JP2008088192A - Eye lotion - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an eye lotion containing tranilast that can be safely applied even when the contact lenses are worn. <P>SOLUTION: The eye lotion comprises tranilast or a pharmacologically acceptable salt thereof, polyvinyl pyrrolidone and 0.075 to 1 wt.% of a nonionic surfactant. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an eye drop containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient, and more particularly to an eye drop which can be used while wearing a contact lens.

Conventional technology

  Tranilast (3,4-dimethoxycinnamoyl anthranilic acid) is effective for oral administration of diseases such as allergic bronchial asthma and allergic rhinitis as well as ophthalmic diseases such as spring catarrh and allergic conjunctivitis. Yes. Generally, tranilast and its salts are sparingly soluble in water, but methods for producing a stable aqueous solution formulation have been developed (for example, JP-A-1-294620, JP-B-7-116029, JP-A-11-302162). And eye drops for allergic diseases containing tranilast are also on the market (Rizaben). However, eye drops that can be used during contact lens wearing containing tranilast have not yet been provided.

  Contact lenses are roughly classified into hard types and soft types. As a result of the gradual improvement of safety and wearing comfort, it has continued to spread widely, especially among young people, and now it has two weeks for high water content soft contact lenses, oxygen permeable hard contact lenses, and soft contact lenses. There are various types of lenses on the market, such as frequent replacement lenses and single-use contact lenses. Thus, the range of user's choices has been expanded and convenience has increased, but on the other hand, there are increasing examples of causing eye disorders.

  Giant Papillary Conjunctivitis (GPC) is well known as a complication associated with wearing contact lenses (hereinafter sometimes referred to as “CL”). GPC is a CL wearer with increased secretion, pruritus, and papillary proliferation of the upper eyelid conjunctiva, and is an allergic conjunctivitis with the contamination of contact lenses as an antigen. This disease can occur in both soft and hard types, but tends to occur frequently in soft contact lenses.

  Furthermore, the contact lens user is not limited to the above GPC, but also suffers from allergic eye diseases (seasonal / perennial allergic conjunctivitis, etc.). In any case, an antiallergic drug is used for the treatment, but since it is accompanied by severe itching in the eye, local administration with eye drops or the like is preferable to oral administration. Regarding the preparation of tranilast, for example, in the above-mentioned JP-A-1-294620, 4 times or more, preferably 6 times or more of polyvinylpyrrolidone is used as a solubilizing agent with respect to tranilast, and if necessary basic By adding a substance, a clear aqueous solution of tranilast can be obtained. In JP-A-2-264716, polyvinyl pyrrolidone is further soluble by adding a nonionic surfactant or an amphoteric surfactant of HLB 10-16 to polyvinyl pyrrolidone. Is described as improving. Japanese Patent Application Laid-Open No. 11-302162 describes that a tranilast-containing aqueous solution preparation was obtained without using polyvinylpyrrolidone by combining an organic amine with a small amount of a nonionic surfactant.

  Conventionally, eye drops containing various anti-allergic drugs as active ingredients have been provided. However, in order to avoid the adverse effects of anti-allergic drugs on lenses, it is premised that the eye drops are removed. However, it is not only troublesome for the contact lens user to take off the lenses one after another and wear them again, but this may increase the chance of bacterial infection. Also, depending on the location, it may not be suitable for such work and may not be instilled. Furthermore, many people with high myopia are wearing contact lenses, but it is particularly difficult for such people to remove the lens and instill them. Thus, for contact lens wearers, the application of eye drops containing antiallergic drugs is cumbersome, and there are even cases in which eye drops are accidentally worn. In addition, it is difficult to confirm how long it will take after the instillation to reduce the concentration of antiallergic drugs and additives in tears and make it possible to attach the lens. Is difficult to measure. Furthermore, among the frequently exchanged lenses, there is a type of lens that cannot be removed and reattached from the viewpoint of preventing contamination. In such a case, the timing of eye drops becomes a problem.

  In addition, if the patient is instilled with a contact lens attached, for example, the following accident (detriment) may occur. <1> Components such as active ingredients, preservatives, and surfactants adsorb to the lens and contaminate the lens. <2> The active ingredient mainly changes the size (standard) of the lens itself. <3> As a result of the adsorption, the concentration of the active ingredient is lowered to affect the effectiveness. <4> Concentration of components is highly accumulated in the lens, and conversely, it is toxic to the eye tissue.

  Tranilast is an excellent antiallergic agent as described above and has already been used as an eye drop, but an eye drop that can be used while wearing a contact lens has not been developed yet. If an ophthalmic solution that can be used during such lens wearing can be obtained, it is thought that it will greatly contribute to the prevention and treatment of allergic diseases in the ophthalmic field including GPC.

However, the aqueous solution preparation described in the above-mentioned publication, as described in the test examples described later, has a problem that it has some effect on the lens and makes the diameter larger than the standard, and the benzalkonium chloride and benzethonium chloride that are mixed There is a problem that it is toxic to the cornea because it is easily adsorbed on contact lenses, particularly soft contact lenses and oxygen-permeable contact lenses. Therefore, these known aqueous solutions cannot be used as they are as allergic eye drops for contact lens wearers.
Moreover, neither of these describes the effect of tranilast itself, which is an active ingredient, on contact lenses.
Accordingly, there has been a demand for the development of a tranilast-containing ophthalmic solution useful for the treatment of allergic conjunctivitis that can be applied while wearing any contact lens while avoiding the above problems.

As a result of intensive investigations aimed at developing a tranilast-containing eye drop that can be applied (used) during contact lens wearing, tranilast is the size of a contact lens in the presence of polyvinylpyrrolidone. It was found that a change was caused (see Test Example 1). Such a phenomenon has not been reported so far, and the cause has not been elucidated, but is thought to be due to the interaction between tranilast and PVP. American Standards Institute ANSI (American National Standards Institute) contact lens standard ANSI Z80.8 (1986) soft contact lens size tolerance 0.5mm reference, the difference in size before and after the test exceeds the allowable range This may make the user feel uncomfortable and may cause damage such as corneal damage.
Furthermore, as already mentioned, some solubilizing agents and preservatives essential for the preparation of aqueous eye drops may be adsorbed on or adversely affected by the lens, and it is necessary to prevent such effects.
Therefore, in order to prepare eye drops containing tranilast and usable during contact lens wearing, all of the above various problems must be solved.

As a result of intensive research aimed at providing a stable and safe aqueous solution preparation containing tranilast which contains an effective amount of tranilast and does not adversely affect the contact lens, a certain amount of nonionic It has been found that when a surfactant is blended, a safe eye drop having no influence on the lens can be obtained.
That is, the present invention is applicable when a contact lens is mounted, characterized by containing tranilast or a pharmacologically acceptable salt thereof, polyvinylpyrrolidone, and 0.075 to 1% by weight of a nonionic surfactant. Providing an ophthalmic solution.

The ophthalmic solution of the present invention configured as described above is a tranilast aqueous solution formulation that stably maintains a solution state, and can be applied while wearing without affecting any contact lenses. Useful for prevention or treatment of patients. In addition, as an ophthalmic medium, any ophthalmologically acceptable medium can be used, but an aqueous medium is preferable.
The pharmacologically acceptable salt of tranilast used in the present invention is a sodium salt or potassium salt. The effective amount of tranilast or a pharmacologically acceptable salt thereof in the eye drop of the present invention is in the range of 0.1 to 1.0%, preferably 0.2 to 0.5%.
In addition, in this specification, the content rate of each component is represented by weight%.

The eye drop of the present invention contains polyvinylpyrrolidone in order to increase the solubility of tranilast and maintain the stability in an aqueous solution.
As the polyvinyl pyrrolidone, any ophthalmically acceptable one may be used, but one having an appropriate polymerization degree is selected in consideration of the viscosity of the preparation. Preferably an average molecular weight in the range of about 25000 to about 120,000, more preferably in the range of about 25000 to about 40000 can be used. Specifically, polyvinyl pyrrolidone K-25, polyvinyl pyrrolidone K-30, polyvinyl pyrrolidone K-90, etc. can be used. In the eye drop, it can be used 4 to 6 times, preferably 5 to 6 times the tranilast by weight%.
Polyvinylpyrrolidone is important for enhancing the solubility of tranilast and ensuring its stabilization in an aqueous solution, but under the coexistence, it causes a change in the size of the contact lens. However, this effect is avoided in eye drops containing a constant concentration of nonionic surfactant of the present invention.

  As the nonionic surfactant, those having HLB of 10 to 16 are suitable and are appropriately selected from those which can be used as eye drops. Polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 60 and the like Examples thereof include polyoxyethylene sorbitans such as ethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate. Among them, polyoxyethylene sorbitans are preferable, and polyoxyethylene sorbitan monooleate (polysorbate 80) is particularly preferable. The concentration of the nonionic surfactant is 0.075 to 1%, preferably 0.10 to 1.0%. In order to prevent size change of contact lenses in an aqueous solution containing tranilast and polyvinylpyrrolidone, 0.075% or more is preferable, and if it exceeds 1%, it is sticky and is preferable because it causes discomfort when applied to the eyes. Absent. Therefore, the concentration of the nonionic surfactant in the eye drop of the present invention is more preferably from 0.10% to less than 1.0%, more preferably from 0.10% to less than 1.0%, more preferably from 0.15 to 0.95. % Is preferable. An even more preferable range is 0.2% to 0.90%.

  In addition, unless it is contrary to the objective of this invention, the amphoteric surfactant may also be contained. Examples of such amphoteric surfactants include lauryl dimethylaminoacetic acid betaine, lauryl dimethylamine oxide, lauryl carboxymethylhydroxyethyl imidazolinium betaine, and the like. When the amphoteric surfactant is contained, the concentration is 0.001 to 1%, preferably 0.05 to 0.5%.

  Examples of basic substances include, but are not limited to, organic amines, urea and creatinine. Examples of organic amines include alkanolamines such as trometamol, monoethanolamine, diethanolamine, and triethanolamine, HEPES, 1,4-bis (2-sulfoethyl) piperazine, 1,4-bis (3-sulfopropyl) piperazine, 1, A sulfoalkylpiperazine such as 4-bis (4-sulfobutyl) piperazine and a sulfoalkylalkylenediamine such as N, N′-bis (3-sulfopropyl) ethylenediamine are preferred, and trometamol and monoethanolamine are particularly preferred. The concentration of the basic substance is 0.01 to 5.0%, preferably 0.1 to 4.0%.

  It is necessary to adjust the eye drop of the present invention within an ophthalmically acceptable range with an appropriate pH adjuster. In consideration of the solubility and irritation of tranilast, it is desirable to maintain the pH within the range of 5.0 to 9.0, preferably 6.5 to 8.5. That is, at pH 5 or less, the solubility of tranilast is insufficient and irritating.

The eye drop of the present invention contains an appropriate preservative. Such preservatives are selected from those known in the art, but certain are undesirable in terms of adsorption to the lens because they are used by contact lens wearers. Accordingly, a preservative selected from the following is suitable for the eye drop of the present invention.
Chlorhexidine and its salts (eg, chlorhexidine gluconate), alkylpolyaminoethylglycine, sorbic acid and its salts (eg, potassium sorbate), thimerosal, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoate 1 or 2 from the group consisting of butyl acid, chlorobutanol, benzyl alcohol, cetylpyridinium chloride, benzalkonium chloride having an alkyl group of 12 carbon atoms, quaternary ammonium polymers and salts thereof, biguanide compounds and salts thereof, etc. More than seeds can be used. Preferred are chlorhexidine and salts thereof, sorbic acid and salts thereof, benzalkonium chloride having an alkyl group of 12 carbon atoms, quaternary ammonium polymers and salts thereof, biguanide compounds and salts thereof, and the like.
For example, quaternary ammonium polymers and salts thereof are polydronium chloride (polyquarterium-1), Glokill PQ (trade name, manufactured by Rhodia), Unisense CP (trade name, poly (diallyldimethylammonium chloride), Senka And WSCP (trade name, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethylene dichloride] containing about 60 wt%, manufactured by Bachman Laboratories). The biguanide compound or a salt thereof can be obtained from Cosmosil CQ (trade name, containing about 20% by weight of polyhexamethylene biguanide hydrochloride, manufactured by ICI Americas).

  The concentration of the preservative may be determined within a known concentration range for each preservative. For example, the concentration of chlorhexidine gluconate is 0.0001-0.02%, preferably 0.001-0.01%. The concentration of alkyl polyaminoethylglycine is 0.001 to 0.2%, preferably 0.01 to 0.1%. The concentration of sorbic acid and potassium sorbate is 0.001 to 0.2%, preferably 0.01 to 0.1%. The concentration of thimerosal is 0.001 to 0.2%, preferably 0.01 to 0.1%. The concentration of methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate is 0.001 to 0.1%, preferably 0.01 to 0.05%. The concentration of chlorobutanol is 0.001 to 0.5%, preferably 0.1 to 0.2%. The concentration of benzyl alcohol is 0.001 to 0.5%, preferably 0.1 to 0.2%. The concentration of polydronium chloride is 0.00001 to 0.5%, preferably 0.00001 to 0.01%. The concentration of polyhexamethylene biguanide hydrochloride is 0.00001% to 0.5%, preferably 0.00001% to 0.01%. The concentration of poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio) ethylene dichloride] is 0.00001 to 0.5%, preferably 0.00001% to 0.01%. In order to prevent the preservative from adsorbing to the contact lens, the nonionic surfactant is suitably 0.075 to 1%, and preferably 0.10 to 1.0%.

  Thus, the eye drop of the present invention contains the nonionic surfactant and polyvinyl pyrrolidone, and optionally a basic substance and a preservative within the above-mentioned concentration range within the above-mentioned fixed pH range. . These additives do not affect the stability of tranilast or its pharmacologically acceptable salt under light shielding in this concentration range, irritation as an eye drop, formulation stability, packaging container Therefore, tranilast or a pharmacologically acceptable salt thereof is optimal as a compounding component.

Furthermore, the eye drop of the present invention contains an isotonic agent, a pH regulator, a preservative other than the above, a thickening agent, a dissolution agent, as long as the object of the present invention can be achieved. Adjuvants, stabilizers, solubilizers, chelating agents and other active ingredients can be blended.
Examples of the isotonic agent include potassium chloride, calcium chloride, sodium chloride, glycerin, D-mantle, aminoethylsulfonic acid, glucose and the like.

  Examples of the pH adjuster include hydrochloric acid, dilute hydrochloric acid, glacial acetic acid, sodium hydroxide and the like.

  Examples of the thickening agent include dextran, hydroxyethyl cellulose, hydroxy cellulose, carboxymethyl cellulose, carbopol, hydroxypropyl methyl cellulose, polyvinyl alcohol, methyl cellulose, sodium chondroitin sulfate, agarose, tragacanth, and xanthan gum.

  Examples of solubilizers include urea, ethanol, propylene glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil, polyoxyl 40 stearate, polysorbate 80, macrogol 4000, and monoethanolamine.

  Examples of the stabilizer include sodium bisulfite, sodium sulfite, sodium thiosulfate, sodium pyrosulfite, sodium metabisulfite and the like. Examples of chelating agents include sodium edetate and sodium citrate.

Examples of the solubilizer include sterilized purified water, water for injection, and purified water.
Other medicinal ingredients include anti-inflammatory agents, antiallergic agents, antibacterial agents, antibiotics, vitamins, corneal wound healing promoters, and the like.

The content of the present invention will be described in more detail in the following examples, but the present invention is not limited to the content.
Examples 1-23
Tranilast 0.5% eye drops were prepared according to the formulations described in Table 1 and Examples 1 to 23 below (Tables 1 to 4).
Method: Dissolve the ingredients of each formulation in purified water and add purified water so that the total volume is 100 mL. Furthermore, the prepared liquid was aseptically filtered in an aseptic environment. This was aseptically filled into a plastic eye drop container that had been washed and sterilized, and then closed to obtain a clear eye drop.

By the same method, a composition (Comparative Examples 1 to 3) having a low concentration of the nonionic surfactant and a composition containing no tranilast (Comparative Example 4) were prepared.

Test Example 1 Effects of eye drop components on contact lens size (1) The ophthalmologically acceptable contact lens size change is determined by the American National Standards Institute (ANSI) standard for contact lenses. Followed. That is, ANSI Z80.8 (1986) defines the allowable width of the soft contact lens size change as 0.5 mm. Therefore, in the following tests, those having a difference in size before and after the test of 0.5 mm or less were appropriate, and those exceeding 0.5 mm were inappropriate.

(2) Influence of ophthalmic solution containing nonionic surfactant on lens size A test was conducted according to the test method of ANSI 280.8 (1986). After measuring the size of the soft contact lens in physiological saline, the lens was immersed in 10 mL of each test solution for 3 minutes, removed from the test solution, and immediately measured again in physiological saline.
Lens used: SUREVUE (Johnson & Johnson, Group IV lens with a moisture content of 58%)
Test solution: Compositions of Examples 5 and 7 to 11 and Composition of Comparative Example 2 Size measuring method: Using a universal projector, the diameters of two perpendicularly intersecting lenses were measured in physiological saline. (N = 1)
The results are shown in Table 6.

表６に記載の結果から、トラニラスト及びポリビニルピロリドンとを含有する水性組成物は、0.05％の非イオン性界面活性剤の存在下では、レンズサイズの拡大程度が許容範囲を超える（比較例２）が、0.075％以上の非イオン性界面活性剤の存在下では、許容範囲内に抑制されることが分かる。この結果は、トラニラスト及びポリビニルピロリドン含有組成物のコンタクトレンズサイズへの影響に対する非イオン性界面活性剤の抑制効果が、濃度0.05%の場合に比較して、濃度0.075％の場合には飛躍的に向上することを示している。なお、非イオン性界面活性剤の濃度が1.0％の場合にも優れた効果が認められるが、1.0％を超えた濃度で非イオン性界面活性剤を含有する組成物は、物理的な性質（粘性）に鑑みて、本発明の点眼剤として不適であることから、この値を本発明組成物中の非イオン性界面活性剤の濃度の上限値としている。

From the results shown in Table 6, in the aqueous composition containing tranilast and polyvinylpyrrolidone, in the presence of 0.05% nonionic surfactant, the degree of enlargement of the lens exceeds the allowable range (Comparative Example 2). However, in the presence of 0.075% or more of a nonionic surfactant, it is found to be suppressed within an acceptable range. This result shows that the inhibitory effect of the nonionic surfactant on the influence on the contact lens size of the composition containing tranilast and polyvinylpyrrolidone is dramatically higher when the concentration is 0.075% than when the concentration is 0.05%. It shows improvement. In addition, although the excellent effect is recognized when the concentration of the nonionic surfactant is 1.0%, the composition containing the nonionic surfactant at a concentration exceeding 1.0% has physical properties ( In view of (viscosity), this value is not suitable as the eye drop of the present invention, and this value is set as the upper limit of the concentration of the nonionic surfactant in the composition of the present invention.

Test Example 2 Adsorption of tranilast to contact lens 5 mL of a test solution was prepared, 5 soft contact lenses were immersed, and the adsorption to the lens after 24 hours was quantified by high performance liquid chromatography.
Lens used: SCL-A (Group I lens with a moisture content of 43%)
SCL-B (Group IV lens with a moisture content of 55%)
Test solution: composition of Example 3 (Group I lens means a non-ionic material having a water content of less than 50%, and Group IV lens means a compound made of an ionic material having a water content of 50% or more. Point to.)
The results are shown in Table 7.

上記の結果から、トラニラストはほとんどレンズに吸着しないことが分かる。

From the above results, it can be seen that tranilast hardly adsorbs to the lens.

Test Example 3 Adsorption of preservative in preparation to contact lens 1 soft contact lens was immersed in 5 mL of test solution, and preservative (chlorhexidine gluconate, potassium sorbate, benzalkonium chloride) in the immersion solution after 24 hours ) Content was measured.
Lens used: SCL-A (Group I lens with a moisture content of 43%)
Test solution: compositions of Examples 1 to 6 and Comparative Examples 1 to 4.
Determination method: Determination of chlorhexidine gluconate, potassium sorbate, and benzalkonium chloride by high performance liquid chromatography.
The test results are shown in Table 8.

表に記載の通り、本願製剤の場合には、保存剤の吸着が防止されている。

As shown in the table, in the case of the preparation of the present application, the preservative is prevented from being adsorbed.

Test Example 4 Stability in Formulation 5 mL of a test solution was filled in a plastic container, stored at room temperature for 1 week, and visually confirmed. Any liquid agent of Examples 1-6 was maintained clearly, and the foreign material was not recognized.

  The ophthalmic solution of the present invention containing tranilast as an active ingredient or a pharmacologically acceptable salt thereof can be applied without affecting the lens even while wearing a contact lens, so that various ophthalmology such as allergic conjunctivitis can be applied. This is convenient for patients with common abnormalities and makes it easier to obtain compliance.

Claims (6)

An ophthalmic solution applicable when wearing a contact lens, comprising tranilast or a pharmacologically acceptable salt thereof, polyvinylpyrrolidone, and 0.075 to 1% by weight of a nonionic surfactant. The eye drop according to claim 1, wherein the nonionic surfactant is a surfactant having an HLB of 10 to 16. The eye drop according to claim 1 or 2, wherein the polyvinyl pyrrolidone is selected from polyvinyl pyrrolidone having an average molecular weight of 25,000 to 120,000. The ophthalmic solution according to any one of claims 1 to 3, further comprising a basic substance. The eye drop according to any one of claims 1 to 4, wherein the basic substance is selected from the group consisting of an organic amine, urea and creatinine. In addition, chlorhexidine and its salts, alkylpolyaminoethylglycine, sorbic acid and its salts, thimerosal, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, chlorobutanol, benzyl alcohol, cetyl chloride It contains at least one preservative selected from the group consisting of pyridinium, benzalkonium chloride having a C12 alkyl group, a quaternary ammonium polymer and a salt thereof, and a biguanide compound and a salt thereof. The ophthalmic solution according to any one of claims 1 to 5.