WO2005079809A1

WO2005079809A1 - Transparent latanoprost eye drops

Info

Publication number: WO2005079809A1
Application number: PCT/JP2005/002552
Authority: WO
Inventors: Nanoko Tsuchimoto; Hiroyuki Asada; Akio Kimura
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2004-02-19
Filing date: 2005-02-18
Publication date: 2005-09-01

Abstract

Transparent and stable eye drops which contain latanoprost as an active ingredient and are useful as a therapeutic agent for glaucoma. At least one antiseptic selected among the following 1) to 4) is added to eye drops containing latanoprost as an active ingredient. Thus, eye drops can be obtained which are prevented from coming into a turbid state caused by a compositional change and are transparent and stable, while retaining an antiseptic effect. 1) Benzethonium chloride, 2) chlorohexidine compounds, 3) p-hydroxybenzoic acid esters, and 4) sorbic acid and salts thereof.

Description

Specification

Clear latanoprost ophthalmic solution

Technical field

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

Background art

[0002] Latanoprost has the chemical name isopropyl (Z) -7 [(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R) -3-hydroxy-5-phenylpentyl] cyclopentyl]- It is a prostaglandin-based glaucoma treatment represented by 5-heptanate. Latanoprost is a selective FP receptor agonist and exerts an intraocular pressure-lowering effect by promoting outflow of aqueous humor (for example, see Patent Document 1). As a therapeutic agent for glaucoma containing latanobrost as an active ingredient, an ophthalmic solution containing 0.005% latanobrost (trade name: xalatan ophthalmic solution) is commercially available.

Patent Document 1: Japanese Patent No. 2721414

Disclosure of the invention

Problems to be solved by the invention

[0003] Ophthalmic solutions are generally compounded with isotonic agents and buffers as additives. The tonicity agent is blended in order to maintain isotonicity, and typical examples thereof include inorganic salts of alkali metal salts such as sodium salt sodium and alkaline earth metal salts such as magnesium salt of sodium salt. Latanoprost ophthalmic solution contains sodium salt. Buffering agents are added to prevent fluctuations in pH.Typical examples are inorganic salts such as sodium phosphate and sodium borate, and organic salts such as sodium acetate, sodium citrate, and sodium carbonate. The rattanoblost ophthalmic solution contains sodium dihydrogen phosphate monohydrate and anhydrous sodium monohydrogen phosphate.

[0004] An antiseptic is generally added to a multi-dose type ophthalmic solution, and commercially available latanoprost ophthalmic solution contains 0.02% of benzalco-dum chloride (hereinafter abbreviated as BAK). ) Is included. Here, BAK has a chemical structure represented by [CH CH N (CH) R] C1. And a mixture of those whose alkyl groups (indicated by R) are CH — CH

8 17 18 37

. However, while BAK has excellent preservative properties, it can cause corneal damage when used at high concentrations.

[0005] Therefore, from the viewpoint of lowering the concentration of BAK, latanoprost ophthalmic solution containing a general-purpose additive was prepared and subjected to various studies. It was found that when the concentration of BAK was 0.01% or less, turbidity occurred. did. This is because the latanoprost BAK complex with highly hydrophobic latanobrost forms a complex, and the latanoprost BAK complex is precipitated by the salting-out effect of the salts, which are the added carotenoids. It is a surprising finding that precipitation occurs only when the concentration is increased. Therefore, in latanoblost ophthalmic solution, it is beneficial to search for a new preservative to replace BAK in order to prevent such clouding due to such a change in the composition. Means for solving the problem

[0006] The present inventors have studied various preservatives compatible with latanoblost ophthalmic solution, and found that the following preservatives can be used if at least one of the following preservatives is added. It was found that, while maintaining the above, white turbidity due to a change in the composition was prevented, and a clear and stable ophthalmic solution was obtained.

[0007] 1) Benzetonium chloride

2) Chlorhexidines

3) Paraoxybenzoates

4) Sorbic acid or its salt

[0008] The concentration of latanobrost, which is an active ingredient of the ophthalmic solution in the present invention, is preferably 0.001 to 0.1% (wZv), particularly preferably about 0.005% (WZV).

[0009] In the present invention, preservatives that can maintain a clear and stable ophthalmic solution without causing turbidity due to compounding even when added to an ophthalmic solution containing latanoprost as an active ingredient include: The following four can be mentioned.

[0010] 1) Benzetonium chloride

2) Chlorhexidines

3) Paraoxybenzoates 4) Sorbic acid or its salt

[0011] The concentration of benzenium chloride is preferably 0.001-0.i% (wZv).

[0012] Examples of chlorhexidines include chlorhexidine dalconate, chlorhexidine acetate, chlorhexidine hydrochloride, and the like, and chlorhexidine dalconate is preferable. The concentration of chlorhexidines is preferably 0.001-0.1% (wZv). [0013] Examples of the nonoxybenzoic acid esters include, for example, ethyl ethyl paraoxybenzoate, methyl ethyl paraoxybenzoate, and noroxybenzoic acid. Propyl, isopropyloxybenzoate, butylbutylparaoxybenzoate, isobutylparaoxybenzoate, and the like, preferably methylparaoxybenzoate and ethylethylbenzoate. The concentration of the paraoxybenzoic acid esters is preferably 0.001 to 0.1% (WZV).

The sorbic acid salt whose concentration of sorbic acid or a salt thereof is preferably 0.01-1% (W / V) is, for example, sorbic acid potassium rim.

[0015] The above four preservatives may be used alone or in combination.

[0016] The ophthalmic solution of the present invention can be prepared by a widely used method, and if necessary, an isotonic agent, a PH buffer, a pH adjuster, a solubilizing agent, a thickener and the like may be added. Can be.

[0017] Examples of the tonicity agent include glycerin, propylene glycol, polyethylene glycol, trihalose, sucrose, sorbitol, mannitol, sodium chloride, lithium chloride, calcium chloride, magnesium chloride, and the like. be able to.

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 And borates such as potassium borate; citrates such as sodium citrate and sodium citrate; acetates such as sodium acetate and potassium acetate; carbonates such as sodium carbonate and sodium hydrogen carbonate. it can.

[0019] Examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

[0020] Examples of the solubilizer include polysorbate 80, polyexylene-ethylene hydrogenated castor oil 60, Macrogol 4000 and the like.

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

The pH of the ophthalmic solution of the present invention is preferably 3-8, particularly preferably 417.

The invention's effect

[0023] By blending benzethonium chloride, chlorhexidine dalconate, methyl paraoxybenzoate, and sorbic acid as preservatives for latanoprost ophthalmic solution, it is possible to provide a clear latanoprost ophthalmic solution that does not cause any change in the formulation. it can.

BEST MODE FOR CARRYING OUT THE INVENTION

1. Formulation Examples and Solution Appearance

Latanobrost ophthalmic solutions having the following formulations were prepared, and their appearance was observed. The results are shown in Table 1.

[0025] Prescription 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 100 mL of purified water by adding purified water. And a base was obtained. 5 mL of latanobrost was charged with 100 mL of the base material, and the resulting mixture was stirred while being heated 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.

[0026] Prescription 2

An ophthalmic solution was obtained in the same manner as in Formulation 1 except that chlorhexidine dalconate 0.1 Olg was used instead of benzenitonium chloride 0.1 Olg. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

[0027] Prescription 3

Approximately 90 mL of purified water is added to 0.2 g of sodium dihydrogen phosphate, 0.9 g of sodium salt, and 0.9 Olg of methyl parahydroxybenzoate, and the resulting mixture is added in a water bath at about 70 ° C. The mixture was stirred with a warm force S to dissolve the above additives. The resulting solution was returned to room temperature, the pH was adjusted to 6.7, and the total amount was made up to 100 mL with purified water to obtain a base. After that, it is the same as prescription 1. The same operation was performed to obtain an ophthalmic solution. The ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

[0028] Prescription 4

An ophthalmic solution was obtained in the same manner as in Formulation 3, except that 0.2 g of sorbic acid was used in place of 0.1 g of methyl paraoxybenzoate. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

[0029] Comparative prescription 1

An ophthalmic solution was obtained by performing the same operation as in Formulation 1 except that no preservative (Shiidai Benzetonium) was used. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

[0030] Comparative prescription 2

An ophthalmic solution was obtained in the same manner as in Formulation 1 except that benzalcodium chloride 0.1 Olg was used instead of benzethonium chloride 0.1 Olg. This ophthalmic solution was returned to room temperature, and it was confirmed that the pH was 6.7.

[table 1]

q.s .: Jli:

As is evident from Table 1, the latanoprost ophthalmic solution containing Shioi-Dani Benzalco-Pharma. Latanop containing chlorhexidine, methyl paraoxybenzoate or sorbic acid The lost ophthalmic solution was clear and colorless without causing any change in the composition of V and deviation.

2.Preservation efficacy test

Formulation The ophthalmic solutions of Formulation 2 and Comparative Formulation 1 were subjected to a preservative efficacy test according to the preservative efficacy test method of the 14th Revised Japanese Pharmacopoeia (JP14). The results are shown in Table 2. The numerical values in Table 2 represent the logarithm of the degree of decrease in the viable cell count from the initial cell count on the 7th, 14th and 28th days after inoculation.

[Table 2]

The preservative efficacy of Formulations 1 and 2 met the USP24 criteria, not just the JP14 criteria. On the other hand, Comparative Prescription 1 did not meet any of the criteria, and was incompatible.

Claims

The scope of the claims

[1] A clear ophthalmic solution comprising latanoblost as an active ingredient, and at least one of the following preservatives selected from 1) -1).

1) Benzetonium chloride

2) Chlorhexidines

3) Paraoxybenzoates

4) Sorbic acid or its salt

[2] A clear ophthalmic solution characterized by containing 0.0001-0.01% (WZV) of latanoprost as an active ingredient, and containing at least one preservative selected from the following 1) -1) 4). liquid.

1) 0.001-0. I% (wZv) Benzetonium chloride

2) 0.00001-0. I% (wZv) of chlorhexidines

3) 0.001-0.i% (wZv) of paraoxybenzoic acid esters

4) 0.01-1% (W / V) sorbic acid or its salt

[3] Chlorhexidine analog The clear ophthalmic solution according to claim 1 or 2, which is chlorhexidine dalconate.

[4] Nonoxybenzoic acid ester The clear ophthalmic solution according to claim 1 or 2, which is methyl paraoxybenzoate.