Ophthalmic compositions containing vitamin E or an ester thereof as an active ingredient

Abstract: This invention relates to novel aqueous ophthalmic compositions containing vitamin E or ester thereof as an active ingredient, sorbic acid or salts thereof as a preservative, and surfactant. The composition of this invention is useful for treatment of various eye diseases, especially for cataract.

Description: BACKGROUND OF THE INVENTION As vitamin E, a natural type of vitamin E, namely d-α-tocopherol, and synthesized vitamin E such as dl-α-tocopherol are known, and various kinds of esters thereof, for example, acetic acid ester, nicotinic acid ester, and succinic acid ester, are also well known. In this invention, such vitamin E or ester thereof is called as V-E. In medical field, various utilities of V-E have been known, for example, drug for defects in peripheral circulation or suppressor for increase of lipid peroxide. Further, V-E is also known to be useful for treatment of various eye diseases. Especially, it has been reported that ophthalmics containing V-E in higher concentration could be useful for treatment of cataract (Journal of the Eye, 8, 93 (1991)). V-E, however, is sparingly soluble in water. Therefore it is necessary to use a surfactant to formulate V-E in an aqueous ophthalmic preparation. As a prior art, a technology to dissolve or emulsify V-E in water by using surfactant such as polysorbate 80, polyoxyethylene hydrogenated castor oil or lecithin has been reported(Japanese Unexamined Patent Publication 106018/87). It is also described in prior art that rather a large amount of surfactant was needed to make an aqueous ophthalmic preparation of V-E. To prepare multi-use type ophthalmics, which are generally used ophthalmics, a preservative is needed to prevent secondary contamination, while a surfactant may decrease the effect of the preservative. Therefore, the decrease of the preservative effect becomes a very important problem to prepare aqueous ophthalmics of V-E which needs rather a large amount of surfactant. Furthermore, if a preservative is formulated in higher concentration to solve such problem, it may cause defects to eye tissues and an increase of eye irritation. In conclusion, a study of a preservative is very important to make an aqueous ophthalmic preparation containing V-E. DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel aqueous ophthalmic compositions containing V-E as an active ingredient, sorbic acid or salts thereof as a preservative and a surfactant. An ophthalmic preparation of V-E is useful for treatment of various eye diseases. Especially ophthalmics containing V-E in higher concentration is expected to be useful for treatment of cataract. V-E, however, is sparingly soluble in water, and it is necessary to use rather a large amount of surfactant to make an aqueous ophthalmic preparation of V-E. Generally used aqueous ophthalmics, a multi-use type, need a preservative to prevent secondary contamination, while a surfactant may decrease the effect of the preservative. An aqueous ophthalmic preparation of V-E needs rather a large amount of surfactant, and the decrease of the preservative effect caused by the surfactant is a very important problem. Furthermore, use of higher concentration of a preservative should be avoided not to cause defects in eye tissues or an increase of eye irritation. Therefore, it is very important to study a preservative which can be preferably used for an aqueous ophthalmic preparation of V-E. The inventors studied to find a preferable preservative for an aqueous ophthalmic preparation of V-E. Benzalkonium chloride or ester of p-hydroxybenzoic acid is widely used for an aqueous ophthalmic preparation as a preservative, so the inventors prepared an aqueous ophthalmic preparation using such preservative in a combination with a surfactant and examined the preservative effect. As the surfactant, polysorbate 80, a widely used surfactant, was used. The experimental result showed that the preservative effect was extremely decreased by the surfactant. It is reported that benzalkonium chloride, if the concentration is increased over 0.01%, caused corneal defects (Invest. Ophthalmol. Vis. Sci., 21, 842 (1981)). So the inventors prepared an aqueous ophthalmic preparation of V-E formulating benzalkonium chloride in a concentration of 0.01%, the upper limit which does not cause corneal defects, and examined the preservative effect. However, the preservative effect was not satisfactory for the ophthalmic preparation. Ester of p-hydroxybenzoic acid has property similar to benzalkonium chloride. That is to say, the increased formulating amount causes defects in eye tissues or increase of eye irritation. Thus the inventors made a study to find a preferable preservative which has a satisfactory presevative effect, does not cause defects in eye tissues and causes little eye irritation, and to prepare an aqueous ophthalmic preparation using the preferable preservative. The inventors presumed that the decrease of the preservative effect depended on taking the preservative in the surfactant, and investigated a preservative which could hardly be taken in a surfactant. As the result of the precise study, the inventors found that sorbic acid or salts thereof (hereinafter called merely sorbic acid if not specified) shows a satisfactory preservative effect in an concentration of 0.1% or over even if rather a large amount of surfactant is used. Further, the inventors examined possibility of causing defects in eye tissues or eye irritation, which is another important problem for an ophthalmic preparation, and found that the aqueous ophthalmic preparation using sorbic acid as a preservative hardly caused defects in eye tissues and eye irritation. The test was made using rabbits eyes. In conclusion, the inventors succeeded in preparing an aqueous ophthalmic preparation of V-E, which showed satisfactory preservative effect and hardly caused defects in eye tissues and eye irritation, by formulating sorbic acid as a preservative. WO-A-89/03689 discloses stable liposome compositions containing vitamin E. The present invention relates to aqueous ophthalmic compositions containing vitamin E and includes sorbic acid or a salt thereof as a preservative. WO-A-89/03689 does not disclose any preservative technique. FR-A-2306684 discloses preparations containing vitamin E. Examples of the preparations using glycols as a preservative are described in such document. However, FR-A-2306684 does not disclose the use of sorbic acid or a salt thereof as a preservative, nor does such document disclose that addition of sorbic acid or a salt thereof, is required in a specific concentration. According to the present invention there is provided an aqueous ophthalmic composition comprising 0.5 to 5% by weight of vitamin E or an ester thereof as active ingredient, 0.1 to 2.5% by weight of sorbic acid or a salt thereof as preservative, and a surfactant in an amount of 0.2 to 30 times the amount of said vitamin E or ester thereof. Definition of various terms utilised in this invention are explained as follows. "An aqueous ophthalmic composition" means a clear solution in which V-E is dissolved in an aqueous vehicle, an emulsion in which V-E is emulsified in an aqueous vehicle, or a suspension in which V-E is suspended in an aqueous vehicle. V-E means natural or synthesized vitamin E such as d-α-tocopherol or dl-α-tocopherol, or an ester thereof such as the acetic acid ester, the nicotinic acid ester or the succinic acid ester. "A salt of sorbic acid" is exemplified by the sodium salt or the potassium salt. Examples or surfactant are polysorbate 80, polyoxyethylene hydrogenated castor oil, lecithin, a fatty acid ester of sucrose, a polyoxyethylene alkyl ether, polyoxyl stearate, and polyoxyethylene polyoxypropylene glycol. A preferred surfactant is polysorbate 80 or polyoxyethylene hydrogenated castor oil. The amount of the surfactant is 0.2 - 30 times the amount of V-E, preferably 0.3 - 10 times. The concentration of sorbic acid or salt thereof depends on the amount of V-E or the surfactant and is from 0.1-2.5% by weight, preferably 0.1 - 1.0%. If edetic acid or a salt thereof is formulated in the composition of this invention, the preservative effect of the sorbic acid can be increased. The preferred amount of edetic acid or a salt thereof, which can be formulated according to necessity, is 0.001 - 0.1% by weight, more preferably 0.003 - 0.05%. According to the invention, a preferred aqueous ophthalmic composition comprises 0.5-5% by weight of the acetic acid ester of d-α-tocopherol, 0.25 - 2.5% by weight of polysorbate 80 or polyoxyethylene hydrogenated castor oil, and 0.1 - 1.0% by weight of sorbic acid or a salt thereof. The ophthalmic composition of this invention can be prepared by admixing V-E with a surfactant followed by addition of sterile purified water containing sorbic acid, and if necessary, an isotonic agent such as sodium chloride or glycerol, a buffering agent such as sodium phosphate, a pH adjusting agent such as dilute hydrochloric acid or sodium hydroxide, and sodium edetate which plays a role in increasing the preservative effect, can be added. The generally used range of pH can be used for this preparation, but a preferable range is 4-8. Examples are shown below. Example 1 Formulation 1 (100ml) d-α-tocopherol acetate 1.0g potassium sorbate 0.1g polysorbate 80 0.5g sodium chloride 0.9g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Preparation Method : To a mixture of acetic acid ester of d-α-tocopherol and polysorbate 80, sterile purified water dissolving potassium sorbate, sodium chloride and sodium edetate was added while stirring, followed by addition of sodium hydroxide and diluted hydrochloric acid to adjust pH to 6.5. White emulsion was thus obtained. The following ophthalmics, formulations 2 to 6, can be prepared by a similar procedure. Formulation 2 (100ml) d-α-tocopherol acetate 1.0g potassium sorbate 0.2g polysorbate 80 0.5g sodium chloride 0.81g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Formulation 3 (100ml) d-α-tocopherol acetate 0.5g potassium sorbate 0.2g polysorbate 80 0.25g sodium chloride 0.81g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Formulation 4 (100ml) d-α-tocopherol acetate 0.1g potassium sorbate 0.1g polysorbate 80 0.2g sodium chloride 0.81g sodium edetate 0.003g sodium hydroxide q.s. diluted hydrochloric acid q.s. Formulation 5 (100ml) d-α-tocopherol 5.0g potassium sorbate 1.0g polyoxyethylene hydrogenated castor oil 2.5g sodium chloride 0.8g sodium edetate 0.05g sodium hydroxide q.s. diluted hydrochloric acid q.s. Formulation 6 (100ml) d-α-tocopherol acetate 1.0g sodium sorbate 0.2g polysorbate 80 0.3g sodium chloride 0.8g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Example 2 Formulation 7 (100ml) d-α-tocopherol acetate 0.5g potassium sorbate 0.2g polysorbate 80 5.0g sodium chloride 0.81g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Preparation Method : To a mixture of acetic acid ester of d-α-tocopherol and polysorbate 80, sterile purified water dissolving potassium sorbate, sodium chloride and sodium edetate was added while stirring, followed by addition of sodium hydroxide and diluted hydrochloric acid to adjust pH to 6.5. Clear solution was thus obtained. The following ophthalmics, formulations 8, can be prepared by a similar procedure. Formulation 8 (100ml) d-α-tocopherol nicotinate 0.2g potassium sorbate 0.5g polyoxyethylene hydrogenated castor oil 2.0g sodium chloride 0.8g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Examination of preservative effect To examine the preservative effect of sorbic acid, a preservative test was performed on the ophthalmic preparations of formulations 1 and 2 according to US pharmacopoeia. For comparison, a preservative test was also performed on the following comparative formulations 1, 2 and 3 which contain benzalkonium chloride or ester of p-hydroxybenzoic acid. Comparative Formulation 1 (100ml) d-α-tocopherol acetate 1.0g benzalkonium chloride 0.005g polysorbate 80 0.5g sodium chloride 0.9g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Comparative Formulation 2 (100ml) d-α-tocopherol acetate 1.0g benzalkonium chloride 0.01g polysorbate 80 0.5g sodium chloride 0.9g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Comparative Formulation 3 (100ml) d-α-tocopherol acetate 1.0g methyl paraben 0.052g propyl paraben 0.028g polysorbate 80 0.5g sodium chloride 0.9g sodium edetate 0.01g sodium hydroxide q.s. diluted hydrochloric acid q.s. Test Result : The decrease of bacteria, which was incubated in the medium (3.86 x 10 5 /ml), was calculated after two weeks and the result was shown in Table 1 by the percentage of the decrease of bacteria. As shown in Table 1, Pseudomonus aeruginosa was decreased by 99% in the formulations 1 and 2 of this invention. On the contrary, in the comparative formulations Pseudomonus aeruginosa was increased. Furthermore, formulation 1 and 2 containing sorbic acid showed excellent suppressive effect on Aspergillus niger. The results clearly show the preservative effect of sorbic acid. Test for safety to eye Experimental method : The ophthalmic preparation of the formulation 2, an example of the preparation of this invention, was instilled to Japanese white male rabbits (5 rabbits a group) for 4 weeks, 5 times a day. After 4 weeks, visual observation was made on anterior segment. Result : Disorders such as redness and edema were not observed on cornea, conjunctiva or iris. Eye irritation was also examined according to improved Draze method (Gendai no Rinsho, 4(7) , 277 (1970)), and eye irritation was hardly found on the ophthalmic preparation of this invention.

Claims: An aqueous ophthalmic composition comprising 0.5 to 5% by weight of vitamin E or an ester thereof as active ingredient, 0.1 to 2.5% by weight of sorbic acid or a salt thereof as preservative, and a surfactant in an amount of 0.2 to 30 times the amount of said vitamin E or ester thereof. A composition as claimed in claim 1, wherein the sorbic acid or salt thereof is present in an amount of from 0.1 to 1% by weight. A composition as claimed in claim 1 or 2, wherein the surfactant is present in an amount of from 0.3 to 10 times the amount of said vitamin E or ester thereof. A composition as claimed in any preceding claim, in which the vitamin E is natural or synthesised vitamin E such as d-α-tocopherol or dl-α-tocopherol, and the ester thereof is the acetic acid ester, the nicotinic acid ester or the succinic acid ester. A composition as claimed in any preceding claim, in which the salt of sorbic acid is the sodium or potassium salt. A composition as claimed in any preceding claim, in which the surfactant is polysorbate 80, polyoxyethylene hydrogenated caster oil, lecithin, a fatty acid ester of sucrose, a polyoxyethylene alkyl ether, polyoxyl stearate or polyoxyethylene polyoxypropylene glycol. A composition as claimed in any preceding claim, wherein the composition is present in the form of a clear solution, an emulsion or a suspension. A composition as claimed in any preceding claim additionally including edetic acid or a salt thereof to increase the preservative effect of the sorbic acid or salt thereof. A composition as claimed in claim 8, wherein the edetic acid or salt thereof is present in an amount of from 0.001 to 0.1% by weight, preferably from 0.003 to 0.05%. An aqueous ophthalmic composition comprising 0.5-5% by weight of acetic acid ester of d-α-tocopherol, 0.25-2.5% by weight of polysorbate 80 or polyoxyethylene hydrogenated castor oil, and 0.1-1.0% of sorbic acid or a salt thereof. A method for preparing an aqueous ophthalmic composition as claimed in any preceding claim, comprising mixing vitamin E or an ester thereof with a surfactant followed by addition of sterile purified water containing sorbic acid or a salt thereof. A method as claimed in claim 11, wherein an isotonic agent, such as sodium chloride or glycerol, a buffering agent, such as sodium phosphate, a pH adjusting agent such as dilute hydrochloric acid or sodium hydroxide, and sodium edetate are also added. A method as claimed in claim 11 or 12, wherein the method of preparation is carried out at a pH in the range of 4 to 8.

Inventors: KAWASHIMA YOICHI, KUWANO MITSUAKI, KAWASHIMA, YOICHI, KUWANO, MITSUAKI
Applicants: SANTEN PHARMA CO LTD, SANTEN PHARMACEUTICAL CO., LTD.
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61K9