JP2008094839A - Ophthalmic agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an ophthalmic agent stably formulated with vitamin A and its derivatives and having a transparent appearance, improving conventional opaque and not stable ophthalmic agents because the vitamin A and its derivatives are known as the substance causing oxidative degradation, thermolysis or photolysis and being unstable. <P>SOLUTION: The ophthalmic agent is characterized by formulating (a) the vitamin A and its derivatives, (b) 0.005-0.15 w/v% in the ophthalmic agent of a liquid paraffin with less than 90 mm<SP>2</SP>/s of viscosity at 37.8°C, (c) a nonionic surfactant. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a clear ophthalmic preparation containing vitamin A.

  Vitamin A is an essential component for maintaining biological functions, but is particularly important for maintaining eye function. It is known that various eye diseases such as night blindness and keratoconjunctivitis occur due to lack of vitamin A. For this reason, attempts have been made to supplement vitamin A as an ophthalmic preparation, but vitamin A is known to cause oxidative degradation, thermal degradation, and photolysis, and may be a substance with poor stability. Are known. In order to suppress the oxidative degradation of vitamin A and improve the stability, a technique for blending an antioxidant (see Patent Documents 1 and 2), a technique for blending an oxygen scavenger (see Patent Document 3), Techniques for filling active gas (see Patent Documents 4 and 5) and the like are known. Moreover, the technique (refer patent document 6) which suppresses photolysis of vitamin A using a special container is known. Further, as a technique different from these, a technique for blending liquid paraffin and stabilizing vitamin A as an emulsified eye drop (see Patent Document 7) is also known. However, the emulsion type has the disadvantages that the appearance is cloudy, the usability when instilling is poor, and that it is difficult to confirm insoluble foreign substances in terms of quality control of ophthalmic agents. Patent Document 7 discloses a prescription in which vitamin A and liquid paraffin are blended, but the blending amount of liquid paraffin is 1 to 4%. However, it is indispensable to use an emulsifying type at this blending amount, resulting in a liquid agent with a white turbid appearance. Further, it is described that the stability is good when the emulsion type is used, but the stability is poor when the solubilized type has a clear appearance.

JP-A-5-17350 JP2001-72584 Patent No. 3199475 JP-A-11-292151 JP2003-113078 JP 7-33650 A Patent No. 2827295

  An object of the present invention is to provide an ophthalmic agent that is stably formulated with vitamin A and has a clear appearance.

  As a result of diligent research to solve such problems, the present inventors have blended specific liquid paraffin with vitamin A at a specific ratio, so that vitamin A is stabilized and the appearance becomes clear. The present invention has been completed.

That is, the present invention relates to (1) (a) vitamin A, (b) ophthalmic preparation having a blending amount of 0.005 to 0.15 w / v% and having a viscosity at 37.8 ° C. of less than 90 mm ² / s. An ophthalmic agent characterized by containing paraffin and (c) a nonionic surfactant;
(2) The ophthalmic preparation according to (1), wherein the vitamin A is retinol palmitate,
(3) The ophthalmic agent according to (1), wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil,
It is.

  It was found that the ophthalmic preparation of the present invention has a clear appearance and can stably store vitamins A for a long period of time.

  The vitamin A that can be used in the present invention is not particularly limited as long as it is pharmacologically or physiologically acceptable, and preferred examples include retinol palmitate and retinol acetate.

  The blending amount of vitamin A is preferably 0.005 to 0.05 w / v% in the ophthalmic preparation. This is because if the blending amount of vitamin A is small, the medicinal effect is insufficient, and if the blending amount is large, it is difficult to maintain a clear appearance.

  Nonionic surfactants that can be used in the present invention include polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil such as polyoxyl 35 castor oil, polyoxyethylene sorbitan fatty acid. Polyesters such as esters (polysorbates), polyoxyethylene-polyoxypropylene block copolymers (poloxamers), polyoxyethylene-polyoxypropylene block copolymer adducts of ethylenediamine (poloxamines), polyoxyethylene (9) lauryl ether, etc. Polyoxyethylene / polyoxypropylene alkyl ethers such as oxyethylene alkyl ethers, polyoxyethylene (20) polyoxypropylene (4) cetyl ether, polyoxyethylene (10 Polyoxyethylene alkyl phenyl ethers such as nonylphenyl ether. Among these, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil or poloxamers are preferable, and polyoxyethylene hydrogenated castor oil is particularly preferable. Here, in the notation of nonionic surfactant, the number in parentheses represents the number of added moles.

  In the present invention, the blending amount of the nonionic surfactant is preferably 0.1 to 1.0 w / v% in the ophthalmic preparation.

The liquid paraffin that can be used in the ophthalmic preparation of the present invention needs to have a viscosity of less than 90 mm ² / s at 37.8 ° C., specifically, high coal (trade name: manufactured by Kaneda Corporation), white mineral Oils having a suitable viscosity such as oil (trade name: manufactured by Crompton Co., Ltd.) and liquid paraffin manufactured by Oriental Pharmaceutical Co., Ltd. can be appropriately selected and used.

  The blending amount of the liquid paraffin needs to be 0.005 to 0.15 w / v% in the ophthalmic preparation, and preferably 0.010 to 0.10 w / v%. This is because when the amount of liquid paraffin is small, the stabilization of vitamin A is insufficient, and when the amount is large, the appearance of the ophthalmic agent becomes cloudy and the stability of vitamin A is deteriorated.

  In the present invention, the viscosity is a numerical value measured according to the 15th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method First Method.

  In the ophthalmic preparation of the present invention, other pharmaceutically acceptable components can be blended as necessary within a range not impeding the effects of the present invention, such as epsilon aminocaproic acid, dipotassium glycyrrhizinate, Anti-inflammatory drugs such as allantoin, berberine chloride, zinc sulfate, zinc lactate, sulfa drugs such as sulfamethoxazole sodium, vasoconstrictors such as tetrahydrozoline hydrochloride, phenylephrine hydrochloride, naphazoline hydrochloride, pyridoxine hydrochloride, riboflavin phosphate, cyanocobalamin, bread Vitamins such as tenol, flavin adenine dinucleotide sodium, d-α tocopherol acetate, focus regulators such as neostigmine methyl sulfate, amino acids such as sodium chondroitin sulfate, aminoethylsulfonic acid, potassium aspartate, sodium chloride, chloride Inorganic salts such as lithium and other base components such as sodium edetate, dibutylhydroxytoluene, borax, boric acid, citric acid, sodium citrate, benzalkonium chloride, paraoxybenzoate (methyl paraoxybenzoate, paraoxybenzoate) Ethyl acrylate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), glycerin, propylene glycol, sorbitol and mannitol. In producing an ophthalmic preparation, it is common to adjust the osmotic pressure with sodium chloride, glycerin or the like. Further, it is considered that the effect of the present invention is not affected by the osmotic pressure.

  The ophthalmic preparation in the present invention is an eye drop or an eye wash.

  The ophthalmic preparation of the present invention can be produced and prepared by a conventional method. An eye drop can be administered once to several times a day, once to a few drops at a time. Wash eyes one to several times a day.

Example The manufacturing process of the ophthalmic preparation according to the present invention is shown below. In this embodiment, it is used as an eye drop. Further, as a liquid paraffin, Kaneda Corporation's High Coal (trade name) was used. Viscosity at each of 37.8 ° C., Haikoru M-202 is 43.0~47.5mm ² / s, Haikoru M-352 is 74.0~88.0mm ² / s, Haikoru M-502 98.0 ˜125.0 mm ² / s.

  In purified water (85 mL), 0.5 g of polyoxyethylene hydrogenated castor oil 60, 0.037 g of retinol palmitate, 0.005 g of liquid paraffin (Hycol M-202), 0.043 g of citric acid, 0.087 g of sodium citrate and 0.005 g of benzalkonium chloride was dissolved to make a total amount of 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The appearance was clear.

  0.5 g of polyoxyethylene hydrogenated castor oil 60 in purified water (85 mL), 0.037 g of retinol palmitate, 0.01 g of liquid paraffin (Hycol M-202), 0.043 g of citric acid, 0.087 g of sodium citrate, 0.005 g of benzalkonium chloride was dissolved to make a total amount of 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The appearance was clear.

  In purified water (85 mL), 0.5 g of polyoxyethylene hydrogenated castor oil 60, 0.037 g of retinol palmitate, 0.05 g of liquid paraffin (Hycol M-202), 0.043 g of citric acid, 0.087 g of sodium citrate and 0.005 g of benzalkonium chloride was dissolved to make a total amount of 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The appearance was clear.

  In purified water (85 mL), 0.5 g of polyoxyethylene hydrogenated castor oil 60, 0.037 g of retinol palmitate, 0.02 g of liquid paraffin (Hycol M-352), 0.043 g of citric acid, 0.087 g of sodium citrate and 0.005 g of benzalkonium chloride was dissolved to make a total amount of 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The appearance was clear.

  0.5 g of polyoxyethylene hydrogenated castor oil 60 in purified water (85 mL), 0.037 g of retinol palmitate, 0.05 g of d-α tocopherol acetate, 0.005 g of neostigmine methylsulfate, 1.0 g of aminoethylsulfonic acid, asparagine 1.0 g of potassium acid, 0.25 g of zinc sulfate, 0.015 g of 1-menthol, 0.010 g of dl-camphor, 0.005 g of geraniol, 0.08 g of chlorobutanol, 0.005 g of dibutylhydroxytoluene, disodium edetate 06 g, liquid paraffin (Hycol M-202) 0.06 g, boric acid 0.5 g, bocha 0.035 g, citric acid 0.010 g, sodium citrate 0.100 g and benzalkonium chloride 0.010 g were dissolved, and the total amount To 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The appearance was clear.

[Comparative Example 1] (Formulation without liquid paraffin)
0.5 g of polyoxyethylene hydrogenated castor oil 60, 0.037 g of retinol palmitate, 0.043 g of citric acid, 0.087 g of sodium citrate and 0.005 g of benzalkonium chloride were dissolved in purified water (85 mL) To 100 mL. Thereafter, the solution was sterilized by filtration to obtain a sterile eye drop. The appearance was clear.

[Comparative Example 2] (liquid paraffin increase formula)
In purified water (85 mL), 0.5 g of polyoxyethylene hydrogenated castor oil 60, 0.037 g of retinol palmitate, 0.2 g of liquid paraffin (Hycol M-202), 0.043 g of citric acid, 0.087 g of sodium citrate and 0.005 g of benzalkonium chloride was dissolved to make a total amount of 100 mL. At this time, the appearance was cloudy, but sterilized by filtration to obtain a sterile eye drop. The appearance remained cloudy.

[Comparative Example 3] (Different types of liquid paraffin)
In purified water (85 mL), 0.5 g of polyoxyethylene hydrogenated castor oil 60, 0.037 g of retinol palmitate, 0.05 g of liquid paraffin (Hycol M-502), 0.043 g of citric acid, 0.087 g of sodium citrate and 0.005 g of benzalkonium chloride was dissolved to make a total amount of 100 mL. At this time, the appearance was cloudy, but sterilized by filtration to obtain a sterile eye drop. The appearance remained cloudy.

[Test Example 1]
The appearance immediately after the adjustment of the eye drops obtained in Examples and Comparative Examples was observed. Moreover, when these were filled in a glass ampule and stored at 65 ° C., the residual amount of retinol palmitate was measured by high performance liquid chromatography. The results are shown in Table 1. In the table, “actual” indicates an example, “ratio” indicates a comparative example, and the numerical value of the formulation is “mg / 100 mL”.

  Even if vitamin A is blended according to the present invention, the stability of vitamin A is improved and the appearance is clear, so it is effective as an eye drop and eye wash for pharmaceuticals, quasi drugs and the like.

Claims (3)

(A) Vitamin A, (b) Liquid paraffin having a blending amount of 0.005 to 0.15 w / v% in an ophthalmic preparation and a viscosity at 37.8 ° C. of less than 90 mm ² / s, and (c) An ophthalmic agent characterized by containing a nonionic surfactant.   The ophthalmic preparation according to claim 1, wherein the vitamin A is retinol palmitate.   The ophthalmic agent according to claim 1, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil.