JP2005263792A - Clear latanoprost eye lotion - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a clear and stable latanoprost eye lotion containing latanoprost useful as a treating agent for glaucoma as an active component. <P>SOLUTION: A clear and stable eye lotion resistant to clouding by the change of formulation is produced while keeping the antiseptic effect by adding at least one kind of antiseptic agent selected from (1) benzethonium chloride, (2) chlorhexidines, (3) p-hydoxybenzoates and (4) sorbic acid or its salt to an eye lotion containing latanoprost as an active component. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a clear and stable ophthalmic solution containing latanoprost useful as a glaucoma therapeutic agent as an active ingredient.

Latanoprost is the chemical name isopropyl- (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R) -3-hydroxy-5-phenylpentyl] cyclopentyl] -5-heptanoate. It is a prostaglandin glaucoma therapeutic agent represented by Latanoprost is a selective FP receptor agonist and exerts an intraocular pressure lowering effect by promoting outflow of aqueous humor (see, for example, Patent Document 1). As a therapeutic agent for glaucoma containing latanoprost as an active ingredient, an ophthalmic solution containing 0.005% latanoprost (trade name: xalatan ophthalmic solution) is commercially available.
Japanese Patent No. 2721414

 An ophthalmic solution usually contains an isotonic agent and a buffer as additives. Isotonizing agents are formulated to maintain isotonicity, and typical ones are inorganic salts of alkali metal salts such as sodium chloride and alkaline earth metal salts such as magnesium chloride, and commercially available latanoprost ophthalmic solutions. Contains sodium chloride. Buffering agents are formulated to prevent pH fluctuations, and typical ones are inorganic salts such as sodium phosphate and sodium borate and organic salts such as sodium acetate, sodium citrate and sodium carbonate, which are commercially available. Latanoprost ophthalmic solution contains sodium dihydrogen phosphate monohydrate and anhydrous sodium monohydrogen phosphate.

In general, a multidose type ophthalmic solution contains a preservative, and a commercially available latanoprost ophthalmic solution contains 0.02% benzalkonium chloride (hereinafter abbreviated as BAK). Yes. Here, BAK has a chemical structure represented by [C ₆ H ₅ CH ₂ N (CH ₃ ) ₂ R] Cl, and its alkyl group (indicated by R) is C ₈ H _{17 to} C _18. a mixture of what is H _37. However, BAK has excellent antiseptic power, but may cause corneal damage when used at a high concentration.

 Therefore, from the viewpoint of reducing the concentration of BAK, a latanoprost ophthalmic solution containing general-purpose additives was prepared and variously examined, and it was found that white turbidity was produced when the concentration of BAK was 0.01% or less. This is thought to be because latanoprost and BAK, which are highly hydrophobic, form a complex, and the latanoprost-BAK complex precipitates due to the salting-out effect of the additive salt, but the BAK concentration is 0.01% or less. It is a surprising discovery that precipitation occurs for the first time at a concentration of. Therefore, it is beneficial to search for a new preservative to replace BAK in order to prevent white turbidity due to such a change in formulation in latanoprost ophthalmic solution.

  The present inventors have examined various preservatives that are compatible with latanoprost ophthalmic solution. When at least one of the preservatives selected from the following 1) to 4) is added, the preservative effect is maintained while being added. The present inventors have found that clear and stable ophthalmic solution can be obtained by preventing cloudiness due to change.

1) Benzethonium chloride 2) Chlorhexidines 3) Paraoxybenzoates 4) Sorbic acid or its salts

  The concentration of latanoprost, which is an active ingredient of the eye drop in the present invention, is preferably 0.001 to 0.01% (W / V), particularly preferably about 0.005% (W / V).

 In the present invention, even when added to an ophthalmic solution containing latanoprost as an active ingredient, the following four examples are given as preservatives that can maintain a clear and stable ophthalmic solution without causing white turbidity due to a change in formulation. it can.

1) Benzethonium chloride 2) Chlorhexidines 3) Paraoxybenzoates 4) Sorbic acid or its salts

  The concentration of benzethonium chloride is preferably 0.001 to 0.1% (W / V).

 Examples of chlorhexidine include chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine hydrochloride, and the like, preferably chlorhexidine gluconate. The concentration of chlorhexidine is preferably 0.001 to 0.1% (W / V).

 Examples of the paraoxybenzoic acid esters include ethyl paraoxybenzoate, methyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, isobutyl paraoxybenzoate, etc., preferably methyl paraoxybenzoate, paraoxybenzoate Ethyl benzoate. The concentration of paraoxybenzoic acid esters is preferably 0.001 to 0.1% (W / V).

 The concentration of sorbic acid or a salt thereof is preferably 0.01 to 1% (W / V). Examples of the sorbic acid salt include potassium sorbate.

 The above four preservatives may be used alone or in combination.

 The ophthalmic solution of the present invention can be prepared by a widely used method, and an isotonic agent, a pH buffering agent, a pH adjusting agent, a solubilizing agent, a thickener and the like can be added as necessary.

 Examples of the isotonic agent include glycerin, propylene glycol, polyethylene glycol, trihalose, sucrose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.

  Examples of the pH buffer include phosphates such as sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate; sodium borate, boric acid Examples thereof include borates such as potassium; citrates such as sodium citrate and disodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium bicarbonate.

  Examples of the pH regulator include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

  Examples of the solubilizer include polysorbate 80, polyethylene ethylene hardened castor oil 60, macrogol 4000, and the like.

  Examples of the thickener include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, carboxyvinyl polymer, and polyvinylpyrrolidone.

 The pH of the ophthalmic solution of the present invention is preferably 3 to 8, particularly 4 to 7.

 By adding benzethonium chloride, chlorhexidine gluconate, methyl paraoxybenzoate, and sorbic acid as a preservative for latanoprost ophthalmic solution, a clear latanoprost ophthalmic solution that does not cause a change in the composition can be provided.

1. Formulation Examples and Solution Appearance Latanoprost ophthalmic solutions having the following formulations were prepared, and their appearances were observed. The results are shown in Table 1.

Formula 1
Dissolve 0.2 g of sodium dihydrogen phosphate, 0.9 g of sodium chloride and 0.01 g of benzethonium chloride in about 90 mL of purified water, adjust the pH to 6.7, and add purified water to make the total volume 100 mL. An agent was obtained. 100 mL of the base was added to 5 mg of latanoprost, and the resulting mixture was stirred while warming in a water bath at about 80 ° C. to dissolve latanoprost. The ophthalmic solution thus obtained was returned to room temperature, and it was confirmed that the pH was 6.7.

Formula 2
An ophthalmic solution was obtained in the same manner as in Formulation 1, except that 0.01 g of chlorhexidine gluconate was used instead of 0.01 g of benzethonium chloride. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

Formula 3
About 90 mL of purified water was added to 0.2 g of sodium dihydrogen phosphate, 0.9 g of sodium chloride and 0.01 g of methyl paraoxybenzoate, and the resulting mixture was stirred while warming in a water bath at about 70 ° C. The additive was dissolved. After returning the obtained solution to room temperature and adjusting the pH to 6.7, the total amount was adjusted to 100 mL by adding purified water to obtain a base. Thereafter, the same operation as in Formulation 1 was performed to obtain an ophthalmic solution. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

Formula 4
An ophthalmic solution was obtained in the same manner as in Formulation 3, except that 0.2 g of sorbic acid was used instead of 0.01 g of methyl paraoxybenzoate. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

Comparative prescription 1
An ophthalmic solution was obtained in the same manner as in Formula 1 except that no preservative (benzethonium chloride) was used. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

Comparative prescription 2
An ophthalmic solution was obtained in the same manner as in Formula 1 except that 0.01 g of benzalkonium chloride was used instead of 0.01 g of benzethonium chloride. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

<Result>
As is apparent from Table 1, latanoprost ophthalmic solution formulated with 0.01% (W / V) benzalkonium chloride was clouded due to a change in the composition, whereas benzethonium chloride, chlorhexidine gluconate, paraoxybenzoic acid. All of the latanoprost ophthalmic solutions formulated with methyl or sorbic acid were colorless and clear without causing any change in the formulation.

2. Preservative Efficacy Test Prescription 1, Prescription 2 and Comparative Prescription 1 ophthalmic solutions were subjected to a preservative efficacy test according to the Preservation Efficacy Test Method of the 14th revised Japanese Pharmacopoeia (JP14). The results are shown in Table 2. In addition, the numerical value in Table 2 is a logarithmic display of the degree of decrease with respect to the initial bacterial count of each viable bacterial count on the 7th, 14th and 28th days after inoculation.

<Result>
The preservative efficacy of Formula 1 and Formula 2 met not only JP14 criteria but also USP24 criteria. On the other hand, Comparative prescription 1 did not satisfy any of the criteria and was incompatible.

Claims (4)

A clear ophthalmic solution characterized by containing latanoprost as an active ingredient and blending at least one preservative selected from the following 1) to 4).
1) Benzethonium chloride 2) Chlorhexidines 3) Paraoxybenzoates 4) Sorbic acid or its salts A clear ophthalmic solution comprising 0.001 to 0.01% (W / V) of latanoprost as an active ingredient and at least one preservative selected from the following 1) to 4).
1) 0.001 to 0.1% (W / V) benzethonium chloride 2) 0.001 to 0.1% (W / V) chlorhexidine 3) 0.001 to 0.1% (W / V) ) Paraoxybenzoates 4) 0.01-1% (W / V) sorbic acid or a salt thereof   The clear ophthalmic solution according to claim 1 or 2, wherein the chlorhexidine is chlorhexidine gluconate. The clear ophthalmic solution according to claim 1 or 2, wherein the paraoxybenzoic acid ester is methyl paraoxybenzoate.