WO2021195256A1 - Pharmaceutical preparation - Google Patents

Abstract

Provided herein are pharmaceutical preparations comprising an aqueous ophthalmic composition that comprises a therapeutically effective amount of WS-12 (1R,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxy lie acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia in a subject, wherein the amount of WS-12 per dose in the aqueous ophthalmic composition is not cytotoxic, and the aqueous ophthalmic composition is housed in a package formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof. The housing of such an aqueous ophthalmic composition in such a package provides a residual rate, i.e. the amount of active WS-12 contained in such an ophthalmic aqueous composition after exposure to an external effects such as light, high temperature of at least about 40° C, increased humidity of up to 25%, or any combination thereof for 1, 2, 3 or more months of at least 80%, at least 90%, at least 95% or at least 98% or more as compared to the amount of active WS-12 in such an aqueous ophthalmic composition before such exposure to any of the external effects.

Description

PHARMACEUTICAL PREPARATION

RELATED APPLICATIONS

[0001] This application claims priority of U.S. provisional patent application no. 62/994,149, filed March 24, 2020, the entire content of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates generally to a pharmaceutical preparation and the like.

BACKGROUND OF THE INVENTION

[0003] Wetness of the ocular surface and other exposed mucosae is maintained by a continuous aqueous fluid secretion produced by exocrine glands. Disturbances of this process lead to eye, mouth and vaginal dryness syndromes that are highly prevalent, particularly among aged persons (Moss, S. E., et al. 2008. Optom. Vis. Sci. 85:668-674; Barker, K. E. & Savage, N. W. 2005. Aust. Dent. J. 50:220- 223; Leiblum, S. R., et al. 2009. I. Sex Med 6:2425-2433). In the eye, basal tear flow is adjusted to variations in environmental conditions and blinking rate. Tear flow occurring in the absence of emotional or exogenous irritant stimuli (‘basal’ tear secretion) is adjusted to variations in environmental conditions and blinking rate (Dartt, D. A. 2009, Prog. Retin. Eye Res. 28:155-177). Tearing also increases markedly upon ocular surface irritation (Acosta, M. C. et al. 2004. Invest Ophthalmol. Vis. Sci. 45:2333-2336). Irritating stimuli are detected by mechano-nociceptor and polymodal nociceptor trigeminal nerve endings sensitive to injurious mechanical forces, noxious heat and irritant chemicals, that evoke pain (Belmonte, C., et al. 2004. Exp. Eye Res. 78:513-525) and irritation-induced tearing. However, the neural structures responsible of sensing ocular surface dryness to regulate basal tearing rate remain undefined.

[0004] Xerophthalmia or dr eye syndrome is a disease characterized by persistent dryness of the conjunctiva and opacit of the cornea. As used herein, xerophthalmia also encompasses the disorder known as meibomian gland dysfunction, or MGD.

[0005] Multiple causes can lead to xerophthalmia, which is more common in elderly people. Among the diseases or disorders that cause or are related to xerophthalmia are, reduced function, inflammation or obstruction of the meibomian glands, vitamin A deficit, Sjogren syndrome, rheumatoid arthritis and other rheumatologic diseases, chemical or thermal bums, drugs such as atenolol, chlorpheniramine, hydrochlorothiazide, isotretinoin, ketorolac, ketotifen, levocabastin, levofloxacin, oxybutynin, or tolterodine.

[0006] Treatments used to treat xerophthalmia include corticosteroids, which may be effective in early stages of the disease, vitamin A supplements and pilocarpine, which is a drug that increases tear production. Among improving dryness preparations (artificial tears) solutions of hydroxypropyl methylcellulose and carbomer gels, which are applied to the conjunctiva, are used. However, these treatments have clear limitations regarding their respective efficacy and toxicity. Therefore, there is a need to provide new improved treatments for xerophthalmia.

[0007] US Patent 9095609 (US’609 patent) and its family members, i.e. US9433679, US9901549, and US 10028920, all of which are hereby in incorporated by reference herein in their entireties, disclose, inter alia, a new, useful and unobvious pharmaceutical ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide for effectively treating or reducing the likelihood of xerophthalmia in a subject thereof, wherein the amount of WS-12 is not cytotoxic. WS-12 has a chemical structure of:

[0008] Pharmaceutical ophthalmic formulations, such as the pharmaceutical ophthalmic composition claimed and disclosed in the US’609 patent, are in liquid form and comprise water. Thus, they can be referred to as “aqueous ophthalmic compositions.”

[0009] It is important to maintain the stability of WS-12 aqueous ophthalmic compositions in order to maximize the pharmaceutical activity of WS-12 in each dose administered. According, what is needed is a pharmaceutical preparation in which an aqueous ophthalmic composition comprising WS-12 is contained a container that is able to maintain stability of WS-12 with respect to increased temperature, humidity, and exposure to light, among other types of external effects.

[0010] The citation of any reference herein should not be deemed as an admission that such reference is available as prior art to the instant invention.

SUMMARY OF THE INVENTION

[0011] Provided herein is a new and useful pharmaceutical preparation that decreases or eliminates degradation of a WS-12 aqueous ophthalmic composition. In particular, the present invention is based upon the discovery that, surprisingly and unexpectedly, housing an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl- cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia in a subject thereof, wherein the amount of WS-12 is not cytotoxic in a package or container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof when exposed to external effects such as light, particularly ultraviolet light, increased humidity of at least about 25%, at least about 40%, and at least about 65%, increased temperature of at least about 2° to about 8° C, at least about 25° C, at least about 30°, C and at least about 40° C, or any combination thereof for 1, 2, or 3 months or more, retards or slows the decrease of stability of WS-12 in the aqueous ophthalmic composition. As a result, the residual rate, i.e. the amount of active WS-12 contained in such an ophthalmic aqueous composition after exposure to an external effect is at least 80%, at least 90%, at least 95% or at least 98% or more as compared to the amount of active WS-12 in the aqueous ophthalmic composition before such exposure to external effects.

[0012] Broadly, the present invention extends to a pharmaceutical preparation comprising an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2- isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia in a subject thereof, wherein the amount of WS-12 is not cytotoxic, and the aqueous ophthalmic composition is housed in a package that blocks the transmittance of light. In a particular embodiment the transmittance of light that a package of a pharmaceutical preparation of the present invention blocks has a wavelength ranging from about 1 nm to about 400 nm. Moreover, ultraviolet light is a particular type of light the transmittance of which a package of a pharmaceutical preparation of the present invention blocks.

[0013] Furthermore, the present invention further extends to an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl- cyclohexanecarboxylic acid (4-methoxy phenylj-amide) for effectively treating or reducing the likelihood of xerophthalmia in a subject thereof, wherein the amount of WS-12 not cytotoxic, wherein the ophthalmic composition is housed in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination of one or more polyolefin resins or one or more polyester resins.

[0014] In addition, the present invention extends to a method of improving light stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2- isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl )-amidc) for effectively treating or reducing the likelihood of xerophthalmia in a subject, wherein the amount of WS-12 is not cytotoxic, comprising the step of housing the aqueous ophthalmic composition in a package that blocks transmittance of light, and in particular, light having a wavelength of about 1 nm to about 400 nm. In a particular embodiment, a package that blocks transmittance of light in a method of improving light stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS- 12 of the present invention blocks transmittance of ultraviolet light.

[0015] Also provided is a method of improving light stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl- cyclohexanecarboxylic acid (4-methoxy phenylj-amide) for effectively treating or reducing the likelihood of xerophthalmia in a subject, wherein the amount of WS-12 is not cytotoxic, comprising the step of housing the aqueous ophthalmic composition in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

[0016] In addition, the present invention extends to a method of improving heat stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 for effectively treating or reducing die likelihood of xerophthalmia in a subject, wherein the amount of WS-12 is not cytotoxic, comprising the step of housing the aqueous ophthalmic composition in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

[0017] Numerous polyolefin resins have applications in a pharmaceutical preparation package, container or method of the present invention. Particular examples include, but certainly are not limited to saturated and unsaturated polyolefins, e.g. polyethylene, polypropylene, polystyrene, or any combination thereof, to name only a few.

[0018] Likewise, numerous polyester resins also have applications in a pharmaceutical preparation of the invention or a method of the invention. A particular example is polyethylene terephthalate.

[0019] In a particular embodiment of a pharmaceutical preparation and a method of the present invention, a package of a pharmaceutical preparation or method of the present invention blocks transmittance of ultraviolet light. Such ultraviolet light can have a wavelength that ranges from about 1 nm to about 400 nm.

[0020] Moreover, in a pharmaceutical preparation or container method of the invention, the package can further comprise at least one substance that interferes with the transmittance of light and in particular, ultraviolet light. Such a substance may absorb ultraviolet light, scatter ultraviolet light, or reflect ultraviolet light from package. Particular examples of such substances include, but certainly are not limited to titanium dioxide (TiCh), Zinc oxide (ZnO), a benzotriazole-based UV absorbing agent, or any combination thereof.

[0021] Also, in a package of a pharmaceutical preparation or a method of the present invention, the package can comprise a primary package and a secondary package. Generally, a primary package is a container for an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention. Such a container can be formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof. Optionally, the primary package may further comprise at least one substance that blocks transmittance of light, and in particular ultraviolet light as described herein. In a particular embodiment, a primary package of a pharmaceutical preparation or method of the present invention blocks ultraviolet light having a wavelength ranging from about 1 nm to about 400 nm. In particular embodiment of a pharmaceutical preparation of the present invention, the primary container, which contacts the aqueous ophthalmic composition, is housed in the secondary package. Specific examples of a secondary package of the present invention include but are certainly not limited to a packaging bag (e.g., a bag for eye drop instillation), a box (e.g., a paper box), a bottle (e.g., a glass bottle), and a can (e.g., an aluminum can).

[0022] Optionally, a secondary package of a pharmaceutical preparation or a method of the present invention blocks transmittance of light, and in particular the transmittance of ultraviolet light. Such ultraviolet light generally has a wavelength ranging from about 1 nm to about 400 nm. Moreover, a secondary package of a pharmaceutical preparation or a method of the present invention may comprise at least one substance that blocks transmittance of light. In a particular embodiment, the at least one substance that blocks transmittance of ultraviolet light comprises titanium dioxide, zinc oxide, a benzotriazole -based UV absorbing agent, or any combination thereof.

[0023] Furthermore, a package of a pharmaceutical preparation or method of the present invention may optionally permit transmittance of light in the visible spectrum.

[0024] In addition, the present invention extends to an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia, wherein the amount of WS-12 is not cytotoxic, and the aqueous ophthalmic composition is housed in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof. Examples of one or more polyolefin resins having applications in an aqueous ophthalmic composition of the present invention include, but certainly are not limited to low density polyethylene, high density polyethylene, low density polypropylene, or high density polypropylene. Likewise, numerous one or more polyester resins having applications herein include polyethylene terephthalate.

[0025] Optionally, a container of an aqueous ophthalmic composition blocks transmittance of light, and in particular, ultraviolet light. In a particular embodiment, a container of an ophthalmic composition of the present invention blocks transmittance of light having a wavelength ranging from about 1 nm to about 400 nm.

[0026] Moreover, a container of an aqueous ophthalmic composition of the present invention may comprise at least one substance that blocks transmission of light. Examples of such substances include, but certainly are not limited to, titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof. Such a substance can readily be kneaded into one or more polyolefin resins, one or more polyester resins, or any combination thereof used to form a package or container of the present invention.

[0027] These and other aspects of the present invention will be better appreciated by reference to the following drawings and Detailed Description. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Fig. 1 is the absorption spectrum of WS-12 at a concentration of 1.0 mg/ml in methanol at pH

20

[0029] Fig. 2 is the absorption spectrum of WS-12 at a concentration of 1.0 mg/ml in methanol at pH 7.0

[0030] Fig. 3 is the absorption spectrum of WS-12 at a concentration of 1.0 mg/ml in methanol at pH 100

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention is based upon the discovery that surprisingly and unexpectedly, the degradation of WS-12 in a pharmaceutical aqueous ophthalmic composition can be retarded or slowed when the aqueous ophthalmic composition is housed in a package or a container that blocks transmittance of light, and in particular transmittance of ultraviolet light. In particular, it has been discovered that, surprisingly and unexpectedly, housing an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 for effectively treating or reducing the likelihood of xerophthalmia in a container comprising one or more polyolefin resins, one or more polyester resins, or any combination thereof results in a residual rate, i.e. the amount of active WS-12 contained in such an ophthalmic aqueous composition after exposure to an external effect, is at least 80%, at least 90%, at least 95% or at least 98% or more as compared to the amount of active WS-12 in the aqueous ophthalmic composition before such exposure to external effects. Such external effects include light, particularly ultraviolet light, increased humidity of at least about 25%, at least about 40%, and at least about 65%, increased temperature of at least about 2° to about 8° C, at least about 25° C, at least about 30° C and at least about 40° C, or any combination thereof for 1, 2, or 3 months or more.

[0032] Thus broadly, the present invention extends to a pharmaceutical preparation comprising:

[0033] an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia in a subject, wherein:

(a) the amount of WS- 12 is not cytotoxic; and

(b) the aqueous ophthalmic composition is housed in a package that blocks light.

[0034] The present invention also extends to a pharmaceutical preparation comprising an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2- isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide), wherein:

(a) the amount of WS- 12 not cytotoxic; and (b) the aqueous ophthalmic composition is housed in a container formed of one or more polyolefin resins, one or more polyester resins, or a combination thereof.

[0035] Also provided is a method of improving light stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl- cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) wherein the amount of WS-12 per dose is not cytotoxic, comprising the step of housing the aqueous ophthalmic composition in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

[0036] Another method of the present invention is a method of improving heat stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2- isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide), wherein the amount of WS-12 is not cytotoxic, comprising the step of housing the aqueous ophthalmic composition in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0038] All numerical designations, e.g. volume, mass, number of resin particles, etc. are approximations which are varied by (+) or (-) by increments of 1.0 or 0.1, as appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term "about".

[0039] Numerous terms and phrases are used throughout the instant specification and claims and are defined below.

[0040] “About” and “approximately” are interchangeable and mean plus or minus a percent (e.g. ±5%) of the number, parameter, or characteristic so qualified, which would be understood as appropriate by a skilled artisan to the scientific context in which the term is utilized.

[0041] As used here, the singular form “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.

[0042] As used herein, the terms “comprising”, “comprises” and “comprise” are intended to mean that the compositions, preparations and methods disclosed herein include recited elements, but do not exclude others.

[0043] As used herein, the term “cytotoxic” with respect to a chemical compound intended to act upon particular target cells means the compound is toxic to target cells such that it: (a) inhibits the growth of target cells; or (c) kills the target cells. Cell growth is a measure of cell proliferation. Consequently, a compound or aqueous ophthalmic composition that is not cytotoxic does not (a) inhibit the growth of the target cells; and (b) does not kill the target cells in the amount or concentration used.

[0044] As used herein, “aqueous ophthalmic composition^" means a composition comprising at least water and, is not particularly limited as long as it can be contained in a container described infra. An aqueous ophthalmic composition includes, for example, a liquid (solution or suspension) or a semisolid (ointment). The water of an aqueous ophthalmic composition can be, for example, purified water, water for injection or sterile purified water. The content of water contained in an aqueous ophthalmic composition is not particularly limited, and in particular can be about 5% by mass of the composition, more particularly about 20% by mass or more, still more particularly about 50% by mass or more, even more particularly about 90% by mass or more, and even still more particularly about 99% by mass.

[0045] In addition to the above, an aqueous ophthalmic composition of a pharmaceutical preparation or method of the present invention may further contain an additive used in a pharmaceutical or quasidrug or a quasi-drug, depending on the dosage form. Examples of such additives include inorganic salts, isotonizing agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, thickeners, surfactants, solubilizers, suspending agents, refreshing agents, dispersing agents, preservatives, oily bases, emulsifiable bases, and water-soluble bases.

[0046] Examples of such additives include ascorbic acid, potassium aspartate, sodium bisulfite, alginate, sodium benzoate, benzyl benzoate, cp.v/Yon-amino-caproic acid, fennel oil, ethanol, and ethylene-vinyl acetate copolymer sodium edetate, disodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyl diaminoethyl hydrochloride, carboxy vinyl polymer, dried sodium sulfite, dried sodium carbonate and D-camphor, D,L-camphor, xylitol, citric acid hydrate, sodium citrate hydrate, glycerin, gluconic acid, L-glutamic acid, L-glutamic acid sodium salt, creatinine chlorhexidine gluconate solution, chlorobutanol, crystalline sodium dihydrogen phosphate, geraniol, sodium chondroitin sulfate, acetic acid, potassium acetate, sodium acetate hydrate, titanium oxide, gellan gum, dibutyl hydroxytoluene, potassium bromide, and other pharmaceutically -acceptable bromide salts, tartaric acid, sodium hydroxide, stearic acid, polyoxyl 45, purified lanolin, D-sorbitol, sorbitol liquid, sorbic acid, potassium sorbate, taurine, sodium bicarbonate, sodium carbonate hydrate, sodium thiosulfate hydrate, thimerosal, tyloxapol, sodium dehydroacetate, trometamol, concentrated glycerin, concentrated mixed tocopherol, white petrolatum, mentha water, mentha oil, benzalkonium chloride concentrated solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl , sodium parahydroxybenzoate, sodium hyaluronate, human serum albumin, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, glacial acetic acid, sodium pyrosulfite, phenylethyl alcohols, glucose, propylene glycol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, sodium borate, boric acid or a salt thereof (For example, boric acid ammonium, sodium borate), povidone, polyoxyethylene (200), sodium polystyrene sulfonate, polysorbate 80, polyoxyethylene, cured castor oil 60, polyvinyl alcohols (partially saponified products). D-bomeol, Macrogol 4000, Macrogol 6000, D-mannitol, anhydrous citric acid, anhydrous sodium dihydrogen phosphate, anhydrous sodium dihydrogen phosphate, methane sulfonic acid, methyl cellulose, L-menthol, monoethanolamine, aluminum monostearate, monostearic acid, polyethylene glycol, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, luno, phosphoric acid, dibasic sodium phosphate hydrate, potassium phosphatemonobasic, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, malic acid, and vaseline.

[0047] An aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention can be formulated in various dosage forms according to a known method described, for example, in the Japanese Pharmacopoeia, Seventeenth Edition, General Rules for Preparation or the like. Examples of the dosage form include injection, inhalation liquid, eye drop, eye ointment, ear drop, nasal drop liquid, enema formulation, topical liquid, spray, ointment, gel, oral liquid, and syrup. From the viewpoint of advantageously utilizing the pharmacological actions of WS-12, the dosage form is preferably, a dosage form for eye disease, specifically, eye drop or eye ointment, and particularly preferably, eye drop.

[0048] Moreover, an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention can comprise one or more additional active pharmaceutical ingredients, depending upon disease or disorder for which an aqueous ophthalmic composition of a pharmaceutical preparation of the present invention is to be used to treat or prevent. Examples include, but certainly are not limited to al receptor blockers including bunazosin or a salt thereof or a solvate thereof such as bunazosin hydrochloride; al receptor agonists including brimonidine or a salt thereof or a solvate thereof such as brimonidine tartrate, and apraclonidine or a salt thereof or a solvate thereof; b-blockers including carteolol or a salt thereof or a solvate thereof such as carteolol hy drochloride, nipradilol or a salt thereof or a solvate thereof, timolol or a salt thereof or a solvate thereof such as timolol maleate, betaxolol or a salt thereof or a solvate thereof such as betaxolol hydrochloride, levobunolol or a salt thereof or a solvate thereof such as levobunolol hydrochloride, befunolol or a salt thereof or a solvate thereof, and metipranolol or a salt thereof or a solvate thereof; carbonic anhydrase inhibitors including dorzolamide or a salt thereof or a solvate thereof such as dorzolamide hydrochloride, brinzolamide or a salt thereof or a solvate thereof, acetazolamide or a salt thereof or a solvate thereof, dichlorphenamide or a salt thereof or a solvate thereof, and methazolamide or a salt thereof or a solvate thereof; prostaglandins and their analogs and derivatives (e.g., prostaglandin F2a derivatives) including isopropyl unoprostone or a solvate thereof, tafluprost or a solvate thereof, travoprost or a solvate thereof, bimatoprost or a solvate thereof, latanoprost or a solvate thereof, cloprostenol or a solvate thereof, and fluprostenol or a solvate thereof. Rho kinase inhibitors including Netarsudil, Ripasudil or a salt thereof or a solvate thereof, Y- 39983, and H-1129; sympathomimetic drugs including dipivefrine or a salt thereof or a solvate thereof such as dipivefrin hydrochloride, and epinephrine or a salt thereof or a solvate thereof such as epinephrine, epinephrine borate, or epinephrine hydrochloride; parasympathomimetic drugs including distigmine bromide or a salt thereof or a solvate thereof, pilocarpine or a salt thereof or a solvate thereof such as pilocarpine, pilocarpine hydrochloride or pilocarpine nitrate, and carbachol or a salt thereof or a solvate thereof; calcium antagonists including lomerizine or a salt thereof or a solvate thereof such as lomerizine hydrochloride; and cholinesterase inhibitors including demecarium or a salt thereof or a solvate thereof, echothiophate or a salt thereof or a solvate thereof, and physostigmine or a salt thereof or a solvate thereof. These APIs can be mixed with WS-12 in an aqueous ophthalmic composition of a pharmaceutical preparation of the present invention singly, or as combinations of two or more.

[0049] The pH of an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention (at about 25 °C) is not particularly limited, but preferably from about 3 to about 9, more preferably from about 3.5 to about 8, still more preferably from about 5 to about 7.5.

[0050] In a particular embodiment, an aqueous ophthalmic composition of the present invention is set forth in Table 1.

Table 1. Ingredients of 50 mΐ WS-12 Aqueous Ophthalmic Composition

[0051] As used herein, the phrase “therapeutically effective amount” refers to the amount of an aqueous ophthalmic composition that is effective to achieve an intended purpose without undesirable side effects (such as toxicity, irritation or allergic response), and is not cytotoxic. Although individual needs may vary , optimal ranges for effective amounts of such an aqueous ophthalmic composition can be readily determined by one of ordinary skill in the art using routine laboratory techniques. Human doses can be extrapolated from animal studies (Katocs et al., Chapter 27 In. Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990). Generally, the dosage required to provide a therapeutically effective amount of an aqueous ophthalmic composition, which, if necessary, may be adjusted by one skilled in the art, will vary depending on the age, health, physical condition, weight, type and extent of the disease or disorder, e.g. xerophthalmia, of the recipient, frequency of treatment, the nature of concurrent therapy (if any) and the nature and scope of the desired effect (s) (Nies et al., Chapter 3 In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, N.Y., 1996).

[0052] As used herein, a "container" means a package for directly housing an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention. Such a container includes any of "well-closed container", "tight container" and "hermetic container" which are defined in the Japanese Pharmacopoeia, Seventeenth Edition, General Notices.

[0053] The form of the container is not particularly limited as long as it is capable of housing an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention and may be appropriately selected and set depending on the dosage form, the application of the pharmaceutical preparation, and the like. Specific examples of the container in such a form include a container for injection, a container for inhalation, a container for spray, a bottle-shaped container, a tube-shaped container, an eye drop container, a nasal drop container, an ear drop container, a bag shaped container, and the like. The container, from the viewpoint of advantageously utilizing pharmacological action an aqueous ophthalmic composition comprising WS-12, is preferably an eye drop container.

[0054] In the present specification, the "container formed of one or more polyolefin resins" means a container of which at least a part in contact with an aqueous ophthalmic composition of a pharmaceutical preparation comprises, at least in part, one or more polyolefin resins. For example, the one formed of a mixture of two or more kinds of resin (polymer alloy) of a polyolefin resin and one or more other kinds of resin also correspond to the one "formed of one or more polyolefin resins". Thus, for example, a container having a polyolefin resin layer as an inner layer in contact with an aqueous ophthalmic composition, and further having a layer of other resin material laminated on the outside of the inner layer also corresponds to the "polyolefin resin container". Polyolefin resins having applications in a container of a pharmaceutical preparation or a method of the present invention are not particularly limited and may be a polymer composed of single kind of monomer (homopolymer) or a copolymer composed of multiple kinds of monomers (copolymer). In the case of a copolymer, the polymerization mode is not particularly limited, and the copolymer may be a random copolymer or a block copolymer. Furthermore, the stereoregularity (tacticity) of the copolymer is not particularly limited.

[0055] The polyolefin resins may be saturated or unsaturated. Specific examples of polyolefin resins having applications herein include polyethylene (i.e. low density polyethylene (linear low density polyethylene, high density polyethylene, medium density' polyethylene), polypropylene, cyclic polyolefin, poly(4-methylpentene), polytetrafluoroethylene, an ethylene-propylene copolymer, an ethylene-a-olefin copolymer, an ethylene-acrylic acid copolymer, an ethylene-methacrylic acid copolymer, an ethylene-vinyl acetate copolymer, an ethylene-ethyl acrylate copolymer, a polystyrene resin, as well as any combination of any of these polyolefin resins.

[0056] Further, as used herein, the phrase "formed of one or more polyester resins" means that the material comprises, at least in part, a polyester resin. For example, a material formed of a mixture of two or more kinds of resin (polymer alloy) of a polyester resin and one or more other kinds of resin also corresponds to the one "formed of a polyester resin". Numerous types of polyester resins have applications in a container or package of a pharmaceutical preparation or a method of the present invention. Examples include, but certain are not limited to dicarboxylic acids and diols such as phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid, and examples of the diol include, but certainly are not limited to, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,4- cyclohexanedimethanol, and bisphenol. A polyester resin may be a polymer composed of single kind of polyester unit or a polymer composed of plural kinds of polyester units. In the case of a polymer composed of plural kinds of polyester units, the polymerization mode is not particularly limited, and the copolymer may be a random copolymer or a block copolymer. Furthermore, the stereoregularity (tacticity) of the polymer is not particularly limited.

[0057] Specific examples of polyester resins having applications in a package (and a container) of a pharmaceutical preparation of the present invention include homopolyester such as polyalkylene terephthalate (e.g., polyethylene terephthalate, polybutylene terephthalate), polyalkylene naphthalate (e.g., polyethylene naphthalate, polybutylene naphthalate), polycycloalkylene terephthalate (e g., poly(l, 4-cyclohexylene dimethylene terephthalate) or polyarylate (e.g., resin composed of bisphenol and phthalic acid); copolyester comprising units of the homopolyester as the main component; and a copolymer of the homopolyester. These resins can be used singly or in a combination of two or more. From the viewpoint of suppressing the content reduction of WS-12 at the time of storage at high temperature, the polyester resin can be polyethylene terephthalate.

[0058] The container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof, may be one blocking light, or in particular block ultraviolet light having a wavelength range known to interact with WS-12. Particular wavelengths that may be blocked resulting in a suppression of a reduction of WS- 12 in a pharmaceutical aqueous composition of a pharmaceutical preparation or a method of the present invention are dependent upon the wavelengths that WS-12 may absorb. One of ordinary skill can readily determine the wavelengths that WS-12 absorbs using routine laboratory techniques, e.g., the measurement of an average value of the transmittance of the light in a certain wavelength range can be carried out by measuring the transmittance of the light of the container in air in the certain wavelength range at 5 nm intervals using a spectrophotometer, and then calculating the average value of the measured transmittance. Numerous spectrophotometers can be used to determine the wavelengths that WS-12 may absorb. A particular example is the U-3900 (Hitachi High- Technologies Corporation).

[0059] As used herein, the phrase "blocking transmittance of light" means the average value of transmittance of light through a package or a container of a method, pharmaceutical preparation or ophthalmic aqueous composition of the present invention is about 40% or less.

[0060] As explained herein, the transmittance of light that a package or container of the present invention that is blocked has a wavelength ranging from about 1 nm to about 400 nm.

[0061] As used here, “light’ means is electromagnetic radiation within a portion of the electromagnetic spectrum. Light can be visible light, which has a wavelength ranging as broadly as about 400 nm to about 800 nm. As used herein “light” also refers to infra-red light, has a wavelength ranging from about the nominal red edge of the visible light at 700 nm to wavelength of about 1 mm. In addition, as used herein, “light” refers to ultraviolet light, which has a wavelength ranging from about 1 nm to about 400 nm.

[0062] From the viewpoint of further improving light stability, the average value of the transmittance of the light of the aforesaid wavelength range of the container is preferably 35% or less, more preferably 30% or less, still more preferably 25% or less, even more preferably 20% or less, still even more preferably 15% or less, furthermore preferably 10% or less, and particularly preferably 5% or less.

[0063] By housing an aqueous ophthalmic composition in such a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof, which blocks transmittance of light, and in particular transmittance of ultraviolet light having a wavelength ranging from about 1 nm to about 400 nm, the residual rate of WS-12 in such aqueous ophthalmic composition after irradiation about 80% or more, about 85% or more, about 90% or more, and particularly about 95% or more. The “residual rate” of WS-12 in an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention can readily be obtained using routine laboratory techniques, such as measuring the concentrations of WS-12 in an aqueous ophthalmic composition before and after exposure to external effects such as light, particularly ultraviolet light, increased humidity of at least about 25%, increased temperature of at least about 40° C, or any combination thereof for 1, 2, or 3 months or more. Calculating the residual rate by the following expression using the measured concentrations:

[0064] Residual rate % WS-12 = Concentration of WS-12 in an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention after exposure to external effects / Concentration of WS-12 in the aqueous ophthalmic composition before exposure to external effects ^c 100 [0065] Numerous methods of placing an aqueous ophthalmic composition in a package or container of a pharmaceutical preparation or a method of the present invention in order to house the aqueous ophthalmic composition in such a container or package have applications herein, and can be performed by filling or the like with an ordinary method, depending on the form of the container or the like.

[0066] As used herein, the term "package" means a package for directly or indirectly housing an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention. Among the package, the container, which directly houses the aqueous ophthalmic composition (for example, an eye drop container or the like in which an aqueous ophthalmic composition of a pharmaceutical preparation of the present invention is directly filled) is particularly referred to as "primary package". Also, among the package, the package which indirectly houses the aqueous ophthalmic composition (i.e., the package which houses the primary package: for example, a bag for eye drop instillation (a bag housing the eye drop container)) is particularly referred to as "secondary package". An example of a package that has applications herein is one that can block transmittance of light, and in particular, block transmittance of ultraviolet, particularly light having a wavelength ranging from about 1 nm to about 400 nm under the typically expected storage condition for an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention. Optionally, the package may have a re sealing mechanism.

[0067] The concept of the package includes any of "well-closed container", "tight container" and "hermetic container" which are defined in the Japanese Pharmacopoeia, Seventeenth Edition, General Notices.

[0068] When a pharmaceutical preparation of the present invention includes the secondary package, it is sufficient if at least one of the primary or secondary' packages block transmittance of light, and in particular blocks transmittance of ultraviolet light. In a particular embodiment, the transmittance of light that is blocked has a wavelength ranging from about 1 nm to about 400 nm. From the viewpoint of suppressing the content reduction of WS-12, maximizing residual rate of WS-12 in such an aqueous ophthalmic composition after exposure to external effects such as light, particularly ultraviolet light, increased humidity of at least about 25%, increased temperature of least about 2° to about 8° C, at least about 25° C, at least about 30° C and at least about 40° C, or any combination thereof for 1, 2, or 3 months or more, not only during distribution or storage but also during the use, the package or container is formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof. In a particular embodiment, at least the primary package blocks transmittance of light, and in particular, blocks transmittance of light having a wavelength ranging from about 1 nm to about 400 nm, such as ultraviolet light.

[0069] The form of the package is not particularly limited as long as it is capable of housing an aqueous ophthalmic composition of a pharmaceutical preparation or method of the present invention, and may be appropriately selected and set depending on the dosage form, the application of the pharmaceutical preparation, or whether the package is the primary package or the secondary package. Specific examples of a primary package having applications herein include, but certainly are not limited to a container for injection, a container for inhalation, a container for spray, a bottle-shaped container, a tube-shaped container, an eye drop container, a nasal drop container, an ear drop container, a bag shaped container, and the like. Specific examples of a secondary package include a packaging bag (e.g., a bag for eye drop instillation), a box (e.g., a paper box), a bottle (e.g., a glass bottle), and a can (e.g., an aluminum can). In a particular embodiment, the primary package is an eye drop container have a removable top and a nozzle such that upon placing the nozzle directly above the eye and squeezing the container, the aqueous ophthalmic composition is administered to the surface of the eye.

[0070] When a pharmaceutical preparation or method of the present invention includes as a package a primary package and a secondary package, the primary package is preferably an eye drop container, and the secondary package is preferably a bag for eye drop instillation, from the viewpoint of advantageously utilizing the pharmacological action of WS-12.

[0071] A package as described herein (including a primary package and a container) for packaging and housing an aqueous ophthalmic solution according to the invention includes all container forms suitable for user-friendly topical ophthalmic delivery'. Consequently, a package may be selected for example from the group consisting of bottles, tubes, ampoules, pipettes and fluid dispensers, in single unit dose form or in multidose form.

[0072] Optionally, a package (which includes, in particular a primary package and container as described herein) having applications in the present invention can be a single-dose unit container. As used herein, "single-dose unit container" means a container of an aqueous ophthalmic composition wherein each container houses or is prefilled with a single dosage amount of an aqueous ophthalmic composition for a single patient. Examples of single-dose unit packages are vials, ampules, prefilled solutions, etc. In a particular embodiment, a single dosage of an aqueous ophthalmic solution of the present invention is housed in each prefilled single-dose container. Upon use, the patient permanently removes a cap of die single-dose unit container, leaving a sterile orifice. The patient then holds the single-dose unit container over the eye and squeezes it, resulting in delivery of a single dosage amount an aqueous ophthalmic composition through the orifice directly above eye. The principal advantage to single-dose unit package is that because they are only used once, and are sterilized in their manufacture due to the high temperatures their manufacture involves, it is unnecessary to include a preservative in an aqueous ophthalmic composition, such as benzalkonium chloride

[0073] Single-dose unit containers housing an ophthalmic aqueous composition as described herein are preferably manufactured via an extrusion blow molding method. Extrusion blow molding gives a smoother inner surface of the container compared to injection blow molding, which is commonly used to manufacture multi-dose units.

[0074] Generally, a single-dose unit package having applications here, and manufactured by blow molding method, houses an aqueous ophthalmic composition having a volume, for example, of about 0.2 to about 0.5 ml or more. A large variety of shapes are known for such single-dose unit packages and have applications herein. There are numerous manufacturers of single-dose unit containers that have applications herein, including but not limited to Addipak, CareFusion, Airlife, and LF America, to name only a few.

[0075] Optionally, the package can be formed or materials other than one or more polyolefin resins, one or more polyester resins, or any combination thereof. For example, the package can also be formed of glass, cellulose, pulp, rubber and metal.

[0076] The material of the primary package for directly housing an ophthalmic aqueous composition is, from the viewpoint of processability, squeezability, durability and the like, preferably plastic or the like, i.e. formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof. The material of the secondary package is, from the viewpoint of processability, preferably plastic, cellulose, pulp, paper, or the like.

[0077] When the material of the package is plastic, the plastic is preferably a thermoplastic resin, which may be a synthetic resin or a natural resin. Specific examples of the resin include one or more polyolefin resins, one or more polyester resins, one or more polyphenylene ether resins, one or more polycarbonate resins, one more polysulfone resins, one or more polyamide resins, one or more polyvinyl chloride resins, or any combination thereof.

[0078] In one embodiment, the material of the primary package comprises one or more polyolefin resins, one or more polyester resins, or any combination thereof. In such a case, it is sufficient if at least a portion of the primary package in contact with an aqueous ophthalmic composition of a pharmaceutical preparation or method of the invention is formed of one or more polyester resins, one or more polyolefin resins, or any combination thereof, in contact with the aqueous ophthalmic composition, even having a layer of other material laminated on the outside of the portion, also corresponding to the primary package formed of one or more kinds of resin selected from the group consisting of one or more polyester resins, one or more polyolefin resins, or any combination thereof.

[0079] Applicable diseases or disorders for which a pharmaceutical preparation, an aqueous ophthalmic composition and a method of the present invention can be used to treat or prevent are not limited. A specific disease or disorder that can be prevented or treated with a pharmaceutical preparation or a method of the present invention includes but certainly is not limited to xerophthalmia. As used herein “xerophthalmia” or “dry eye syndrome” is a disease characterized by persistent dry ness of the conjunctiva and opacity of the cornea. Multiple causes can lead to xerophthalmia, which is more common in elderly people. Among the causes of xerophthalmia are: MGD and other ocular inflammatory processes, vitamin A deficiency, Sjogren syndrome, rheumatoid arthritis and other rheumatological disease and disorders, chemical or thermal burns, drugs such as atenolol, chlorpheniramine, hydrochlorothiazide, isotretinoin, ketorolac, ketotifen, levocabastin, levofloxacin, oxybutynin, and tolterodine.

[0080] In the case of using an aqueous ophthalmic composition, pharmaceutical preparation, or method of the present invention as a prevention or treatment agent for an eye disease or disorder, the aqueous ophthalmic composition of a pharmaceutical preparation or method of the present invention may be administered, for example, about 1 to 3 times a day in a suitable dose.

[0081] In a method or a pharmaceutical preparation or method of the present invention, a package that blocks transmittance of light, and in particular light having a wavelength ranging from about 1 nm to about 340 m, such as ultraviolet light, may include as a primary package, a container that is opaque or transparent with respect to visible light. Optionally a package, and particular at least one of a primary or secondary package of a pharmaceutical preparation or method of the present invention can comprise at least one substance that blocks transmittance of ultraviolet light. Examples of substances having applications herein are substances that interfere with transmittance of ultraviolet light, such as an ultraviolet absorbing agent or an ultraviolet light scattering agent. Specific examples of an ultraviolet scattering agent having applications herein include titanium oxide and zinc oxide. Examples of the ultraviolet absorbing agents include but certainly are not limited to a benzotriazole-based ultraviolet absorbent such as 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P: BASF), 2-(2H-benzotriazol-2-yl)- 4,6-bis(l-methyl-l-phenylethyl)phenol (e.g., Tinuvin 234: BASF), 2-(3,5-di-tert-butyl-2- hydroxyphenyl)benzotriazole (e.g., Tinuvin 320: BASF), 2-[5-chloro-(2H)-benzotriazol-2-yl]-4- methyl-6-t-butyl-phenol (e.g., Tinuvin 326: BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5- chlorobenzotriazole (e.g., Tinuvin 327: BASF), 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (e.g., Tinuvin PA328: BASF), 2-(2H-benzotriazol-2-yl)-4-(l,l,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 329: BASF), 2,2’-methylenebis[6-(2H-benzotriazol-2-yl)-4-(l,l,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 360: BASF), a reaction product of methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4- hydroxyphenyl)propionate and polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol- 2-yl)-6-dodecyl-4-methylphenol (e.g., Tinuvin 571: BASF), 2-(2’-hydroxy-3’,5’-di-t- amylphenyl)benzotriazole, 2-|2^‘-hvdroxy-3^‘-(3 .4 .5^‘‘.6^‘‘-tctrahvdrophthalimidcmcthvl)-5^‘- methylphenyl]benzotriazole, and 2,2’-methylenebis[4-(l,l,3,3-tetramethylbutyl)-6-(2H-benzotriazol- 2-yl)phenol]; cyanoacrylate-based ultraviolet absorbing agent such as 2,2-bis{[2-cyano-3,3- diphenylacryloyloxy]methyl}propane-l ,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (for example, Uvinul 3030 FF: BASF), ethyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3035: BASF), and 2- ethylhexyl 2-cyano-3,3-diphenylacrylate (e.g., Uvinul 3039: BASF) and others; triazine-based ultraviolet absorbing agent such as 2-(4,6-diphenyl-l,3,5-triazin-2-yl)-5-[(hexyl)oxy]-phenol (e g., Tinuvin 1577 ED: BASF); benzophenone-based ultraviolet absorbing agent such as octabenzone (e.g., Chimassorb 81: BASF), 2,2^,-dihydroxy-4,4’-dimethoxybenzophenone (e.g., Uvinul 3049: BASF), 2,2’-4,4’-tetrahydrobenzophenone (e.g., Uvinul 3050: BASF), oxybenzone, hydroxymethoxybenzophenone sulfonic acid, sodium hydroxymethoxybenzophenone sulfonate, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone disulfonate, dihydroxybenzophenone, and tetrahydroxybenzophenone; cinnamic acid-based ultraviolet absorbing agent such as methyl diisopropylcinnamate, cinoxate, glyceryl mono-2-ethylhexanoate diparamethoxycinnamate, a mixture of isopropyl paramethoxycinnamate and diisopropyl cinnamate, 2- ethylhexyl paramethoxycinnamate, and benzyl cinnamate; benzoic acid ester-based ultraviolet absorbing agent such as para-aminobenzoic acid, ethyl para-aminobenzoate, glyceryl para- aminobenzoate, amyl para-dimethylaminobenzoate, 2-ethylhexyl para-dimethylaminobenzoate, and ethyl 4-[N,N-di(2-hydroxypropyl)amino]benzoate; salicylic acid-based ultraviolet absorbing agent such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, and methyl salicylate; guaiazulene; 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidine propionate; 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino] 1,3,5-triazine; para- hydroxyanisole; 4-tert-butyl-4’-methoxydibenzoylmethane; phenylbenzimidazole sulfonate; and hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate. As a substance that blocks transmittance of light having a wavelength ranging from about 1 nm to about 400 nm may be used singly or in a suitable combination of two or more. Particular substances having applications herein include but are not limited to titanium oxide, zinc oxide, and a benzotriazole-based ultraviolet absorbing agent.

[0082] When a substance that blocks light having a wavelength ranging from about 1 nm to about 400 nm is added to formation of a package (primary or secondary) as described herein, it can be kneaded into the one or more polyolefin resins, one or more polyester resins, or any combination thereof used to form the package. The blending ratio for the at least one substance is determined depending on the substance or substances to be added, the resins used to form the package or additional member, and the like. It may be, for example, from about 0.001 to about 50 % by mass, about 0.002 to about 25 % by mass, particularly from about 0.01 to about 10 % by mass relative to the material of the package.

[0083] In the present specification, a “package that blocks transmittance of light” includes a package in which only a portion of the package blocks light. In such a package, based on the inner surface of the package, the portion which blocks transmittance of light is in particular about 10% or more, about 30% or more, and particularly about 50% or more, and more particularly about 70% or more of the area of the inner surface of the package compared to the total area of the inner surface of the package.

[0084] Optionally, the inside of the package is visible (observable) to the naked eye or the like. When the inside is visible, there are some advantages in that it is possible to examine the presence or absence of contamination or the like in the manufacturing process of an aqueous ophthalmic composition of a pharmaceutical preparation or a method of the present invention; and that one who uses a pharmaceutical preparation of the present invention can check the remaining content (aqueous composition), and the like. As used herein, the phrase “inside is visible” means a state that the inside of the package is visible from at least a portion of the outer surface of the package. (For example, an eye drop container, which usually has a nearly cylindrical shape, having a bottom surface allowing the inside of the container to be visible corresponds to the container whose “inside is visible”, even when the inside of the container is not visible from the side surface owing to a shrink film or the like). Such a package having an inside that is visible can readily block transmittance of light, and in particular block transmittance of light having ultraviolet light having a wavelength ranging from about 1 nm to about 400 nm, such as ultraviolet light, due to the insertion of at least one substance that blocks transmittance of ultraviolet light, e g. zinc oxide, titanium oxide, and a benzotriazole-based ultraviolet absorbing agent, to name only a few.

[0085] The visibility is sufficient if the package has a transparency of no less than a certain level, and specifically, for example, it is sufficient that the average value of the transmittance of the light in the visible light region (450 to 750 nm) is around 30% or more (more suitably around 40% or more, and particularly suitably around 50% or more), but the visibility is not limited thereto.

[0086] Optionally, a package that blocks transmittance of light, and in particular blocks transmittance of light having a wavelength ranging from about 1 nm to about 400 nm, e.g. ultraviolet light, in a pharmaceutical preparation or method of the present invention can include a secondary package, such as a bag, which comprises at least one substance that interferes with transmission of ultraviolet light.

[0087] Similarly, in a pharmaceutical preparation or a method of the present invention, the container can be (a) or (b) as follows:

(a) a container (preferably, a container whose inside is visible) formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof, kneaded with at least one substance that interferes with transmission of ultraviolet light (one or more substances selected from the group consisting of an UV scattering agent and an UV absorbing agent, particularly one or more substances selected from the group consisting of: (i) zinc oxide, (ii) titanium oxide, (iii) a benzotriazole-based UV absorbing agent, and (iv) any combination of (i), (ii) and (iii), wherein (i), (ii), and (iii) need not all be included in such combinations.

[0088] a container (optionally whose inside is visible) formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof, wherein the container has a member, such as a heat- shrinkable film (a shrink film) having kneaded thereon at least one substance that interfere with transmittance of ultraviolet light. [0089] As explained herein, an aqueous ophthalmic composition of a pharmaceutical preparation or method of the present invention comprises, inter alia, WS-12, which modulates, and in particular is an agonist of Transient Receptor Potential cation channel subfamily M member 8, or TRPM8 receptor, also known as cold and menthol receptor 1 or CMR1. The TRPM8 receptor is a protein that is coded by the TRPM8 gene in humans (Clapham D E, et al. 2005. Pharmacological Reviews 57 (4): 427-50). TRPM8 is an ion channel that, after activated, allows sodium ions (Na⁺) and calcium ions (Ca²⁺) to enter the cell, thus generating depolarization of said cell, leading to a change in the membrane potential. The TRPM8 protein is expressed in sensory neurons and is activated by cold temperatures (approximately below 26° C), by chemical agents, such as menthol, and by voltage. TRPM8 is also expressed in the prostate, the lungs, and the bladder.

[0090] The human TRPM8 gene is located in chromosome 2 in the 2p37.1 region; and codes for a protein of 1104 amino acids (NP-076985.4, SEQ ID NO: 1) coded by the sequence of nucleotides NM_ 024080.4 (SEQ IS NO: 2). The TRPM8 gene has six trans-membrane segments, with the C and N terminal ends on the cytoplasmic side. Four subunits tetramerise to form active channels.

[0091] The TRPM8 receptor is involved in the control of tearing and its activation using agonists thereof results in increased tearing. Specifically, cold thermoreceptors innervating the cornea in mammals keep tonic trigger activity at normal corneal temperature and are markedly sensitive to minor thermal variations in the eye surface, such as those resulting from evaporation of the precorneal tear fdm that occurs in the intervals between blinking and during exposure to dry environments. This marked cold sensitivity is the result of a high expression of TRPM8 channels, that critically determine a spontaneous basal activity and an increase in the frequency of triggering in response to cold. Moreover, the removal of TRPM8 channels with genetic techniques halves tear secretion in mice. Partial silencing by corneal heating also reduces tear secretion in humans.

[0092] In light of the above, TRPM8 is a molecular target for the detection of moisture in cold thermoreceptor nerve fibers innervating the exposed eye surface in land animals.

[0093] Therefore, the present invention relates to the treatment of xerophthalmia, with an agonist of the TRPM8 receptor. US Patent 9095609, which is hereby incorporated by reference in its entirety, discloses an ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxyphenyl)- amide), wherein the amount of WS-12 can effectively treat or reduce the likelihood of xerophthalmia in a subject in need thereof, wherein the amount of WS-12 is not cytotoxic. Such an ophthalmic composition is readily an aqueous ophthalmic composition of a pharmaceutical preparation or method of the present invention.

[0094] Likewise, US Patent 9433679 (the US’679 patent), which is hereby incorporated by reference in its entirety, discloses, inter alia, a method for treating an ophthalmic disease or condition, the disease or condition involving tearing and/or relieving symptoms thereof comprising administering a therapeutically effective amount of a composition comprising a molecule binding specifically to the TRPM8 (Transient Receptor Potential Cation Channel subfamily M member 8) receptor to a subject in need thereof,

[0095] wherein the binding of the molecule to the TRPM8 receptor modulates the activity of the TRPM8 channel;

[0096] (ii) wherein the binding of the molecule to the TRPM8 receptor increases or decreases tear secretion caused by ophthalmic disease or condition; and

[0097] (iii) wherein the concentration of the molecule needed to bind and modulate the TRPM8 receptor in tissues is not sufficient to be cytotoxic to the subject in need thereof.

[0098] The US’679 patent further discloses that WS-12 is an agonist of the TRPM8 receptor and readily has applications in the disclosed method for treating xerophthalmia.

[0099] The words “treating” or “treatment” designate both therapeutic and prophylactic treatment or preventive measures, where the object is to prevent or stop (reduce) an unwanted physiological change or disorder, such as dryness of the eyes, vagina, or mouth. For the purpose of this invention, beneficial or wanted clinical outcomes include, without limitation, symptom relief, reduction of disease extent, stabilized pathological condition (specifically not worsened), delayed or stopped disease progression, improved or palliated pathological condition and remission (both partial and total), both detectable and non-detectable. Subjects needing treatment include subjects already suffering the disease or disorder, as well as those susceptible of suffering the disease or disorder or those for whom the disease or disorder should be prevented.

[0100] The “treatment method” is defined as the administration to a subject needing this treatment of pharmaceutical composition comprising a TRPM8 agonist, e.g. WS-12.

[0101] In the present invention, “TRPM8 receptor agonist” is defined as any molecule binding specifically to the TRPM8 receptor and that, upon binding, can cause an increase in the activity of the TRPM8 channel, i.e., that increases sodium and calcium flow through the channel causing a cell depolarization. These agonists increase the stimulation of tear secretion by cold-sensitive fibers. There is a great variety of studies available to detect the activity of TRPM8 receptor agonists, such as the whole-cell, patch-clamp electrophysiological tests mentioned in the examples of this invention (see example 1), the calcium microscopy methods (Bodding et al., 2007, Cell Calcium, 42, 618-628) and the methods based on the fluorometric imaging plate reader assay (Behrendt et al., 2004. J. Pharmacol. 141, 737-745), amongst others. As explained above, WS-12 is a TRPM8 receptor agonist.

[0102] The present invention may be better understood by reference to the following non-limiting examples, which are provided as exemplary of the invention. The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.

EXAMPLES

[0103] Example 1: Determination the UV-VIS absorption spectrum for WS-12.

[0104] Introduction and Purpose. The primary environmental purpose in determining the ultraviolet- visible (UV-Vis) absorption spectrum of a chemical compound is to receive some indication of the wavelength at which the compounds may be susceptible to photochemical degradation. Since photochemical degradation likely occurs in both the atmosphere and the aquatic environment, spectra appropriate to these media will be informative concerning the purpose for further persistence testing.

[0105] Regulatory Testing Guidelines: The study was performed in compliance with the following regulations or guidelines: 1) Organization for Economic Co-operation and Development (OECD) Guideline for Testing of Chemicals: Guideline: 101; UV-Vis Absorption Spectra (Spectrophotometric Method) (Adopted May 12, 1981); and 2) OECD Guideline for Testing of Chemicals: Guideline: 432; In vitro 3T3 NRU phototoxicity test (Revised and approved by the National Coordinators in May 2002, approved by Council April 2004).

[0106] Materials and Methods. Identification of Compound WS-12: CAS-No.: 68489-09-8; Purity: 99.93% (HPLC); Molecular Weight: 389.4 g/mol; Appearance: Grey Powder; and Storage Conditions: In the Refrigerator 2-8 °C, protected from light.

[0107] Test Item Preparation. The UV-vis absorption of the test item was determined in methanol since the solubility data provided by the Sponsor stated no water solubility and since methanol is the preferred organic solvent according to OECD 101. The solvent was divided into three glass bottles. For the preparation of the test solutions the test item was dissolved three different methanol aliquots at a weight/volume ratio of 1 mg/ml. Afterwards, the pH values of the solutions were adjusted to three different pH values: acidic (pH 2.0 using 2 N HC1), basic (pHlO.O with 2 N NaOH) and neutral (pH 7.0; no additive).

[0108] Test Symptom Supporting Information. The three solutions were measured against a specific blank which contains nothing but the solvent. After rinsing the measuring cell (cuvette) with the specific solvent the test item solution was filled in the cuvette and the absorption spectrum was determined in the range from 270-800 nm.

[0109] Data Recording. The molar absorption coefficient e (e = A/(C *d)) will be calculated for all absorbance maxima of the test item: A = absorbance maximum; C, = m (used concentration)/M(molecular weight) = concentration [mol/L]; and d = pathlength of the cuvette = 1 cm.

[0110] Results. The results are set forth in Table 2. Table 2. Absorbance Maxima and Corresponding Absorption Coefficients for WS-12.

[0111] Discussion. The UV-Vis absorption of the test item was determined in methanol adjusted to three different pH values: acidic, basic and neutral. Methanol proved to be a suitable solvent. The concentration of the test item solutions was 1 mg/ml. The solutions were measured against a specific blank which contained nothing but the solvent. Fig 1. Sets forth the absorption spectrum of WS-12 in methanol at pH 2.0. Fig. 2 sets forth the absorption spectrum of WS-12 in methanol at pH 7.0, and Fig. 3 sets forth the absorption of WS-12 in methanol at pH 10.0. The absorption spectra were determined in the range from 270-800 nm. The molar absorption coefficients were: for pH 2.0: between 467.09 and 480.98 L/(mol.cm); for neutral pH: between 724.09 and 870.81 L/(mol.cm); and for pH 10.0: between 571 and 639.57 L/(mol.cm).

[0112] Based upon these data, aqueous ophthalmic compositions comprising WS-12 were housed in polyolefin containers, and light to which the containers were exposed had a wavelength range of from about 270 to about 800 nm. The greatest amount of absorption occurred for light having a wavelength of about 1 nm to about 400 nm, which is set forth in Figs 1-3.

[0113] Example 2: Stability analyses of aqueous ophthalmic composition comprising WS-12 housed in a container comprising a polyolefin resin. [0114] In this example, two aqueous ophthalmic compositions comprising WS-12 were prepared. They were housed in a polyethylene container, and the following properties were analyzed: WS-12 loss (mg content); pH; osmolality; viscosity; appearance; particulate matter; and impurities.

[0115] Preparation of WS-12 Aqueous Ophthalmic Compositions

Table 3. Composition AK Aqueous Ophthalmic Composition Comprising WS-12.

^Considering average of 3% for initial retention in container. This value needs to be corrected by potency to calculate the weight to be added to the formulation for every batch.

WFI: Water for Injection

Table 4. Composition AL Aqueous Ophthalmic Composition Comprising WS-12.

^Considering average of 3% for initial retention in container. Please note that this value needs to be corrected by potency to calculate the weight to be added to the formulation for every batch.

WFI: Water for Injection

[0116] A placebo aqueous composition was also prepared and has the ingredients shown in Table 5. Table 5. Composition of Placebo for Aqueous Ophthalmic Compositions AK and AL.

[0117] The raw materials for compositions AK, AL, and the placebo were obtained from the suppliers shown in Table 6.

Table 6. Raw Materials for Compositions AK, AL and Placebo.

[0118] Filters. Dual layer borosilicate glass/mixed cellulose esters 2.0/1.2 pm 1-1/2 in. TC/TC. Those prefilters reduce particle and bioburden before sterilizing filtration and contribute to reduce the chances for chocking the sterilizing grade filters during the process.

[0119] PES dual membrane 0.5/0.2 pm capsule 14 in. TC/TC.

[0120] Manufacturing Strategy. Part A - Dissolution of NaCl/NaH₂P0₄-2H₂0 stock solution preparation in a reactor equipped with homogenizer using 90% of the amount of water required for the whole formulation. Part B - WS-12/Cremophor mixture: WS-12 solution in Cremophor EL (Kolliphor EL) of the following concentrations in mg WS-12 per g of Kolliphor EL (this considers already an overage of 3% for WS-12). Prepare 10% in excess from the prescribed amount to account for losses in transfer from the beaker to the reactor. Table 7. Mg of WS-12 in g of Cremophor.

[0121] Part C - Methocel dispersion into Part A (using the same reactor). Part D - WS-12/Cremophor mixture (Part B) dispersion into the reactor containing Part C (for the placebo, add directly the required amount of Cremophor only and no WS-12) Followed by pH adjustment and final weight adjustment. Part E - Sterile filtration of formulas. Part F - Packaging into single-dose unit packages.

[0122] Detailed Manufacturing Description. A. (Dissolution of salts). Introduce into a reactor equipped with an homogenizer 90-95% of the total amount of water required by the formula and add the prescribed amounts of NaCl and NaH₂P0₄-2H₂0 under stirring (700 rpm) until the complete dissolution (10 minutes are usually sufficient). B. (Stock of Cremophor and WS-12). 10% additional to the prescribed amount of Cremophor EL is placed into a suitably sized beaker that is heated at 60°C in a hot plate with a magnetic needle stir bar or an overhead motor stirring (paddle). Then, 10% excess from the corresponding amount of WS-12 is added stepwise and the solution is stirred until complete dissolution (typically 5 minutes are sufficient). Allow to cool down to room temperature and test content of WS-12 by dispersing three grams of the obtained solution in 97 g of water and proceeding to test as per what is described in the assay method for the Formula AK. C. Make sure that the paddle in the reactor containing the water and the salts is stirring at not less than 1300 rpm. Add the prescribed amount of Methocel F4M slowly to facilitate dispersion. The stirring was kept until the Methocel F4M is completely dissolved (1 hour and 30 minutes is required). If the reactor has vacuum facility, the same should be on to prevent excess foaming. If not available, the solution needs to be stirred at slow rotation 200 rpm until the foam is completely gone. D. For the formulas AK/AL. The required amount of stock solution of WS-12/Cremophor is to be added stepwise into the reactor (containing Part C) while maintaining vigorous stirring 1200 rpm until complete dispersion. If the equipment is having vacuum facility, it should be on to prevent excessive foaming (20 minutes for dispersion are usually sufficient). The pH is adjusted to 7.0 with NaOH 1 N. Finally, the system is brought to final weight by addition of water. Sample 10 ml of the solution and proceed to test as per the described method of the assay to certify content of WS-12 before starting the filtration/filling operation. E. For the placebo. The required amount of Cremophor is to be added stepwise into the reactor (containing Part C) while maintaining vigorous stirring 1200 rpm until complete dispersion. If the equipment is having vacuum facility, it should be on to prevent excessive foaming (20 minutes for dispersion are usually sufficient). The pH is adjusted to 7.0 with NaOH 1 N. Finally, the system is brought to final weight by addition of water. [0123] Analysis of Formulations. The tests shown in Table 8 were performed on formulation AK and Formulation AL, as well as the placebo, each contained in a low-density polyethylene container (LDPE), and in a high-density polyethylene container (HDPE).

Table 8. Stability Tests Performed on Compositions AK and AL Housed in LDPE and HDPE Containers at Various Storage Temperatures and Humidities.

[0124] The assays of the compositions housed in LDPE containers were performed for three months, and the assays of the compositions housed in HDPE containers were performed for two months.

[0125] Results.

[0126] Compositions housed in LDPE containers. Table 9. Osmolality (units mOsm/L) Analysis of Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Release Specifications: 280-310 mOsm/Kg Shelf Life Specifications: 260-340 mOsm/Kg N/A = Not Applicable

Table 10. Viscosit (units cps) Analysis of Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Release specifications: NLT 12 andNMT 20 Shelf life specifications: NLT5 andNMT 30

N/A = Not Applicable

Table 11. Appearance Analysis of Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Release Specifications: Slightly yellowish solution

C = Complies

N/A = Not Applicable Table 12. Particulate Matter Analysis of Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Release Specifications: Essentially free from particles

C = Complies

N/A Not applicable

Table 13. WS-12 Identification Analysis of Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Release Specifications: Main peak in the assay has retention time consistent with the one found in the Standard

C = Complies

N/A = Not Applicable

ND = No Detection

Table 14. Assay of % Content of WS-12 In Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Table 15. Impurities Analysis of Compositions AK and AL at Various Temperatures and Humidities for Three Months Stored in LDPE Containers.

Release Specifications: Individual Impurities NMG 0.2%. Total Impurities NMG 0.5% Shelf Life Specification: Individual Impurities NMT 1 %. Total Impurities NMG 2%. N.D. = None Detected [0127] Compositions Housed in HDPE Containers.

[0128] As explained above, these analyses were also performed on aqueous ophthalmic compositions comprising WS-12 housed in HDPE Containers. The results are set forth below.

Table 16. WS-12 Assay (% Content) of Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: 95-105% of the Label Strength Shelf Life Specifications: 90-110% of the Label Strength Table 17. pH Study of Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: pH 7.1 ±0.2 Shelf Life Specifications: pH 7.1±0.4 N/A = Not Applicable

Table 18. Osmolality (units mOsm/L) Study of Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Table 19. Viscosity (units cps) Study of Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: NLT 12 andNMT 20 Shelf Life Specifications: NLT 5 andNMT 30 N/A = Not applicable Table 20. Appearance Study of Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: Slightly Yellowish Solution

C = Complies

N/A = Not Applicable

Table 21. Particulate Matter Study of Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: Essentially free from particles C Complies

N/A = Not Applicable

Table 22. Study of WS-12 Identification in Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: Main peak in the assay has retention time consistent with the one found in the standard.

C = Complies

N/A = Not Applicable Table 23. Study of Percent Content of WS-12 in Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: 95 - 105% of the Label Strength Shelf Life Specifications: 90-110% of the Label Strength N/A = Not Applicable Table 24. Study of Impurities in Compositions AK and AL at Various Temperatures and Humidities for Two Months Stored in HDPE Containers.

Release Specifications: Individual Impurities NMG 0.2%. Total impurities NMT 0.5%_> Shelf Life Specifications: Individual Impurities NMT 1 %_>. Total Impurities NMT 2% N.D. = None Detected

[0129] These data make clear that housing an aqueous ophthalmic composition comprising WS-12 in a polyolefin container, and in particular in, an LDPE or HDPE container, clearly provides stability to the composition for a substantial period of time, e.g. 1, 2 or even three months, even if the containers are exposed to external effects, such as light, increased temperature up to and including 40° C, and/or increased humidity up to 25%.

[0130] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

What is claimed is:

1. A pharmaceutical preparation, comprising: an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia, wherein:

(a) the amount of WS-12 is not cytotoxic; and

(b) the aqueous ophthalmic composition is housed in a package that blocks transmittance of light.

2. The pharmaceutical preparation of claim 1, wherein the transmittance of light the package blocks is ultraviolet light.

3. The pharmaceutical preparation of claim 1 or 2, wherein the transmittance of light the package blocks has a wavelength ranging from about 1 nm to about 400 nm.

4. The pharmaceutical preparation of any of claims 1-3, wherein the package comprises at least one substance that blocks the transmittance of ultraviolet light.

5. The pharmaceutical preparation of claim 4, wherein the at least one substance that blocks transmittance of ultraviolet light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

6. The pharmaceutical preparation of any of claims 1-5, wherein the package is formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

7. The pharmaceutical preparation of claim 6, wherein the one or more polyolefin resins comprise low density polyethylene, high density polyethylene, low density polypropylene, or high density polypropylene.

8. The pharmaceutical composition of claim 6, wherein the one or more polyester resins comprises polyethylene terephthalate.

9. The pharmaceutical preparation of any of claims 1-8, wherein the package includes, as a primary package, a container comprising at least one substance which blocks transmittance of light.

10. The pharmaceutical preparation of claim 9, wherein the transmittance of light the container blocks is ultraviolet light having a wavelength ranging from about 1 nm to about 400 nm.

12. The pharmaceutical preparation of either of claims 9 or 10, wherein the at least one substance one substance that blocks transmittance of ultraviolet light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

13. The pharmaceutical preparation of any of claims 1-12, wherein the package includes, as a secondary package, a bag comprising a substance that blocks transmittance of light.

14. The pharmaceutical preparation of claim 13, wherein the transmittance of light the secondary package blocks is ultraviolet light.

15. The pharmaceutical preparation of claim 14, wherein the ultraviolet light has a wavelength ranging from about 1 nm to about 400 nm.

16. The pharmaceutical preparation of any of claims 13-15, wherein the at least one substance that blocks transmittance of ultraviolet light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

17. The pharmaceutical preparation of any of claims 1-16, wherein the package permits transmittance of light in the visible light spectrum.

18. A method of improving light stability of an aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia, wherein the amount of WS-12 is not cytotoxic, comprising the step of housing the aqueous ophthalmic composition in a package that blocks transmittance of light.

19. The method of claim 18, wherein the transmittance of light the package blocks is ultraviolet light.

20. The method of claim 18 or 19, wherein the transmittance of light the package blocks has a wavelength ranging from about 1 nm to about 400 nm.

21. The method of any of claims 18-20, wherein the package comprises at least one substance that blocks the transmittance of ultraviolet light.

22. The method of claim 21, wherein the at least one substance that blocks transmittance of UV light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

23. The method of any of claims 18-22, wherein the package is formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

24. The method of claim 23, wherein the one or more polyolefin resins comprise low density polyethylene, high density polyethylene, low density polypropylene, or high density polypropylene.

25. The method of claim 23, wherein the one or more polyester resins comprises polyethylene terephthalate.

26. The method of any of claims 18-25, wherein the package includes, as a primary package, a container comprising at least one substance which blocks transmittance of light.

27. The method of claim 26, wherein the transmittance of light the container blocks is ultraviolet light having a wavelength ranging from about 1 nm to about 400 nm.

28. The method of either of claims 27 or 28, wherein the at least one substance that blocks transmittance of ultraviolet light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

29. The method of any of claims 18-28, wherein the package includes, as a secondary package, a bag comprising at least one substance that blocks transmittance of light.

30. The method of claim 29, wherein the transmittance of light the secondary package blocks is ultraviolet light.

31. The method of claim 30, wherein the ultraviolet light has a wavelength ranging from about 1 nm to about 400 nm.

32. The method of any of claims 29-31, wherein the at least one substance that blocks transmittance of ultraviolet light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

33. The method of any of claims 18-32, wherein the package permits transmittance of light in the visible light spectrum.

34. An aqueous ophthalmic composition comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl-cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia, wherein:

(a) the amount of WS-12 is not cytotoxic; and

(b) the aqueous ophthalmic composition is housed in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

35. The aqueous ophthalmic composition of claim 34, wherein the one or more polyolefin resins comprise low density polyethylene, high density polyethylene, low density polypropylene, or high density polypropylene.

36. The aqueous ophthalmic composition of claim 35, wherein the one or more polyester resins comprises polyethylene terephthalate.

37. The aqueous ophthalmic composition of any of claims 34-36, wherein the container blocks transmittance of light.

38. The aqueous ophthalmic composition of claim 37, wherein the transmittance of light the container blocks is ultraviolet light.

39. The aqueous ophthalmic composition of claim 38, wherein the transmittance of ultraviolet light the container blocks has a wavelength ranging from about 1 nm to about 400 nm.

40. The aqueous ophthalmic composition of any of claims 37-39, wherein the container comprises at least one substance which blocks transmittance of light.

41. The aqueous composition of any of claims 37-40, wherein the at least one substance that blocks transmittance of light comprises titanium dioxide, zinc oxide, a benzotriazole-based UV absorbing agent, or any combination thereof.

42. The aqueous ophthalmic composition of any of claims 34^11, wherein the container is transparent in the visible light spectrum.

43. A method for improving heat stability of WS-12 or a salt, solvate or tautomer thereof in an aqueous ophthalmic comprising a therapeutically effective amount of WS-12 (lR,2S,5R-2-isopropyl-5-methyl- cyclohexanecarboxylic acid (4-methoxy phenyl)-amide) for effectively treating or reducing the likelihood of xerophthalmia, comprising the step of housing the aqueous ophthalmic composition in a container formed of one or more polyolefin resins, one or more polyester resins, or any combination thereof.

44. The method of claim 43, wherein the one or more polyolefin resins comprise low density polyethylene, high density polyethylene, low density polypropylene, or high density polypropylene.

45. The method of claim 44, wherein the one or more polyester resins comprises polyethylene terephthalate.

46. The pharmaceutical preparation of any of claims 1-17, wherein the package is a single-dose unit package.

47. The method of any of claims 18-33, wherein the package is a single-dose unit package.

48. The aqueous ophthalmic composition of any of claims 34-42, wherein the container is single-dose unit container.

49. The method of any of claims 43-45, wherein the container is a single-dose unit container.