| Medicinal composition for ophthal use containing acetylated hyaluronic acid -> Monitor Keywords |
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Medicinal composition for ophthal use containing acetylated hyaluronic acidRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, PolysaccharideMedicinal composition for ophthal use containing acetylated hyaluronic acid description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060166930, Medicinal composition for ophthal use containing acetylated hyaluronic acid. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the priority of Japanese application No. 2003-051161 filed on 27.sup.th Feb. 2003, which is incorporated by reference. FIELD OF THE INVENTION [0002] The present invention relates to an ophthalmic pharmaceutical composition that contains acetylated hyaluronic acid and has excellent moisture retention. BACKGROUND OF ART [0003] The number of patients or pseudo-patients complaining of dry eye (dryness of the eyes) is expected to continue to climb as our society ages and as people increasingly strain their eyes by watching television and using office equipment such as word processors and personal computers. The cause of dry eye is a reduction in lacrimal quantity or a qualitative change in the components thereof, and this disorder can result in scratching or other damage when the surface of the eye becomes dry. Symptoms include eye pain or fatigue, increased blinking, and bloodshot eyes. Further, bacteria may enter through a scratch and cause infection, and if the scratch is deep enough it can even affect the vision of the person. In addition to eyestrain, causes of dry eye include Sjogren's syndrome, Stevens-Johnson syndrome, burns and injury to the eye, and side effects of hypotensive drugs, tranquilizers, eyedrops for treating glaucoma, and other such drugs. [0004] Eyedrops are an effective way to treat dry eye, and dry-eye treatment drugs whose main component is hyaluronic acid are currently attracting much attention and are widely used. Hyaluronic acid is a biologically derived macromolecular substance, has extremely high water retention and characteristic properties such as a high viscoelasticity, a good thickening property, and a good thread-forming, ability, and has been used as a humectant in topical agents for treating various kinds of skin problems and so forth. In the case of dry eye caused by Sjogren's syndrome, in which dryness is seen over the entire body, the application of eyedrops containing hyaluronic acid is effective all by itself, but when the symptoms are severe, hyaluronic acid-containing eyedrops alone may not provide a sufficient effect, and it is sometimes necessary for the treatment to entail tear duct blockage by means of a tear duct plug. Also, hyaluronic acid has a relatively short residence time on the cornea, so the effect of hyaluronic acid eyedrops lasts only about 2 or 3 hours, which means that the patient must apply the drops more frequently (such as 5 to 10 times a day). There is therefore a need for an ophthalmic pharmaceutical composition that would provide a long-lasting humectant effect, and therefore require fewer applications and improve the QOL (quality of life) of the patient. [0005] Japanese Laid-Open Patent Application S62-68402 discloses a derivative of hyaluronic acid, namely, a hyaluronic acid that has undergone partial esterification of its carboxyl groups, and suggests that this derivative is effective as a drug carrier. However, it has yet to be confirmed that an ophthalmic preparation containing this carboxyl group partially esterified hyaluronic acid derivative as a carrier is effective in pharmaceutical compositions used for dry eye, which must provide a long-lasting humectant effect. DISCLOSURE OF THE INVENTION [0006] It is an object of the present invention to provide pharmaceutical composition for dry eye, which remains on the cornea and exhibits a humectant effect for a longer period. [0007] The inventors were surprised to learn that when an acetylated derivative of hyaluronic acid is used as an ophthalmic pharmaceutical composition, this derivative stays longer than hyaluronic acid on a soft contact lens, which is a model for the corneal epithelium. Thus, an ophthalmic pharmaceutical composition that contains acetylated hyaluronic acid was found to exhibit a humectant effect over a longer period than an ophthalmic pharmaceutical composition containing just hyaluronic acid. [0008] Therefore, the present invention provides an ophthalmic pharmaceutical composition containing acetylated hyaluronic acid and a pharmacologically acceptable carrier. Preferably, the average molecular weight of the acetylated hyaluronic acid is from 10,000 to 1,000,000, and the acetyl group substitution number is 2.5 to 4.0, even more preferably the average molecular weight of the acetylated hyaluronic acid is approximately 100,000 and the acetyl group substitution number is approximately 3.3. In a preferred aspect, this ophthalmic pharmaceutical composition is used for the treatment or prevention of dry eye, and in an even more preferred aspect, it is a dry-eye instillation. BEST MODE FOR CARRYING OUT THE INVENTION [0009] When applied to the eye, the acetylated hyaluronic acid-containing ophthalmic pharmaceutical composition pertaining to the present invention exhibits better moisture retention than an ophthalmic pharmaceutical composition containing hyaluronic acid. The corneal epithelium of the eye is composed of about five cell layers, and it some ways is similar to the horny layer of the skin, but the cellular surface of the topmost layer of the cornea is not at all hydrophilic, and in fact is believed to be somewhat hydrophobic. This hydrophobic property can also be predicted from the fact that the lacrimal film has a three-layer structure comprising an oil layer (the uppermost layer), a water layer (the middle layer), and a mucous layer (the lowermost layer) that is contact with the corneal epithelium, and mutin, which is a mucous component made up primarily of polysaccharide, is present in this lowermost layer. Because its hydroxyl groups have been acetylated, acetylated hyaluronic acid is more highly hydrophobic than hyaluronic acid. Therefore, while not particularly bound to theory, the reason that the moisture retention of acetylated hyaluronic acid is better than that of hyaluronic acid, that is, that acetylated hyaluronic acid remains on the cornea longer than hyaluronic acid does, is believed to be that acetylated hyaluronic acid is hydrophobic just like the corneal layer. Also, because it is so highly hydrophilic, there is the danger that hyaluronic acid will absorb moisture from the corneal epithelial tissue. In this regard, acetylated hyaluronic acid is believed to absorb less moisture from the corneal epithelial tissue because it is somewhat less hydrophilic than hyaluronic acid. [0010] The acetylated hyaluronic acid in the present invention is a derivative in which the hydroxyl groups of hyaluronic acid have been acetylated, and more specifically has the following structural formula. [0011] n is a natural number [0012] Acetylated hyaluronic acid can be manufactured by any method known to persons skilled in the art, and examples of such methods are disclosed in Japanese Laid-Open Patent Application H8-53501. [0013] Preferably, the acetylated hyaluronic acid in the present invention is obtained by suspending powdered hyaluronic acid in an acetic anhydride solvent, and adding concentrated sulfuric acid to bring about acetylation. With this method, an acetylated hyaluronic acid with a high degree of acetylation can be obtained if acetic acid is mixed with the acetic anhydride solvent and the ratio of acetic acid to acetic anhydride is set between 1:4 and 1:1. Also, acetylation will proceed more moderately and the degree of acetylation can be fine tuned if acetic acid is mixed with the acetic anhydride solvent and the ratio of acetic acid to acetic anhydride is set between 2:1 and 4:1. The concentrated sulfuric acid is preferably added to the solvent in an amount of 2 to 7 vol %. [0014] There are no particular restrictions on the acetyl group substitution number of the acetylated hyaluronic acid pertaining to the present invention, but 2.5 to 4.0 is preferable, 2.8 to 3.8 is even better, and 3.0 to 3.8 is better yet. Ideally, the acetyl group substitution number of the acetylated hyaluronic acid pertaining to the present invention is approximately 3.3. It is believed that the humectant effect attributable to hyaluronic acid being inherently hydrophilic will be lost if the acetyl group substitution number is too high, but that the humectant effect attributable to acetylated hyaluronic acid being inherently hydrophobic (which is assumed because the cornea is hydrophobic) will be lost if the acetyl group substitution number is too low. There are four alcoholic hydroxyl groups present in the repeating units of hyaluronic acid, as indicated by Chemical Formula 1 above, and "acetyl group substitution number" refers to how many of these have been substituted with an acetyl group. [0015] The above-mentioned acetylated hyaluronic acid can be refined into high-purity acetylated hyaluronic acid by adding crude acetylated hyaluronic acid to an acetone aqueous solution, adding and dissolving sodium lactate, and adding a high concentration of acetone. The above-mentioned sodium lactate is preferably added in an amount of 1 to 3 wt % with respect to the acetone aqueous solution. [0016] "Hyaluronic acid" as used in the present invention means hyaluronic acid and hyaluronates, and types of various molecular weight can be used. There are no particular restrictions on the average molecular weight of the acetylated hyaluronic acid pertaining to the present invention, but it is preferably 1,000 to 1,000,000, and even more preferably 10,000 to 1,000,000. The ideal average molecular weight is approximately 100,000. [0017] The amount of acetylated hyaluronic acid contained in the ophthalmic pharmaceutical composition of the present invention is 0.01 to 10 weight/volume (weight)%, and preferably 0.05 to 5 weight/volume (weight)%, and even more preferably 0.1 to 1 weigh/volume (weight)%, based on the total volume (or total weight) of the pharmaceutical composition. The acetylated hyaluronic acid concentration refers to the weigh/volume (w/v)% in the case of a liquid eye wash or eyedrops, and to weigh/weight (w/w)% in the case of a solid eye ointment. While it will depend on the hyaluronic acid and its molecular weight, an aqueous solution in which the concentration is over 3% usually cannot be used for eyedrops because its viscosity will be too high, but preparing an aqueous solution of acetylated hyaluronic acid with a concentration of about 10% is quite possible. [0018] The pH of the ophthalmic pharmaceutical composition of the present invention is preferably close to neutral, and is usually from 6.5 to 7.5. The osmotic pressure ratio is preferably adjusted to about 0.5 to 4.0, with a range of 1.0 to 1.5 being even better. Any means commonly employed for ophthalmic pharmaceutical compositions can be used to adjust the pH and osmotic pressure. [0019] The ophthalmic pharmaceutical composition pertaining to the present invention is effective against symptoms of eye dryness, and particularly in the treatment and prevention of dry eye. Dry eye can be caused by a variety of factors, such as eyestrain, Sjogren's syndrome, Stevens-Johnson syndrome, burns and injury to the eye, and side effects of hypotensive drugs, tranquilizers, eyedrops for treating glaucoma, and other such drugs. The ophthalmic pharmaceutical composition of the present invention is formulated as eyedrops, an eye wash, an eye ointment, or the like. [0020] Depending on its formulation, the ophthalmic pharmaceutical composition of the present invention can also be used together with a pharmacologically acceptable carrier. The carrier for eyedrops and eye washes can be any type ordinarily used for such purposes, and purified water is favorable. Continue reading about Medicinal composition for ophthal use containing acetylated hyaluronic acid... 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