments, the formulation is packaged in a multi-dose container.
• formulations described herein are delivered to the surface of the eye one to six times a day, depending on the routine discretion of the skilled clinician. In some
• the formulations are administered, one, two, three, or four times a day.
• the formulation exhibits settling of less than about 10% after storage at room temperature for six months. In some embodiments, the formulation exhibits settling of less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% after storage at room temperature for six months. Settling behavior is measured by methods commonly known to those of skill in the art, for example as described herein. In some embodiments, the amount of compound I in the formulation is at least 90% of the initial amount after about 6 months of storage under refrigeration (e.g., about 4 °C).
• the amount of compound I in the formulation is at least about 90% of the initial amount after about 8 months, about 10 months, about 12 months, about 15 months, or about 18 months of storage under refrigeration. In some embodiments, the amount of compound I in the formulation is at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least about 97% or at least about 98% of the initial amount after about 6 months of storage under refrigeration (e.g., about 4 °C).
• the amount of compound I in the formulation at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least about 97% or at least about 98% of the initial amount after about 18 months of storage under refrigeration.
• the amount of compound I in the formulation is measured using methods commonly known to those of skill in the art, for example, HPLC, LC/MS, etc.
• the formulation comprises no more than about 10% of a degradation product after 6 months under refrigeration, wherein the degradation product has a relative retention time of 1.23, compared to compound I, when analyzed by HPMC using a gradient 0.1 % trifluoroacetic acid (TFA) water/acetonitrile mobile phase.
• the formulation comprises no more than about 9%, no more than about 8%, no more than about 7%, no more than about 6%, no more than about 5%, no more than about 4%, no more than about 3%, or no more than about 2% of a degradation product after 6 months under refrigeration.
• no more than about 10% of compound I in the formulation degrades upon storage for 12 weeks at 40 °C. In particular embodiments, no more than about 9%, no more than about 8%, no more than about 7%, no more than about 6%, no more than about 6%, no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2% of compound I in the formulation degrades upon storage for 12 weeks at 40 °C.
• the pharmaceutical formulations of the invention may include an additional therapeutic agent in addition to Compound (I).
• Further therapeutic agents may include, for instance, other compounds and antibodies useful for treating ocular surface disorders.
• a non-limiting list of such agents incudes nonsteroidal anti-inflammatory drugs such as ketorolac, nepafenac, bromfenac, corticosteroids; drugs for dry eye disease such as cyclosporine, lifitegrast, or other TRPV1 inhibitors.
• the additional therapeutic agent is an ophthalmic steroid such as dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, prednisone, medrysone, triamcinolone, betamethasone, rimexolone, or pharmaceutically acceptable salts thereof.
• additional therapeutic agents that may be included in the pharmaceutical composition include Xiidra® (lifitegrast), Restasis® (cyclosporine), minocycline, doxycycline, or other tetracycline antibiotics.
• Other examples include keratolytic agents such as selenium disulfide, salicylic acid, glycolic acid etc., or pharmaceutically acceptable salts thereof.
• the formulation is prepared by mixing an amount of 4-(7- hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or a salt, co crystal, or polymorph thereof, and one or more excipients selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative.
• compound I 4-(7- hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile
• a salt co crystal, or polymorph thereof
• excipients selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative.
• the present invention provides a method of making the pharmaceutical formulations of compound I.
• the formulation is prepared by mixing an amount of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)- benzonitrile (compound I) or a salt, co-crystal, or polymorph thereof,
• adjusting the pH to a range of from about 5.5 to about 8.0.
• the compound I is added as a stock suspension in water, optionally with the surfactant. In some embodiments, the compound I is present in an amount of 10% in the stock suspension. In alternative or additional embodiments, the stock suspension of compound I further includes 0.2% tyloxapol. In some embodiments, the stock suspension of compound I is milled to achieve a desired particle size of compound I. In some embodiments, the D90 of compound I in the formulation (diameter at which 90% of compound I is comprised of smaller particles) is below about 10 pm, below about 8 pm, below about 6 pm, below about 4 pm, below about 3 pm, or about 2 pm.
• the D50 of compound I in the formulation is below about 10 pm, below about 8 pm, below about 6 pm, below about 4 pm, below about 3 pm, below about 2 pm, or about 1 pm.
• the Dio of compound I in the formulation is below about 5 pm, below about 4 pm, below about 3 pm, below about 2 pm, below about 1 pm, or about 0.3 pm.
• the non-ionic surfactant, the suspending agent, the tonicity agent, buffer, and salt are as noted supra.
• the formulation does not include a preservative.
• tonicity agent surfactant, and salt, and pH adjusted to final pH) to the bottle.
• TRPV1 Transient Receptor Potential Vanilloid 1
• the invention provides a method of treating ocular surface pain in a subject , said method includes administering to the subject an effective amount of compound (I), or a pharmaceutically acceptable salt, solvate, or co crystal thereof.
• the invention provides a method of reducing ocular surface pain in a subject in need thereof, said method includes administering to the subject an effective amount of compound (I), or a pharmaceutically acceptable salt, solvate, or co crystal thereof.
• the invention provides for the use of the compound of formula I, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, in the treatment or reduction of ocular surface pain.
• the compound of formula I is in polymorphic form B.
• the methods described herein are carried out by administering the formulations of compound I described supra.
• the invention provides a method of treating ocular surface pain by administering a formulation of compound I as described herein. In some embodiments, the method results in a reduction in ocular surface pain.
• the subject suffers from episodic or acute ocular pain. In some embodiments, the subject suffers from chronic ocular surface pain, which lasts for at least three months. In some embodiments, the subject suffers from chronic ocular surface pain, which lasts for at least two months. In some embodiments, the subject suffers from chronic ocular surface pain, which lasts for at least one month. In some embodiments, the subject suffers from chronic ocular surface pain, which lasts for at least four months. In some embodiments, the subject suffers from chronic ocular surface pain, which lasts for at least five months.
• the invention provides a method of treating chronic ocular surface pain in a subject by administering to the subject an effective amount of compound of formula I, or a salt, solvate, polymorph, or co-crystal thereof.
• the invention provides a method of reducing chronic ocular surface pain in a subject by administering to the subject an effective amount of compound of formula I, or a salt, solvate, polymorph, or co-crystal thereof.
• the invention provides for the use of the compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, or co crystal thereof, in the treatment of chronic ocular surface pain.
• the compound of formula I is in a formulation as described herein.
• the formulation is administered to the ocular surface of the subject, e.g., any part of the cornea, conjunctiva, or to the cul de sac of the eye.
• the invention provides for the administration of the compound of formula I to a subject in need thereof in a ophthalmically compatible formulation at a concentration of about 0.5% w/v to about 3.5% w/v.
• concentrations for administration range from about 0.5% to about 3.5% w/v, about 0.5% to about 2.5% w/v, about 0.5% to about 1.5% w/v, about 0.5% to about 3.0% w/v, about 1.0% to about 2.5% w/v, about 1.5% to about 3.0% w/v, about 0.5% to about 2.5% w/v.
• the concentration of the compound I in an ophthalmically compatible formulation is at least about 0.5% w/v, at least about 1.0% w/v, at least about 1.5% w/v, at least about 2.0% w/v, or at least about 2.5% w/v. In some embodiments, the concentration of the compound of formula I in a formulation for topical use is no more than about 5.0% w/v, no more than about 4.5% w/v, no more than about 4.0% w/v, no more than about 3.5% w/v, or no more than about 3.0 %w/v.
• the concentration of the compound of formula I in a formulation for topical use is about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, about 2.5% w/v, about 3.0% w/v, or about 3.5% w/v.
• the dose per administration per eye is from about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, or about 1.15 mg.
• the dose per administration per eye is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg.
• the total daily dose per eye is about 0.5 to about 3.5 mg, or about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 3.5 mg.
• the compound of formula I is administered to the subject one to six times a day, e.g., one, two, three, or four times a day.
• the compound of formula I is administered to the subject for a period of at least about one month, at least about two months, or at least about three months.
• the compound of formula I is administered to the subject for a period of at least about 12 weeks.
• the ocular surface pain or the chronic ocular surface pain is associated with one or more of dry eye disease, Sjogren’s Syndrome, conjunctivitis
• the subject suffers from ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery
• the ocular surface pain or the chronic ocular surface pain is associated with dry eye disease or Sjogren’s Syndrome.
• the subject suffers from conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membranes, conjunctival ulceration, superficial punctate epithelial erosions, epithelial defects, lid margin ulceration, lid margin keratinization, symblepharon,
• ankyloblepharon trichiasis, anterior blepharitis, punctal auto-occlusion, meibomian gland disease, corneal opacification, dry eye, districhiasis, limbal stem cell failure, or corneal vascularization.
• the administration of compound of formula I results in a reduction in the subject’s ocular pain, compared to a placebo.
• the reduction in the subjects ocular pain is at least about 3 when measured on the VAS score, compared to a placebo.
• the administration results in a reduction in the subject’s ocular pain of at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10, when measured on the VAS score, compared to a placebo.
• the administration results in a reduction in the subject’s pain of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to a placebo.
• the administration of the compound of formula I results in a reduction in the subject’s pain of at least about 2 compared to a placebo, as measured by the VAS score, about half hour after the administration, about one hour, about 2 hours, or about 2-4 hours after the administration. In some embodiments, the administration results in a reduction in the subject’s pain, when measured after 7 days of administration of the compound of formula I. In some embodiments, the administration results in a reduction in the subject’s pain, when measured after 14 days of administration of the compound of formula I.
• the reduction in pain score arises from the difference in pain scores prior to and after administration of compound I to the subject. In some embodiments, the reduction in pain score as measured by the VAS, arises from the difference in pain scores prior to and after administration of compound I to the subject. In some embodiments, the reduction in pain score occurs within about half hour after administration of compound I to the subject. In some embodiments, the reduction in pain score occurs within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours after
• the administration results in a reduction in the subject’s pain, when measured after 7 days of administration of the compound of formula I. In some embodiments, the administration results in a reduction in the subject’s pain, when measured after 14 days of administration of the compound of formula I.
• the administration of the compound of formula I results in an improved score on at least one question of the OPAS of at least about 10%, at least about 20%, or at least about 30%.
• the administration of the compound of formula I results in an improved score on at least one question of the Visual Tasking Questionnaire of at least about 10%, at least about 20%, or at least about 30%.
• the administration of the compound of formula I results in reduced ocular hyperemia (redness of the eye), compared to placebo.
• the administration of the compound of formula I results in reduced grade 1, grade 2, grade 3, or grade 4 hyperemia compared to placebo.
• the administration results in a reduction in ocular hyperemia score of at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5, on the McMonnies scale.
• the present invention relates to a method of treating or reducing ocular hyperemia in a subject in need thereof, comprising administering to the subject an effective amount of compound of formula I, or a salt, solvate, polymorph, or co crystal thereof.
• the invention provides for the use of the compound of formula I, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, in the treatment of ocular hyperemia.
• the administration results in a reduction in ocular hyperemia score of at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5, on the McMonnies scale.
• the invention provides for the administration of the compound of formula I to a subject in need thereof in a ophthalmically compatible formulation at a concentration of about 0.5% w/v to about 3.5% w/v.
• concentrations for administration range from about 0.5% to about 3.5% w/v, about 0.5% to about 2.5% w/v, about 0.5% to about 1.5% w/v, about 0.5% to about 3.0% w/v, about 1.0% to about 2.5% w/v, about 1.5% to about 3.0% w/v, about 0.5% to about 2.5% w/v.
• the concentration of the compound of formula I in a formulation for topical use is about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, about 2.5% w/v, about 3.0% w/v, or about 3.5% w/v.
• the dose per administration per eye is from about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, about 0.25 mg, 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, or about 1.15 mg.
• the dose per administration per eye is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg.
• the total daily dose per eye is about 0.5 to about 3.5 mg, or about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 3.5 mg.
• the compound of formula I is administered to the subject one to six times a day, e.g., one, two, three, or four times a day.
• the compound of formula I is administered to the subject for a period of at least about one month, at least about two months, or at least about three months.
• the compound of formula I is administered in a formulation described herein.
• the ocular hyperemia is associated with one or more of dry eye disease, Sjogren’s Syndrome, conjunctivitis (including keratoconjuctivitis, vernal
• keratoconjunctivitis keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis,
• corneal epitheliopathies corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), crizis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia,
• the ocular hyperemia persists for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.
• PRK photorefractive keratectomy
• LASIK laser-assisted in situ keratomileusis
• the ocular surface pain or chronic ocular surface pain is associated with dry eye disease.
• the administration of the compound of formula I results in a decrease in the symptoms of dry eye disease.
• Dry eye disease is generally understood to be a complex, multifactorial condition characterized by inflammation of the ocular surface and lacrimal glands and reductions in the quality and/or quantity of tears. It is believed that up to 30 % of dry eye disease patients suffer from ocular surface pain that may be chronic.
• the invention results in a decrease of at least about 10%, at least about 15%, at least about 20%, or at least about 30% in the symptoms of dry eye disease, including one or more of ocular dryness, ocular discomfort, ocular hyperemia, ocular burning or stinging, grittiness or foreign body sensation, or photophobia.
• the invention relates to a method of treating dry eye disease in a subject in need thereof, comprising administering to the subject an effective amount of compound of formula I, or a salt, solvate, polymorph, or co-crystal thereof.
• the invention relates to a method of treating dry eye disease in a subject in need thereof, comprising administering to the subject an effective amount of compound of formula I, or a salt, solvate, polymorph, or co-crystal thereof, wherein the compound of formulat I is safe for administration over a period of at least 2 months, at least 3 months, at least 4 months, or at least 5 months.
• the invention provides for the use of the compound of formula I, or a pharmaceutically acceptable salt, solvate, or co crystal thereof, in the treatment of dry eye disease.
• the invention results in a decrease of at least about 10% in the symptoms of dry eye disease, including one or more of ocular dryness, ocular discomfort, ocular hyperemia, ocular burning or stinging, grittiness or foreign body sensation, or photophobia.
• the invention provides for the administration of the compound of formula I to a subject in need thereof in a ophthalmically compatible formulation at a concentration of about 0.5% w/v to about 3.5% w/v.
• concentrations for administration range from about 0.5% to about 3.5% w/v, about 0.5% to about 2.5% w/v, about 0.5% to about 1.5% w/v, about 0.5% to about 3.0% w/v, about 1.0% to about 2.5% w/v, about 1.5% to about 3.0% w/v, about 0.5% to about 2.5% w/v.
• the concentration of the compound of formula I in a formulation for topical use is about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, about 2.5% w/v, about 3.0% w/v, or about 3.5% w/v.
• the dose per administration per eye is from about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, about 0.25 mg, 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, or about 1.15 mg.
• the dose per administration per eye is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg.
• the total daily dose per eye is about 0.5 to about 3.5 mg, or about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 3.5 mg.
• the compound of formula I is administered to the subject one to six times a day, e.g., one, two, three, or four times a day.
• the compound of formula I is administered to the subject for a period of at least about one month, at least about two months, or at least about three months.
• the compound of formula I is administered as a formulation described herein.
• the administration of the compound of formula I does not result in a change (e.g., of less than 5% difference, less than 4% difference, or less than 3% difference) in one or more of best corrected visual acuity, slit- lamp biomicroscopy, dilated eye exam, blink rate, tear production, intraocular pressure or corneal staining, compared to a placebo.
• the administration of compound of formula I does not result in a delay in wound healing compared to a placebo in a patient in need thereof.
• a subject to be treated by methods provided herein suffers from an ocular surface disorder.
• ocular surface disorders include chronic ocular surface pain (COSP), dry eye disease, Sjogren’s Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot- Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven- Johnson’s syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal
• corneal dystrophies including recurrent corneal dystrophies
• epithelial basement membrane dystrophy corneal erosions or abrasions (including recurrent corneal erosions or abrasions)
• ocular surface diseases blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), crizis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or patients recovering from neurotrophic keratitis.
• the subject suffers from ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.
• PRK photorefractive keratectomy
• LASIK laser-assisted in situ keratomileusis
• methods provided herein is for treating, or reducing, ocular surface pain, such as acute ocular surface pain.
• methods provided herein is for treating, or reducing, ocular surface pain, such as chronic ocular surface pain (COSP).
• COSP is characterized as persistent ocular surface pain (e.g., persistent severe ocular surface pain) that can distract from, or can interfere with, regular daily activities.
• COSP can result in poor quality of life, and can persist for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months.
• COSP can persist for at least about 2 months or at least about 3 months.
• COSP can persist for at least 3 months or at least 4 months.
• subject with COSP remain symptomatic despite adherence to other therapies indicated for their underlying disease (e.g., an ocular surface disorder such as dry eye disease or Sjogren’s Syndrome).
• ONP ocular neuropathic pain
• Symptoms of ONP may include one or more of eye pain, sensitivity to light, hyperalgesia or dysesthesia (abnormal sensations) such as a sensation of dryness, stinging, or foreign body, pain from normally non-painful stimuli (allodynia).
• Gabapentin and other neuropathic pain medications may be used to blunt sensory nerve stimulation or the perception of nerve stimulation.
• the subject to be treated suffers from exposure keratopathy.
• EK is damage to the cornea that occurs primarily from prolonged exposure of the ocular surface to the outside environment. EK can lead to ulceration, microbial keratitis, and permanent vision loss from scarring. Patients at risk for EK include those who suffer from conditions that interfere with the ability to protect the cornea; either by incomplete eyelid closure (e.g., lagophthalmos, proptosis, lid malposition), inadequate blink reflex, inadequate blink rate (for example, caused by a neurologic disease, e.g., Parkinson disease, a
• Keratoconjuctivitis is an inflammatory process that involves both the conjunctiva and the cornea.
• Superficial inflammation of the cornea occurs commonly in association with viral and bacterial conjunctivitis, for example in adults.
• the following types of keratoconjuctivitis are distinguished based on the potential cause of inflammation:
• Keratoconjunctivitis sicca is cause by the inflammation due to dryness
• VKC Vernal keratoconjunctivitis
• Atopic keratoconjunctivitis is one manifestation of atopy
• IBK Infectious bovine keratoconjunctivitis
• Keratoconjunctivitis photoelectrica means inflammation caused by
• the subject to be treated suffers from dry eye.
• dry eye refers to inadequate tear production and/or abnormal tear composition.
• Dry eye syndrome disease also known as dry eye syndrome, keratoconjunctivitis sicca or keratitis sicca, or tear dysfunction syndrome, or burning eye syndrome results from deficiency of any of the tear film layers.
• Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear 'film instability with potential damage to the ocular surfaceocular surface characterized by loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammatoin and damage, and neuro-sensory abnormalities play etiological roles (Craig JP, et al, The Ocular Surface 2017;15:276-83). It may be accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Dry eye disorder may range from mild to moderate to severe forms.
• Symptoms of dry eye syndrome disease include gritty, foreign body sensations, burning, photophobia, and decreased visual acuity, tearing, stinging, itching, sandy or gritty feeling, discharge, frequent blinking, mattering or caking of the eyelashes (usually worse upon waking), redness, blurry or fluctuating vision (made worse when reading, computer, watching television, driving, or playing video games), light-sensitivity, eye pain and/or headache, heavy eye lids, eye fatigue.
• causes of dry eye disease include, but are not limited to, the following: idiopathic, congenital alacrima, xerophthalmia, lacrimal gland ablation, and sensory denervation; collagen vascular diseases, including rheumatoid arthritis, Wegener's granulomatosis, and systemic lupus erythematosus; Sjogren's Syndrome and autoimmune diseases associated with Sjogren's syndrome; abnormalities of the lipid tear layer caused by blepharitis or rosacea; abnormalities of the mucin tear layer caused by vitamin A deficiency; trachoma, diphtheric
• keratoconjunctivitis mucocutaneous disorders; aging; menopause; and diabetes.
• Dry eye signs and/or symptoms as defined herein may also be provoked by other circumstances, including but not limited to the following: prolonged visual tasking; working on a computer; being in a dry environment; warm or cold wind or air flow; seasonal changes; ocular irritation; contact lenses, LASIK and other refractive surgeries; fatigue; and medications such as isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atropine, and pain relieving opiates such as morphine.
• Diagnostic testing for dry eye includes evaluation of cornea sensation (corneal hyperesthesia and/or reduced sensation may be present in severe and chronic dry eye disease) using, for example, a cotton tip applicator or more precisely with a Cochet-Bonnet esthesiometer; measuring tear break up time using, for example, a fluorescein-impregnated strip wet with non-preserved saline solution or more objective computerized methods without the need for fluorescein instillation; performing oculr surface staining, e.g., fluorescein sodium, rose bengal, lissamine green; performing Schirmer test (relatively insensitive for patients with mild dry eye), testing delayed tear clearance; tear meniscus height; measuring level of MMP-9 (MMP-9 has been shown to be elevated in the tears of patient with dry eye disease, and levels correlate with examination findings in patients with moderate to severe dry eye); measuring tear osmolarity and tear film interferometry; performing Sjo test
• SP-1 salivary gland protein 1
• CA6 carbonic anhydrase 6
• PSP parotid secretory protein
• cyclosporine lifitegrast, diquafosol, rebamepide, corticosteroids (e.g., loteprednol 0.5% eyedrops four times a day).
• tear film dysfunction refers to a state when the tear film breaks down in different places on the cornea and conjunctiva, leading not only to symptoms of irritation, but also to unstable and intermittently changing vision.
• dry eye syndrome disease is characterized by tear film dysfunction.
• the symptoms of tear film dysfunction include tearing, burning, stinging, itching, sandy or gritty feeling, scratchy or foreign-body sensation, discharge, frequent blinking, mattering or caking of the eyelashes (usually worse upon waking), redness, blurry or fluctuating vision (made worse when reading, computer, watching television, driving, or playing video games), light-sensitivity, eye pain and/or headache, heavy eye lids, eye fatigue.
• Adenoviral keratoconjunctivitis also known as Keratoconjunctivitis epidemica is a common and highly contagious viral infection of the eye.
• the clinical course of Adenoviral keratoconjunctivitis is divided into an acute phase with conjunctival inflammation of varying intensity with or without corneal involvement and a chronic phase with corneal opacities.
• Vernal keratoconjunctivitis is an atopic condition of the external ocular surface characterized by symptoms consisting of severe itching, photophobia, foreign body sensation, mucous discharge (often described as“ropy”), blepharospasm, and blurring of vision ( Buckley , R.J., Int Ophthalmol Clin, 1988 28(4): p. 303-8; Kumar, S., Acta
• Ophthalmologica 2009. 87(2): p. 133-147. It is typically bilateral but may be asymmetric in nature. It characteristically affects young males in hot dry climates in a seasonal manner; in 23% of patients may have a perennial form (Kumar, S., Acta Ophthalmologica, 2009. 87(2): p. 133-147; Bonini, S., et al, Ophthalmology, 2000. 107(6): p. 1157-63).
• VKC conjunctival, limbal and corneal signs
• Conjunctival signs include diffuse conjunctival injection and upper tarsal giant
• Limbal signs include thickening and opacification of the limbal conjunctiva as well as gelatinous appearing and sometime confluent limbal papillae.
• Peri-limbal Horner- Trantas dots are focal white limbal dots consisting of degenerated epithelial cells and eosinophils (Buckley, R.J., Int Ophthalmol Clin, 1988. 28(4): p. 303-8);
• Corneal signs vary according to the severity of the disease process and include macro erosions, comal ulcers and scars (Buckley, R.J., Int Ophthalmol Clin, 1988. 28(4): p. 303-8).
• Active VKC patients (defined as moderate to severe ocular discomfort including photophobia, papillae on the upper tarsal conjunctiva, or limbal Horner-Trantas dots clearly recognizable at the time of the examination) showed significantly increased symptoms and signs of ocular surface disease.
• Inactive VKC patients (defined as no symptoms or mild discomfort, and absence of corneal abnormalities at the time of the examination) showed increased photophobia, conjunctival lissamine green staining and Schirmer test values, and reduced fluorescein break-up time (BUT) and corneal sensitivity.
• VKC VKC
• IgE IgE mediate reaction via mast cell release
• activated eosinophils, mononuclear cells and neutrophils as well as the CD4 T-helper-2 driven type IV hypersensitivity with immunomodulators such as IL-4, IL-5, and bFGF
• immunomodulators such as IL-4, IL-5, and bFGF
• Treatment consists of cool compresses and lid scrubs, saline eyedrops, which may help to relieve symptoms, along with topical antihistamines, nonsteroidal anti-inflammatory drugs or corticosteroids, e.g., low-absorptions corticosteroids (fluoromethelone, loteprednol, remexolone, etc.), opical mast cell stabilizers (cromolyn sodium, nedocromil sodium, and lodoxamide), topical cyclosporin-A, or tacrolimus.
• corticosteroids e.g., low-absorptions corticosteroids (fluoromethelone, loteprednol, remexolone, etc.), opical mast cell stabilizers (cromolyn sodium, nedocromil sodium, and lodoxamide), topical cyclosporin-A, or tacrolimus.
• corticosteroids e.g., low-absorption
• Atopic keratoconjunctivitis typically has an older age of onset in the 2nd to 5th decade, as opposed to onset prior to age 10 with VKC. Conjunctival involvement is classically on the upper tarsus in VKC and on the lower tarsus in AKC. AKC is typically more chronic in nature and more commonly results in scarring of the cornea and conjunctival cicatrization.
• Sjogren’s Syndrome is a chronic inflammatory disorder characterized by exocrine gland dysfunction including the salivary and lacrimal glands that in many cases results in a severe dry eye.
• Primary symptoms are dry eyes (keratitis sicca or keratoconjunctivitis sicca) and dry mouth (xerostomia). Severe dry eyes can cause corneal pain, corneal scarring, ulceration, infection, and even perforation.
• the differential diagnosis includes conditions such as adult blepharitis, dry eye disease, and juvenile idiopathic arthritis uveitis, as well keratopathies, e.g., superficial punctate, filamentary, neurotrophic, exposure).
• Treatment of Sjogren’s syndrome is aimed at maintaining the integrity of the tear film through preservation, augmentation, and/or replacement of the deficient tear secretion.
• Treatment of Sjogren’s syndrome thus includes artificial tears and lubricating ointments; autologous serum eyedrops; oral omega-6 essential fatty acids; fluid-ventilated, gas permeable scleral lenses; topical corticosteroids; punctal occlusion to decrease tear drainage; a small lateral tarsorrhaphy; humidification of the environment; hydrophilic bandage lenses; bromhexine and 3-isobutyl 1-methylxanthine (IB MX) (augmentation of tear production/secretion); agents to stimulate muscarinic receptors (pilocarpine and cevimeline); immunosuppressive agents, e.g., methotrexate, antimalarials, cyclophosphamide, leflunomide, or tumor necrosis factor (TNF), e.g., inflix
• SJS Steven- Johnson’s syndrome
• the constellation of high fever (>102.2), malaise, arthralgia, a macular rash involving the trunk, neck and face, and recent history of new medication exposure or recently increased dosage of an existing medication are indicators used for diagnosis of SJS.
• a skin biopsy of an effected area can be performed for a confirmation of the diagnosis.
• Granulysin can be used as a marker for the diagnosis of SJS.
• the concentration of granulysin within bullous fluid correlates with the severity of the acute phase of SJS (Chung WH, et al. Nat Med.
• Ocular manifestations in SJS include conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membranes, conjunctival ulceration, superficial punctate epithelial erosions, epithelial defects, lid margin ulceration, lid margin
• Eye treatment in SJS consists of saline eyedrops, preservative-free artificial tears and ointments to provide adequate lubrication and reduce epithelial injury. Patients with any corneal or conjunctival epithelial defects are treated with prophylactic topical antibiotics, e.g., a fourth generation fluoroquinolone.
• Patients having mild or moderate ocular involvement are typically treated with topical moxifloxacin 0.5% four times a day, cyclosporine 0.05% twice daily, and topical steroids (prednisolone acetate 1% four to eight times a day or
• dexamethasone 0.1% twice daily Patients having severe or extremely severe ocular involvement (greater than one-third lid margin involvement, conjunctival defects greater than 1 cm, and corneal epithelial defects) undergo an amniotic membrane (AM) grafting in addition to the treatments listed above.
• AM amniotic membrane
• Corneal epitheliopathy is a disease involving corneal epithelium, e.g., manifested in altered corneal epithelial barrier function.
• the subject to be treated suffers from corneal neuropathy or corneal neuralgia.
• Corneal neuropathy or corneal neuralgia is a disorder associated with corneal pain caused by the damaged nerve fibers in the cornea, the sensory fibers.
• One of the examples of corneal neuropathy is a LASIK induced corneal neuropathy.
• Corneal neuropathy generally could be identified and diagnosed through dry eye investigations. Though the causes and risk factors are unclear yet, patients with dry eye-like symptoms, increased corneal sensitivity and changes of corneal nerve morphology, but no signs of dryness may suffer from corneal neuropathy.
• the subject to be treated suffers from ocular surface disease or disorder.
• ocular surface diseases or“ocular surface disorders” encompasses disease entities as well as related symptoms that result from a variety of abnormalities, including abnormal lid anatomy or function, abnormal or altered tear production or composition, and related subclinical signs. Many diseases can cause ocular surface disorders. Patients with ccular surface disorders may exhibit clinical signs common to several diseases, and include chronic punctate keratopathy, filamentary keratopathy, recurrent corneal erosion, bacterial conjunctivitis, culture-negative conjunctivitis, cicatrising (scarring) conjunctivitis, persistent epithelial defect, infectious keratitis, corneal melt and ocular surface failure.
• the most common ocular surface disorders stem from tear-film abnormalities and/or lid-gland dysfuntion (“blepharitis”).
• the subject to be treated suffers from neurotrophic keratitis or neurotrophic keratopathy.
• Neurotrophic keratitis or neurootrophic keratopathy is a corneal degenerative disease characterized by a reduction or absence of corneal sensitivity.
• NK is usually graded in three different stages in accordance to the“Mackie classification”.
• Stage II NK is defined by a recurrent or persistent epithelial defects, most commonly in the superior half of the cornea.
• One of the treatments that may be used in Stage II NK includes topical Nerve Growth Factor. Patients typically experience pain during treatment with NGF due to reforming of the nerves.
• the subject to be treated suffers from blepharitis.
• Blepharitis is an inflammatory condition of the eyelid margin, which can lead to permanent alterations in the eyelid margin or vision loss from superficial keratopathy, corneal neovascularization, and ulceration.
• blepharitis can be divided into anterior and posterior.
• Anterior blepharitis affects the eyelid skin, base of the eyelashes, and the eyelash follicles and includes the traditional classifications of staphylococcal and seborrheic blepharitis.
• Posterior blepharitis affects the meibomian glands and gland orifices, the primary cause being meibomian gland dysfunction.
• Treatment includes topical or systemic antibiotics e.g., bacitracin or erythromycin; oral antibiotics, e.g., tetracyclines (tetracycline, doxycycline, minocycline) or macrolides (erythromycin, azithromycin); topical steroids, e.g., corticosteroid, e.g., loteprednol etabonate, fluorometholone; topical combinations of an antibiotic and
• corticosteroid such as tobramycin/dexamethasone or tobramycin/loteprednol; topical cyclosporine 0.05%.
• the subject to be treated suffers from Meibomian gland dysfunction.
• the meibomian gland is a holocrine type of exocrine gland, at the rim of the eyelid inside the tarsal plate, responsible for the supply of meibum, an oily substance that prevents evaporation of the eye's tear film.
• Meibomian gland dysfunction also known as meibomitis, posterior blepharitis or inflammation of the meibomian glands, is a chronic, diffuse abnormality of the meibomian glands, commonly characterized by terminal duct obstruction and/or qualitative/ quantitative changes in the glandular secretion (.
• IPL Intense pulsed light
• the subject to be treated suffers from graft-versus-host disease.
• Graft-versus-host disease is an inflammatory disease that is unique to allogeneic transplantation. It is an attack by transplanted leukocytes against the recipient's tissues that can occur even if the donor and recipient are HLA-identical.
• Acute graft-versus-host disease typically occurs in the first 3 months after transplantation and may involve the skin, intestine, or the liver.
• Corticosteroids such as prednisone are a standard treatment.
• Chronic graft- versus-host disease may also develop after allogeneic transplant and is the major source of late complications. In addition to inflammation, chronic graft-versus-host disease may lead to the development of fibrosis, or scar tissue, similar to scleroderma or other autoimmune diseases and may cause functional disability, and the need for prolonged immunosuppressive therapy.
• the subject to be treated suffers from ocular graft versus host disease.
• GVHD occurs in patients who have undergone allogenic hematological stem cell transplantation. It can occur in patients who have acute or chronic GVHD, though it is more common in patients with the chronic form. Approximately 40-90% of patients with chronic GVHD will develop ocular symptoms. Ocular manifestations can include moderate to severe keratoconjuncitvitis sicca, bilateral marginal keratitis, anterior uveitis, corneal ulceration or neovascularization.
• Treatment includes topical lubricants including preservative free artificial tears, autologous serum tears and other topical and systemic immunosuppressive treatments; systemic steroids; topical cyclosporine 0.5%.
• the X-ray powder diffraction (XRPD) patterns described herein were recorded on a Bruker D8 Advance diffractometer using CuK a radiation.
• the XRPD pattern was recorded between 2° and 40° (2 -theta).
• an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
• intensities in a X-ray diffraction pattern may fluctuate depending upon measurement conditions employed.
• relative intensities may also vary depending upon experimental conditions and wavelength of X-ray radiation used. The agreement in the 2-theta-diffraction angles between specimen and reference is within 0.2° for the same crystal form and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
• crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal forms that provide X- ray diffraction patterns substantially identical to those disclosed in the accompanying Figures fall within the scope of the present invention.
• the ability to ascertain substantial identities of X-ray diffraction patterns is within the purview of one of ordinary skill in the art. Thermogravimetric method
• the TGA instalments used to test the crystalline forms was a Metter TGA851e TGA850. Samples of 10 to 20 milligrams were analyzed at a heating rate of 20°C per minute in the temperature range between 30°C and about 300°C.
• the DSC instrument used to test the crystalline forms was a Mettler DSC822e or a Perkin Elmer DSC7.
• the DSC cell/sample chamber was purged with 20-50 ml/min of ultra- high purity nitrogen gas.
• the instrument was calibrated with high purity indium.
• the sample was placed into an open aluminum DSC pan and measured against an empty reference pan.
• About 1-3 mg of sample powder was placed into the bottom of the pan and lightly tapped down to make contact with the pan.
• the weight of the sample was measured accurately and recorded to a hundredth of a milligram.
• the instrument was programmed to heat at 10°C per minute in the temperature range between 30°C and 300°C.
• Crystal form A was obtained by converting the hydrochloride salt of compound I to free base. The final crystallization was done by cooling from hot methanol to 0°C, where the compound crystallized as crystal form A.
• the differential scanning calorimetry curve of crystal form A showed a small endothermic event at about 264°C followed by melting at about 269°C.
• Figure 1 shows the superposition of the simulated and actual X-ray diffraction patterns of crystal form A.
• the X-ray powder diffraction pattern of crystal form A is shown in Figure 2 and the peak listing is as shown in Table 1.
• the single crystal data for crystal form A of compound I is as follows:
• Crystal form C was obtained by heating crystal form A in therm ogravimetric analyzer to about 250°C or by heating crystal form B for 80 minutes at 250°C. In a 1 :1 mixture with crystal form B, crystal form C converted in isopropanol to crystal form B. In a 1 : 1 mixture with crystal form A, crystal form C converted in methanol to Solvate SB (crystal form G).
• Figure 3 shows the superposition of the simulated and actual X-ray diffraction patterns of crystal form C.
• the X-ray powder diffraction pattern of crystal form C is shown in Figure 4 and the peak listing is as shown in Table 2.
• the lattice parameters for crystal form C is as follows:
• Crystal form E was found to be non-hygroscopic.
• the maximum water uptake is less than 0.1% at 25 °C up to 92% relative humidity.
• Crystal form E demonstrated a melting onset temperature of about 281°C, as measured by DSC. As seen in Table 4, crystal form E converts into crystal form B when equilibrated in ethanol. Solubility of crystal form E was measured at 25°C. Analysis was done by HPLC and the results are shown in Table 5. Table 5. Solubility and dissolution rate parameters of Crystal form E at 25 °C and 37 °C.
• Figure 5 shows the superposition of the simulated and actual X-ray diffraction patterns of crystal form E.
• the X-ray powder diffraction pattern of crystal form E is shown in Figure 6 and the peak listing is as shown in Table 6.
• the lattice parameters for crystal form E is as follows:
• Hydrate HA (crystal form F) was obtained by equilibration of a slurry of crystal form A or crystal form B in acetone/water (1 : 1) at 25°C.
• the DSC curve shows a broad endotherm at about 89°C due to evaporation of water, followed by several endothermic transitions above 264°C.
• Single crystal analysis confirmed the presence of one mole of water in the crystal structure (calculated water content is 5.6%).
• Methanol solvate SB crystal form G of compound I was obtained by equilibration of a slurry of crystal form A in methanol at 25°C. Single crystal structure analysis which was performed at 100K showed the presence of one mole of methanol. The solvents evaporates easily as TGA analysis of the samples showed only small amounts of residual solvents of up to 0.2% (calculated methanol content is 9.5% for a mono- solvate).
• Figure 8 shows the superposition of the simulated and actual X-ray diffraction patterns of crystal form G.
• the X-ray powder diffraction pattern of crystal form G is shown in Figure 9 and the peak listing is as shown in Table 8.
• the lattice parameters for crystal form G is as follows:
• Acetonitrile solvate SA (crystal form J) of compound I was obtained by equilibration a slurry of crystal form A in acetonitrile at 25°C. Single crystal analysis showed the presence of one mole of acetonitrile in the crystal structure (calculated acetonitrile content is 11.9%).
• the X-ray powder diffraction pattern of crystal form J is shown in Figure 10 and the peak listing is as shown in Table 9.
• the lattice parameters for crystal form J is as follows:
• Crystal form K was obtained by evaporation crystallization of compound I in acetone at 25°C. Specifically, crystal form A was dissolved in sufficient acetone at room temperature and the solvent was allowed to evaporate at ambient conditions to obtain crystal form K.
• the X-ray powder diffraction pattern of crystal form K is shown in Figure 11 and the peak listing is as shown in Table 9.
• the X-ray powder diffraction pattern of crystal form L is shown in Figure 12 and the peak listing is as shown in Table 11.
• Figure 14A and Figure 14B Results from the testing for compound I stability at room temperature and 40 °C are shown in Figure 14A and Figure 14B, respectively.
• the formulation with percent of compound I at about 70% of original at 12 weeks is the formulation of compound I as a solution.
• Figure 14B the formulation with percent of compound I at about 20% of original at 12 weeks is the formulation of compound I as a solution.
• compound I remains in stable form in the suspensions, without significant degradation even at 12 weeks at 40 °C.
• the part of compound I in solution in the supernatant degrades to about 20% of initial amount after 12 weeks at 40 °C.
• compound I was recovered from the four suspensions and evaluated for changes in crystalline form by x-ray powder diffraction.
• the x-ray diffraction patterns of compound I recovered from the 12-week stability samples and that of compound I stored at room temperature (control) are presented in Figure 15.
• compound I in each of the four exploratory formulations maintains its polymorphic form even after storage at room temperature or 40 °C for 12 weeks.
• the suspension FID 121744 (shown below in Table 17) and a 10% compound I slurry in 1% tyloxapol were subjected to heat sterilization 171 °C for 1 hour.
• the X-ray diffraction pattern of compound I after sterilization was identical to an untreated sample.
• the suspensions were evaluated visually for uniformity.
• Sodium chloride is known to reduce the viscosity of Carbomer- containing suspensions, so sodium chloride was added to aliquots of the remaining four suspensions to obtain a total of 28 suspensions with concentrations of 0.2, 0.3, 0.4 and 0.5% Carbomer and 0, 0.05, 0.1, 0.15, 0.2, 0.25 and 0.3% sodium chloride.
• a further set of unpreserved suspensions of compound I containing carbopol as a suspending agent were prepared for viscosity range finding and settling studies.
• the compositions, their viscosities and settling times of 10 ml of suspension after 6 months are shown in Table 17.
• the amount of compound I in the stability samples was tested at 0, 4, 7, and 11 days by high performance liquid chromatography (HPMC), using a Waters XBridge Shield RP18 Column (3.5 pm, 3.0 x 150 mm, 30 °C), using a gradient of mobile phase A 0.1% TFA in water and mobile phase B 0.1% TFA in acetonitrile, with an injection volume of 10 pi and a flow rate of 0.8 ml/min.
• HPMC high performance liquid chromatography
• RRT relative retention time
• Example 13 Stability of 2.5%, 1.5%, 0.5% and 1.5% ophthalmic
• the stability of a number of lots of compound I ophthalmic suspensions 0.15%, 0.5%, 1.5% and 2.5% (initial pH of 7.34-7.7) as described below in Table 29 were evaluated by monitoring the chemical, physical and microbiological stability characteristics of the product over time.
• the chemical stability was evaluated by monitoring compound I and its impurities.
• the physical stability was evaluated by monitoring the pH, osmolality, viscosity, appearance, identity by X-ray Powder Diffraction (XRPD), and particle size.
• XRPD X-ray Powder Diffraction
• microbiological stability was evaluated by conducting sterility tests. A summary of the results (in ranges from different lots and various sampling times over the testing period) from the tests and stability monitoring limits for compound I ophthalmic suspensions are presented in Table 24.
• viscosity was monitored and found to be within 10% of the initial visocity at each tested time point under each storage condition. Particle size measurements and sterility were also within stability monitoring limits.
• C max for the suspension with Poloxamer 407 was approximately 2 times the Cmax for the two suspensions with hypromellose and approximately 38 times the Cmax for the solution formulation.
• Cmax in the cornea ranged from approximately 500 to 1200 times the IC50 of 30 nM, while ranged from approximately 50 to 130
• C max and C min for compound I show that the highest exposures of compound I were in the cornea, with levels approximately 3 to 6 times the levels observed in the aqueous humor.
• C max for the 0.5% suspension was approximately 3 times that of the 0.05% suspension and approximately 16 times that of the 0.01% suspension.
• C max for the 0.5% suspension was approximately 3 times that of the 0.05% suspension and approximately 9 times that of the 0.01% suspension.
• C max in the cornea ranged from approximately 38 to 600 times the IC50 of 30 nM, while ranged from
• a toxicology wound healing study was conducted to evaluate corneal wound healing following QID bilateral topical ocular dosing of compound I after unilateral laser photorefractive keratectomy in rabbits with and without bandage contact lenses.
• the compound I formulations used in the study are described in Table 29.
• ketorolac tromethamine (ACULAR LS®) and dexamethasone (MAXIDEX®) formulations were used.
• MAXIDEX with bandage contact lenses vehicle without bandage contact lenses and for untreated corneas.
• the mean wound areas for the corneas treated with 0.5, 1.5 and 2.5% compound I suspensions with bandage contact lenses were comparable to those for the corneas treated with vehicle with bandage contact lenses and 2.5% compound I without bandage contact lenses.
• a series of five prototype sterile suspension formulations containing 0.5% compound I were prepared and screened for bacteriostasis/fungistasis with five compendial organisms: S. aureus , P. aeruginosa , E. coli , C. albicans and A. brasiliensis.
• the criterion for stasis was no more than 0.5 log increase in microbial counts (CFU/mL). All the tested formulations demonstrated an acceptable level of bacteriostasis/fungistasis .
• a 2.5% compound I suspension (otherwise identical to FID 121744), and suspension vehicle were also prepared and screened for bacteriostasis/fungistasis screening. Bacteriostasis/fungistasis was observed through 3 days with an inoculum of ⁇ 10 6 and/or an inoculum of ⁇ 10 5 .

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