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(12) Patent Application Publication (10) Pub. No.: US 2012/0095097 A1 Tabuchi Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0095097 A1 Tabuchi Et Al 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.
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