US 20120095097A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0095097 A1 Tabuchi et al. (43) Pub. Date: Apr. 19, 2012
(54) OPHTHALMIC COMPOSITION Publication Classification (76) Inventors: Nobuhito Tabuchi, Tokyo (JP): ( 51) Int. Cl. Chieko Inoue, Tokyo (JP); st 12g CR Manabu Hattori, Tokyo (JP): ( .01) Miyuki Miyake, Tokyo (JP); EC, C Hazuki Tsutsui, Tokyo (JP) ( .01) (21) Appl. No.: 13/377.867 (52) U.S. Cl...... 514/552; 514/546; 514/559 y x- - - 9 (22) PCT Filed: Jun. 25, 2009 (57) ABSTRACT (86). PCT No.: PCT/UP2009/061591 Disclosed is an ophthalmic composition containing (A) not less than 50,000 units/100 mL of vitaminA, (B) not less than S371 (c)(1), 0.4W/V 9% of a polyoxyethylene polyoxypropylene glycol, (2), (4) Date: Dec. 13, 2011 and (C) trometamol. US 2012/0095097 A1 Apr. 19, 2012
OPHTHALMC COMPOSITION 0012 (1 An ophthalmic composition including (A) at least 50,000 units/100 mL of vitaminA, (B) at least 0.4W/V TECHNICAL FIELD % of polyoxyethylene polyoxypropylene glycol and (C) trometamol. 0001. This invention relates to an ophthalmic composition 0013 2. The ophthalmic composition as recited in 1. containing vitamin A at a high concentration. wherein a content of the ingredient (A) is at least 100,000 units/100 mL. BACKGROUND ART 0014) 3 The ophthalmic composition as recited in 1. 0002 Attention has been drawn to vitamin A as being an wherein a content of the ingredient (A) is at least 200,000 effective ingredient for preventing or treating keratoses Such units/100 mL. as of the cornea and conjunctiva and also of the skin mucosa. 00.15 4 The ophthalmic composition as recited in 1. On the other hand, vitamin A that is a lipophilic vitamin is wherein a content of the ingredient (A) is at least 300,000 very sensitive to air, light, heat, acids, metal ions and the like units/100 mL. and is particularly very unstable in aqueous solutions, with a 0016 5. The ophthalmic composition as recited in any difficulty involved in stably formulating it in ophthalmic one of 1 to 4, further including (D) an antioxidant. compositions such as eye drops and the like. 0017 6. The ophthalmic composition as recited in 5. 0003 For techniques of stabilizing such unstable vitamin wherein the ingredient (D) is vitamin E and/or dibutylhy A, there have beenhitherto proposed a method of stabilization droxytoluene. with nonionic Surfactants such as polyethylene hardened cas 0018 7. The ophthalmic composition as recited in any tor oil and the like (see, for example, JP-A H05-331056: one of 1 to 6, wherein the ingredient (A) is retinol palmi Patent Document 1), a method of stabilization with vitamin tate, retinol acetate or retinoic acid. Es that area hydrophobic antioxidant (see, for example, JP-A 0019 8. The ophthalmic composition as recited in any H06-247853: Patent Document 2), and a technique of stabi one of 1 to 7, wherein a ratio by weight between the lization from the aspect of a container or package (see, for ingredient (B) and the ingredient (C) expressed as (B):(C) is example, JP-A H06-40907: Patent Document 3, and JP-A at 1:30 to 30:1. 2003-113078: Patent Document 4), and a stabilization tech 0020 9A method for stabilizing vitamin A comprising: nique wherein preparation is carried out by high-energy 0021 formulating at least 0.4W/V% of polyoxyethylene emulsification (see, for example, JP-A 2002-332225: Patent polyoxypropylene glycol and (C) trometamol in an oph Document 5). However, the prior-art techniques have not thalmic composition containing at least 50,000 units/100 mL been well satisfactory with respect to the level of stability of vitamin A. necessary for medical products in high concentration systems (of not lower than 50,000 units). In view of the above, there Advantageous Effect of the Invention has been demanded a technology of further increasing the 0022. According to the invention, there can be provided a stabilization of vitaminA in ophthalmic compositions formu Vitamin A-containing ophthalmic composition wherein Vita lated with a high concentration of vitamin A. min A is stabilized even when the vitamin A is formulated at PRIOR ART DOCUMENTS high concentration and also a method for stabilizing vitamin A. Patent Documents 0004 Patent Document 1: JP-A H05-331056 EMBODIMENT FOR CARRYING OUT THE 0005 Patent Document 2: JP-A H06-247853 INVENTION 0006 Patent Document 3: JP-A H06-40907 0023 The invention is now described in detail. The oph 0007 Patent Document 4: JP-A 2003-113078 thalmic composition of the invention includes (A) at least 0008 Patent Document 5: JP-A 2002-332225 50,000 units/100 mL of vitaminA, (B) at least 0.4W/V% of polyoxyethylene polyoxypropylene glycol and (C) trometa SUMMARY OF THE INVENTION mol. It will be noted that another purpose of the invention is to Problems to be Solved by the Invention provide an ophthalmic composition having a dry eye-improv ing effect, and a further effect of the invention is a dry eye 0009. The invention has been made under such circum improving effect. stances as set out above and has for its object the provision of an ophthalmic composition formulated with a high concen (A) Vitamin A tration of stabilized vitaminA and also of a stabilizing method of vitamin A. 0024. As vitamin A, there may be mentioned, aside from Vitamin A itself. Vitamin A-containing mixtures such as Vita min A oil, vitamin A derivatives such as vitamin A fatty acid Means for Solving the Problems esters, and the like. More particularly, vitamin A includes 0010 We made intensive studies in order to achieve the retinol palmitate, retinol acetate, retinol, retinoic acid, retin above object and, as a result, found that when at least 0.4W/V oide and the like. Of these, retinol palmitate, retinol acetate, % of polyoxyethylene polyoxypropylene glycol and trometa and retinoic acid are preferred. Retinol palmitate is commer mol are formulated in an ophthalmic composition containing cially sold usually as having one million to 1.8 million inter at least 50,000 units/100 mL of vitamin A, the stability of national units (hereinafter abbreviated as units or I.U.), for Vitamin A can be significantly enhanced, thereby arriving at which specific mention is “Retinol palmitate' (1.7 million completion of the invention. I.U./g), made by Roche Vitamin Japan Co., Ltd.). 0011. Accordingly, the invention provides the following 0025. The ingredients (A) may be used singly or in appro ophthalmic composition and Stabilizing method of vitamin A. priate combination of two or more. The content is at least US 2012/0095097 A1 Apr. 19, 2012
50,000 units/100 mL relative to the total amount of the oph the ophthalmic composition of the invention. For the first thalmic composition. Vitamin A has a corneal and conjuncti time, we have found that trometamol has an effect of improv Val disorder treating effect and an improving effect of dry ing the storage stability of vitamin A. This mechanism is not eyes, tired eyes and bleary eyes, and Such effects can be more clearly known and may be considered, for example, in the pronouncedly shown when its content of at least 50,000 units/ following way. Polyoxyethylene polyoxypropylene glycol is 100 mL is used. From the standpoint of these effects, the a nonionic Surfactant that has a polyoxyethylene (EO) chain amount of the ingredient (A) is preferably at least 100,000 and a polyoxypropylene (PO) chain. Vitamin A is wrapped units/100 mL, more preferably at least 200,000 units/100 mL and much more preferably at least 300,000 units/100 mL. The with the EO chain kept outside and also with the PO chain upper limit is preferably not greater than 500,000 units/100 kept inside, thereby forming a micelle. The coexistence of mL from the viewpoint of stability. When expressed in terms trometamol permits the —NH group present in trometamol of W(weight)/V(volume)%(g/100 mL), the above amount is to be directly bound to the ether bond of the EO chain, preferably at 0.03 to 0.3 W/V 96 although depending on the resulting in the strong structure of the micelle. Moreover, units of vitamin A being formulated. trometamol binds to the EO chain located at the outside of the (B) Polyoxyethylene polyoxypropylene glycol micelle so that the micelle structure is rendered strong with 0026. In the invention, when using (B) polyoxyethylene the degree of freedom being lowered, eventually leading to polyoxypropylene glycol, even an ophthalmic composition the lowering of molecular mobility of the PO chain inside the containing at least 50,000 units/100 mL is able to keep sta micelle. In view of the above, it is considered that trometamol bility thereof, does not have eye irritation and improve the contributes to the stabilization of the micelle formed from effects of treating a cornea damage and dry eyes. These Vitamin A and polyoxyethylene polyoxypropylene glycol effects are unsatisfactory when using Surfactants, such as and, as a consequence, contributes to the storage stability of Sorbitan fatty acid esters, polyoxyethylene hardened castor Vitamin A. oil and the like, which have been well used, for example, in 0032. The content of trometamol (C) is preferably at 0.01 eye drops. Polyoxyethylene polyoxypropylene glycol is not to 5 W/V%, more preferably at 0.05 to 5 W/V%, much more critical in type and those described in Japanese Pharmaceu preferably at 0.1 to 3 W/V% and most preferably at 0.5 to 2 tical Excipients (JPE) may be used. The preferred average W/V 96, relative to the total amount of the ophthalmic com degree of polymerization of ethylene oxide is 4 to 200, more position. If the content is less than 0.01 W/V '%, there is preferably 20 to 200 and the average degree of polymeriza concern that the effect on the storage stabilization of vitamin tion of propylene oxide is preferably 5 to 100, more prefer A becomes unsatisfactory. Over 5 W/V '%, there is concern ably 20 to 70, and either a block copolymer or a random that eye irritation occurs. From the standpoint of the storage polymer may be used. stabilization of vitamin A, the ratio by weight between the 0027. In particular, mention is made of polyoxyethylene ingredient (B) and the ingredient (C) expressed by (B):(C) is (200) polyoxypropylene (70) glycol: Lutrol F127 (made by preferably at 1:30 to 30:1, more preferably at 1:20 to 20:1, BASF), Uniloob 70DP-950B (made by NFO Corporation), much more preferably at 1:10 to 10:1 and most preferably at polyoxyethylene (120) polyoxypropylene (40) glycol (Plu 1:10 to 3:1. ronic F-87), polyoxyethylene (160) polyoxypropylene (30) glycol (Pluronic F-68, otherwise known as Poloxamer 188): (D) Antioxidant Pronon #188P (made by NFO corporation) and the like, poly oxyethylene (42) polyoxypropylene (67) glycol (Pluronic 0033. The ophthalmic composition of the invention is P123, otherwise known as Poloxamer 403), polyoxyethylene preferably formulated with an antioxidant from the stand (54) polyoxypropylene (39) glycol (Pluronic P85): Pronon point of improving the storage stability of vitamin A. As an #235P (made by NFO Corporation) and the like, polyoxyeth antioxidant, mention is made of vitamin ES Such as ylene (20) polyoxypropylene (20) glycol (Pluronic L-44), d-C-tocopherol, d-B-tocopherol, d-y-tocopherol, Tetronic and the like. Of these, polyoxyethylene (200) poly d-ö-tocopherol, dl-C-tocopherol, d-C-tocopherol acetate, oxypropylene (70) glycol, polyoxyethylene (160) polyox dl-C-tocopherol acetate, d1-Ö-tocopherol acetate, ypropylene (30) glycol, and polyoxyethylene (54) polyox dl-y-tocopherol acetate, d1-8-tocopherol acetate, ypropylene (39) glycol are preferred. dl-C-tocopherol nicotinate and the like, 0028. The ingredients (B) may be used singly or in appro lipophilic antioxidants such as dibutylhydroxytoluene, butyl priate combination of two or more. The content is at least 0.4 hydroxyanisole and the like, vitamin C, water-soluble anti W/V%, preferably 0.4 to 5 W/V%, more preferably 0.5 to 3 oxidants such as hydroquinone, cysteine, glutathione and the W/V %, much more preferably 0.6 to 2W/V %, and most like, etc. Of these, lipophilic antioxidants such as vitamin E preferably 1 to 2 W/V '%, relative to the total amount of the and the like are preferred, among which d-C-tocopherol ophthalmic composition. If the amount is less than 0.4W/V acetate and dibutylhydroxytoluene are more preferred and %, a difficulty is involved in solubilizing vitamin A and in d-C-tocopherol is much more preferable. It is also preferred to view of storage stability of vitamin A, the amount is prefer use vitamin E and dibutylhydroxytoluene in combination. ably not greater than 5 W/V%. 0034. The antioxidants may be used singly or in combina 0029. From the standpoint of the storage stabilization of tion of two or more. The content is preferably at 0.005 to 5 Vitamin A, the ratio between ingredient (A) and ingredient W/V 96 relative to the total amount of the ophthalmic com 0030 (B), expressed as (A) VitaminA units/100 mL/(B) position, within which the storage stability of vitamin A can polyoxyethylene polyoxypropylene glycol g/100 mL), is be improved, and is more preferably at 0.005 to 1 W/V% and preferably at 10,000 to 150,000, more preferably at 15,000 to much more preferably at 0.005 to 0.2 W/V%. 100,000 and much more preferably at 25,000 to 50,000. 0035. The ophthalmic composition of the invention may beformulated, aside from the above ingredients, with a vari (C) Trometamol ety of ingredients being formulated in ophthalmic composi 0031. From the standpoint of improving the storage sta tions without detracting the effect of the invention. These bility of vitamin A, it is preferred to formula trometamol in ingredients include polyhydric alcohols, Surfactants other US 2012/0095097 A1 Apr. 19, 2012 than the ingredient (B), buffering agents, thickening agents, adjuster relative to the total amount of the ophthalmic com Sugars, pH adjusters, antiseptics, tonicity agents, stabilizing position is, for example, at 0.00001 to 10 W/V %, preferably agents, algefacients, drugs, water and the like. These may be at 0.0001 to 5 W/V % and much more preferably at 0.001 to used singly or in appropriate combination of two or more and 3 W/V 96. can be formulated in appropriate amounts. 0042. As an antiseptic, mention is made, for example, of 0036 Polyhydric alcohols include glycerine, propylene benzalkonium chloride, benzethonium chloride, sorbic acid glycol, butylene glycol, polyethylene glycol and the like. The or its salts, para-oxybenzoic acid esters (methylparaben, eth content of the polyhydric alcohol is preferably at 0.01 to 5 ylparaben, propylparaben and the like), chlorhexidine glu W/V %, more preferably at 0.05 to 3 W/V %, relative to the conate, thimerosal, phenylethyl alcohol, alkyldiaminoethyl total amount of the ophthalmic composition. glycine hydrochloride, polyhexanide hydrochloride, polidro 0037 Surfactants other than the ingredient (B) may be nium chloride and the like. The content of the antiseptic used in combination, for which mention is made of polyoxy relative to the total amount of the ophthalmic composition is, ethylene hardened castor oil, a polyoxyethylene sorbitan fatty for example, at 0.00001 to 5 W/V%, preferably at 0.0001 to acid ester (Polysorbate 80) and the like. The parallel usage 3 W/V % and more preferably at 0.001 to 2 W/V%. permits stability to be improved. The content of the surfactant 0043. It will be noted that in the practice of the invention, is preferably at 0.0001 to 5 W/V%, more preferably at 0.005 the content of a cationic Surfactant selected from benzalko to 3 W/V 96, relative to the total amount of the ophthalmic nium chloride and benzetonium chloride (part of which is a composition. It will be noted that from the standpoints of the cationic antiseptic) and a hydrophobic antiseptic selected effect of treating corneal and conjunctival damages and the from a para-oxybenzoic acid ester (methylparaben, ethylpa healing effect of dry eyes, it is favorable to use these surfac raben, propylparaben or the like) and chlorobutanol is pref tants in reduced amounts and their content is preferably at not erably, from the standpoints of the corneal and conjunctival greater than 0.5 W/V%. disorder treating effect and the dry eye improving effect, at 0038 Examples of the buffering agent include boric acid not greater than 0.004W/V%, more preferably at not greater or borates (borax and the like), citric acid or citrates (sodium than 0.003 W/V %, provided that it is much more preferred citrate and the like), phosphoric acid or phosphates (sodium that these are not formulated without incorporation thereof. hydrogen phosphate and the like), tartaric acid or tartarates The mechanism of impeding the corneal and conjunctival (sodium tartarate and the like), gluconic acid or gluconates disorder treating effect is not known, but is considered as (sodium gluconate and the like), and acetic acid or acetates follows. Polyoxyethylene polyoxypropylene glycol (B) (sodium acetate and the like), of which boric acid and borax wraps around vitaminA while keeping the EO chain outside are preferred when they are used in combination because a and the PO chain inside thereby forming a micelle. This high antiseptic effect is obtained therefrom. The content of micelle adsorbs on the cornea Surface to permit vitamin A to the buffering agent is preferably at 0.001 to 10 W/V%, more be absorbed in the cornea. Because the condition of the preferably at 0.01 to 5 W/V%, relative to the total amount of micelle Surface is changed owing to the Surface activity of the the ophthalmic composition. The formulation of boric acid or cationic surfactant and also to the high hydrophobicity of the citric acid allows vitamin A to be more stabilized. hydrophobic antiseptic, thereby inhibiting the adsorption of 0039. The thickening agents include, for example, polyvi the vitamin A on the cornea. Eventually, the corneal and nylpyrrolidone, hydroxyethyl cellulose, hydroxypropyl conjunctival disorder treating effect and a dry eye improve methyl cellulose, methyl cellulose, polyvinyl alcohol, ment are impeded. On the other hand, those having high Sodium hyaluronate, sodium chondroitin Sulfate, polyacrylic hydrophilicity such as sorbic acid or its salt do not influence acid, carboxyvinyl polymer and the like. The formulation of the condition of the micelle surface, so that the absorption these ingredients permits retentivity to be enhanced and the expediting effect on vitamin A is not inhibited. The above corneal and conjunctival disorder treating effect to be more ingredient is a sort of antiseptic, and if no antiseptic is for improved. The content of the thickening agent is, for mulated, antiseptic power is ensured by formulating one or example, at 0.001 to 10 W/V%, preferably at 0.001 to 5 W/V more, preferably two or more, of sodium edetate, boric acid % and more preferably at 0.01 to 3 W/V%. and trometamol. In addition, if there is used a unit dose 0040 Sugars include glucose, cyclodextrin, xylitol, sorbi container or a filter-attached container, no formulation of an tol, mannitol and the like. It will be noted that these may be in antiseptic is possible. any form of a D isomer, L isomer or DL isomer. The content 0044) The tonicity agent includes, for example, sodium of the sugar relative to the total amount of the ophthalmic chloride, potassium chloride and the like. The content of the composition is, for example, at 0.001 to 10 W/V 96, prefer tonicity agent relative to the total amount of the ophthalmic ably at 0.005 to 5 W/V % and more preferably at 0.01 to 3 composition is, for example, at 0.001 to 5 W/V%, preferably W/V 96. at 0.01 to 3 W/V % and more preferably at 0.1 to 2 W/V%. 0041 As a pH adjuster, it is preferred to use an inorganic 0045. The stabilizing agent includes, for example, sodium acid or inorganic alkaline agents. Examples of the inorganic edetate, cyclodextrin, a sulfite, dibutylhydroxytoluene and acid include (diluted) hydrochloric acid. Examples of the the like. It is to be noted that in the practice of the invention, inorganic alkaline agent include Sodium hydroxide, potas when a stabilizing agentis formulated, the stability of vitamin sium hydroxide, sodium carbonate, Sodium hydrogen carbon A is more improved. The content of the stabilizing agent ate, and the like. Of these, hydrochloric acid and sodium relative to the total amount of the ophthalmic composition is, hydroxide are preferred. The pH (20°C.) of the ophthalmic for example, at 0.001 to 5 W/V%, preferably at 0.01 to3 W/V composition of the invention is preferably at 4.0 to 9.0, more % and more preferably at 0.1 to 2 W/V%. preferably at 5.0 to 8.0 and much more preferably at 6.0 to 8.0. 0046. The algefacient includes, for example, menthol, It will be noted that in the practice of the invention, the pH is camphor, borneol, geraniol, linalool, cineol and the like. The measured by use of a pH osmometer (HOSM-1, made by content of the algefacient relative to the total amount of the DKK-Toa Corporation) at 20° C. The content of the pH ophthalmic composition is preferably at 0.0001 to 5 W/V%. US 2012/0095097 A1 Apr. 19, 2012 more preferably at 0.001 to 2 W/V%, much more preferably particularly includes eye drops (e.g. an ordinary eye drop, an at 0.005 to 1 W/V% and most preferably at 0.007 to 0.8 W/V eye drop for contact lenses and the like), eye washes (e.g. an %. ordinary eye wash, an eye wash used after removal of contact 0047. As a drug (pharmaceutically effective ingredient), lenses and the like), solutions used upon wearing of contact there may be appropriately formulated, for example, a decon lenses, Solutions used when removing contact lenses and the gestant (e.g. naphazoline hydrochloride, tetrahydrozoline like. hydrochloride, phenylephrine hydrochloride, epinephrine, 0.058 Where the ophthalmic composition of the invention ephedrine hydrochloride, d1-methylephedrine hydrochloride, is in liquid form and is used as an eye drop, its viscosity is preferably at 1 to 100 mPa-second, more preferably at 1 to 50 tetrahydrozoline nitrate, naphazoline nitrate or the like), an mPa-second and much more preferably at 1 to 30 mPa-sec antiphlogistic/astringent agent (e.g. neostigmine methylsul ond. It will be noted that the viscosity is measured by use of fate, e-aminocaproic acid, allantoin, berberine chloride, Zinc an E-type viscometer (VISCONIC ELD-R, made by Tokyo Sulfate, Zinc lactate, lysozyme chloride, dipotassium glycyr Keiki Inc.) at 20' C. rhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, 0059. The ophthalmic composition of the invention is not methyl salicylate, tranexamic acid, aZulene Sodium sulfonate critical with respect to its preparation method. For instance, or the like), an antihistamine agent (e.g. iproheptine hydro the composition can be obtained by solubilizing vitamin A in chloride, diphenhydramine hydrochloride, diphenhy sterilized purified water with the aid of polyoxyethylene dramine, isothipendyl hydrochloride, chlorpheniramine polyoxypropylene glycol, followed by adding trometamol maleate or the like), a water-soluble vitamin (activated vita and other formulation ingredients and adjusting a pH thereof. min B vitamin B vitamin B or the like), an amino acid Thereafter, the composition can be aseptically filled, for (e.g. potassium L-aspartate, magnesium L-aspartate, amino example, in a polyethylene terephthalate container. ethylsulfonic acid, sodium chondroitin sulfate or the like), a 0060 According to the invention if vitamin A is formu Sulfa drug or bactericide (e.g. Sulfur, isopropylmethylphenol, lated in amounts of at least 50,000 units/100 mL, the formu hinokitiol or the like), an anti-allergenic agent (e.g. cro lation of polyoxyethylene polyoxypropylene glycol and moglycic acid, ketotifen fumarate, tranilast or the like), a trometamol enables the vitamin A to be stabilized. regional anesthetic (e.g. lidocaine, lidocaine hydrochloride, 0061 The method for stabilizing vitamin A according to procaine hydrochloride, dibucaine hydrochloride or the like), the invention is one wherein at least 0.4W/V 9% of polyoxy a mydriatic drug (e.g. cyclopentolate hydrochloride, tropica ethylene polyoxypropylene glycol and trometamol (C) are mide or the like), and a cataract drug (pirenoXine, glutathione formulated in an ophthalmic composition containing at least or the like). 50,000 units/100 mL of vitamin A, and favorable additive 0048. The content of these ingredients may be appropri ingredients and contents thereof are similar to those of the ately selected depending on the types of preparations and the above-stated ophthalmic composition. The invention is types of drugs, and the content of the respective ingredients is directed to a formulation for an ophthalmic composition con known in this field of technology. For instance, the content taining at least 50,000 units/100 mL and can provide a stabi can be appropriately chosen from a range of 0.0001 to 30W/V lizer for Such vitamin A made up of polyoxyethylene poly %, preferably from 0.001 to 10 W/V %, relative to the total oxypropylene glycol and trometamol. In this case, amount of the ophthalmic composition. More particularly, the polyoxyethylene polyoxypropylene glycol is formulated in contents of the respective ingredients relative to the total an amount of at least 0.4W/V 96 in an ophthalmic composi amount of the ophthalmic composition are just as follows. tion containing at least 50,000 units/100 mL. 0049. With a decongestant, the content is, for example, at 0062 Since vitamin A is formulated at a high concentra 0.0001 to 0.5 W/V%, preferably at 0.0005 to 0.3 W/V% and tion, the composition of the invention is Suited as a corneal more preferably at 0.001 to 0.1 W/V%. damage-treating ophthalmic composition showing a better 0050. With an antiphlogistic/astringent agent, the content effect and also as a dry eye drug. It is to be noted that dry eyes is, for example, at 0.0001 to 10 W/V%, preferably at 0.0001 mean Such a state that the cornea and conjunctiva on the to 5 WV 9/6. Surface of the eyeball are damaged owing to the qualitative 0051. With an antihistamine agent, its content is, for and quantitative abnormality of the lacrimal fluid. The lacri example, at 0.0001 to 10 W/V%, preferably at 0.001 to 5 W/V mal fluid is constituted of three layers including an oil layer, %. an aqueous layer and a mucin layer, and if the qualitative and quantitative balance of this three-layered structure is dis 0.052 With a water-soluble vitamin, its content is, for rupted, the lacrimal fluid becomes unstable, thereby leading example, at 0.0001 to 1 W/V %, preferably at 0.0001 to 0.5 to a corneal disorder and bringing about dry eyes. In the dry W/V 96. eye treatment, importance is placed on the recovery of the 0053 With an amino acid, the content is, for example, at three-layered structure of an oil layer, aqueous layer and 0.0001 to 10 W/V %, preferably at 0.001 to 3 W/V%. mucin layer of the lacrimal fluid and the treatment of the 0054 With a sulfur drug or bactericide, the content is, for corneal disorder. Since contact lens users are liable to suffer example, at 0.00001 to 10 W/V%, preferably at 0.0001 to 10 dry eyes, the ophthalmic composition of the invention is W/V 96. Suitable as an eye drop for contact lens, an eye wash to be used 0055 With an anti-allergenic agent, the content is, for after removal of contact lenses, a solution to be used upon example, at 0.0001 to 10 W/V%, preferably at 0.001 to 5 W/V wearing of contact lenses, and a solution to be used when %. removing contact lenses. Where used as a dry eye treating 0056. With a regional anesthetic, a mydriatic drug or a agent, a better effect is shown by placing drops of 30 to 60 uL cataract drug, the content is, for example, at 0.001 to 1 W/V per single use and 3 to 6 cycles per day in the eye. %, preferably at 0.005 to 1 W/V%. 0057 The ophthalmic composition of the invention may EXAMPLES be used as it is in liquid form, or may be prepared as a 0063. The invention is particularly described by way of Suspension, a gelling agent or the like. The type of usage Examples and Comparative Examples, and the invention US 2012/0095097 A1 Apr. 19, 2012
shoulds not be construed as limited to the Examples. It will be
TABLE 1. Example Comparative Example
Formulation (WV 9.6) 1 2 3 4 5 (A) Retinol palmitate 50,000 50,000 50,000 50,000 50,000 50,000 units units units units units units (B) Polyoxyethylene (200) 1 O.1 polyoxy propylene (70) glycol (C) Trometamol 1 1 Others Polyoxyethylene 1 hardened castor oil 60 Polysorbate 80 1 1 Sodium chloride O.9 O.9 O.9 O.9 O.9 Diluted hydrochloric Appropriate Appropriate Appropriate Appropriate Appropriate Appropriate acid sodium hydroxide amount amount amount amount amount amount (ph = 7) Purified water Balance Balance Balance Balance Balance Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol 66.5 59.7 Not 57.2 57.0 57.2 palmitate (%) solubilized units of (A)/g of (B) 50,000 50,000 500,000 50,000 50,000 50,000 (B):(C) 1:1 1:10
TABLE 2 Example
Formulation (W/V%) 2 3 4 5 (A) Retinol palmitate 50,000 units 50,000 units 50,000 units 50,000 units (B) Polyoxyethylene (200) 0.4 1.5 3 5 polyoxypropylene (70) glycol (C) Trometamol 1 1 1 1 Others Sodium chloride O.9 O.9 O.9 O.9 Diluted hydrochloric Appropriate Appropriate Appropriate Appropriate acid sodium hydroxide amount amount amount amount (pH = 7) Purified water Balance Balance Balance Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol 64.3 66.4 65.5 64.1 palmitate (%) Units of (A)/g of (B) 125,000 33,333 16,667 10,000 (B):(C) 1:2.5 1.5:1 3:1 5:1 US 2012/0095097 A1 Apr. 19, 2012
TABLE 3 Example
Formulation (W/V%) 6 7 8 9 10 (A) Retinol palmitate 50,000 50,000 50,000 50,000 50,000 units units units units units (B) Polyoxyethylene (200) 1 1 1 1 1 polyoxypropylene (70) glycol (C) Trometamol O.OS O.1 O.S 3 5 Others Sodium chloride O.9 O.9 O.9 O.9 O.9 Diluted hydrochloric Appropriate Appropriate Appropriate Appropriate Appropriate acid sodium hydroxide amount amount amount amount amount (ph = 7) Purified water Balance Balance Balance Balance Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol 65.3 65.8 66.4 66.7 66.9 palmitate (%) units of (A)/g of (B) 50,000 50,000 50,000 50,000 50,000 (B):(C) 20:1 10:1 2:1 1:3 1:5
TABLE 4 TABLE 4-continued Example - Example
Formulation (W/V%) 11 12 13 Formulation (WV 9.6) 11 12 13 Sodium chloride O.9 O.9 O.9 (A) Retinol palmitate 50,000 50,000 50,000 Diluted hydrochloric Appropriate Appropriate Appropriate units units units acid sodium hydroxide amount amount amount (B) Polyoxyethylene (200) 1 1 1 (pH = 7) polyoxypropylene (700) Purified water Balance Balance Balance glycol (C) Trometamol 1 1 1 Total 100 mL. 100 mL. 100 mL. (D) d-C-Tocopherol acetate O.OS O.OS Residual ratio of retinol 68.5 68.7 70.9 palmitate (%) Dibutylhydroxytoluene 0.005 O.OOS units of (A)/g of (B) 50,000 50,000 50,000 Others Polyoxyethylene (B):(C) 1:1 1:1 1:1 hardened castor oil 60
TABLE 5 Example Formulation (WV 9.6) 14 15 16 17 18 19 (A) Retinol palmitate 50,000 50,000 50,000 100,000 200,000 300,000 units units units units units units (B) Polyoxyethylene (200) 1 1 1 3 5 5 polyoxypropylene (70) glycol (C) Trometamol O.1 O.S 2 2 3 5 (D) d-C-Tocopherol acetate O.OS O.OS O.OS O.2 O.OS O.OS Dibutylhydroxytoluene O.OOS O.OOS O.OOS O.OOS O.OOS O.OOS Others Sodium hyaluronate O.O2 O.O2 Hypromellose O.1 O.1 Polyvinylpyrrollidone O.1 O.1 Sodium chondroitin O.1 O.1 sulfate Taurine O.1 O.1 O.1 Potassium L-aspartate 1 1 Boric acid O.S O.S O.S O.S O.S O.S Borax O.2 I-Menthol O.OOS di-Camphor O.OO2 d-Borneo O.OO3 Sodium edietate O.1 O.1 O.1 O.1 O.1 O.1 Potassium sorbate O.1 Glycerine O.S US 2012/0095097 A1 Apr. 19, 2012
TABLE 5-continued Example
Formulation (W/V%) 14 15 16 17 18 19 Sodium chloride O.9 O.9 O.9 O.9 O.9 O.9 Dilute hydrochloric Appropriate amount acid sodium hydroxide (pH = 7) Purified water Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol 70.5 70.6 70.8 67.3 66.5 66.1 palmitate (%) units of (A)/g of (B) 50,000 50,000 50,000 33,333 40,000 60,000 (B):(C) 10:1 2:1 1:2 1.5:1 1.7:1 1:1
TABLE 6 Example
Formulation (W/V%) 2O 21 22 23 24 (A) Retinol palmitate 50,000 50,000 50,000 50,000 100,000 units units units units units (B) Polyoxyethylene (200) 0.4 1 2 5 3 polyoxypropylene (70) glycol (C) Trometamol 1 1 2 2 O.S (D) d-C-Tocopherol acetate O.OS O.OS O.1 O.OS 1 Dibutylhydroxytoluene O.OOS O.OOS O.OOS O.OOS O.OOS Others Tetrahydrozoline O.OS O.OS hydrochloride NeoStigmine O.OOS O.OOS methysulfate Chlorpheniramine O.O3 O.O3 O.O3 O.O3 O.O3 maleate Pyridoxine O.OS O.OS O.OS O.OS hydrochloride Dipotassium O.25 glycyrrhizate Sodium hyaluronate O.O2 O.O2 Boric acid 1 1 1 1 1 Borax O.S O.S O.S O.S O.S I-Menthol O.OOS O.OOS di-Camphor O.OO2 O.OO2 d-Borneo O.OO3 O.OO3 Sodium edetate O.1 O.1 O.1 O.1 O.1 Potassium sorbate O.1 Glycerine O.2 Glucose O.1 Sodium chloride O.9 O.9 O.9 O.9 O.9 Diluted hydrochloric Appropriate amount acid sodium hydroxide (pH = 7) Purified water Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol 70.1 70.5 70.6 70.7 67.1 palmitate (%) units of (A)/g of (B) 125,000 50,000 25,000 10,000 33,333 (B):(C) 1:2.5 1:1 1:1 2.5:1 6:1
TABLE 7 Example
Formulation (WV 9.6) 25 26 27 28 (A) Retinol palmitate 200,000 300,000 300,000 500,000 units units units units (B) Polyoxyethylene (200) 5 5 2.5 2.5 polyoxypropylene (70) glycol US 2012/0095097 A1 Apr. 19, 2012
TABLE 7-continued Example
Formulation (WV 9.6) 25 26 27 28 Polyoxyethylene (160) 2.5 polyoxypropylene (30) glycol Polyoxyethylene (54) 2.5 polyoxypropylene (39) glycol (C) Trometamol 2 5 3 (D) d-C-Tocopherol acetate O.OS O.OS O.OS Dibutylhydroxytoluene O.OOS O.OOS O.OOS Others Tetrahydrozoline hydrochloride O.OS Neostigmine methylsulfate O.OOS Chlorpheniramine maleate O.O3 O.O3 O.O3 Pyridoxine hydrochloride O.OS O.OS O.OS Dipotassium glycyrrhizate O.25 Sodium hyaluronate Boric acid 1 1 1 Borax O.S O.S O.S -Menthol O.OOS di-Camphor O.OO2 d-Borneol O.OO3 Sodium edietate O.1 O.1 O.1 O.1 Potassium sorbate O.1 Propylene glycol O.1 Glucose O.1 Sodium chloride O.9 O.9 O.9 Dilute hydrochloric acid/ Appropriate amount sodium hydroxide (pH = 7) Purified water Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol palmitate (%) 66.8 66.2 66.4 66.1 units of (A)/g of (B) 40,000 60,000 120,000 200,000 (B):(C) 2.5:1 1:1 1:1-2 1:1-2
Comparative Examples 6 and 7
Polyoxyethylene (54) polyoxypropylene (39) glycol: TABLE 8-continued I0081 Prononi235P, Japanese Pharmaceutical Excipients, NFO Corporation Example Comparative Example Polyoxyethylene hardened castor oil 60: I0082 HCO-60 (for medical purposes), Japanese Pharma Formulation (W/V%) 1 6 7 ceutical Excipients, Nikko Chemicals Co., Ltd. (C) Trometamol 1 1 1 Others Polyoxyethylene 1 hardened castor oil 60 Polysorbate 80: Polysorbate 80 I0083. RheodolTW-0120V. Japanese Pharmacopoeia, Kao Sodium chloride O.9 O.9 O.9 Diluted hydrochloric Appropriate Appropriate Appropriate Corporation Hypromellose: acid sodium hydroxide amount amount amount I0084 Metolose 65SH-4000, Japanese Pharmacopoeia, (pH = 7) Shin-Etsu Chemical Co., Ltd. Purified water Balance Balance Balance Polyvinylpyrrolidone: Total 100 mL. 100 mL. 100 mL. Corneal and conjunctival 9 13 12 I0085 Kollidon 90F, Japanese Pharmacopoeia, BASF disorder treating effect Eye irritation O O O 1. An ophthalmic composition comprising (A) at least 50,000 units/100 mL of vitaminA, (B) at least 0.4W/V% of polyoxyethylene polyoxypropylene glycol and (C) trometa mol. Examples 29 to 33 2. The ophthalmic composition as defined in claim 1, 0077. The ophthalmic compositions of Table 9 were pre wherein a content of the ingredient (A) is at least 100,000 pared according to Example 1 and the residual ratio of retinol units/100 mL. palmitate, corneal and conjunctival disorder treating effect 3. The ophthalmic composition as defined in claim 1, and eye irritation were evaluated according to the above wherein a content of the ingredient (A) is at least 200,000 stated methods. The results are also shown in the Table. units/100 mL.
TABLE 9 Example
Formulation (W/V%) 29 30 31 32 33 (A) Retinol palmitate 100,000 150,000 200,000 300,000 500,000 units units units units units (B) Polyoxyethylene (200) 2 1 5 5 5 polyoxypropylene (70) glycol (C) Trometamol 1 1 1 5 5 (D) d-C-Tocopherol acetate O.OS O.OS O.OS O.OS O.OS Dibutylhydroxytoluene O.OOS O.S O.OOS O.OOS O.OOS Others Sodium chloride O.9 O.9 O.9 O.9 O.9 Diluted hydrochloric Appropriate Appropriate Appropriate Appropriate Appropriate acid sodium hydroxide amount amount amount amount amount (pH = 7) Purified water Balance Balance Balance Balance Balance
Total 100 mL. 100 mL. 100 mL. 100 mL. 100 mL. Residual ratio of retinol 67.2 66.4 66.3 66.5 66.2 palmitate (%) Corneal and coniunctival 9 8 8 6 6 disorder treating effect Eye irritation O O O O O Units of (A)/g of (B) 50,000 150,000 40,000 60,000 100,000 (B):(C) 2:1 1:1 5:1 1:1 1:1
0078. The starting materials used in the examples are indi 4. The ophthalmic composition as defined in claim 1, cated below. wherein a content of the ingredient (A) is at least 300,000 Polyoxyethylene (200) polyoxypropylene (70) glycol: units/100 mL. 0079 Uniloob 70DP-950B, Japanese Pharmaceutical Excipients, NFO Corporation, or Lutrol F127, Japanese Phar 5. The ophthalmic composition as defined in any one of maceutical Excipients, BASF Japan Ltd. claims 1 to 4, further comprising (D) an antioxidant. Polyoxyethylene (160) polyoxypropylene (30) glycol: 6. The ophthalmic composition as defined in claim 5, 0080 Prononil 188P, Japanese Pharmaceutical Excipients, wherein the ingredient (D) is vitamin E and/or dibutylhy NFO Corporation droxytoluene. US 2012/0095097 A1 Apr. 19, 2012 10
7. The ophthalmic composition as recited in claim 1, 9. A method for stabilizing vitamin comprising: formulat wherein the ingredient (A) is retinol palmitate, retinol acetate ing at least 0.4W/V% of polyoxyethylene polyoxypropylene or retinoic acid. glycol and (C) trometamol in an ophthalmic composition 8. The ophthalmic composition as defined in claim 1, containing at least 50,000 units/100 mL of vitamin A. wherein a ratio by weight between the ingredient (B) and the ingredient (C) expressed as (B):(C) is at 1:30 to 30:1. ck