JP4168071B2 - Ophthalmic composition - Google Patents

Description

  The present invention provides a stable ophthalmic solution containing (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof. The present invention relates to a composition for use.

  (S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine is known as a compound having a Rho kinase inhibitory action (Patent Document 1). . A Rho kinase inhibitor is expected as a candidate for a glaucoma therapeutic drug based on a new mechanism of action because it has an effect of lowering intraocular pressure by promoting aqueous humor outflow from the trabecular meshwork outflow pathway (Non-patent Document 1). ing.

  On the other hand, when a drug is administered for an eye disease, usually two preparation forms, that is, an oral preparation or an ophthalmic preparation are selected. Among these, in the case of systemic administration by oral formulation, the drug concentration in the target tissue in the eye is difficult to reach an effective concentration, and the possibility of more severe side effects than ophthalmic formulations is taken into consideration. Therefore, an ophthalmic preparation is mainly selected as the form of the preparation to be administered. Moreover, in ophthalmic preparations, eye drops are often selected because of the ease of administration. Therefore, it is desirable to develop the above (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine as an eye drop for treating glaucoma.

  The preparation is required to be stable in order to withstand environmental changes such as the distribution process and use / storage state of the patient who is the user and the passage of time. Since eye drops are liquid preparations, in general, in addition to active ingredients that exert pharmacological action, isotonic agents, chelating agents, stabilizers, pH adjusters, Preservatives, antioxidants, solubilizers, thickeners, etc. are blended as necessary, but depending on the drug concentration and physicochemical properties, the properties of the resulting solution, storage conditions such as refrigeration, etc. Crystallization often exists as a problem to overcome.

As a means for suppressing crystallization over time, a method (Patent Document 2) is generally known in which a sugar alcohol, a saccharide, and a polyhydric alcohol are blended in a composition formulation. However, the nature and state of the precipitated crystals differ depending on the type of active ingredient, and such a method is not widely used.
JP 11-349482 A JP-A-8-231403 IOVS, 42 (1), 137-144 (2001)

  The present invention contains (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof as an active ingredient. An object of the present invention is to provide an ophthalmic composition that is useful for the prevention and treatment of glaucoma and is pharmaceutically stable.

As a result of intensive studies in view of such circumstances, the present inventors have found (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof. Alternatively, a patent application was filed based on the finding that phosphoric acid or a salt thereof was added to these solvates to enhance the effect of lowering intraocular pressure (US Patent Application No. 60 / 638,118). Further, as a result of further study on the ophthalmic preparation, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1 was obtained by adding glycerin to such a component. It has been found that a stable ophthalmic composition can be obtained in which crystals of 1,4-homopiperazine or a salt thereof are hardly precipitated.

  That is, the present invention relates to (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, or a solvate thereof, phosphoric acid or a salt thereof. The present invention relates to an ophthalmic composition containing a salt and glycerin.

  The present invention also relates to (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and phosphoric acid or a salt thereof. (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homo, characterized by blending glycerin with an ophthalmic composition containing a salt The present invention relates to a method for suppressing crystal precipitation of piperazine or a salt thereof or a solvate thereof.

  The present invention also relates to (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, or a solvate thereof, which comprises glycerin. This relates to a crystal precipitation inhibitor.

  According to the present invention, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a salt thereof that does not cause crystal precipitation over time An ophthalmic composition containing a solvate of the above can be provided. Since the composition has an excellent intraocular pressure lowering effect, it is useful as an ophthalmic preparation for preventing or treating glaucoma. Further, according to the present invention, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a salt thereof in the ophthalmic composition It is possible to provide a crystal precipitation inhibitor effective in suppressing crystal precipitation of the solvate.

The ophthalmic composition of the present invention comprises (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof, It contains phosphoric acid or a salt thereof and glycerin.
(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine has substance P antagonistic action and leukotriene D4 antagonistic action in addition to Rho kinase inhibitory action. is a known compound having (Patent Document 1), a known method, for example, can be prepared by methods described in the pamphlet International Patent Publication No. 99/20620.

  Examples of the salt of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and hydrofluoric acid. , Salts of inorganic acids such as hydrobromic acid or acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, Examples thereof include salts of organic acids such as camphorsulfonic acid, and hydrochloride is particularly preferable.

In addition, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof is not only an unsolvated type but also a hydrate or It can also exist as a solvate, and in the present invention includes all crystal forms and hydrates or solvates.

  The amount of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof is the total amount of the ophthalmic composition. 0.05-5 weight% is preferable with respect to a weight, More preferably, it is 0.1-3 weight%, Especially preferably, it is 0.1-2 weight%.

  (S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof has an excellent intraocular pressure lowering effect. However, it is useful as a preventive or therapeutic agent for glaucoma, but when it is used in combination with phosphoric acid or a salt thereof, it exerts a stronger action for reducing intraocular pressure (see Reference Example, US Patent Application No. 60 / 638,118). reference).

  Examples of phosphoric acid or a salt thereof include disodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, dipotassium hydrogen phosphate and the like. Sodium dihydrogen phosphate and anhydrous sodium dihydrogen phosphate are preferred. Examples of commercially available products include monosodium phosphate (manufactured by Wako Pure Chemical Industries, Ltd.), disodium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.), and anhydrous sodium dihydrogen phosphate (manufactured by Taihei Chemical Industrial Co., Ltd.). And potassium dihydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.), potassium hydrogen phosphate (manufactured by Wako Pure Chemical Industries, Ltd.) and the like.

  The amount of phosphoric acid or a salt thereof is preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, particularly preferably 0.1 to 1%, based on the total weight of the eye drop composition. % By weight.

The above (S)-(-)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof and phosphoric acid or a salt thereof are used for eye drops. In the case of a preparation, (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof over time Precipitation was observed, but when glycerin was added thereto, the crystal precipitation was effectively suppressed (see Examples below). In this case, xylitol or D-sorbitol, which is a sugar alcohol that has been conventionally blended for the purpose of suppressing crystal precipitation, and glucose or fructose, which are sugars, can be effectively suppressed compared to before mixing. Moreover, even in the case of blending propylene glycol or polyethylene glycol among the polyhydric alcohols, the crystal precipitation was not suppressed in the same manner (see Comparative Examples described later). Accordingly, glycerin is (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvent thereof in the ophthalmic composition. It is useful as a crystallization inhibitor for Japanese products.
As the glycerin, one having a purity that can be used as an eye drop may be used. For example, commercially available glycerin (manufactured by Sakamoto Pharmaceutical Co., Ltd.) can be used. Moreover, it can replace with glycerin and can also use it so that concentrated glycerin may become the same density | concentration, for example, commercially available concentrated glycerin (The Sakamoto Pharmaceutical Co., Ltd. make, etc.) can be used.

  The amount of glycerin is determined by crystal precipitation of (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof. From the viewpoint of suppression, the content is preferably 0.5 to 5% by weight, more preferably 0.5 to 3% by weight, and particularly preferably 1 to 3% by weight with respect to the total weight of the ophthalmic composition.

The pH and osmotic pressure of the ophthalmic composition of the present invention are not particularly limited, but the pH is preferably 5-9, more preferably 5.5-8, and particularly preferably 5.5-7. The osmotic pressure is preferably 200 to 700 mOsm, more preferably 200 to 600 mOsm, and the osmotic pressure ratio with respect to physiological saline is preferably 0.6 to 3, and more preferably 0.6 to 2. By setting the pH and osmotic pressure within these ranges, a preparation that does not irritate the eyes during application can be obtained.

  The ophthalmic composition of the present invention includes (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof, or a solvate thereof. In addition to phosphoric acid or its salts and glycerin, inorganic salts, isotonic agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, thickeners, other medicinal properties as necessary Components and the like can be blended.

  Examples of the inorganic salts include sodium chloride, potassium chloride, calcium chloride and the like, and the blending amount is preferably 0 to 1% by weight with respect to the total amount of the composition.

  Examples of tonicity agents include sugars such as trehalose, lactose, fructose, mannitol, xylitol, sorbitol, polyhydric alcohols such as polyethylene glycol and propylene glycol, inorganic salts such as sodium chloride and potassium chloride, and the like. The amount is preferably 0 to 3% by weight based on the total amount of the composition.

  Examples of the chelating agent include nitrilotriacetic acid or a salt thereof, sodium hexametaphosphate, citric acid, and the like, and the blending amount is preferably 0 to 0.2% by weight with respect to the total amount of the composition.

  Examples of the stabilizer include sodium bisulfite, titanium oxide and the like, and the blending amount is preferably 0 to 1% by weight with respect to the total amount of the composition.

  Examples of the pH regulator include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, bases such as alkali metal carbonates or hydrogen carbonates such as sodium carbonate, and the blending amount thereof is the total amount of the composition. The content is preferably 0 to 1% by weight.

  Examples of the preservatives include parahydroxybenzoic acid esters such as sorbic acid, potassium sorbate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, and chlorhexidine gluconate. Quaternary ammonium salts, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine and the like can be mentioned, and the blending amount thereof is preferably 0 to 0.2% by weight based on the total amount of the composition.

  Examples of the antioxidant include sodium hydrogen sulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like, and the blending amount is preferably 0 to 0.4% by weight with respect to the total amount of the composition.

  Examples of the thickening agent include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, etc. 0 to 70% by weight is desirable based on the total amount of the product.

As other medicinal ingredients, for example, receptor non-selective sympathomimetic drugs, sympathomimetic drugs such as α2 receptor selective sympathomimetic drugs, non-selective β receptor blockers, β1 receptor blockers, Sympathomimetic drugs such as αβ receptor blockers and α1 receptor blockers, parasympathomimetic drugs, prostaglandin drugs, carbonic anhydrase inhibitors, hypertonic osmotic drugs, muscarinic agonists, cholinesterase inhibitors, glutamate antagonists Examples include drugs.

  The form of the eye drop composition of the present invention may be any of aqueous eye drops, suspension eye drops, emulsion eye drops, and the like. For example, the desired components are prepared by sterilized purified water, physiological saline. It is performed by dissolving or suspending in an aqueous solvent such as water or a non-aqueous solvent such as cottonseed oil, soybean oil, sesame oil, peanut oil, etc., adjusting to a predetermined osmotic pressure, and performing sterilization such as filter sterilization. be able to.

The ophthalmic composition of the present invention thus obtained has an excellent intraocular pressure lowering action and does not cause crystal precipitation over time. Therefore, it is useful as an eye drop for preventing or treating glaucoma and an eye drop for preventing or treating ocular hypertension. Here, as glaucoma, for example, primary open angle glaucoma, normal pressure glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed angle glaucoma, chronic closed angle glaucoma, plateau iris syndrome, mixed glaucoma, Examples include steroid glaucoma, capsular glaucoma, pigment glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.
Hereinafter, the present invention will be described in more detail, but the present invention is not limited thereto.

Example 1
(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine hydrochloride 1.1 g, anhydrous sodium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.) 50 g of purified water added to 0.4 g and 1.96 g of glycerin (manufactured by Sakamoto Yakuhin Kogyo Co., Ltd.), stirred and dissolved completely, and sodium hydroxide dissolved in purified water was added to adjust the pH to 6.0. Further, purified water was added to make up a total volume of 100 mL to prepare eye drops. The osmotic pressure was 300 mOsm / Kg.

Example 2
The pH was adjusted to 6.5 and adjusted in the same manner as in Example 1. The osmotic pressure was 305 Osm / Kg.

Comparative Example 1
1.96 g of glycerin was prepared in the same manner as in Example 1 as 0.65 g of sodium chloride (sodium chloride: manufactured by Tomita Pharmaceutical Co., Ltd.). The osmotic pressure was 310 mOsm / Kg.

Comparative Example 2
1.96 g of glycerin was prepared in the same manner as in Example 1 with 1.81 g of glucose (eclipse medicalose: manufactured by Nippon Shokuhin Kako Co., Ltd.). The osmotic pressure was 299 mOsm / Kg.

Comparative Example 3
1.96 g of glycerol was prepared as 1.81 g of fructose (fructose: manufactured by Wako Pure Chemical Industries, Ltd.) and prepared in the same manner as in Example 1. The osmotic pressure was 311 mOsm / Kg.

Comparative Example 4
1.96 g of glycerin was prepared in the same manner as in Example 1 as 1.53 g of xylitol (Xylit: manufactured by Towa Kasei Kogyo Co., Ltd.). The osmotic pressure was 299 mOsm / Kg.

Comparative Example 5
1.96 g of glycerin is D-sorbitol (D-sorbitol: manufactured by Nikken Kasei Co., Ltd.) 1
. 81 g was prepared in the same manner as in Example 1. The osmotic pressure was 315 mOsm / Kg.

Comparative Example 6
1.96 g of glycerin was prepared in the same manner as in Example 1 with 0.76 g of propylene glycol (propylene glycol: manufactured by Showa Denko KK). The osmotic pressure was 317 mOsm / Kg.

Comparative Example 7
1.96 g of glycerin was prepared in the same manner as in Example 1 as 3.24 g of polyethylene glycol (Macrogol 400: manufactured by NOF Corporation). The osmotic pressure was 327 mOsm / Kg.

Test example 1
The eye drops obtained in Examples 1 and 2 and Comparative Examples 1 to 7 were stored in a −5 ° C. cool box, and the visual evaluation of the appearance immediately after production, 14, 21, and 28 days later was examined.
Visual evaluation of appearance: ○ No crystal precipitation was observed.
X Precipitation of crystals was observed.
The results are shown in Table 1.

Instead of glycerin, sodium chloride (Comparative Example 1), glucose (Comparative Example 2), fructose (Comparative Example 3), xylitol (Comparative Example 4), D-sorbitol (Comparative Example 5), propylene glycol (Comparative Example 6), In the preparation containing the preparation containing polyethylene glycol (Comparative Example 7), crystals were deposited in a period not reaching 4 weeks.
On the other hand, the formulations containing glycerin (Examples 1 and 2) were excellent in storage stability without crystal precipitation even when stored under low temperature conditions for 28 days.
Furthermore, with regard to Example 1, no crystal precipitation occurred even after 6 months of storage.

Reference Example Eye Drop Reduction Action Eye drops shown in Reference Examples 1 and 2 and Comparative Example 8 below were prepared, and intraocular pressure was measured by the method described below.

Reference example 1
(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine hydrochloride 1.1 g, anhydrous sodium dihydrogen phosphate (Taihei Chemical Industry Co., Ltd.) 50 g of purified water was added to 0.8 g and 0.5 g of potassium chloride and stirred until completely dissolved. Sodium hydroxide dissolved in purified water was added to adjust the pH to 6.7, and further purified water was added. The total amount was 100 g to prepare eye drops. The osmotic pressure was 348 mOsm / Kg.

Reference example 2
An eye drop was prepared in the same manner as in Reference Example 1 with 0.6 g of anhydrous sodium dihydrogen phosphate. The osmotic pressure was 332 mOsm / Kg.

Comparative Example 8
(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine hydrochloride (1.1 g) and potassium chloride (1 g) were added with 50 g of purified water and stirred. Sodium hydroxide dissolved in purified water was added to adjust the pH to 6.7, and purified water was added to make the total amount 100 g to prepare an eye drop. The osmotic pressure was 344 mOsm / Kg.

Test Example A male Japanese white rabbit (2.0-2.5 Kg) with normal intraocular pressure was fixed to a rabbit fixator without anesthesia, and local ocular anesthesia with one drop of Benokiseal (Santen Pharmaceutical) was performed on both eyes. . Thereafter, the intraocular pressure of both eyes was measured with an air pressure applanation tonometer (Alcon Applanation Pneumatonograph ^™ , Nippon Alcon) and set to a value of 0 hour. Immediately after the 0-hour measurement, 50 μl of the eye drops of Reference Examples 1 and 2 and Comparative Example 8 were administered to the left eye of the rabbit, and the eyes of both eyes were 1 hour, 2 hours, 3 hours and 4 hours after the instillation. The pressure was measured (n = 4-6). The results are shown in Table 2.

  From Table 2, a preparation containing (S)-(−)-1- (4-fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof and phosphoric acid or a salt thereof (Reference Example) It can be seen that 1-2) has an excellent intraocular pressure-reducing effect even from normal intraocular pressure, as compared with a preparation not containing phosphoric acid (Comparative Example 8).

Claims (2)

(S)-(−)-1- (4-Fluoro-5-isoquinolinesulfonyl) -2-methyl-1,4-homopiperazine or a salt thereof or a solvate thereof, phosphoric acid or a salt thereof, and glycerin 0 An aqueous ophthalmic composition for preventing or treating glaucoma or for preventing or treating ocular hypertension, containing 5 to 5% by weight. The composition according to claim 1, wherein the pH is 5-9.