JP2001114700A - Eye drop composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for obtaining pH which is stable in eye drop. SOLUTION: This eye drop composition is characterized in that a mixture of ε-aminocaproic acid with boric acid is compounded therein as a buffer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an ophthalmic solution comprising a mixture of epsilon-aminocaproic acid and boric acid as a buffer. The present invention also relates to an eye drop composition containing sodium cromoglycate and chlorpheniramine maleate as active ingredients.

[0002]

2. Description of the Related Art Boric acid-borax, citric acid-sodium citrate, sodium hydrogen phosphate-sodium dihydrogen phosphate and the like have been used as buffering agents for eye drops, but epsilon-aminocaproic acid has been used. And boric acid combinations have not been reported.

[0003] Further, eye drops containing sodium cromoglycate (general name: Intal: described below) as an active ingredient are already on the market, but these eye drops have irritation to the eyes or crystal precipitation. From the viewpoint, the pH is adjusted by adding a buffer to keep the pH of the eye drops at 5 to 8.

[0004] Patent documents relating to ophthalmic solutions containing intals include, for example, JP-B-6-39379, JP-A-4-9339, and JP-B-4-66452. There is no description. Japanese Patent Publication No. 57-56448 discloses sodium citrate-citric acid and boric acid-sodium borate as buffers.
JP-A-54-25082 discloses sodium acid phosphate-sodium phosphate and JP-A-6-336.
No. 429 exemplifies boric acid, sodium monohydrogen phosphate and sodium dihydrogen phosphate. Also PCT WO98
/ 13040 exemplifies a borate buffer, a phosphate buffer, a carbonate buffer, and an acetate buffer, but there is no description about a specific combination. PCT WO97 / 2414 discloses sodium phosphate-boric acid. Further, Japanese Patent Publication No. 7-5456 discloses epsilon-aminocaproic acid in the examples, but this compounded epsilon-aminocaproic acid as an active ingredient and not a buffering agent.

[0005] As described above, the patent documents relating to ophthalmic preparations containing intal do not disclose examples in which the epsilon-aminocaproic acid and boric acid of the present invention are blended as a buffer. On the other hand, in the case of an antiallergic eye drop containing intal and chlorpheniramine maleate,
It has been reported that the use of benzalkonium chloride as a preservative produces a water-insoluble precipitate. Various methods have been proposed to prevent the formation of this precipitate. For example, an example in which a chelating agent or a sequestering agent is added (Japanese Patent Publication No. 54-25082), an example in which an alkanolamine is blended (PCT WOJP95 / 02724), polysorbate 80, polyoxyethylene cured Example in which a surfactant such as castor oil 60 is blended (Japanese Patent Publication No. 4-66452).
Although polyoxyethylene (200) polyoxypropylene glycol (70) is used as a suspending agent.
Is not disclosed.

[0006]

In particular, in the case of antiallergic eye drops containing intal and chlorpheniramine maleate, maintaining the pH at 5 to 7.5 is extremely difficult for the above reasons. is important. That is, when the pH is lowered, irritation to the eyes is increased, and precipitation of a water-insoluble precipitate is observed. Further, when benzalkonium chloride is blended as a preservative, a water-insoluble precipitate is formed, so that it is necessary to blend a solubilizer. In addition, antiallergic eye drops containing intal and chlorpheniramine maleate are known to be irritating when instilled.

[0007] Accordingly, an object of the present invention is to provide a method for obtaining a stable pH in eye drops, and further to prevent the formation of a water-insoluble precipitate when benzalkonium chloride is used as a preservative. In addition, the purpose is to reduce irritation during instillation.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a method for obtaining a stable pH, epsilon-aminocaproic acid and boric acid as buffering agents for eye drops. When a mixture of the above was blended, it was found that the change in pH was small over time,
The present invention has been completed.

That is, the present invention relates to an ophthalmic solution comprising a mixture of epsilon-aminocaproic acid and boric acid as a buffer. In addition, the present invention relates to the ophthalmic composition, wherein epsilon-aminocaproic acid is 0.2 to 1.5% by weight / volume and boric acid is 0.5 to 1.5% by weight / volume. The present invention also provides polyoxyethylene (200) polyoxypropylene glycol (70) as a suspending agent in an amount of 0.04 to 0.5% by weight / volume.
The present invention relates to the ophthalmic composition, which is characterized by being blended. Furthermore, the present invention relates to the above eye drop composition, characterized in that chlorobutanol is incorporated in an amount of 0.05 to 0.5% by weight / volume as a stimulant improving agent. Also, the present invention provides
Is from 5 to 7.5.

[0010] The present invention further relates to the ophthalmic composition, wherein the active ingredients are sodium cromoglycate and chlorpheniramine maleate. The eye drop composition of the present invention can suppress undesired phenomena as eye drops, such as reduction of eye tissue irritation caused by pH fluctuation, securing of drug stability, or formation of precipitates. It is possible to prevent crystal deposition of the derived drug, generation of a precipitate, irritation of eye mucosa, and the like. In particular, when chlorobutanol is used as a preservative, a decrease in pH due to the temporal decomposition of chlorobutanol can be suppressed. In addition, polyoxyethylene (20
0) When polyoxypropylene glycol (70) is blended, the formation of water-insoluble precipitates can be prevented when benzalkonium chloride is used as a preservative. In the case of Intal-containing eye drops, the initial irritation can be reduced by adding chlorobutanol.

[0011] Epsilon-aminocaproic acid has conventionally been
As an antiplasmin agent, hemostatic action, antiallergic action,
Since it has a pharmacological action such as an anti-inflammatory action, 1 to 5% by weight / volume% has been blended into eye drops as an active ingredient. The buffering agent is usually used in a blending amount of 0.5% by weight or less, and among them, the buffering ability increases as much as possible. If the amount of epsilon-aminocaproic acid is too small, the buffering capacity is not obtained, and if it is too large, a pharmacological effect as an active ingredient is exhibited, so that 0.2 to 1.5% by weight / volume, preferably 0.3 to 1.0% Weight / volume% is blended. When the amount of boric acid to be added at the same time is too small, the buffer capacity cannot be obtained.
Since H cannot be maintained, 0.5 to 1.5% by weight / volume, preferably 0.5 to 1.2% by weight / volume is blended. Epsilon-
The mixing ratio of aminocaproic acid and boric acid can be appropriately increased or decreased in order to maintain a pH of 5 to 7.5 within the above range, but epsilon-aminocaproic acid is used to make the osmotic pressure isotonic with tears. And the amount of boric acid are limited to some extent. In particular, with respect to boric acid, it is difficult to mix 1.5% by weight or more by volume since the salt equivalent is 0.50 from the viewpoint of isotonicity with tears.

On the other hand, when benzalkonium chloride is used as a preservative, in order to prevent the formation of a water-insoluble precipitate, polyoxyethylene (200) polyoxypropylene glycol (70) is used as a dissolving agent. However, if it is less than 0.02% by weight / volume, the effect as a solubilizer is insufficient.
When the content is 0.5% by weight or more, irritation to eye tissue is considered, so that the content is 0.04 to 0.5% by weight, preferably 0.1 to 0.3% by weight.
% By volume. In order to reduce the initial irritation of the ointment containing the Intal, chlorobutanol, which is usually added as a preservative, is added. When the content is more than the volume%, it becomes difficult to mix it with an aqueous ophthalmic solution. Therefore, the content is 0.05 to 0.5% by weight / volume, preferably 0.06 to 0.2% by weight / volume.

Examples of active ingredients include intal and chlorpheniramine maleate as anti-allergic eye drops. The compounding amount is, for example, the compounding amount of a commercially available product (intal 1-2% by weight / volume%, chlorpheniramine maleate 0.01-0.03% by weight / volume).

[0014] In addition, active ingredients which are usually incorporated into commercially available eye drops, such as anti-inflammatory agents such as dipotassium glycyrrhizinate and berberine sulfate, astringent components, tocopherol acetate, cyanocobalamin, pyridoxine hydrochloride, retinolace acetate , Vitamins such as flavin adenine, decongestants such as naphazoline hydrochloride and naphazoline nitrate, amino acids such as potassium L-aspartate, magnesium L-aspartate and aminoethylsulfonic acid, sulfamethoxazole, sulfamethoxine Sulfur agents such as sodium sazol; inorganic salts such as potassium chloride and sodium chloride; celluloses such as hydroxyethyl cellulose and hydroxypropylmethyl cellulose; calcium pantothenate; lysozyme chloride; sodium azulene sulfonate , Allantoin Ketotifen fumarate, sodium hyaluronate, Panteno - Le, diphenhydramine hydrochloride, ephedrine hydrochloride, polyvinyl alcohol - le, polyvinylpyrrolidone, alkylpolyaminoethylglycine,
Epsilon-aminocaproic acid, sodium chondroitin sulfate, boric acid and the like can be blended within the range of the blending standard.

As an additive, a base component usually used for eye drops can be blended. Examples of these include cooling agents such as l-menthol, camphor, and borneol; pH adjusting agents such as sodium hydroxide and hydrochloric acid; tonicity agents such as potassium chloride, glycerin and propylene glycol; Viscosity agents such as hydroxyethyl cellulose, ethanol, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, dissolution aids such as propylene glycol and polyethylene glycol, sodium bisulfite, sodium edetate , Sodium hydrogen sulfite and the like, and sterilized water. These can be generally added in the amount used as eye drops. Further, the eye drop of the present invention can be produced by a method for producing an eye drop. For example, an active ingredient and an additive ingredient are 40-80 degreeC.
After stirring and dissolving in sterilized purified water heated to room temperature, cool to room temperature. Next, the solution is sterilized and filtered through a membrane filter, and the solution is filled in an ophthalmic solution container.

[0016]

The present invention will be described below with reference to examples, comparative examples and test examples, but the present invention is not limited to these examples. Example 1 dipotassium glycyrrhizinate 100 mg chlorpheniramine maleate 15 mg methyl paraben 25 mg boric acid 1000 mg epsilon-aminocaproic acid 500 mg propylene glycol 500 mg sterile purified water qs 100 ml

Example 2 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Boric acid 1000 mg Epsilon-aminocaproic acid 500 mg Ethanol 500 mg Polyoxyethylene (200) Polyoxypropylene glycol (70) 300 mg d -Camphor 15mg Sodium edetate 10mgSterile purified water qs 100mL

Example 3 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Boric acid 1500 mg Epsilon-aminocaproic acid 1000 mg Ethanol 500 mg Polyoxyethylene (200) Polyoxypropylene glycol (70) 300 mg d -Camphor 15mg Sodium edetate 10mgSterile purified water qs 100mL

Example 4 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Boric acid 1000 mg Epsilon-aminocaproic acid 400 mg Ethanol 500 mg Polyoxyethylene (200) Polyoxypropylene glycol (70) 300 mg d -Camphor 15mg Sodium edetate 10mgSterile purified water qs 100mL

Example 5 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Boric acid 630 mg Epsilon-aminocaproic acid 200 mg Ethanol 500 mg Polyoxyethylene (200) Polyoxypropylene glycol (70) 200 mg d -Camphor 15mg Sodium edetate 10mgSterile purified water qs 100mL

Example 6 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Methyl paraben 25 mg Chlorobutanol 100 mg Boric acid 1000 mg Epsilon-aminocaproic acid 400 mg Propylene glycol 500 mg d-Camphor 15 mg Sodium edetate 10 mg Sterilized purified water Total volume 100 mL

Comparative Example 1 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Epsilon-aminocaproic acid 500 mg Propylene glycol 500 mg Polyoxyethylene (200) polyoxypropylene glycol (70) 400 mg d-Camphor 15mg sodium edetate 10mg sterile purified water qs 100mL

Comparative Example 2 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Citric acid 500 mg Epsilon-aminocaproic acid 500 mg Propylene glycol 500 mg Polyoxyethylene (200) Polyoxypropylene glycol (70) 400 mg d-Camphor 15mg Sodium edetate 10mg Sterile purified water qs 100mL

Comparative Example 3 Sodium cromoglycate 1000 mg Chlorpheniramine maleate 15 mg Benzalkonium chloride 2 mg Boric acid 1000 mg Borax 500 mg Propylene glycol 500 mg Polyoxyethylene (200) polyoxypropylene glycol (70) 400 mg d- Camphor 15mg Sodium edetate 10mg Sterile purified water qs 100mL

Test Example 1: Comparison of Buffering Capacity of Buffer To test the buffering capacity of buffer in eye drops,
0.1 mol / L NaOH was added to the eye drops (pH 6) of Examples and Comparative Examples.
Solution (pH 6 or higher) or 0.1 mol / L HCl (pH 6 or lower)
Was added and the change in pH was measured to prepare a titration curve. The results are shown in Table 1 and FIG. Example 2: Epsilon-aminocaproic acid (500 mg) -boric acid (1000 mg) Example 3: Epsilon-aminocaproic acid (1000 mg) -boric acid (1500 mg) Example 4: Epsilon-aminocaproic acid (400 mg) -boric acid (1000 mg) Example 5: Epsilon-aminocaproic acid (200 mg) -boric acid (630 mg) Comparative example 1: Epsilon-aminocaproic acid (500 mg) Comparative example 2: Epsilon-aminocaproic acid (500 mg) -citric acid (3 mg) Comparative example 3: Boric acid (1000mg)-Borax (500mg)

[0026]

[Table 1]

As is clear from the results shown in Table 1 and FIG.
The ophthalmic solution using the mixture of epsilon-aminocaproic acid-boric acid shown in Examples 2, 3, 4, and 5 as a buffer was more pH-equal than the ophthalmic solution using the buffer shown in Comparative Examples 1, 2, and 3. Change was small. Test Example 2: Dissolution experiment In the eye drops of Example 2, polyoxyethylene (200) polyoxypropylene glycol (70) was used as a dissolving agent.
(Solubilizer 1) and instead propylene glycol
Prepare an eye drop added by changing the amount of (Solubilizer 2),
The presence or absence of a precipitate was observed. Table 2 shows the results.

[0028]

[Table 2] As is clear from the results in Table 2, polyoxyethylene (200) polyoxypropylene glycol (70) was strong in suppressing the formation of precipitates. When the amount was 40 mg or more, no precipitate was observed. However, considering the irritation to the ocular tissue, the smaller the amount of the surfactant, the more preferable it is, and it is considered that the amount to be usually added as an additive to eye drops, that is, 500 mg or less is desirable.

[0029]

According to the present invention, there is provided an ophthalmic composition comprising a mixture of epsilon-aminocaproic acid of 0.2 to 1.5% by weight / volume and boric acid of 0.5 to 1.5% by weight / volume as a buffer for an ophthalmic solution. And a method for stably maintaining the pH of eye drops. With this formulation, the pH of the ophthalmic solution is stably maintained over time from 5 to 7.5.
To reduce irritation to the eye tissue due to an increase or decrease in pH, and to form crystal precipitates or water-insoluble precipitates derived from active ingredients or additive components such as benzalkonium chloride. It has the effect of suppressing. In particular, it is effective when applied to eye drops containing sodium cromoglycate (intal), which is an antiallergic eye drop, and chlorpheniramine maleate as active ingredients. By blending polyoxyethylene (200) polyoxypropylene glycol (70) as a solubilizer, it is effective to suppress the formation of crystals or water-insoluble precipitates derived from active ingredients or additive components. . Further, a formulation containing chlorobutanol can reduce irritation caused by inhal when instilled.

[Brief description of the drawings]

FIG. 1 shows titration curves of various buffers in eye drops.

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Claims (6)

[Claims] 1. An ophthalmic composition comprising a mixture of epsilon-aminocaproic acid and boric acid as a buffer. 2. The method according to claim 1, wherein the epsilon-aminocaproic acid is 0.2 to
The ophthalmic composition according to claim 1, characterized in that 1.5% by weight / volume and boric acid is 0.5 to 1.5% by weight / volume. 3. A polyoxyethylene (200) polyoxypropylene glycol (70) is used as a precipitation inhibitor in an amount of 0.04.
2. The composition according to claim 1, wherein the amount is 0.5% by weight / volume.
Or the ophthalmic solution composition according to 2. 4. A stimulant improving agent, chlorobutano-
Characterized in that 0.05 to 0.5% by weight / volume
The ophthalmic solution composition according to claim 1. 5. The ophthalmic composition according to claim 1, wherein the pH is 5 to 7.5. 6. The ophthalmic composition according to claim 1, wherein the active ingredients are sodium cromoglycate and chlorpheniramine maleate.