CN116847841A

CN116847841A - Composition and storage method for stabilizing ophthalmic drug

Info

Publication number: CN116847841A
Application number: CN202180081410.1A
Authority: CN
Inventors: 杰拉尔德·霍恩
Original assignee: Lenz Therapeutics Inc
Current assignee: Lenz Therapeutics Inc
Priority date: 2020-10-13
Filing date: 2021-04-28
Publication date: 2023-10-03
Also published as: KR20230131822A; JP2023544918A; MX2023004298A; CA3195422A1; AU2021361731A1; EP4228636A1; WO2022081204A1

Abstract

The present invention relates to a method of stabilizing an ophthalmic drug, the method comprising: adding a surfactant and a viscosity enhancing agent to the ophthalmic drug to form a composition, wherein the composition has a viscosity of about 25 centipoise or less at 25 ℃ at a shear rate of 1/1000 per second and a viscosity of about 70 centipoise or more at 25 ℃ at a shear rate of 1 per second; filling the composition into a container; and storing the container at a temperature of about 2 ℃ to about 25 ℃. The invention also relates to a container prepared by the method of the invention.

Description

Composition and storage method for stabilizing ophthalmic drug

Background

Some ophthalmic drugs must be diluted prior to instillation or, if pre-formulated, have a limited shelf life or require refrigeration. Ophthalmic drugs that currently present stability problems include aceclidine, latanoprost-timolol, chloramphenicol, azithromycin, cyclopent-on, proteins, polypeptides, amino acids, and derivatives thereof.

Acaclidinium has been shown to be effective in treating glaucoma. Current aceclidine formulations require that aceclidine be lyophilized and mixed with a diluent prior to instillation. Acaclidinium has also been shown to treat presbyopia, an ocular condition that occurs in nearly everyone from around 40 years old. See U.S. patent No. 9089562;9314427;9320709;9833441;9844537;9968594;10052313;10064818;10307408;10617763 and 10959990.

Latanoprost has also been shown to be effective in treating glaucoma. Like aceclidine, latanoprost also requires refrigeration because of its limited shelf life at room temperature.

The instability of these ophthalmic drugs, including aceclidine and latanoprost, presents inconveniences to the subjects in need of these treatments and to the companies that manufacture, sell and package these drugs, reducing efficacy and increasing costs.

Thus, there is a need in the art for a method of stabilizing ophthalmic drugs in order to achieve an extended shelf life.

Disclosure of Invention

In certain other embodiments, the present invention relates to a method of stabilizing an ophthalmic drug, the method comprising the steps of:

a) Adding a surfactant and a viscosity enhancing agent to the ophthalmic drug to form a composition, wherein the composition has a viscosity of about 25 centipoise or less at 25 ℃ at a shear rate of 1/1000 per second and a viscosity of about 70 centipoise or more at 25 ℃ at a shear rate of 1 per second;

b) Filling the composition from step a) into a container; and

c) The container is stored at a temperature of about 2 ℃ to about 25 ℃, preferably about 2 to 8 ℃, and more preferably about 5 ℃.

In certain other embodiments, the ophthalmic drug is selected from the group consisting of aceclidine, latanoprost-timolol, chloramphenicol, azithromycin, cyclopentene, proteins, polypeptides, amino acids, salts thereof, derivatives thereof, and combinations thereof.

In certain other embodiments, the container of the present invention comprises a closure and a vessel, wherein a portion of the closure and a portion of the vessel are sealed with a leaching resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, preferably biaxially oriented polyethylene terephthalate.

In certain other embodiments, the container of the present invention is disposed in a second container formed from or lining a leaching resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, preferably biaxially oriented polyethylene terephthalate.

In certain other embodiments, the present invention relates to a method of stabilizing a composition comprising aceclidine, the method comprising: storing the composition in a container having a headspace at a temperature of about 22 ℃ to about 25 ℃, wherein the container comprises a closure and a vessel, wherein a portion of the closure and a portion of the vessel are sealed with a leaching resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil, and/or the container is disposed in a second container formed from or lined with biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

In certain other embodiments, the second container comprises a second closure, wherein the second closure provides an airtight seal.

In certain other embodiments, the hermetic seal is resealable.

In certain other embodiments, the ophthalmic drug is aceclidine, which is aceclidine at a concentration of about 0.25% to about 4.0% w/v.

In certain other embodiments, the methods of the invention provide an ophthalmic drug stability of at least 90% for at least 7 months, at least 8 months, at least 12 months, at least 15 months, at least 18 months, at least 20 months, or at least 22 months, or at least 24 months.

In certain other embodiments, the compositions of the present invention have a viscosity of about 0.5 centipoise or less at 25 ℃ at a shear rate of 1/1000 per second, and a viscosity of about 150 centipoise or more at 25 ℃ at a shear rate of 1 per second, preferably 300 centipoise or more at 25 ℃ at a shear rate of 1 per second.

In certain other embodiments, the compositions of the present invention have a viscosity of about 75 to about 1000 centipoise at a shear rate of 0.

In certain other embodiments, the present invention relates to a method of stabilizing a composition comprising aceclidine, hydroxypropyl methylcellulose, polysorbate 80, mannitol, sorbate salt, and an antioxidant selected from sodium ascorbate, sodium bisulfate, sodium metabisulfite (soidum metabisulfite), n-acetylcysteine, or a combination thereof, the method comprising: the composition is stored in a container having a headspace at a temperature of from about 2 ℃ to about 8 ℃, wherein the container is filled with the composition under a blanket of inert gas (preferably nitrogen) and the headspace is purged with inert gas, preferably nitrogen.

In certain other embodiments, the concentration of aceclidine is about 0.25% to about 4.00% w/v, the concentration of hydroxypropyl methylcellulose is about 0.75% to about 1.25% w/v, the concentration of polysorbate 80 is about 2% to about 4% w/v, the concentration of mannitol is about 2% to about 4% w/v, the concentration of sorbate is about 0.10% to about 0.12% w/v, and the concentration of antioxidant is about 0.10% to about 0.25% w/v.

In certain other embodiments, the present invention relates to a container comprising an ophthalmic drug, the process of making comprising the steps of:

a) Providing a container;

b) Filling the container with a composition comprising an ophthalmic drug, a surfactant, and a viscosity enhancing agent, preferably under an inert gas blanket, preferably nitrogen, wherein the composition has a viscosity of about 25 centipoise or less at 25 ℃ at a shear rate of 1/1000 per second, and a viscosity of about 70 centipoise or more at 25 ℃ at a shear rate of 1 per second;

c) Optionally, purging the headspace generated during filling step b) with an inert gas, preferably nitrogen;

d) Capping the container; and

e) Optionally, the container is stored at a temperature of about 2 to 25 ℃, preferably about 2 to 8 ℃, and more preferably about 5 ℃.

In certain other embodiments, the present invention relates to a method of stabilizing a composition comprising aceclidine, the method comprising storing the composition in a container having a headspace at a temperature of about 2 ℃ to about 8 ℃, preferably at about 5 ℃.

In certain other embodiments, the composition of the present invention is filled into the container under an inert gas blanket, preferably nitrogen, and the headspace is preferably purged with an inert gas blanket, preferably nitrogen.

In certain other embodiments, the present invention relates to a composition comprising from about 0.25% to about 4.0% w/v aceclidine, and one or more means of stabilizing the composition selected from the group consisting of filling the composition into a container under an inert gas blanket (preferably nitrogen), preferably purging the headspace created during filling with an inert gas blanket (preferably nitrogen) to provide the composition with a total viscosity of at least 50 centipoise or more, adding to the composition a preservative selected from the group consisting of sorbate, benzalkonium chloride (benzalkonim chloride), sodium ascorbate, sodium bisulfate, sodium metabisulfite, n-acetylcysteine, and combinations thereof,

Wherein the composition is stored at a temperature of about 2 to 8 ℃, and wherein w/v represents the weight to total volume ratio of the composition.

In certain other embodiments, the present invention relates to a method of treating presbyopia comprising administering to a subject in need thereof a composition of the present invention.

In certain other embodiments, the present invention relates to a method of treating refractive error of an eye of a subject in need thereof, the method comprising administering to the subject in need thereof a pharmaceutically acceptable amount of a composition of the present invention, wherein the refractive error of the eye is selected from presbyopia, myopia, hyperopia, astigmatism, or a combination thereof.

The present invention also relates to a method of reducing the pupil and, in turn, increasing the depth of field (i.e., depth of focus) of vision, comprising administering to a subject in need thereof a pharmaceutically effective amount of an ophthalmic pharmaceutical composition of the present invention.

The invention also relates to a method of reducing the side effects of administration of ophthalmic aceclidine by modulating the effect of an agonist on the ciliary body of the eye such that ciliary muscle cramps, supraorbital neuralgia caused by the ciliary muscle, and/or headache caused by the ciliary muscle are significantly reduced or eliminated.

The invention also relates to a method for allowing the physiological partial presbyopia correction of both eyes.

The invention also relates to a method of eliminating the need for monocular restriction due to distance blur or reducing myopia blur normally associated with pilocarpine or a combination of pilocarpine and an alpha agonist caused by treatment to mild hyperopia counteraction.

The invention also relates to a method of improving near vision by increasing accommodation without reducing presbyopic clarity. This is accomplished by simultaneously increasing the incremental accommodation that maintains the induction rate and overall accommodation while providing sufficient additional near vision enhancement so that the associated near vision blur does not break through the ability to simultaneously cause the pupil narrowing pinhole effect to affect the filtered refractive error and maintain distance sharpness.

The present invention also relates to a method of improving visual depth perception while improving near vision in bare eyes, the method comprising administering to both eyes (binocular vision) of a subject in need thereof a pharmaceutically effective amount of an ophthalmic composition of the present invention, wherein such binocular vision further enhances near vision beyond either eye.

The present invention also relates to a method of improving vision in a subject suffering from ametropia (vision abnormality), comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition of the present invention.

The present invention also relates to a method of improving vision in a subject suffering from ametropia, comprising administering to a subject in need thereof a pharmaceutically effective amount of a composition of the present invention, wherein the ametropia is selected from myopia, hyperopia, regular astigmatism, irregular astigmatism, and highly regular astigmatism.

The invention also relates to the elimination of optical aberrations caused by corneal irregularities, haze or extremely high regular astigmatism, including regions adjacent to or surrounding the central 1.5mm optical zone, thereby causing an improvement in visual acuity and vision quality by filtering out abnormal optics in those subject to irregular astigmatism or highly more regular astigmatism, such as occurs in conditions such as keratoconus, photodioptric keratomileusis-induced corneal haze, diffuse lamellar keratitis ("DLK") (DLK after excimer laser keratomileusis), other iatrogenic cornea-induced irregularities such as cataract incisions, glaucoma filtration blebs, implanted glaucoma valves, removed or non-removed corneal inlays, post-corneal surgical dilation (excimer laser keratomileusis), and secondary infections.

The invention also relates to an improvement in sensitivity over existing uncorrected Qu Guangbu. In light of this increased sensitivity, patients who now need toric contact lenses with reduced comfort for astigmatism and optics that can move during each blink may in many cases need only non-toric soft contact lenses or no contact lenses. Further, those patients who require gas permeable contact lenses may no longer require contact lenses or only require much more comfortable soft contact lenses. Patients with high astigmatism may now not need correction or need reduced astigmatism correction. Patients with low to moderate myopia may require less correction or no correction. Patients with low to moderate presbyopia (hyperopia) may not require correction or require reduced correction.

The present invention relates to methods and ophthalmic compositions for improving vision in the eye. In a preferred embodiment, the present invention relates to methods and ophthalmic compositions for treating presbyopia. In a more preferred embodiment, the present invention relates to an ophthalmic composition comprising aceclidine.

The present invention relates to a method of treating irregular astigmatism, keratoconus and low-grade myopia or hyperopia with or without astigmatism, comprising administering to a subject in need thereof an ophthalmic composition of the present invention.

The present invention also relates to a method of stabilizing aceclidine comprising providing in a first chamber a first composition comprising about 1.75% w/v aceclidine and about 2.5% w/v mannitol, and providing in a second chamber a second composition comprising about 0.01% w/v topiramate, about 4.0% w/v polysorbate 80, about 1.25% w/v hydroxypropyl methylcellulose, about 0.10% to 0.12% w/v sorbic acid, about 0.1% w/v ethylenediamine tetraacetic acid dihydrate, about 0.02% w/v benzalkonium chloride, and optionally about 0.1% w/v sodium citrate or citrate buffer, wherein the efficacy of aceclidine remains for at least one month upon mixing the first and second compositions.

The invention also relates to a method of stabilizing aceclidine comprising storing the composition of the invention at 0 ℃ to 8 ℃.

Drawings

Fig. 1 is a graphical representation of the effect of pilocarpine and aceclidine with or without topicamine and with or without a carrier on near and far vision in patients over 45 years of age.

Fig. 2 is a graphical representation of the effect of adding nonionic surfactant and viscosity agent on near visual acuity and duration of action. Line-hours represent the duration of the improved effect of the line.

FIG. 3 is a graphical representation of the efficacy index of formulations #L33#L94. The color of the square indicates comfort level, white is good, cross-hatching is general, and black is poor.

Figure 4 is a graphical representation of the percent stability of aceclidine refrigeration compositions at 5 and 25 ℃ for more than 30 months.

Detailed Description

The present invention relates to compositions and methods for stabilizing ophthalmic drugs by formulating the drug in a combination of a surfactant and a viscosity enhancing agent that imparts a non-linear viscosity to the composition and storing the composition in a container.

Definition of the definition

As used herein, the term "composition" is intended to include products comprising specific amounts of specific ingredients, as well as any products that come directly or indirectly from combinations of specific amounts of specific ingredients.

As used herein, the term "stable" refers to any process that facilitates and/or enables an active agent to remain in solution. As used herein, the term "stable" also refers to any means or process that inhibits and/or reduces the propensity of an active agent comprising a muscarinic agonist comprising aceclidine to degrade.

As used herein, all values defined as "about" each particular value in relation to content, weight, etc., are plus or minus 10%. For example, the phrase "about 5% w/v" is understood to mean "4.5% to 5.5% w/v". Accordingly, amounts within 10% of the claimed values are included within the scope of the claims.

As used herein, "%w/v" refers to the weight percent of the total composition.

As used herein, the term "subject" refers to, but is not limited to, a human or other animal.

As used herein, the term "container" refers to a pharmaceutically acceptable chamber containing a drug suitable for containing a liquid. Containers include, for example, vials, syringes, capsules, and ampoules.

As used herein, "headspace" refers to the area within the chamber of the container between the composition and the lid when the lid is oriented away from the pulling force of gravity.

As used herein, the term "cap" or "closure" refers to any item capable of preventing the composition from exiting the container.

The term muscarinic receptor agonist ("muscarinic agonist") includes agonists that activate the muscarinic acetylcholine receptor ("muscarinic receptor"). The muscarinic receptors are divided into five subtypes, designated M1-M5. The muscarinic agonists of the present invention include those which preferentially activate the M1 and M3 receptors over the M2, M4 and M5 receptors ("M1/M3 agonists"). M1/M3 agonists include, but are not limited to, aceclidine, xanomeline, tasalidine, sabcomeline, cevimeline, atorvastatin, arecoline, melamet, SDZ-210-086, YM-796, RS-86, CDD-0102A (5- [ 3-ethyl-1, 2, 4-oxadiazol-5-yl ] -1,4,5, 6-tetrahydropyrimidine hydrochloride), N-arylurea-substituted 3-morpholinecabinine, VUO-255-035 (N- [ 3-oxo-3- [4- (4-pyridinyl) -1-piperazinyl ] propyl ] -2,1, 3-benzothiadiazole-4-sulfonamide), benzylquinolonecarboxylic acid (BQCA), WAY-132983, AFB267B (NGX 267), AC-42, AC-260584, chloropyrazine (including but not limited to L-687, 306, L-689-660-LH-28, one or more carbon-containing substituents including one or more of the carbon, especially one or more of the carbon, nitrogen, carbon, ring, and optionally one or more of the like, and optionally one or more of the pharmaceutically acceptable salts, and the like, 62 or the top-up to one or more of the top-half-rings thereof. A preferred M1/M3 agonist is aceclidine. In a preferred embodiment, the muscarinic agonists of the present invention comprise preferential activation of M1 and M3 over M2, M4 and M5; even more preferably those muscarinic agonists that activate M1 than M3. In a more preferred embodiment, the muscarinic agonists of the present invention include those which activate only M1.

The term "aceclidine" includes salts, esters, analogs, prodrugs and derivatives thereof, including, but not limited to, those disclosed as racemic mixtures, aceclidine (+) enantiomer, aceclidine (-) enantiomer, aceclidine analogs, including, but not limited to, highly M1-selective 1,2,5 thiadiazole-substituted analogs, like ward.j.s.et al, 1,2,5-Thiadiazole analogues of aceclidine as potent M1 muscarinic agonists, JMed Chem,1998, jan.29,41 (3), 379-392, and aceclidine prodrugs, including, but not limited to, carbamates.

The term "selective alpha-2 adrenergic receptor agonist" or "alpha-2 agonist" includes all alpha-2 adrenergic receptor agonists having an affinity for the alpha-2 adrenergic receptor that is greater than 900 times or greater than the affinity for the alpha-1 adrenergic receptor, or an affinity for the alpha-2 a or alpha-2 b adrenergic receptor that is greater than 300 times or greater than the affinity for the alpha-1 adrenergic receptor. The term also includes pharmaceutically acceptable salts, esters, prodrugs and other derivatives of selective alpha-2 adrenergic receptor agonists.

The term "inert gas" refers to a gas that is chemically inert and does not react with other compounds. Inert gases include, but are not limited to, helium, neon, argon, krypton, xenon, radon, and nitrogen.

The term "low concentration" or "low dose" of an adrenergic receptor agonist refers to about 0.0001% to about 0.065% w/v; more preferably, about 0.001% to about 0.035% w/v; even more preferably, about 0.01% to about 0.035% w/v; even more preferably, a concentration of about 0.03% to about 0.035% w/v.

The term "brimonidine" includes, but is not limited to, brimonidine salts and other derivatives, including, in particular, but not limited to, brimonidine tartrate, 5-bromo-6- (2-imidazolin-2-ylamino) quinoxaline D-tartrate, and

the terms "treatment" and "treatment" refer to a disease, condition (disorder), or disorder to which such terms apply, or a reversal, alleviation, inhibition, or slowing of the progression of one or more symptoms of such disease, condition, or disorder.

The term "pharmaceutically acceptable" describes materials that are not biologically or otherwise undesirable (i.e., do not produce unacceptable levels of undesirable biological effects or interactions in a deleterious manner).

As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to produce a desired biological effect (e.g., a beneficial result, including, without limitation, preventing, reducing, ameliorating, or eliminating signs or symptoms of a disease or condition). Thus, the total amount of each active component of the pharmaceutical composition or method is sufficient to exhibit a significant subject benefit. Thus, a "pharmaceutically effective amount" will depend on the context in which it is administered. The pharmaceutically effective amount may be administered in one or more prophylactic or therapeutic administration modes.

The term "prodrug" refers to compounds, including but not limited to monomers and dimers of the compounds of the invention, which have cleavable groups and become pharmaceutically active in vivo under physiological conditions.

As used herein, "salts" refer to those salts that retain the biological effectiveness and properties of the parent compound and are not biologically or otherwise detrimental at the dosage administered. Salts of the compounds of the invention may be prepared from inorganic or organic acids or bases.

The term "higher order aberration" refers to an aberration in a field of view selected from the group consisting of star burst, halo (spherical aberration), double vision, multiple images, blurred vision, coma, and trefoil.

The term "cold chain" refers to storage at a temperature of about 2 to 8 ℃ from manufacture to immediately prior to application.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids or bases. The phrase "pharmaceutically acceptable salts" means those salts which are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals, have no abnormal toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al at J. Pharmaceutical Sciences,Pharmaceutically acceptable salts are described in detail in 1977,66:1, et al.

The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or by reacting the free base functionality with a suitable organic acid alone. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methylsulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Moreover, lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides may be used; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and other agents quaternize the basic nitrogen containing groups. Thus obtaining a water or oil soluble or dispersible product. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hyaluronic acid, malic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, malic acid, maleic acid, methanesulfonic acid, succinic acid and citric acid.

Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety with a suitable base (such as a pharmaceutically acceptable hydroxide, carbonate or bicarbonate of a metal cation) or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, and non-toxic quaternary ammonium and amine cations, including ammonium, tetramethyl ammonium, tetraethyl ammonium, methyl ammonium, dimethyl ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium, and ethyl ammonium, and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

The term "ester" as used herein is defined by the formula-OC (O) A ¹ or-C (O) OA ¹ Representation, wherein A ¹ May be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl group, or other suitable substituent.

The method of the invention

In certain embodiments, the present invention relates to a method of stabilizing an ophthalmic drug, the method comprising the steps of:

a) Adding a surfactant and a viscosity enhancing agent to the ophthalmic drug to produce a composition, wherein the composition has a viscosity of about 25 centipoise or less at 25 ℃ at a shear rate of 1/1000 per second, and a viscosity of about 70 centipoise or more, preferably about 150 centipoise or more, and more preferably about 300 centipoise or more at 25 ℃ at a shear rate of 1 per second;

b) Filling the composition from step a) into a container; and

In certain other embodiments, the composition of the present invention is filled into the container under an inert gas blanket, preferably nitrogen, preferably purging the headspace with an inert gas blanket, preferably nitrogen.

In certain other embodiments, the hermetic seal is resealable.

a) Providing a container;

b) Filling the container with a composition comprising an ophthalmic drug, a surfactant, and a viscosity enhancing agent, preferably under an inert gas blanket, preferably nitrogen, wherein the viscosity of the composition at 25 ℃ at a shear rate of 1/1000 per second is about 25 centipoise or less and the viscosity at 25 ℃ at a shear rate of 1 per second is about 70 centipoise or more;

d) Capping the container; and

Compositions of the invention

Ophthalmic drugs suitable for use in the present invention include, but are not limited to, aceclidine, latanoprost-timolol, chloramphenicol, azithromycin, cyclopent-on, proteins, polypeptides, amino acids, salts thereof, derivatives thereof, and combinations thereof.

Surfactants suitable for use in the present invention include nonionic, ionic and amphoteric (zwitterionic) surfactants. In a preferred embodiment, the concentration of surfactant used in the present invention is above the critical micelle concentration of the surfactant.

Nonionic surfactants suitable for use in the present invention include cyclodextrins, alkyl polyethylene glycols, poloxamers, polysorbates, or combinations thereof. Preferred embodiments include poloxamer 108, poloxamer 188, poloxamer 407, polysorbate 20, polysorbate 80, with or without Ding Suanhua saltsBeta-cyclodextrin 2-hydroxypropyl beta cyclodextrin ("HP beta CD"), alpha cyclodextrin, gamma cyclodextrin, polyethylene glycol 35 castor oil, and polyethylene glycol 40 hydrogenated castor oil, or a combination thereof. Further, alternatives to other nonionic surfactants compatible with ophthalmic use allow similar formulation advantages to be achieved, which may include, but are not limited to, one or more nonionic surfactants such as poloxamers, poloxamer 103, poloxamer 123 and poloxamer 124, poloxamer 407, poloxamer 188 and poloxamer 338, any poloxamer analogs or derivatives, polysorbates, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate analogs or derivatives, cyclodextrins, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, any methylated beta-cyclodextrin, beta-cyclodextrin sulfobutyl ether, gamma-cyclodextrin Sulfobutyl ether or glucosyl-beta-cyclodextrin, any cyclodextrin analogue or derivative, polyoxyethylene (polyoxyyethylene), polyoxypropylene glycol, polysorbate analogue or derivative, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (200), polyoxypropylene glycol (70), polyethylene glycol hydrogenated castor oil 60, polyethylene glycol stearate, nonylphenol ether, octylphenol polyoxyethylene ether (octyphenol ethoxylates), nonylphenol polyoxyethylene ether, propylene glycol monocaprylate (capryols), propylene glycol monolaurate glycerol, polyethylene glycol ("PEG"), polyethylene glycol>35. 78, 98, 700 (polyoxyethylene glycol alkyl ether), glycerol laurate, lauryl glucoside, decyl glucoside, or cetyl alcohol; or zwitterionic surfactants such as palmitoyl carnitine, cocamiddea derivatives, cocamidopropyl betaine, or trimethylglycine betaine, N-2 (2-acetamido) -2-aminoethanesulfonic Acid (ACES), N-2-acetamido iminodiacetic acid (ADA), N-bis (2-hydroxyethyl) -2-aminoethanesulfonic acid (BES), 2- [ bis- (2-hydroxyethyl) -amino]-2-hydroxymethyl-propane-1, 3-diol (bis-tri), 3-cyclohexylamino-1-propane sulfonic acid (CAPS), 2-cyclohexylamino-1-ethane sulfonic acid (CHES), N-bis (2-hydroxyethyl) -3-amino-2-hydroxypropane sulfonic acid (DIPSO), 4- (2-hydroxyethyl) -1-piperazine propane sulfonic acid (EPPS), N-2-hydroxyethylpiperazine-N '-2-ethane sulfonic acid (HEPES), 2- (N-morpholino) -ethane sulfonic acid (MES), 4- (N-morpholino) -butane sulfonic acid (MOBS), 2- (N-morpholino) -propane sulfonic acid (MOPS), 3-morpholino-2-hydroxy propane sulfonic acid (MOPSO), 1, 4-piperazine-bis- (ethane sulfonic acid) (PIPES), piperazine-N, N' -bis (2-hydroxy propane sulfonic acid) (POPSO), N-tris (hydroxymethyl) methyl-2-amino propane sulfonic acid (TAPS), N- [ tris (hydroxymethyl) methyl sulfonic acid (MOPS) ]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid (TES), 2-amino-2-hydroxymethyl-propane-1, 3-diol (III), tyloxapol, solullan ^TM C-24 (2- [ [10, 13-dimethyl)]-17- (6-methylheptan-2-yl) -2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopentadiene [ a ]]Phenanthren-3-yl]Oxy group]Ethanol) and->20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate). In other embodiments, the addition of polysorbate 80 is preferred. Besides the nonionic surfactants described above, any nonionic surfactant is suitable for use in the present invention as long as the concentration of the nonionic surfactant is higher than the critical micelle concentration of the nonionic surfactant. Preferably, the nonionic surfactant used in the present invention achieves sub-micron diameter micelles, more preferably diameters less than 200 nanometers, and more preferably diameters less than 150 nanometers.

Ionic surfactants suitable for use in the present invention include, but are not limited to, anionic surfactants and cationic surfactants. Anionic surfactants suitable for use in the present invention include, but are not limited to, ammonium dodecyl sulfate, sodium diisooctyl succinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctane sulfonate, sodium laurinol sarcosinate, sodium myristate sulfate, sodium alkyl polyether sulfate (sodium pareth sulfate), sodium stearate (sodium stearate), lignin sulfonate, sodium laurate, alpha olefin sulfonate, ammonium dodecyl sulfate, and sodium dodecyl sulfate (sodium ester lauryl sulfate). Suitable cationic surfactants for use in the present invention include, but are not limited to, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkyldimethyldichlorobenzyl ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetrimonium bromide, and cetylpyridinium bromide.

Amphoteric (zwitterionic) surfactants are any surfactant that carries both anionic and cationic charges. Amphoteric surfactants suitable for use in the present invention include, but are not limited to, alkyl or alkenyl amphoacetates, alkyl amphopropionates or dipropionates, alkyl amphoglycol sulfobetaines wherein the alkyl group contains 8 to 24 carbon atoms, such as coco or lauryl.

Surfactants may be used in the present invention at concentrations above their critical micelle concentration. The critical micelle concentration of any particular surfactant can be calculated by those skilled in the art. In a preferred embodiment, the concentration of the surfactant of the present invention is from about 1.5% to about 7% w/v. The choice of nonionic, cationic and or anionic surfactants is based primarily on: 1) Drug interactions; and 2) the ability to penetrate the cornea; the mass of surfactant combined with the viscosity agent is critical to the development of a non-linear (non-newtonian) viscosity.

Ophthalmic in situ gels that may be added in place of or in addition to one or more surfactants include, but are not limited to, gelatin, carbomers of various molecular weights (including carbomers 934P and 974P), xanthan gum, alginic acid (salt), guar gum, locust bean gum, chitosan, pectin, and other gelling agents well known to the expert in the art.

In other preferred embodiments, the nonionic surfactant is polysorbate 80 at a concentration of about 0.5% to about 10% w/v, more preferably about 1% to about 7% w/v, and even more preferably about 2% to about 5% w/v, still more preferably about 2.5% to about 4% w/v, and most preferably about 2.5% or 2.75% or 3% or 4% or 5% w/v.

Viscosity enhancers suitable for use in the present invention include, but are not limited to, gums such as guar gum, hydroxypropyl guar ("hp-guar") and xanthan gum, alginates, chitosan, gellan (gelrite), hyaluronic acid, dextran, and mixtures thereof,(polyacrylic acid or carbomer) comprising +.>900 series, including->940 (carbomer 940)>910 (carbomer 910) and->934 (carbomer 934), cellulose derivatives such as carboxymethyl cellulose ("CMC"), methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl methyl cellulose 2906, carboxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, and hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gellan (gellan), carrageenan, alginic acid, carboxyvinyl polymer, or combinations thereof.

When combined with surfactants above the critical micelle concentration, the viscosity agent can be used in the present invention at a desired concentration to achieve a viscosity of about 0.5 centipoise or less at 25 ℃ at a shear rate of 1/1000 per second, and a viscosity of about 150 centipoise or more, preferably 300 centipoise or more, at 25 ℃ at a shear rate of 1 per second.

In another embodiment, the equilibrium viscosity of the viscosity enhancing agent is less than 100cps, preferably from about 15 to about 35cps, and most preferably about 30cps. In a preferred embodiment, the viscosity agent is940 (carbomer 940) at a concentration of about 0.05% to about 1.5% w/v, preferably about 0.09% to about 1.0% w/v, more preferably 0.09%, 0.25%, 0.5%, 0.75%, 0.9% or 1.0% w/v. In certain combinations, it has surprisingly been found that nonionic surfactant/viscosifier combinations can lead to phase separation over time with precipitate formation. In this case, particularly for polyethylene glycols, in the preferred embodiment polyoxyl 40 stearate and cellulose derivatives, particularly hydroxypropyl methylcellulose, use non-polysaccharide derivatives to increase viscosity, such as polyacrylic acid derivatives (carbomer, carbomer 934 or 940 in the preferred embodiment) may prevent such separation; or alternatively, the use of non-polyethylene glycol type nonionic surfactants may replace the cellulose derivative or non-cellulose derivative viscosity agent with, for example, polysorbate 80.

In another preferred embodiment, the viscosity agent is carboxymethyl cellulose at a concentration of about 1% to about 2% w/v, more preferably about 1.35% to about 1.45% w/v, and most preferably 1.42% w/v or 1.40% w/v.

In another preferred embodiment, the viscosity agent is hydroxypropyl methylcellulose at a concentration of about 0.5% to about 1.75%, and more preferably about 0.75% or 1.5%, still more preferably about 1.0% to about 1.5%, and most preferably about 1.25%.

The composition of the present invention may further comprise cryoprotectants, polyols, bulking agents, solubilizers, antioxidants, tonicity adjusters, preservatives. Cryoprotectants are compounds that prevent freezing or damage to the compound during freezing. As used herein, the term "cryoprotectant" or "cryoprotectant" includes lyoprotectants. Cryoprotectants suitable for use in the present invention include, but are not limited to, polyols, sugars, alcohols, lower alkanols, lipophilic solvents, hydrophilic solvents, bulking agents, solubilizing agents, surfactants, antioxidants, cyclodextrins, maltodextrin, silica colloids, polyvinyl alcohols, glycine, 2-methyl-2, 4-pentanediol, cellobiose, gelatin, polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), formamide, antifreeze protein 752, or combinations thereof.

As used herein, the term "polyol" refers to a compound having a plurality of hydroxyl functional groups available for organic reactions, such as monomeric polyols, such as glycerol, pentaerythritol, ethylene glycol, and sucrose. Further, polyols may refer to polymer polyols that react with propylene oxide or ethylene oxide, including glycerol, pentaerythritol, ethylene glycol, and sucrose. In a preferred embodiment, the polyol is selected from mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide, ethylene glycol, propylene glycol, maltitol, threitol, arabitol and ribitol. In a more preferred embodiment, the polyol is mannitol.

Saccharides suitable for use as cryoprotectants in the present invention include, but are not limited to, glucose, sucrose, trehalose, lactose, maltose, fructose, and dextran.

In another preferred embodiment, the alcohols include, but are not limited to, methanol.

In one embodiment, the present invention excludes each cryoprotectant individually from the definition of cryoprotectant.

The cryoprotectant may be present in the compositions of the present invention at a concentration of about 0.1% to about 99% w/v, preferably about 1% to about 50% w/v, more preferably about 1% to about 10% w/v.

As used herein, "lower alkanol" includes C1-C6 alkanols. Lower alkanols suitable for use in the present invention include, but are not limited to, amyl alcohol, butyl alcohol, secondary butyl alcohol, tertiary butyl alcohol, n-butyl alcohol, ethanol, isobutanol, methanol, isopropanol and propanol.

Bulking agents suitable for use in the present invention include, but are not limited to, sugars, polyvinylpyrrolidone, cyclodextrin, and trehalose.

Solubilizing agents suitable for use in the present invention include, but are not limited to, cyclic amides, gentisic acid and cyclodextrins.

In preferred embodiments, antioxidants suitable for use in the present invention include, but are not limited to, bisulfites, ascorbic acid, disodium or tetrasodium ethylenediamine tetraacetate, citrates, butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), sulfoxylates, propyl gallate, thio-containing amino acids, and thiols. In a preferred embodiment, the antioxidant is disodium ethylenediamine tetraacetate at a concentration of about 0.005% to about 0.50% w/v, citrate at a concentration of about 0.01% to about 0.3% w/w, dicalcium diethylenetriamine pentaacetate ("Ca 2 DTPA") at a concentration of about 0.001% to about 0.2% w/v, preferably about 0.01% w/v Ca2DTPA, by adding 0.0084% w/v Ca (OH) to the formulation ₂ And 0.0032% w/v of triaminopentaacetic acid and slowly mixing.More antioxidant combinations may be used. Other antioxidants that may be used with the present invention include those well known to those skilled in the art, such as ethylenediamine tetraacetic acid at a concentration of about 0.0001% to about 0.015% w/v.

The tonicity modifier may be, but is not limited to, a salt such as sodium chloride ("NaCl"), potassium chloride, mannitol or glycerin, or another pharmaceutically or ophthalmically acceptable tonicity modifier. In certain embodiments, the tonicity modifier is 0.037% w/v NaCl.

Preservatives that may be used with the present invention include, but are not limited to, benzalkonium chloride ("BAK"), sorbic acid, chloroxidite, citric acid, chlorobutanol, thimerosal, phenylmercuric acetate, disodium edetate, phenylmercuric nitrate, perborate, or benzyl alcohol. In a preferred embodiment, the preservative is BAK, sorbic acid, a chloroxidite complex, or a combination thereof. In still more preferred embodiments, the concentration of BAK is from about 0.001% to about 1.0% w/v, more preferably the concentration is about 0.007%, 0.01% or 0.02% w/v. In another preferred embodiment, the preservative is perborate at a concentration of about 0.01% to about 1.0% w/v, more preferably at a concentration of about 0.02% w/v.

Various buffers and means of adjusting the pH may be used to prepare the ophthalmic compositions of the present invention. Such buffers include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, and borate buffers. It will be appreciated that the pH of the composition may be adjusted using an acid or base as required, preferably at a concentration of 1 to 10mM, more preferably about 3mM or 5mM. In preferred embodiments, the pH is from about 4.0 to about 8.0, and in more preferred embodiments, the pH is from about 5.0 to about 7.0.

Acacliding

One ophthalmic drug that may be stabilized by the method of the present invention is aceclidine. Aceclidine has traditionally been used to treat glaucoma. When aceclidine is used to treat glaucoma, it is typically stored in a two-bottle system; one bottle contained lyophilized aceclidine and the second bottle contained the diluent required to reconstitute the lyophilized aceclidine prior to topical instillation. Romano j.h., double-blind cross-over comparison of aceclidine and pilocarpine in open-angle glaucoma, brit J Ophthal, aug 1970,54 (8), 510-521 it is another aspect of the present invention to provide an aqueous phase aceclidine composition that is stable when combined with cold chain storage. It is a further aspect of the present invention to provide a method of stabilizing aqueous aceclidine by combining an effective excipient, a pH range and a temperature range.

The compositions and methods of the present invention treat presbyopia by improving the depth of focus of a presbyopic patient by administering to the eye an ophthalmic composition that reduces pupil dilation in the dark or in dim light, produces pupil constriction of a specific degree and duration without accommodation, provides cosmetic whitening and/or induces redness prevention. The compositions and methods of the present invention also do not cause significant pupil rebound, rapid tolerance, ciliary muscle spasms, near vision induction, or reduced far vision. In addition, the compositions and methods of the present invention allow for further improvements in visual acuity and depth perception treatments for both eyes (both eyes). The ophthalmic compositions of the present invention surprisingly produce a pupil of about 1.5 to about 2.4mm at the anterior iris plane and a pupil of about 2.0mm at the corneal surface. Without being bound by a particular theory, the clinical effect appears to involve both an accommodative increase in accommodative hue and an enhancement in pinhole near depth of focus to improve near vision, estimated to be about-1.25D or less, but limited in ability to remain within the range of distances for pinhole correction, found to be about-1.00D or less, such that the sum increases, in some cases can increase near vision by +2.00D or more without distance blur; and reducing or eliminating redness, which is otherwise indicative of the use of miotics. The pupil constriction of the present invention with such modulation and peak limiting of the modulating hue is superior to And Flexivue->The pinhole effect of the corneal inlay allows binocular treatment without darkening the peaks.The pupil constriction of the present invention with modulated accommodation is also advantageous over an inlay because the constriction of the actual pupil does not result in the concomitant severe night vision interference caused by the light scattering boundary of the anterior corneal pinhole formed by the inlay. Further, pupil constriction provides a greater field of view and more focused light delivery, and the optimal pupil range is found to be about 1.5mm to 2.1mm using the formulation invention, with negligible slight and very tolerable darkening and enhanced contrast, far vision, reduced night glare, and improved near vision.

The use of aceclidine has minimal effect on the longitudinal ciliary muscle, thereby reducing the risk of retinal detachment compared to typical muscarinic agonists such as pilocarpine and cabazitaxel. Further inclusion of the ciliary muscle paralysis agent resulted in a shallowing of the anterior chamber of the eye of only 0.04 mm. Aceclidine, particularly enhanced according to the present invention, also has a greater magnitude, duration, and control of minimum pupil diameter, and has less anterior chamber inflammation for long term use, than traditional pilocarpine with or without an alpha agonist. While not wishing to be bound by a particular theory, it is believed that in a preferred embodiment, the rate of pupil constriction and the rate of accommodation increase remain in synchrony to allow pinhole correction that would otherwise cause accommodation blur in prior art applications of miotics for presbyopia correction. Thus, this combination was found to avoid distance ambiguity as a response to pilocarpine and/or carba-inducible pupil constriction, as well as over-regulated myopia and ciliary muscle spasms that manifest as supraorbital neuralgia or generalized migraine-like headaches, which are typically seen in patients without the formulation invention of the present invention.

In order to achieve any reasonable duration of effect, such conventional pilocarpine formulations are still limited to less than or equal to about 4 hours in most cases, because the high rate of accommodation of pupil constriction requires a minimum concentration of pilocarpine of about 1.0% to minimize but not eliminate distance-induced myopia blur and ciliary muscle spasm. Further, pilocarpine must be instilled monocular to minimize intolerable distance blur to still annoying distance blur of 2-3 lines. Even with single eye instillation, pilocarpine can still cause annoying concomitant distance blurring and must be limited to about 1.0%. At instillation of 1.0% pilocarpine, the pupil size of most subjects is about 2.3mm or greater, limiting pinhole depth perception benefit of any significant pinholes and pinhole filtering of any induced myopic rays. The limit on these traditional pilocarpine is about 1.0%, with a concomitant short duration, and still annoying but reduced distance blur in the emmetropic or near-sighted eyes (slightly neutralized in mild presbyopia), it is well known that extremely strong accommodation in an attempt to prevent 5D to 11D occurs in higher concentrations of pilocarpine.

In a preferred embodiment, any effect on accommodation may be further reduced or completely eliminated by using a miotic agent and a ciliary paralytic agent in a narrow and specific ratio of miotic agent to ciliary paralytic agent, wherein the ratio as found in US9089562, such as about 35:1 for the preferred embodiment, is greatly increased by a factor of, for example, about 300% -700% in the presence of a cryoprotectant for the present invention. Acaclidinium can produce increased depth of focus by pupil constriction below 2.3mm and moderate accommodation as described in the present invention. Particularly enhanced pupil constriction can occur with the compositions of the present invention. This enhanced pupil constriction makes it possible to use alpha-2 agonists at very low concentrations if it is desired to reduce slight redness of the eye. Without such an agonist, the combination of other inactive ingredients reduces or effectively eliminates the resulting redness. Further, due to the apparent and surprising selectivity of aceclidine and the discovery of the commercially stable aceclidine formulations of the present invention, administration of the compositions of the present invention to the eye may achieve net strongly enhanced myopic acuity through a pupil constriction pinhole effect and moderately mediated ciliary muscle accommodation. These benefits are accompanied by a filtered pupil effect that eliminates any distance blur from accommodation, corrects for residual ametropia and optical aberrations that may be present in many cases, and improves distance vision. Thus, administration of aceclidine results in pupil constriction without excessive accommodation and concomitant distance blurring. However, administration of aceclidine alone may result in severe redness and supraorbital neuralgia. Without the formulation enhancement of the present invention (e.g., requiring a ciliary paralytic agent, a cryoprotectant, or both), aceclidine may produce a duration of greater than 3-4 hours that is either less than optimal pupil constriction at low concentrations or requires a reduction beyond the desired peak at higher concentrations to be satisfactory. However, it has been found that the use of a cycloplegic agent is highly sensitive to other inactive ingredients in the formulation that are not normally associated with the effect of the active agent, particularly cryoprotectants, since for aceclidine it is commercially preferred to reduce or eliminate the need for a very low concentration of cycloplegic in the preferred embodiment, 0.042% being high enough to result in a substantial loss of efficacy when cryoprotectant (e.g. a polyol such as mannitol) is present. Further, the absence of formulation-enhanced aceclidine of the present invention results in darkened vision in dim or no light, as well as ciliary muscle pain above a reasonable tolerable threshold, which can last one hour or more and resemble severe migraine.

Certain embodiments of the present invention enhance the preference of the discovered miosis by providing a consistent range of effects of about 1.50-2.20mm for most patients using preferred embodiments of the nonionic surfactant and viscosity agent. Using other penetration enhancers, in particular hydroxypropyl methylcellulose, high viscosity carboxymethylcellulose,Similar benefits can be achieved with (polyacrylic acid or carbomer), as well as various viscosity additives that increase drug residence time, such as xanthan gum, guar gum, alginates, and other in situ gels known to those skilled in the art. As is well known to those skilled in the art, the precise concentration of a particular viscosity agent will depend on the molecular weight and concentration of the agent selected, and thus,the concentration may have the same viscosity for increased molecular weight reduction. Due to the rheological properties of the preferred embodiments, the present invention further prevents nasal obstruction that can occur when large amounts of aceclidine levels reach the nasal mucosa.

The combination of aceclidine and a low concentration of a selective alpha-2 adrenergic receptor agonist (alpha-2 agonist or alpha-2 adrenergic agonist), such as fampridine, brimonidine or guanfacine, allows for the desired miotic effect with reduced or no redness. The use of low concentrations of selective alpha-2 agonist results in a substantial reduction in congestion, greatly reducing the risk of rebound congestion found in concentrations of about 0.06% w/v or higher. Furthermore, the use of low concentrations of selective alpha-2 agonists does not adversely alter the pupil constriction caused by aceclidine. In contrast, the use of brimonidine 0.20% w/v, when applied topically for pupil modulation of night vision, results in rapid tolerance of pupil modulation due to up-regulation of the alpha-2 receptor in nearly 100% of subjects over a four week period of use.

Unexpectedly, by further reducing the extent of ciliary muscle spasms upon topical instillation, the addition of a ciliary muscle paralysis agent can reduce any supraorbital neuralgia or related discomfort without compromising miotic response. More unexpectedly and surprisingly, in a preferred embodiment of U.S. patent No. 9089562, the ratio of 1.40% aceclidine to about 0.040% topiramate (35:1) becomes about 1.75% aceclidine to about 0.004% to 0.010% topiramate (350:1, 175:1, respectively) in the presence of mannitol, wherein 2.5% provides a better effect than 4.0%.

The lack of impairment of the miotic response was surprisingly found because specific ciliary muscle paralytic agents, such as topiramate, have known pupil dilation effects at concentrations as low as 0.01% w/v (Grunerger J.et al., the pupillary response test as a method to differentiate various types of dementia, neurops sychiatr,2009,23 (1), pg 57). More particularly, the ciliary muscle paralysis agent causes mydriasis (i.e., dilation of the iris radiation muscles). Further, the addition of a ciliary paralytic agent to a miotic agent unexpectedly increases the time required for pupil maintenance over a range of sizes without becoming overly restrictive. The peak miotic effect at 30-60 minutes can be titrated in an inversely proportional relationship to the concentration of the ciliary paralytic agent. The concentration of topiramate found in the present invention significantly results in a relaxation of the ciliary muscle than the iris-irradiated muscle. Indeed, it was found that by adding topiramate to a composition containing a concentration of aceclidine used in the present invention, iris mydriasis is inhibited, in contrast, pupil reduction levels are more consistent over the duration of the pupil reduction effect. Furthermore, quite surprisingly, unexpectedly, and advantageously, the addition of topiramate can reduce the extent of peak pupil constriction without causing mydriasis in the entire drug-induced mydriasis, thereby yielding a more constant and ideal pupil size. This more consistent pupil size allows for favorable near and far vision without adverse blurring or resolution loss due to diffraction limitations of the greatly reduced pupil size (e.g., 1.25 mm) seen at peak pupil constriction.

Previously, in US9089562, it has surprisingly been found that in a preferred embodiment, the addition of at least 0.04% w/v of a ciliary muscle paralysis agent alleviates the ciliary muscle side effects caused by administration of aceclidine (1.40%) to the eye, but such a formulation does not constitute a sufficiently stable commercial use and generally has a duration of up to about 5 to 6 hours.

Several other findings of the present invention allow for commercially stable aceclidine formulations with enhanced efficacy and duration:

the finding of the present invention, which is identical or even more surprising with the synergistic effect of 0.040% of a cycloplegic agent added to 1.40% aceclidine, means that aceclidine 1.50% -2.0% and preferably about 1.75% in combination with especially 0.5% -4.0% and most preferably about 2.5% of a cryoprotectant, preferably a polyol, mannitol in a preferred embodiment, can achieve a similar pupil range with reduced or no ciliary side effects. When cryoprotectant is combined with aceclidine, it may then be combined to allow the aceclidine to freeze-dry without degradation, while the present invention further reduces or eliminates the need for a ciliary paralytic agent relative to the teaching of the concentration range of the ciliary paralytic agent required in US 9089562. Optionally, there is a need to further eliminate mild but potentially annoying ciliary side effects, especially in younger presbyopic subjects, and to further modulate pupil constriction by using aceclidine and cryoprotectant compositions alone, reducing and in most cases eliminating any annoying peak concentration darkening, therefore the addition of cryoprotectant can also be used to greatly reduce (i.e., no more than 0.025% w/v of ciliary paralytic agent, preferably 0.004% to 0.015%, and most preferably 0.005% to 0.010%) the concentration of ciliary paralytic agent required, as found in the preferred embodiments of the present invention. In preferred embodiments, it has been found that aceclidine is about 1.50% -2.0%, and more preferably 1.75%, and mannitol is about 0.5% -4.0%, and more preferably 2.5%, providing the present invention with an optimal concentration combination that is necessary but not sufficient for the about 3 line near vision improvement and a duration of 5 or more hours desired for an effective topical presbyopic composition, wherein other formulations have been found to further enhance the desired magnitude and duration of clinical near vision improvement;

Surprisingly it was found that the addition of a viscosity agent in the composition as described in a. Above only moderately improves the magnitude and duration, however, when a non-ionic surfactant such as polyoxyl stearate or polysorbate 80 is first added, an optimal concentration is found which provides the invention with a greatly improved magnitude and duration, and the viscosity agent may provide a significantly greater duration than when added alone. Polysorbate 80 or polyoxyl 40 stearate at a concentration of 1.0% to 10.0%, and more preferably about 2.5% to 5.0% w/v, has been found to be beneficial;

when the formulations of a.and b.above are combined in an improved way, preferred embodiments are for example aceclidine 1.75%, mannitol 2.5% and polysorbate 802.75%. Surprisingly, it was found that viscosity agents such as high viscosity carboxymethyl cellulose ("CMC") moderately increase in magnitude and greatly increase in duration, unlike the formulation used alone in a. Above. The high molecular weight CMC concentration is from 0.75% to 1.75%, and most preferably about 1.40%, or hydroxypropyl methylcellulose ("HPMC") is from about 0.25% to 2.0%, more preferably about 0.50% or 1.50%, and most preferably about 1.0% to 1.25%, which when combined now results in about +3 lines of improved near vision or more for a duration of 5-10 hours, on average 7 hours or more, of 1.0% relative to aceclidine of less than about 4 hours;

Without wishing to be bound by a particular theory, citrate in combination with EDTA as a preferred embodiment buffer appears to 1) reduce redness; 2) Enhancing shelf life of sorbate preservatives, and in combination with BAK0.005% to 0.02% (preferably 0.02%) as described above, further increases near vision to about 4 lines and duration to about 8 to 12 hours.

In addition, in a preferred embodiment, 0.5% or 1.5% sodium chloride is added. Optionally, sodium chloride may be substituted with boric acid, preferably 0.35%, or with potassium borate, preferably 0.47%;

without wishing to be bound by a particular theory, it appears that the addition of nonionic surfactant at an optimal concentration of about 2.5% to 5.0% promotes the infiltration of aceclidine into the eye, which may be related to the optimal micelle size, particularly once the micro-or nano-micelle range is reached. This increased penetration coincides with the desired increase in magnitude and duration, and there is a slight increase and darkening of ciliary muscle perception in the absence of topiramate but in the presence of mannitol. Thus, the addition of a nonionic surfactant at the preferred concentration found in the presence of the combination formulation enhancement of the above a-d, wherein the above a-d is no longer needed for the ciliary paralytic agent, can be further improved with a lower concentration of the ciliary paralytic agent than found in US9089562, for example using about 0.042% topiramate and aceclidine 1.40%. For the present invention, preferred embodiments include about 1.75% aceclidine, 2.5% mannitol, about 2.5% to 5.0% polysorbate 80, about 1.42% CMC, or about 1.8% HPMC, and about 0.004% -0.010%, more preferably about 0.005% to 0.007%, and most preferably about 0.005% -0.006% topiramate. Micelle formers above the critical micelle concentration may allow the micelles to diffuse to the tear film surface and disperse at low concentrations to cover the surface, while at higher concentrations, the micelles gradually shrink and "squeeze" along the surface. Without wishing to be bound by a particular theory, it is believed that at optimal concentrations, the minimum micelle diameter is reached before significant multilayers (delamination) occur. It is believed that at optimal concentrations, about 100 to 250nm of nano-micelles along the surface, achieve a high charge and hydrophilic aceclidine surrounding it, facilitating its penetration through very lipophilic epithelium;

Without wishing to be bound by a particular theory, BAK0.02% is added above the BAK critical micelle concentration in a composition of sorbitol ester about 0.10%, EDTA about 0.10%, preferably aceclidine 1.75%, mannitol 2.5%, topiramate 0.01% and citrate buffer (1 to 100mM, preferably 3-5 mM). BAK as a cationic surfactant as well as BAK micelles, creating an ionic micelle gradient with +charged nh4+ quaternary nitrogen, the resulting lipophilic alkyl chains that aggregate at the outer polar head and at the inner hydrophobic tail can result in a significantly similar aceclidine alignment, since its dipole oriented along the outer polar head with quaternary NH3 nucleophilic or NH4 protonated nitrogen and the more hydrophobic carbonyl c=o along the hydrophobic BAK micelle tail, which can prevent, greatly reduce or moderately reduce the collision of any non-ionic aceclidine molecule-nucleophilic species-if oriented in solution such that they randomly collide with other aceclidine carbonyl groups, will result in the chemical transformation of the aceclidine at its target carbonyl groups by nucleophilic attack, which can be repeatedly oriented in such nucleophilic species and other aceclidines, and without such BAK losing stability by 0.005% and preferably 0.01% to 0.02%, most preferably the orientation of the micelle. In a preferred embodiment, although the concentration of such nonionic nucleophiles is relatively low at the preferred pH, the ability of these nonionic nucleophiles to repeatedly disrupt the equilibrium of adjacent aceclidine without self-degradation is high. The result may be improved efficacy of the mixed solution for more than 1 month, once opened in a double-chambered bottle, and the lyophilized aceclidine/mannitol mixed with the rest of the formulation in a diluent, and/or improved stability of the solution sufficient for commercialization, either at room temperature or by cold chain;

BAK alone was found to not provide adequate bacterial and fungal preservative efficacy, but BAK and sorbate, or sorbate alone, were found to satisfactorily preserve the diluent and or mixed solutions of the present invention;

without wishing to be bound by a particular theory, preferred embodiments of the present invention, such as those containing 1.25% hydroxypropyl methylcellulose, may have a viscosity of about 400cps prior to instillation, but differ from conventional high viscosity artificial tear formulations, such as about 400cpsWhich may obscure vision for 10-20 minutes, or about 100cps +.>It causes a similar but slightly reduced blurring, only about 60 seconds of blurring accompanied by rapid dissipation of tear secretion; of these, both have a non-newtonian decrease in viscosity at high shear (e.g., about 1/1000 seconds during blinking), and aceclidine parasympathetic trigger tear secretion as salivation (sialogen) may contribute.

General miotics, such as pilocarpine, cabac, and diethylphosphinothioyl cholinesterase (phospholine diesterase), can cause pupil constriction, which results in increased near vision in presbyopic patients. However, a retroverted decline from the peak miotic effect of the far vision associated with these general miotics and ocular accommodation not seen with aceclidine occurs. Co-administration of the ciliary muscle paralysis agent with aceclidine unexpectedly resulted in a decrease in this decline in distance vision.

The comfort, safety and efficacy of the preferred embodiment of the ophthalmic composition of the present invention is due to the presence of the following components: nonionic surfactants, e.g. cyclodextrin alpha, beta or gamma chains, preferably 2-hydroxypropyl beta-Cyclodextrins ("HP beta CD") and beta-cyclodextrinsSulfobutyl ether derivatives of (a); alkyl polyethylene glycols, such as polyoxyl 40 stearate and polyethylene glycol 35 castor oil; or poloxamers, such as poloxamer 108 and poloxamer 407; polysorbates, e.g. polysorbate 80 or +.>35 (Brij is a registered trademark of us You Nika, inc.); viscosity enhancers, such as carboxymethyl cellulose ("CMC"); tonicity adjusting agents such as sodium chloride; preservatives, such as benzalkonium chloride, and a pH of about 5.0 to about 8.0. Further, an increase in the concentration of nonionic surfactant can result in reduced redness. Specifically, increasing polysorbate from 0.10% to 0.50-1.0% resulted in reduced redness. Further, CMC or +.>Increasing 940 from 0.50% to 1.5% w/v (preferably 1.40-1.43% w/v) results in enhanced near vision, quantitative improvement and duration improvement.

The viscosity of the composition of the present invention comprising a viscosity enhancing agent may be from about 1 to about 10000cps prior to topical instillation in the eye. The viscosity of the composition decreases to a range of about 1 to about 25cps at high shear forces at blinks and to a range of 50 to 200cps at low shear forces between blinks due to shear forces experienced as it exits the drug delivery device, allowing greater drip retention with less spillage and less drainage of nasal tears and systemic absorption at topical instillation.

In one embodiment, the present invention relates to an ophthalmic composition comprising aceclidine. In a preferred embodiment, the concentration of aceclidine is about 0.25% to about 2.0% w/v, more preferably about 0.50% to about 1.90% w/v, still more preferably about 1.65% to about 1.85% w/v, and most preferably about 1.75% w/v. Since aceclidine is an asymmetric tertiary amine, both the +and-optical isomers are present (in some studies (+) is more potent and in others (-) is thought to be potentially more potent). For the above concentrations, the polarimetry confirmed exactly equal ratios for these concentrations (+) and (-) isomers. Changing the ratio can thus cause the concentration range to change in ratio.

The findings of the present invention are that several modifiers (modifications) may be used, alone or in combination, to enhance cold chain storage stability, including in preferred embodiments, in addition to aceclidine 1.40% -1.75%, topiramate 0.025% -0.10% and optionally nonionic surfactants, such as polyoxy 40stearate (polyoxy 40 stearate) 0.5% -10%, preferably 5.5%, one or more of the following (see table 1):

an acidic pH, preferably less than 5.5, preferably less than 5.0, and most preferably a pH of about 4.75;

A viscosity enhancing agent, preferably having a viscosity of about 15-50cps at 25 ℃, and more preferably 20-45cps, wherein the preferred embodiment is a carbomer 9400.09% -1.5%;

the addition of cryoprotectants, in a preferred embodiment, polyols, preferably mannitol, 2.5% -4%;

addition of a buffer, preferably acetate or phosphate buffer, 2 to 100 millimoles (mmol), preferably 3 to 5 millimoles; and

the addition of preservative, wherein BAK0.015% is preferred.

Muscarinic agonists

The present invention also relates to an ophthalmic composition comprising a muscarinic agonist, preferably a nonionic surfactant which exceeds its critical micelle concentration for the composition, and a viscosity enhancing agent; or alternatively, a gelling agent in situ. In a preferred embodiment, the low shear (1/s) initial viscosity of the topically applied composition is greater than 20cps, preferably 50cps, and more preferably greater than 70cps.

Muscarinic agonists include selective alpha-2 agonists, which selective alpha-2 agonists may be included in the compositions of the invention or administered topically if the sensitive subject requires additional means of reducing nasal flow or redness, preferably several minutes ago or less preferably several minutes later. Selective alpha-2 agonists suitable for the present invention have minimal alpha-1 agonist activity at low concentrations. For example, for brimonidine or fardomidine, 1% to 2% w/v is considered extremely high, and 0.5% to 1.0% w/v is still highly induced and toxic by the alpha-1 receptor for the purposes of the present invention. Further, 0.10% to 0.5% w/v is still too high, and even 0.070% to 0.10% w/v is associated with a higher incidence than the preferred incidence of rebound congestion (however, for dexmedetomidine its stronger lipophilicity and intraocular permeability reduces the risk of rebound within this range). Only 0.065% w/v or less is potentially acceptable, with 0.050% w/v or even more preferably 0.035% w/v or less being desirable for most alpha-2 agonists, depending on the degree of selectivity. On the other hand, a degree of useful activity may occur at further reduced concentrations of one or more orders of magnitude. In a preferred embodiment of the invention, brimonidine, fampridine and guanfacine preferentially stimulate the alpha-2 adrenergic receptor, and even more preferably the alpha-2 b adrenergic receptor, such that the alpha-1 adrenergic receptor is not stimulated sufficiently to cause excessive aortic arteriole constriction and vasoconstrictor ischemia. In addition, agents that have been found to directly cause redness in other ways, such as acetylcholinergic agonists, aceclidine, prevention or alleviation of redness, have increased compliance with sensitive subjects that cause redness or nasal congestion even with formulations of the invention that do not include an alpha-2 agonist. However, since alpha-2 agonists are turned to their ionic equilibrium, the fact that acidic pH is offset by the fact that such agonists exert a greater effect under neutral or alkaline pH conditions. Thus, when added to a composition of the invention containing aceclidine, each alpha-2 agonist has a preferred pH range, depending on its lipophilicity and pKa value. For the present invention, a preferred embodiment is a pH of 5.5 to 7.5, and more preferably 6.5 to 7.0, although a pH range of 5.0 to 8.0 can be tolerated. Further, it has been found that cyclodextrin and/or polyoxyl 40 stearate, when included in the composition as a non-ionic surfactant component or as the sole non-ionic surfactant, results in a stronger whitening effect when an alpha-2 agonist is included in the composition, rather than poloxamer 407. The alpha-2 agonist may optionally be used alone or in certain preferred embodiments with formulations of the invention that do not include an alpha-2 agonist, such as those formulations that use polyoxyl 40 stearate 5.5% w/v as a nonionic surfactant, although an alpha-2 agonist is not necessary except for occasional sensitive subjects. For the purposes of the present invention, fampridine represents the alpha-2 agonist with the highest hydrophilicity and thus high surface fixation. Guanfacine is also highly selective and hydrophilic. Brimonidine is highly selective while being moderately lipophilic. Finally, dexmedetomidine has high selectivity and high lipophilicity, which can be used for the purposes of the present invention, with low redness-reducing efficacy (although fatigue as a side effect may be caused in some patients). In a preferred embodiment, 5.5% w/v polyoxyl 40 stearate is used; CMC0.80% w/v; naCl0.037% w/v; ethylenediamine tetraacetic acid ("EDTA") 0.015% w/v, borate buffer 5mM and BAK0.007% w/v, resulted in 1.0 to 1.5 out of about 4 reddening, for a brief period of about ten minutes, and 30 minutes returning to about baseline.

In one embodiment, the selective alpha-2 adrenergic receptor agonist is a compound having an affinity of about 900-fold or greater, even more preferably about 1000-fold or greater, and most preferably about 1500-fold or greater.

The selective alpha-2 adrenergic receptor agonist can be at about 0.0001% to about 0.065% w/v; more preferably, about 0.001% to about 0.035% w/v; even more preferably, about 0.01% to about 0.035% w/v; and even more preferably, from about 0.020% to about 0.035% w/v.

In one embodiment, the selective alpha-2 adrenergic receptor is selected from brimonidine, guanfacine, fampridine, dexmedetomidine, (+) -(s) -4- [1- (2, 3-dimethyl-phenyl) -ethyl ] -1, 3-dihydro-imidazole-2-thione, 1- [ (imidazolidin-2-yl) imino ] indazole (1- [ (imidozolididin-2-yl) imino ] indazole), and mixtures of these compounds. Analogs of these compounds that act as highly selective alpha-2 agonists may also be used in the compositions and methods of the invention.

In a more preferred embodiment, the selective alpha-2 agonist is selected from the group consisting of fampridine, guanfacine, and brimonidine. In still more preferred embodiments, the selective alpha-2 agonist is brimonidine in salt form at a concentration of 0.025% to 0.065% w/v, more preferably 0.03% to 0.035% w/v. In a preferred embodiment, the salt is a tartrate salt.

In yet a more preferred embodiment, the selective alpha-2 agonist is fampridine in the form of a hydrochloride ("HCl") salt at a concentration of about 0.005% to about 0.05% w/v, more preferably 0.02% to about 0.035% w/v.

In yet another more preferred embodiment, the selective alpha-2 agonist is guanfacine in the form of a HCl salt at a concentration of about 0.005% to about 0.05% w/v, more preferably 0.02% to about 0.035% w/v.

In yet a more preferred embodiment, the selective alpha-2 agonist is dexmedetomidine in the form of a HCl salt at a concentration of about 0.005% to about 0.05% w/v, more preferably 0.04% to about 0.05% w/v.

In another preferred embodiment, a pH below physiological pH is found to enhance the whitening effect of brimonidine, preferably pH4.5 to 6.5, and more preferably pH5.5 to 6.0. However, redness reduction is achieved at all pH, enhancement of aceclidine absorption occurs only at alkaline pH conditions, so better action occurs at a given concentration, and thus while effective at a pH range of 4.5 to 8.0, a pH range of 6.5 to 7.5 is preferred for the present invention, and 7.0 to 7.5 is most preferred.

The invention also relates to an ophthalmic composition comprising a muscarinic agonist and further comprising ciliary muscle paralysis. The surprising and completely unexpected discovery of the present invention is that certain ciliary muscle paralytic agents may be combined with miotic agents, particularly for the present invention, aceclidine without reducing miotic occurrence, intensity or duration; and consistent with the time of peak absorption in the aqueous formulation, further blunting spikes (spikes) commonly associated with miotic effects to provide a constant relationship of miosis to time after 15 to 30 minutes to 6 to 10 hours after onset, depending on the desired formulation. The addition of the ciliary muscle paralysis agent also reduces any residue-related discomfort that may occur rapidly after a partial instillation, which is most likely the result of ciliary muscle cramps or excessive pupil constriction.

Ciliary muscle paralysis agents suitable for use in the present invention include, but are not limited to, atropine,(cyclopentene hydrochloride), scopolamine, pirenzepine, topiramate, atropine, 4-diphenylacetoxy-N-methylpiperidine methyl bromide (4-DAMP), AF-DX384, methoxamine, trimipramine (tripitramine), darifenacin, solifenacin (Wei Xikang), tolterodine, oxybutynin, ipratropium, oxitropium bromide, tiotropium bromide (spriva) and ortzepamide (also known as AF-DX 116 or 11- { [2- (diethylamino) methyl)]-1-piperidinyl } acetyl]-5, 11-dihydro-6H-pyrido [2,3b][1,4]Benzodiazepine-6-one). In a preferred embodiment, the ciliary muscle paralytic agent is topiramate at a concentration of about 0.004% to about 0.025% w/v, more preferably about 0.005% to about 0.015% w/v, and still more preferably about 0.005% to about 0.011% w/v, about 0.005% to about 0.007% w/v, and about 0.005% to about 0.006% w/v. In another preferred embodiment, the ciliary muscle paralytic agent is a mixture of topiramate (at a concentration of about 0.04% to about 0.07% w/v) or pirenzepine or ortvandula (at a concentration of about 0.002% to about 0.05% w/v).

In a preferred embodiment, topiramate is found to slightly reduce supraorbital neuralgia by 0.01% w/v, further reduce supraorbital neuralgia by 0.030% w/v, and completely eliminate supraorbital neuralgia by 0.04% to about 0.07% w/v without reducing the average miosis diameter throughout the duration of action. In a preferred embodiment, topiramate shows a completely unexpected sensitivity of action, wherein supraorbital neuralgia and ciliary spasticity pain are unexpectedly and very effectively reduced or eliminated at about 0.04% w/v, and very significantly further reduced at 0.042% w/v, and in a preferred embodiment disappeared at 0.044% w/v without producing ciliary paralysis (surprisingly, due to its conventional use as a pupil expander). However, topiramate does not reduce the average degree of pupil constriction, the time of occurrence of pupil constriction, or the subsequent visual benefits. In contrast, topiramate blunts the maximum pupil constriction seen in aqueous formulations to produce a smooth consistent pupil-contracting effect over time. It allows for the modulation of peak pupil constriction to achieve a more uniform effect over time without dilation as it was found in previous uses. In particular, in some embodiments, topiramate is useful for preventing transient shrinkage below 1.50mm 30 to 60 minutes after aceclidine and reducing transient excessive and undesirable darkening of vision that would otherwise occur at the peak of onset for about 30 minutes. As an example, a phosphate buffer comprising 1.53% w/v aceclidine, 5% w/vHP βcd, 0.75% w/vCMC, 0.25% w/vcnacl, 0.01% w/vBAK and pH 7.0; or 1.45% w/v aceclidine; 5.5% w/v polyoxyl 40 stearate; 0.80% w/vCMC;0.037% w/vNaCl;0.015% w/v EDTA; ophthalmic compositions of 0.007% w/vBAK and 5mM phosphate buffer pH 7.0 varied from 0.040% w/v topiramate (where moderate darkening was observed) to 0.044% w/v topiramate (where darkening became almost imperceptible except under extremely dim light conditions). This additional pupil size adjustment with the ciliary muscle paralysis agent allows for a concentration of aceclidine sufficient to prolong the effect while inactivating the undesirable concomitant peak excessive constriction and any uncomfortable supraorbital neuralgia. Surprisingly, due to its fugitive nature, topiramate achieves this passivating effect without causing mydriasis. Further, in preferred embodiments, it was found that topiramate 0.014% w/v reduced supraorbital neuralgia, 0.021% w/v further reduced supraorbital neuralgia, 0.028% to 0.060% w/v and in some embodiments up to 0.09% w/v completely eliminated supraorbital neuralgia without producing ciliary paralysis (i.e., paralysis of the ciliary muscles of the eye).

It has been found that for a racemic 50:50 mixture of (+) and (-) aceclidine optical isomers (in some studies (+) is more potent and in other studies (-) is considered to be potentially more potent), the topiramate effect can vary depending on the ratio of aceclidine to topiramate. For example, in an ophthalmic composition of the present invention comprising 1.55% w/v aceclidine, 5.5% w/vHP βcd, or in a preferred embodiment polyoxyl 40 stearate, 0.75% w/vCMC (1% = 2500 centipoise), 0.25% w/vci, and 0.01% w/vBAK and ph7.5, 0.042% w/v topiramate may be different from even 0.035% w/v, the former exhibiting normal indoor night vision, the latter exhibiting a slight darkening which becomes more pronounced at still lower concentrations. At higher concentrations, such as about 0.075% to about 0.090% w/v topiramate, the optimal range of pupil constriction begins to be lost in the range of 1.50mm to 1.80mm, and at higher concentrations significant mydriasis begins to occur. Since the isomer ratio can vary the effective concentration, this must be considered in the expected clinical effectiveness of using aceclidine; for the preferred embodiment of the invention, a polarimeter was used to determine the exact 50:50 isomer ratio used (personal communication Toronto Research Chemicals).

Figure 1 shows the effect of a miotic agent with or without a ciliary paralytic agent and with or without a carrier. The subject was a emmetropic patient over 45 years of age with a baseline near vision of 20.100 and a baseline far vision of 20.20. Local administration of 1% w/v pilocarpine in physiological saline to the eye resulted in an improvement in near vision to 20.40 (8 a), however at the cost of a reduction in far vision to 20.100 (8 b). The addition of 0.015% w/v topiramate increases near vision to 20.25 (9 a) and decreases far vision to 20.55 (9 b), although in some cases some irregular astigmatism (slight spotting areas in the vision reading zone) is caused. Topical administration of 1.55% w/v aceclidine in physiological saline solution resulted in an improvement of near vision to 20.40 (10 a) over an extended period of 6 hours without any effect on baseline distance vision (10 b). 10c and 10d show the effect of administration of aceclidine in a vehicle consisting of 5.5% w/v 2-hydroxypropyl beta cyclodextrin, 0.75% w/vCMC (1% = 2500 centipoise), 0.25% w/vci and 0.01% w/vBAK. As seen in 10c, the carrier improved the beneficial effects of aceclidine, making near vision better than 20.20. As seen in 10d, a similar increase in distance vision occurs. 10e and 10f show the effect of adding 0.042% w/v topiramate to aceclidine carrier. As seen in 10e, near vision improves to 20.15 and maximum visual acuity takes effect faster. As seen in 10f, a similar increase in distance vision occurs. Taken together, fig. 1 shows that aceclidine is capable of temporarily correcting near vision in presbyopic subjects without affecting baseline distance vision. Similar results can be obtained with different miotics, pilocarpine, plus a ciliary paralytic agent such as topiramate. Suitable pharmaceutical carriers may also have beneficial effects.

Surprisingly and unexpectedly it has been found that the topical formulation of the present invention, in particular comprises aceclidine 1.35% to 1.55% w/v;5.5% w/v polyoxyl 40 stearate; 0.80% w/vCMC;0.037% w/vNaCl;0.015% w/v EDTA;0.007% w/vBAK; and a 5mM phosphate buffer, pH7.0, such that contact lens wear and comfort is achieved for a substantial period of time after a single daily dose of topical instillation. The single dose daily use of the preferred embodiment allows subjects with dry eye to sleep with contact lenses for a period of one week, while vision is obscured even before and even at night, and the film coated contact lens requires removal and cleaning or replacement (see example 7).

In a preferred embodiment, the ophthalmic composition of the present invention comprises aceclidine, a cryoprotectant, optionally a ciliary muscle paralysis agent, a nonionic surfactant at a concentration of about 1% to 5% w/v and a viscosity enhancing agent at a concentration of about 0.75% to 1.6% w/v, preferably about 1.25% to 1.5% w/v.

The following representative embodiments are provided for illustrative purposes only and are not intended to limit the invention in any way.

Representative embodiments

In one embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v; and

mannitol at a concentration of about 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v; and

topiramide at a concentration of about 0.02% w/v.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 5.0% w/v;

carboxymethyl cellulose at a concentration of about 1.4% w/v;

BAK at a concentration of about 0.015% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.5% w/v;

NaCl at a concentration of about 0.10% to about 0.50% w/v;

940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

Wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 2.0% w/v;

NaCl at a concentration of about 0.50% w/v;

940 at a concentration of about 1.5% w/v;

BAK at a concentration of about 0.015% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.25.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.25% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

940 at a concentration of about 0.95% w/v; and

BAK at a concentration of about 0.015% w/v;

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.50% w/v;

NaCl at a concentration of about 0.05% w/v;

boric acid at a concentration of about 0.2% w/v;

940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.2% w/v;

940 at a concentration of about 0.9% w/v;

BAK at a concentration of about 0.05% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

Topiramide is present at a concentration of about 0.01% w/v. The method comprises the steps of carrying out a first treatment on the surface of the

Mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 5.0% w/v;

CMC at a concentration of about 1.4% w/v;

BAK at a concentration of about 0.015% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

topiramate at a concentration of about 0.02% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.25% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

940 at a concentration of about 0.95% w/v; and

BAK, at a concentration of about 0.01% w/v,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

topiramate at a concentration of about 0.015% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.75% w/v;

NaCl at a concentration of about 0.05% w/v;

boric acid at a concentration of about 0.2% w/v;

940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises: aceclidine at a concentration of about 1.75% w/v;

topiramate at a concentration of about 0.025% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.2% w/v;

940 at a concentration of about 0.9% w/v;

BAK at a concentration of about 0.05% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.75% w/v;

topiramate at a concentration of about 0.02% w/v;

mannitol at a concentration of about 2.5% w/v;

polysorbate 80 at a concentration of about 0.1% w/v;

NaCl at a concentration of about 0.1% w/v;

boric acid at a concentration of about 0.12% w/v;

940 at a concentration of about 0.95% w/v;

BAK at a concentration of about 0.01% w/v; and

optionally, a phosphate buffer, at a concentration of about 3mM,

wherein the pH is about 5.

In another embodiment, the ophthalmic composition comprises:

Aceclidine at a concentration of about 1.75% w/v;

topiramate at a concentration of about 0.040% w/v;

polysorbate 40 stearate at a concentration of about 5.0% w/v;

mannitol at a concentration of about 2.5% w/v;

optionally, an acetate or phosphate buffer at a concentration of about 3.0mM; and BAK at a concentration of about 0.01% w/v;

wherein the pH of the composition is about 4.75.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.55% w/v;

topiramate at a concentration of about 0.040% w/v;

polysorbate 40 stearate at a concentration of about 5.0% w/v;

citric acid monohydrate at a concentration of about 0.1% w/v;

mannitol at a concentration of about 4.0% w/v;

940 at a concentration of about 0.09% w/v; and

optionally, an acetate or phosphate buffer at a concentration of about 3.0mM; wherein the pH of the composition is about 5.0.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.50% w/v;

topiramate at a concentration of about 0.042% w/v;

polysorbate 40 stearate at a concentration of about 5.5% w/v;

mannitol at a concentration of about 2.5% w/v;

Optionally, a phosphate buffer at a concentration of about 3.0mM;

940 at a concentration of about 0.85% w/v; and BAK at a concentration of about 0.01% w/v;

wherein the pH of the composition is about 4.75.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.45% w/v;

topiramate at a concentration of about 0.042% w/v;

polysorbate 40 stearate at a concentration of about 5.5% w/v;

citric acid monohydrate at a concentration of about 0.1% w/v;

optionally, an acetate buffer at a concentration of about 3.0mM; and

940, at a concentration of about 0.75% w/v,

wherein the pH of the composition is about 4.75.

In another embodiment, the ophthalmic composition comprises:

aceclidine at a concentration of about 1.45% w/v;

topiramate at a concentration of about 0.042% w/v;

polysorbate 40 stearate at a concentration of about 5.5% w/v;

mannitol at a concentration of about 2.0% w/v;

citric acid monohydrate at a concentration of about 0.1% w/v;

optionally, a phosphate buffer at a concentration of about 3.0mM; and940 at a concentration of about 1.0% w/v,

wherein the pH of the composition is about 4.75.

In another embodiment, the ophthalmic composition comprises:

About 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 2.75% w/v polysorbate 80; and

about 1.25%;1.0% -1.80% w/v hydroxypropyl methylcellulose (depending on its molecular weight). In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 0.005% to about 0.011% topiramate;

about 2.5% w/v mannitol;

about 2.75% w/v polysorbate 80; and

about 1.75% w/v aceclidine;

about 0.010% w/v topiramate;

about 2.5% w/v mannitol;

about 5.0% w/v polysorbate 80;

about 1.40% w/v carboxymethylcellulose high viscosity;

optionally, about 3mM phosphate buffer; and

about 0.010% bak=as preservative,

the pH was about 5.0.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 0.006% w/v topiramate;

about 2.5% w/v mannitol;

about 2.5% w/v polysorbate 80;

about 1.25%;1.0% -1.80% w/v hydroxypropyl methylcellulose (depending on its molecular weight); optionally, about 3mM phosphate buffer; and

About 0.020% bak = as preservative,

the pH was about 5.0.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 0.006% w/v topiramate;

about 2.5% w/v mannitol;

about 2.5% w/v polysorbate 80;

about 1.25%;1.0% -1.80% w/v hydroxypropyl methylcellulose (depending on its molecular weight); optionally, about 3mM phosphate buffer;

about 0.50% w/vNaCl; and

about 0.020% bak = as preservative,

the pH was about 5.0.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 3.5% w/v polysorbate 80;

about 0.50% w/vNaCl; and

about 0.020% bak or 0.15% sorbic acid as preservative,

the pH was about 5.0.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 3.5% w/v polysorbate 80; and

about 1.25%;1.0% -1.80% w/v hydroxypropyl methylcellulose (depending on its molecular weight); in another embodiment, the ophthalmic composition comprises:

About 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 3.5% w/v polysorbate 80;

about 1.25%;1.0% -1.80% w/v hydroxypropyl methylcellulose (depending on its molecular weight); and

one or more excipients are selected from about 0.50% w/v sodium chloride, about 0.02% w/v benzalkonium chloride, about 0.10% w/v sorbate, about 0.01% w/v ethylenediamine tetraacetic acid (EDTA), and 0.10% w/v citric acid.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 0.01% w/v topiramate;

about 0.1% w/v sodium citrate, anhydrous;

about 0.02% w/v benzalkonium chloride;

about 0.12% w/v sorbic acid;

about 0.1% w/v disodium ethylenediamine tetraacetate;

about 4.0% w/v polysorbate 80; and

about 1.25% w/v hydroxypropyl methylcellulose,

wherein the pH is about 5.0.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 0.01% w/v topiramate;

about 0.1% w/v sodium citrate, anhydrous;

about 0.02% w/v benzalkonium chloride;

about 0.1% w/v sorbic acid;

about 0.1% w/v EDTA;

about 3.5% w/v polysorbate 80; and

About 1.25%;1.0% -2.25% w/v hydroxypropyl methylcellulose (depending on its molecular weight),

wherein the pH is about 5.0.

In another embodiment, the ophthalmic composition comprises:

about 1.75% w/v aceclidine;

about 2.5% w/v mannitol;

about 0.01% w/v topiramate;

optionally, about 3mM phosphate buffer;

about 0.02% w/v benzalkonium chloride;

about 0.1% w/v sorbic acid;

about 0.1% w/v citrate;

about 3.5% w/v polysorbate 80; and

about 1.25%;0.25% -2.25% w/v hydroxypropyl methylcellulose (depending on its molecular weight);

wherein the pH is about 5.0.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.5% w/v, mannitol at a concentration of 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.55% w/v, mannitol at a concentration of 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.6% w/v, mannitol at a concentration of 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.65% w/v, mannitol at a concentration of 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.7% w/v, mannitol at a concentration of 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.75% w/v, mannitol at a concentration of 2.5% w/v.

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.80w/v, mannitol at a concentration of 2.7% w/v and aceclidine at a concentration of 0.09% w/v940。

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.48% w/v, mannitol at a concentration of 1.5% w/v and aceclidine at a concentration of 0.50% w/v940。

In another embodiment, the ophthalmic composition comprises:

acaclidinium at a concentration of 1.80w/v, mannitol at a concentration of 2.5% w/v and aceclidine at a concentration of 0.9% w/v940。

In certain preferred embodiments, the present invention relates to a composition for treating presbyopia comprising about 1.75% w/w aceclidine, about 4.0% w/w polysorbate 80, about 2.5% w/w mannitol, about 1.2% w/w hydroxypropyl methylcellulose, about 0.1% w/w ethylenediamine tetraacetic acid, about 0.02% w/w benzalkonium chloride, about 0.12% w/w potassium sorbate, and about 0.077% w/w citrate, wherein the pH of the composition is about 5.0.

In certain preferred embodiments, the present invention relates to a composition for treating presbyopia comprising about 1.75% w/w aceclidine, about 4.0% w/w polysorbate 80, about 2.5% w/w mannitol, about 1.2% w/w hydroxypropyl methylcellulose, about 0.1% w/w ethylenediamine tetraacetic acid, about 0.02% w/w benzalkonium chloride, about 0.12% w/w potassium sorbate, and about 0.1% w/w citrate, wherein the pH of the composition is about 5.0.

In certain preferred embodiments, the present invention relates to a composition for treating presbyopia comprising about 1.40% w/w aceclidine, about 2.0% w/w polyethylene glycol stearate, about 2.5% w/w mannitol, about 0.1% w/w ethylenediamine tetraacetic acid, about 0.02% w/w benzalkonium chloride, about 0.12% w/w potassium sorbate and about 0.1% w/w citrate, wherein the pH of the composition is about 5.0.

The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way.

Examples

Example 1 effect of aceclidine on visual acuity in subjects aged 47 to 67 years

Table 1 shows the effect on near-focus ability of presbyopic subjects before and after ophthalmic administration of aceclidine-containing compositions. Each composition included aceclidine and 5.5% w/vHP. Beta. CD, 0.75% w/vCMC, 0.25% w/vNaCl and 0.01% w/vBAK at the concentrations indicated. In addition, the compositions administered to subjects 4 and 5 included 0.125% w/v topiramate. Since aceclidine is an enantiomer, clinical effectiveness varies with the ratio. For the current study, nearly exact 50:50 ratio stereoisomers were measured, as best determined by polarimetry.

TABLE 1 Acetoricidine effect on the visual acuity of presbyopic patients

As shown in table 1, the myopia of the left and right eyes (15 inches of the object from the eye) of all subjects was worse than the perfect near vision (20.20), and the hyperopia of most subjects before application of the composition was worse than the perfect far vision. All subjects experienced an improvement in their near vision lasting from 7 to 12 hours after application of the composition. Surprisingly, most of the subjects also experienced their improvement in far vision during the same time period. Still more surprisingly, the improvement in near points is much closer than 16 "which is typically necessary for comfortable reading, in some cases up to about 8.5", which is more common in individuals 30 or less. The addition of topiramate, a ciliary muscle-paralytic agent, has no additional or deleterious effects on vision correction.

Example 2 concentration Effect of Acetoricidine and Topiramide concentrations

Table 2: concentration effects of concentration of aceclidine and topiramate

#1

#2

#3

#4

#5(OD)

#5(OS)

#6

#7

Brimonidine

0.03％

Poloxamer 407

5.5％

PBCD

5.5％

Acacliding

1.5％

0.75％

1.1％

Topiramide

0.014％

0.021％

0.08％

0.042％

0.062％

NaCl

0.25％

CMC

0.75％

BAK

0.1％

Redness (15 m)

3+

1

0.5

0

Redness (30 m)

1.5

0.5

0.25

0

Neuralgia (60 m)

2+

2

0.5

0.0

Stinging pain (10 m)

2

0.5

0

BD-OD

20.20

BD-OS

20.25

BN-OD

8pt

BN-OS

7pt

BP-photopic vision

3mm

3m

3mm

BP-intermediate vision

5mm

Harmony start (m)

15

Murgantion (OU) (1 hr)

1.63mm

2.0-2.5mm

1.63mm

1.70mm

Remote (OU) (20 m)

20.20

Remote (OD) (1 hr)

20.15+2

20.20

20.15+2

2.15+2

Remote (OS) (1 h)

2.15+2

20.20

20.15+2

Remote (OU) (1 hr)

20.10-3

20.15

20.10-3

Close range (OU) (20 m)

4pt

Time (hr)

12.5

6.5

11

10

Abbreviations: (C) Indicating corrected vision, (m) indicating minutes, (hr) indicating hours, mm indicating millimeters, and BD indicating baseline distance vision; BN represents baseline near vision, BP represents baseline pupil size, OD represents right eye; OS denotes the left eye, and OU denotes both eyes.

All percentages are w/v. "pt" represents the size of the printed material, 4 corresponds to 20/20 vision, and 3 corresponds to 20/15 vision.

"time" refers to the duration of action.

As shown in Table 2, aceclidine at a concentration of at least 1.1% w/v was able to reduce pupil size to 1.63mm after 1 hour of topical instillation, thereby correcting near and far vision for at least 10 hours. The miotic effect was reduced to 2.0-2.5mm after 1 hour by reducing the concentration of aceclidine to 0.75% w/v (formulation # 3), and vision correction continued for only 6.5 hours. The addition of 0.03% w/v brimonidine reduced redness of the eye (4 out of 4 without brimonidine, not shown) to 1.5 out of 4 over 30 minutes after topical instillation, which was maintained throughout the time of vision correction. Changing the nonionic surfactant to HP beta CD (formulations # 2-6) further reduced redness of the eye. While reducing the concentration of aceclidine to 0.75% w/v (formulation # 3) further reduced redness of the eyes, as described above, this also reduced the vision correction duration of the formulation.

In formulations #1-3, supraorbital neuralgia and intraocular stinging were significant, with 2 pain levels out of 4, which were also associated with sensations of mild nausea, gastric discomfort and tiredness. Surprisingly, the addition of the ciliary muscle paralysis agent (topiramate) reduced supraorbital and stinging pain to 0.5 out of 4 and 0 out of 4 respectively, and dissipated after 60 minutes (formulation # 4). Further, increasing the concentration of aceclidine to 1.1% w/v restored the longer duration of vision correction seen in formulation #1-2 without increasing redness of the eye. However, significant supraorbital neuralgia occurred upon re-instillation of formulation #4 at the end of 10 hours. After the partial instillation of formulation #4, formulations #5 (OD) and (OS) with increased topiramate concentrations were partially instilled, alleviating supraorbital neuralgia caused by re-instillation of formulation # 4. At the end of the effective duration of formulation #5, re-instillation of formulation #5 resulted in significant supraorbital neuralgia at the 3 rd partial instillation. Again, in formulation #6, increasing the concentration of topiramate overcomes supraorbital neuralgia. Additionally and unexpectedly, topiramate, although acting as a ciliary muscle-paralytic agent, has no effect on pupil constriction or vision correction. Surprisingly, the addition of topiramate results in an extended duration of optimal pupil size constriction.

To determine the effect of brimonidine on pupil constriction, formulation #7 was administered. Administration of formulation #7 resulted in only a slight decrease in pupil constriction to 1.70mm, with equivalent far vision and near vision enhancement as formulation # 5. The 2-3+ conjunctival injection was recorded.

All baseline vision data is based on vision corrected with presbyopic contact lenses. The subject noted a prominent near vision from 8 inches to the horizon 1.5 hours after instillation. A Marco autorefractor equipped with an infrared camera and superimposed pupil calibration scale was used for all pupil size measurements. Once selected, the image remains on the screen allowing for accurate calibration.

Example 3 Effect of concentration of Acetoricdine, brimonidine, guanfacine, faduo-miadine, topiramide and additives

Table 3: effects of concentration of aceclidine, brimonidine, guanfacine, fampridine, topiramate and additives.

	AB2T	AB4T	AB6T	AB11T	AB12T	PROPH13
							Acacliding	1.55	1.55	1.55	1.55	1.85	1.55
Brimonidine	0.037	0.037	0.037	0.037
							Faduo miazidine						0.037
Guanfacine					0.037
							HPBCD	5.5	5.5	5.5	5.5	5.5	5
Topiramide	0.043	0.043	0.043	0.043	0.042	0.043
							CMC*	0.075	0.075	0.075	0.075	0.075	0.075
NaCl	0.025	0.025	0.025	0.025	0.025	0.025
							BAK	0.01	0.01	0.01	0.01	0.01	0.01
Glycerol	0.1		0.1			0.1
							Poloxamer 188	0.1	0.05
Polyoxyl 40 stearate		0.05
							pH	6.5	7.5	7.5	7.5	7.0	7.5
Nasal obstruction	0	0	0	0	0	0
							Initial stinging pain	0.75	0	1.5	3.5	0	1.5
Stinging for 3min	0.5	0	0	Washing out	0	0
							Reddening, initially	0	0	1	D/C	1	1
Reddening for 15min	0	0	0	D/C	0	0
							Whitening of	0	0	0	D/C	1.5	1.5
Pain and pain	0	0	0	D/C	0	0
							Near vision	20.30	20.15	20.15	D/C	20.15	20.15
Far vision	20.20	20.20	20.20	D/C	20.20	20.20
							Onset of action (min)	20	12	16	D/C	12	16
Duration (hrs)	5.5	7.5	7.5	D/C	7.5	7.5
							Color of	Clear and clear	Yellow colour	Yellow colour	Yellow colour	Yellow colour	Yellow colour
Overall (L)	2.5	3.9	3.8	0	4	3.9

*1％＝2500cps

All percentages are w/v. Nasal obstruction, initial tingling, 3 minutes, initial redness, 15 minutes redness, whitening, pain, and overall 4 points.

"pt" represents the size of the printed material, 4 corresponds to 20/20 vision, and 3 corresponds to 20/15 vision.

Baseline vision is 20.20 binocular distance; 20.70 naked eye right eye near distance; 20.80 left eye near distance (preferably @16 ").

D/C indicates interruption after eye washing due to intolerable stinging.

Aceclidine at a concentration of 1.55% w/v was able to reduce the pupil size to about 1.63mm 30 minutes after topical instillation, such that near and far vision correction to 20.20 or better lasted at least 6 hours, had a significant effect for about 7.5 hours, as shown in table 3. Lowering the concentration of aceclidine to 1.25% w/v (not shown) results in a useful improvement in near vision to about 20.25-20.30, but not as effective at higher dose ranges, alkaline pH results in faster onset, longer duration, and greater efficacy. The addition of brimonidine reduces eye redness (4 out of 4 without brimonidine, not shown) to baseline within 15 minutes after topical instillation, which is maintained throughout the time of vision correction. The addition of 0.10% w/v glycerol significantly reduced stinging. However, the addition of poloxamer 1880.05% w/v and polyoxyl 40 stearate 0.05% w/v instead further reduced the initial stinging, but was more viscous. The combination of 0.1% w/v glycerol, 1880.1% w/v poloxamer was significantly reduced in terms of efficacy, duration, comfort and efficacy at ph 6.5. AB11T does not include glycerol, poloxamer 188 or polyoxyl 40 stearate, which results in substantial stinging and termination of experiments requiring immediate rinsing of the eye after topical instillation. The 0.037% w/v guanfacine in AB12T in place of brimonidine resulted in minimal initial redness, prolonged redness reduction and some degree of whitening, and appeared to generally provide the best aesthetics, although slightly higher concentrations of aceclidine were required for optimal effect.

All baseline vision data is based on vision corrected with presbyopic contact lenses. After 30 minutes of AB4T and AB6T instillation, subjects noted prominent near vision from 8 to 10 inches to the horizon.

AB4T and AB6T were repeated monocular and binocular. When both eyes were treated, substantial improvements in depth perception, near point sensitivity to 3pt (20.15) and near point distance (8 ", 20.20) were noted relative to monocular treatment. Monocular treatment results in poor vision when both eyes are open relative to testing only the treated eyes.

Example 4 Effect of Vinegar Criding, brimonidine, topiramide and additive concentration

Table 4: effects of concentration of aceclidine, brimonidine, topiramate and additives.

As shown in Table 4, formulation #8-9, an increase in brimonidine to 0.42% w/v resulted in a reduction in redness to 0.5, while 0.75% w/vCMC resulted in a thin consistency. Unexpectedly, increasing CMC from 0.75% w/v to 0.80% w/v to 0.87% w/v and increasing NaCl from 0.25% w/v to 0.75% w/v resulted in thicker viscosity and retention time increased from 7 hours to 10-12 hours with reduced drug flow into the nasolacrimal duct in formulation # 10-11. The reduced delivery of the drug to the nasal passages results in less nasal obstruction.

In formulations #13-18, a decrease in aceclidine amount from 1.61% to 1.53% w/v resulted in a pupil size range of 1.8-2.0 mm. As the amount of aceclidine decreases, darkening due to pupil restriction drops straight from 1.5 to 0.5. Specifically, a pupil of 1.8 to 2.0mm produces 41% more light than a pupil of 1.5 to 1.7 mm. Surprisingly, the near depth of the pupil of 1.8 to 2.0mm increases by 1.75D. This only lost 0.25D compared to the beneficial 2.00D seen in the range of 1.5-1.7 mm. Thus, the range of 1.80 to 2.0mm produces 41% more light while still allowing full improvement in near vision for individuals under 60 years old; however, individuals aged 60 years or older still experience full computerized benefits and some enhanced near-distance benefits.

An increase in topiramate concentration from 0.042% w/v (formulation #8- # 11) to 0.044% w/v (formulation #13- # 18) resulted in a negligible reduction in pain. The degree of pain may also be related to the age of the individual. For those individuals under the age of 45, an increase in topiramate concentration to a range of 0.046% to 0.060% w/v may be preferred.

Further, table 4 shows unexpected results, see formulations #13 and #17, wherein an increase in NaCl from 0.25% w/v to a range of 0.50-0.75% w/v resulted in an acceptable redness score of only 1.0, even without the addition of the redness reducing agent brimonidine.

Formulation #15, #16 and #17 all resulted in a combined maximum score of 5 by combining the following benefits: (1) Reduced aceclidine concentration to increase the amount of light produced without significantly affecting the near vision benefits seen in formulations #8- # 12; (2) Increased NaCl concentration, resulting in a further reduction in redness, even in the absence of brimonidine; and (3) increased CMC concentration, resulting in longer residence time on the eye.

Formulation #19 is an excellent alternative to a few individuals with high response of formulations #15- #17 and significant darkening with 1.53% w/v aceclidine. Formulation #20 was an excellent surrogate for a minority of individuals with low response to formulation # 19. Finally, formulation #21 is an excellent alternative to a few individuals who have a low response to formulation #20 and obtain poor pupillary response.

Example 5 comparison of the effects of polyoxyl 40 stearate, HP beta CD and poloxamer 407

Table 5. Effects of polyoxyl 40 stearate, HP beta CD and poloxamer 407 are compared.

	#22	#23	#24
				Acacliding	1.45％	1.45％	1.45％
Topiramide	0.044％	0.044％	0.044％
				Brimonidine	0.040％	0.040％	0.040％
Polyoxyl 40 stearate	5.5％
				HPβCD		5.5
Poloxamer 407			5.5
				CMC	0.80％	0.80％	0.80％
NaCl	0.037％	0.037％	0.037％
				EDTA	0.015％	0.015％	0.015％
BAK	0.007％	0.007％	0.007％
				pH	7.00	7.00	7.00
Phosphate buffer	5mM	5mM	5mM
				Nasal obstruction	0.00	0.50	1.50
Stinging pain	0.25	0.25	0.25
				Moist feel	400	400	4.00
Redness	0.25	0.50	0.50
				Vision blur (< 15 seconds)	0.50	0.50	1.50
Duration of time	6-8hrs	6-8hrs	68hrs
				Overall 0-4	4.00	4.00	4.00

Clinical protocol

The above preparation (# 22- # 23) was administered to 20 presbyopic patients who were corrected over a full distance. All patients received pre-and post-drip far and near visual acuity measurements, zeiss(visante is a registered trademark of calzeiss medical technology, inc.) optical coherence tomography (optical adherence tomography), axial length and contrast sensitivity testing (i.e., colenbrander-Michelson10% Lum target) results were as follows:

all patients achieved 1.5 to 220mm pupil constriction;

no patient experienced ciliary muscle pain, ciliary muscle spasm or induced accommodation;

all patients achieved visual acuity of 20/30+ or better at 14 "and were very satisfactory for their high contrast near vision results with no obvious complaints of burning or pain;

the effect lasts in all cases for a period of 6-8 hours;

binocular vision provides all patients with 1-1.5 additional rows of near visual acuity compared to the monocular test;

testing the last 10 patients at 20 "(i.e., computer distance, cell phone distance), and all achieved near visual acuity of 20/25 or better;

presbyopic persons with moderate hyperopia (approximately +2.25 sphere) uncorrected are very satisfied with far vision acuity in the far and near vision range raised to 20/25 or better levels in the far and near vision range; and

Uncorrected far vision acuity is generally improved for those patients who choose not to routinely correct a slight refractive error.

As shown in table 5, the use of polyoxyl 40 stearate provides the most comfortable aceclidine formulation with minimal visual blurriness and redness. In order to achieve a similar result to formulation #22, formulation #23 requiresA nonionic surfactant at a higher concentration of 10-15%, and formulation #24 required a nonionic surfactant at a higher concentration of 15-20%. Hpβcd causes a color change over time, possibly indicating oxidation.Similar results were obtained with (sulfobutyl ether. Beta. -cyclodextrin).

Example 6 adjustment of aceclidine concentration in a preferred embodiment.

Preferred embodiments:

aceclidine 1.35% -1.55% w/v;

5.5% w/v polyoxyl 40 stearate;

NaCl0.037％w/v；

viscosity enhancers, preferably CMC0.80% w/v or934 or 940 in an amount sufficient to achieve a viscosity of about 5 to 35cps at the time of topical instillation, e.g., at a concentration of about 0.09% to about 1.0% w/v->940；

BAK0.015% w/v; and

optionally, a phosphate, citrate or acetate buffer, about 3 to about 10mM,

wherein the pH is about 4.75 to about 6.0.

For 1.35% w/v aceclidine-

Stinging at local instillation 0.25/4.0 (for about 2-5 seconds);

redness was caused at 10 minutes: 1.0 to 1.5/4.0;

causing redness at 30 minutes: 0.0 to 0.25/4.0;

comfort level: is very high.

Wettability: very high, the eye remained experienced as improved in wettability for most of the time 24 hours after single dose instillation.

Distance depth of focus: excellent.

Near depth of focus: excellent.

In tests on several subjects using the above formulation, it was found that there was a slight difference in clinical effect depending on the concentration of aceclidine, with 1.35% -1.55% w/v aceclidine being preferred, but 1.35% w/v and 1.45% w/v giving the desired benefit to most subjects.

Further, it was found that the clinical effect of 1.35% w/v aceclidine could be improved when instilled as follows:

1) Baseline effect: 1 drop per eye.

2) Enhancement effect: each eye was 2 drops.

3) Better effect: repeating 1) above after 2) above).

4) Maximum effect: repeating the above 2) after the above 2).

Example 7 a preferred embodiment is employed to extend contact lens wear.

Preferred embodiments:

acaclidinium 1.45% w/v;

5.5% w/v polyoxyl 40 stearate;

NaCl0.037％w/v；

viscosity enhancers, preferably CMC0.80% w/v or 934 or 940 in an amount sufficient to achieve a viscosity of about 5 to 35cps, such as a concentration of about 0.09% to about 1.0% w/v, upon topical instillation>940；

BAK0.02% w/v; and

optionally, phosphate, citrate or acetate buffer, about 3 to about 10mM,

wherein the pH is about 4.75 to about 6.0.

As a base line, long wear glasses (AirAir Optix is a registered trademark of nova corporation) only wears these glasses while sleeping overnight. The vision of the subject is blurred every morning when the patient gets up, and the contact lens is required to remove and clean the film and night formed deposits. Distance average vision at bed time: 20.60; near distance average vision on Michelson contrast chart: 20.80.

the formulations were then instilled as single doses between 7 a.m. and 10 a.m. of each day on seven consecutive days. Air is worn by the subject every dayMirror and wear the mirror overnight. Distance vision of the subject every morning when getting up: 20.20+; naked eye near vision 20.40 (consistent with the subject's baseline presbyopia when the subject is not wearing glasses overnight, but is embedded with glasses while getting up).

EXAMPLE 8 polyoxyl 40 stearateComparison of the effects of (sulfobutyl Ether beta-cyclodextrin)

TABLE 6 polyoxyl 40 stearateComparison of the effects of (sulfobutyl Ether beta-cyclodextrin)

As shown in table 6, the exclusion of EDTA resulted in reduced redness and the best overall score in the polyoxyl 40 stearate compositions (formulations #25 and # 26) when polyoxyl 40 stearate was used as a surfactant. Addition of cocamidopropyl betaine ("CAPB") further reduced redness, however resulted in significant pain (formulation # 31). To be used forThe substitution of polyoxyl 40 stearate with (sulfobutyl ether beta-cyclodextrin) and the addition of mannitol achieved similar results in terms of redness reduction as the addition of CAPB to polyoxyl 40 stearate without concomitant pain, resulting in the highest overall score in the aceclidine composition (formulation # 32). After several weeks, contain->The formulation of (sulfobutyl ether β -cyclodextrin) has an orange hue, possibly indicating oxidation.

Example 9 preferred Cold chain composition

Composition and method for producing the same

Aceclidine at a concentration of about 1.40% -1.80% w/v;

topiramate, about 0.42% w/v;

polyoxyl 40 stearate, about 5.5% w/v;

mannitol at a concentration of about 2.5% to 4.5% w/v;

Carbomer 940 at a concentration of about 0.09% to about 2.0% w/v;

optionally, a preservative, such as BAK, at a concentration of about 0.2% w/v;

optionally, citrate at a concentration of about 0.1%;

optionally, acetate or phosphate buffers are used at 2-100mM, more preferably 3-5mM

Wherein the pH of the composition is from about 4.50 to about 5.0; and preferably from about 4.75 to about 5.0; and

wherein w/v represents the weight to volume ratio.

The above composition is administered to a subject 62 years old. Which results in a pupil of 1.8-1.9mm ou, 20.20+ reading vision and 20.20+ distance vision; however, the absence of carbomer 940 reduced the effect of 2.5% mannitol production and did not produce near vision effect at 4% mannitol. No ciliary muscle spasms or loss of distance vision are produced. Onset of action within about 15 minutes. In the absence of the alpha agonist vasoconstrictor, a brief redness of about 1 + of 4 was observed for about 20 minutes. The presence or absence of BAK has no clinical effect and is used to provide an optional preservative.

EXAMPLE 10 stabilized Acetorickettsia customization

The compositions tested:

aceclidine at a concentration of about 1.50% w/v;

topiramate at a concentration of about 0.042% w/v;

polyoxyl 40 stearate at a concentration of about 5.5% w/v;

Mannitol at a concentration of about 2.5% w/v;

citrate at a concentration of about 3mM;

wherein the pH of the composition is about 4.75.

20 samples of the above composition were evenly separated and stored at 25℃and 4 ℃. Prior to storage, the initial concentration of aceclidine was measured using high performance liquid chromatography ("HPLC"). The content of aceclidine in each solution was calculated by comparing the area under the main peak with a reference solution of aceclidine. The samples were then stored for 3 months. Measurements of aceclidine were performed at 1, 2 and 3 months. The results of the stability test are shown in table 7.

TABLE 7 stability of Acetoricdine in Cold chain storage

As shown in table 7, "cold chain storage" or storage of aceclidine compositions at 2 ℃ to 8 ℃ resulted in a significant increase in stability of aceclidine at all 3 time points.

EXAMPLE 11 use of compositions containing little or no ciliary paralytic Agents

Aceclidine alone causes severe ciliary cramps (supraorbital neuralgia) and myopia blur that occur like migraine. These effects are inversely related to age, subjects aged 40 report the highest incidence, and subjects 60+ report the lowest incidence. Addition of the ciliary muscle paralysis agent reduces ciliary muscle spasms and concomitant supraorbital neuralgia, migraine, periocular compression pressure, or other symptoms of ciliary muscle spasms. Surprisingly, the addition of a cycloplegic agent does not reduce the myopic effect of aceclidine. However, the addition of 2.5% w/v mannitol may reduce the myopic effect of aceclidine. Increasing aceclidine concentration overcomes the decrease in near vision effect seen with mannitol addition. Surprisingly, however, the increase in aceclidine is not consistent with the increase in ciliary muscle spasms. Even more surprisingly, the concentration of the ciliary paralytic agent in the presence of mannitol can be reduced or even eliminated without increasing ciliary spasm. Thus, higher concentrations of aceclidine may be used in combination with little to no cycloplegic agent in the presence of mannitol, resulting in improved myopia acuity without concomitant side effects, as would lower concentrations of aceclidine and higher concentrations of cycloplegic agent in the absence of cycloplegic agent.

Further and unexpectedly, the addition of nonionic surfactant increases the quantitative measure and duration of near vision improvement. The effect is concentration sensitive. In a preferred embodiment, the nonionic surfactant is at least 1%, preferably at least 2%, more preferably from about 1% to about 5%, and most preferably about 5%. For example, polysorbate 80 or polyoxyl 40 stearate concentrations of about 1% to about 5% w/v result in improvements of about 1.5 to about 2.0 lines and durations of about 4 to about 5 hours.

Without being bound by a particular theory, the increase in surfactant concentration may cause it to accumulate at the surface of the cornea of the eye, and at optimal concentrations, this accumulation results in small and possibly nanometer diameters, with nonionic being most preferred in view of the bipolar nature of the surfactant, which enhances absorption of the encapsulated highly polar aceclidine molecules by the cornea of the eye.

Further addition of the viscosity enhancing agent alone does not increase the duration. Surprisingly, the addition of a viscosity enhancing agent to a formulation having an optimal ratio of aceclidine, topiramate and a nonionic surfactant significantly increases the duration. For example, a formulation of the invention comprising 1.75% aceclidine, 2.5% mannitol, 0.01% topiramate, 5% polysorbate 80, increases near vision in presbyopic subjects by up to 3 lines of near vision acuity for about 4 to about 5 hours. The addition of 1.4% cmc further improves near vision improvement to about 7 to about 10 hours. Without being bound by a particular theory, the threshold above the critical micelle threshold greatly enhances penetration of the cornea by reducing the micelle size from microns to nanometers. See fig. 2.

Examples of compositions with little or no ciliary muscle-paralytic agent are shown in table 8 below.

TABLE 8 compositions with little or no ciliary paralytic agent

Table 8 (subsequent Table)

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Table 8 (subsequent Table)

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Table 8 (subsequent Table)

All concentrations are in weight to volume ratio.

mm represents millimeters.

cm represents cm.

min represents minutes.

The% represents an amount that may optionally vary from about 0.01% to about 1% w/v.

# indicates that the agent may or may not comprise polysorbate 80.

The ciliary muscle spasticity score is as follows: 0 = no discomfort; 0.5 =light stinging; 1 = significant squeeze/discomfort; 2 = pain for less than 30 minutes; 3 = pain for 1 hour or more; and 4 = pain severe to intolerable.

Efficacy index is shown in figure 3. Briefly, the score is calculated by multiplying the line of improvement in near visual acuity by the number of hours of duration of improvement. For example, a score of 5 equals improvement in near visual acuity +1 line for 5 hours; 10 points equals improvement in near visual acuity +1.5 lines for 6.7 hours; 15 lines equivalent to improvement of near visual acuity for 7.5 hours; 20 minutes equals 2.5 lines of improvement in near visual acuity for 8 hours; 25 is equivalent to 3+ lines of improvement in near visual acuity for 8.3 hours and 35 is equivalent to 3.75+ lines of improvement in near visual acuity for 9 hours.

Formulations containing 1.40% or more of aceclidine are more beneficial in correcting presbyopia than those containing 1.25% of aceclidine, as evidenced by comparison of the readings vs. baseline at 40cm and the efficacy index of formulations #l33—#l37. Conversely, a lower concentration of aceclidine results in a better overall comfort to the user. Adding 2.5% mannitol to a formulation containing 1.45% aceclidine increases overall comfort, but at the cost of reducing the corrective effect of presbyopia (compare #l33 and #l47). The addition of 4.0% mannitol aggravates the decrease in near vision improvement (compare #L47 and #L48). Increasing the concentration of aceclidine to 1.65% or 1.75% overcomes the decrease in near vision improvement following mannitol addition (compare #L47 with #L49 and #L50).

Further, formulations containing 1.75% aceclidine and 2.5% mannitol have increased efficacy and duration in treating presbyopia, which correlates with an increase in polysorbate 80 to 5.0% and a decrease in CMC from 1.45% to 1.40% negatively (compare formulations #l66 to #l78). #L77, #L78 and #L85- #L94 are optimal formulations, each of them having a maximum number of lines of visual acuity of 3.5 to 3.75 and a maximum efficacy index score of 25 to 34, as well as a maximum duration of 7 to 9 hours, read at 40 cm. The increase in potency and duration of #l66 to #l78 formulations also correlated inversely with the decrease in topiramate from 0.0275% to 0.01%. The same trend was also demonstrated by the increase in efficacy (i.e., 40cm reading vs. baseline) when comparing #l85 to #l94.

This data shows that mannitol is effective in reducing aceclidine induced ciliary muscle spasms, thereby reducing the need for cycloplegic agents such as topiramate. Further, the data indicate that the addition of nonionic surfactant and viscosity enhancing agent can further improve the efficacy and duration of compositions comprising aceclidine, mannitol, and low topiramate. The data also shows that the use of a ciliary paralytic agent in a aceclidine composition containing polysorbate 80 and CMC is most beneficial for the correction of presbyopia when the ciliary paralytic agent is closer to 0.006% than 0.025%. Finally, the data indicate that a composition comprising aceclidine and mannitol is sufficient to correct presbyopia with concomitant tolerable pain.

Example 12 use of further Gao Tuobi kamine formulation

The following examples are aceclidine formulations containing more than 0.03% topiramate.

Table 9. Gao Tuobi Carbamine formulations

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Formulations containing about 1.40% to about 1.45% aceclidine, about 0.035% to about 0.04% topiramate, about 5.5% polyoxyl 40 stearate, and about 0.75% cmc are nearly, but not entirely, as effective in treating presbyopia as formulations containing about 1.65% to about 1.75% aceclidine, about 2.5% mannitol, about 5% polysorbate 80, about 1.40% cmc as shown by formulations #l39—#l41 and as compared to formulations #l74#l78 in table 8. This effectiveness is significantly reduced when topiramate is increased to about 0.05% to about 0.08% topiramate.

EXAMPLE 13 use of mannitol-containing compositions

Preparation:

acaclidinium 1.75% w/v

Topiramide 0.006% w/v

Mannitol 2.5% w/v

Polysorbate 802.75% w/v

NaCl 0.5％w/v

Hydroxypropyl methylcellulose 0.5% -1.80% w/v

Phosphate buffer 3mM

Ph5.0, and

BAK 0.020% as preservative.

The method comprises the following steps:

the subject instills 2 drops of the above formulation in each eye and wipes off excess from the eyelid and eyelashes.

Results:

note that within 20 minutes, visual acuity improved by about 3 lines of near vision with very slight darkening. The near vision remains enhanced throughout the day without loss of far vision. Further, the distance vision is improved if the subject has previously had any mild refractive error. Within 5-8 hours, the pupil began to recover slightly, and after a few hours, minimal darkening was no longer noted. At an earlier time of the day, as the pupil slightly increases from its smallest size, excellent near vision near the beginning, and possibly still slightly continues to improve near vision.

EXAMPLE 14 optimization of use of the preferred embodiments of Topiramide and hydroxypropyl methylcellulose

Composition and method for producing the same

Acaclidinium 1.75% w/v

Topiramide 0.010% w/v

Mannitol 2.50% w/v

Polysorbate 80.50% w/v

NaCl 0.50％w/v

HPMC 1.25％w/v

BAK 0.02％w/v

Phosphate buffer 3mM

pH 5.00

Method

The subject instilled 2 drops of the above formulation in each eye, 1 drop per eye, and 2 drops after 5 minutes.

Results:

comfort, duration and efficacy were evaluated. Stinging was minimal at the time of instillation and within the first hour, 0.25 points out of 4. Redness was also minimal within the first hour, and 0.5 points out of 4 were assessed at 20 minutes. The onset of vision improvement occurs the first 20 to 25 minutes after instillation. Baseline near vision (i.e., 40 cm) improved visual acuity by 3.5 lines. Near vision improvement lasted 8.5 hours. The formulations were compared to those in table 8 with a efficacy index score of 29.75. The use of HPMC at 1.65% w/v instead of HPMC at 1.80% w/v resulted in a slight decrease in near vision improvement to 3.25 lines of visual acuity and a slight decrease in duration to slightly above about 6 hours. The formulations were compared to those in table 8 with a efficacy index score of 19.5.

EXAMPLE 15 use of Compounds containing mannitol and various nonionic surfactants

Composition and method for producing the same

Table 10 lists examples of active ingredients, excipients and their concentration in the compositions, as well as the tested and expected nonionic surfactants.

Method

The subject instills 2 drops of the above formulation independently in each eye and wipes off excess from the eyelid and eyelashes.

Results

All of the nonionic surfactants tested showed significant near vision improvement. Of those tested, only35 are marginal due to significant cornea irritation, hyperemia and reduced duration. Polysorbate 80 and poly 35 castor oil are most preferred, and polyoxyl 40 stearate and poloxamer 407 are also excellent. However, polyoxyl 40 stearate causes precipitation reactions with cellulose viscosifiers and adds other stability problems.

The comfort and duration of each nonionic surfactant was also tested and recorded in table 10. Stinging and redness are based on a score of 0 to 4, 0 being absent and 4 being the most severe. Except for35, tingling and redness are slight to almost no. The duration of each nonionic surfactant tested was excellent.

TABLE 10 comparison of efficacy and comfort of various surfactants

EXAMPLE 16 use of Compounds containing optimal surfactants and antioxidant additives and concentrations

Composition and method for producing the same

Acaclidinium 1.75% w/v

Topiramide 0.010% w/v

Mannitol 2.50% w/v

Polysorbate 80.00% w/v

NaCl 0.00％w/v

HPMC 1.25% w/v (high MW equivalent to a viscosity of about 400cps units)

BAK 0.02％w/v

Sorbate 0.12% w/v

BAK 0.02％w/v

EDTA 0.01％

Citrate buffer 3mM

pH 5.00

Method

2 subjects instilled 2 drops of the above formulation in each eye, approximately 5 minutes apart.

Results:

comfort, duration and efficacy were evaluated. For each subject, stinging was minimal at instillation and within the first hour, 0.50 minutes out of 4, for about 15 seconds. Redness was also minimal within the first hour for each subject, assessed as 0.25 point out of 4 points at 20 minutes. The onset of vision improvement occurs the first 20 to 25 minutes after instillation. For subject 1, baseline near vision (i.e., 40 cm) improved visual acuity for lines 4.0-4.25 for 11.5 hours. For subject 2, baseline near vision improved visual acuity by 3.5 lines for 9.5 hours. Efficacy index scores were 47.38 and 33.25, within the highest range achieved for any formulation.

EXAMPLE 17 Acetoclidine composition for Cold chain storage (contemplated)

TABLE 11 Cold chain storage compositions

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Table 11 (follow) Cold chain storage composition

Method

Under a nitrogen blanket, aceclidine cold chain storage compositions CS #1-5 and 11-20 were filled into vials, respectively, and then the remaining headspace was purged with nitrogen. CS #6-10 was filled into vials under ambient air and headspace, respectively. 1 each composition of the vial was stored at 25 ℃, and the other vial was stored at 5 ℃.

Results

TABLE 12 stability of Acaclidinium Cold chain storage compositions

TABLE 12 (follow-up) stability of Acacliding Cold chain storage compositions

As shown in FIG. 4, CS #3-5 containing 0.10% sodium ascorbate, 0.10% sodium bisulfate, or 0.10% sodium metabisulfite was stable at 25℃for about 2 months and at 5℃for about 26 months.

As shown in table 12, the vials were filled under a nitrogen blanket and headspace nitrogen purge, resulting in an increase in refrigeration stability of 4-5 months. The addition of HPMC further increased the stability for an additional 3 months; sodium citrate, sodium bisulfate or sodium metabisulfite is further added for another 3 months; and further addition of sorbic acid and BAK increased the length of stability by an additional 2 months. CS #20 increased stability for up to 22 months.

Example 18 inStability in liner bags

The aceclide formulation of the present invention was placed in a container, which was then placed in biaxially oriented polyethylene terephthalate liner bags at-20, 5 and 25 ℃ for up to 3 months. Acetoclindine total related substances were recorded at 1, 2, 3 and 6 months. The results of this study can be shown in table 13 below.

UsingAs a source of biaxially oriented polyethylene terephthalate. Mylar is a registered trademark of DuPont Di film America, inc. and is available from that company.

Table 13. Acetoclindine total related substances after storage.

As shown in Table 13, useThe liner bag helps to maintain aceclidine efficacy by reducing degradation rate. Specifically, the total% change of the unpackaged (Unpouched) at room temperature (25 ℃) was compared to the total% change of the Pouched (Pouched) at room temperature (25 ℃) to-0.05% and 0.041%.

EXAMPLE 19 Acetoclindine efficacy after storage

The aceclide formulation of the present invention was placed in a container, which was then placed in biaxially oriented polyethylene terephthalate liner bags at-20, 5 and 25 ℃ for up to 3 months. Aceclidine efficacy was recorded at 1, 2, 3 and 6 months. The results of this study can be shown in table 14 below.

TABLE 14 Acetoclidine efficacy after storage

As shown in table 14, storage at 5 ℃ was used to help maintain aceclidine efficacy. Specifically, the total% efficacy change of non-bagged (Unpouched) at room temperature (25 ℃) was compared to 0.8% change of non-bagged (Unpouched) at refrigerated (5 ℃) with an initial result of 99.70%; the total% efficacy change of 3.6% for non-bagged (Unpouched) at room temperature (25 ℃) and 2.6% for non-bagged (Unpouched) at refrigerated (5 ℃) were compared, with an initial result of 99.60%.

Claims

1. A method of stabilizing an ophthalmic drug, the method comprising the steps of:

b) Filling the composition from step a) into a container; and

c) The container is stored at a temperature of about 2 ℃ to about 25 ℃.

2. The method of claim 1, wherein the ophthalmic drug is selected from aceclidine, latanoprost, and combinations thereof.

3. The method of claim 1, wherein the ophthalmic drug is aceclidine.

4. The method of claim 1, wherein the surfactant is selected from the group consisting of polysorbate, poloxamer, alkyl polyethylene glycol, cyclodextrin, ammonium dodecyl sulfate, sodium diisooctyl succinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctane sulfonate, sodium lauroyl sarcosinate, sodium myristeth sulfate, sodium alkyl polyether sulfate, sodium stearate, lignin sulfonate, sodium laurate, alpha olefin sulfonate, ammonium dodecyl sulfate, sodium dodecyl sulfate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkyl dimethyldichlorobenzyl ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetrimonium bromide, cetoamide, alkylamphoacetate, alkenylamphoacetate, alkenylamphodiacetate, alkylamphopropionate, alkylamphopyl sulfobetaine, and combinations thereof.

5. The method of claim 1, wherein the viscosity enhancing agent is selected from the group consisting of gums, cellulose derivatives, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymers, and combinations thereof.

6. The method of claim 1, wherein the viscosity at 25 ℃ at a shear rate of 1 per second is about 150 centipoise or more.

7. The method of claim 6, wherein the viscosity at 25 ℃ at a shear rate of 1 per second is about 300 centipoise or more.

8. The method of claim 1, wherein the temperature is about 2 to about 8 ℃.

9. The method of claim 8, wherein the container is stored at a temperature of about 5 ℃.

10. The method of claim 1, wherein the composition is filled into the container under an inert gas blanket.

11. The method of claim 1, wherein the filling step creates a headspace in the container and the headspace is purged with an inert gas.

12. The method of claim 1, wherein the container comprises a closure and a vessel, wherein a portion of the closure and a portion of the vessel are sealed with a leaching resistant material selected from the group consisting of biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

13. The method of claim 1, wherein the container is disposed in a second container formed of or lined with a leaching resistant material selected from biaxially oriented polyethylene terephthalate, polytetrafluoroethylene, and aluminum foil.

14. A container containing an ophthalmic drug, the process of preparation comprising the steps of:

a) Providing a container;

c) Capping the container; and

c) The container is stored at a temperature of about 2 to about 25 ℃.

15. The container of claim 14, wherein the ophthalmic drug is selected from aceclidine, latanoprost, and combinations thereof.

16. The container of claim 14, wherein the ophthalmic drug is aceclidine.

17. The container of claim 14, wherein the surfactant is selected from the group consisting of polysorbate, poloxamer, alkyl polyethylene glycol, cyclodextrin, ammonium dodecyl sulfate, sodium diisooctyl succinate, sodium laureth sulfate, linear alkylbenzene sulfonate, sodium dodecyl sulfate, perfluorooctane sulfonate, sodium lauroyl sarcosinate, sodium myristeth sulfate, sodium alkyl polyether sulfate, sodium stearate, lignin sulfonate, sodium laurate, alpha olefin sulfonate, ammonium dodecyl sulfate, sodium dodecyl sulfate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, alkyl dimethyldichlorobenzyl ammonium chloride, dequalinium chloride, phenamylinium chloride, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, cetrimonium bromide, cetoamide, alkylamphoacetate, alkenylamphoacetate, alkenylamphodiacetate, alkylamphopropionate, alkylamphopyl sulfobetaine, and combinations thereof.

18. The container of claim 14, wherein the viscosity enhancing agent is selected from the group consisting of gums, cellulose derivatives, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidone, gellan, carrageenan, alginic acid, carboxyvinyl polymers, and combinations thereof.

19. The container of claim 14, wherein the viscosity at 25 ℃ at a shear rate of 1 per second is about 150 centipoise or more.

20. The container of claim 19, wherein the viscosity at 25 ℃ at a shear rate of 1 per second is about 300 centipoise or more.

21. The container of claim 14, wherein the container is stored at a temperature of about 2 to about 8 ℃.

22. The container of claim 21, wherein the container is stored at a temperature of about 5 ℃.

23. The container of claim 14, wherein after step b) and before step c), the headspace created during the filling step is purged with an inert gas.

24. The container of claim 14, wherein the inert gas is nitrogen.