JP2013129605A - Stable film preparation containing glaucoma treating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a film preparation continuing the efficacy of (S)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine or its salt, and excellent in preservation stability.SOLUTION: This film agent includes (S)-(-)-1-(4-fluoroisoquinolin-5-yl)sulfonyl-2-methyl-1,4-homopiperazine or its salt, a water soluble film-forming agent and an antioxidant.

Description

  The present invention relates to a film preparation containing (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof. S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof is related to a film preparation which has excellent medicinal effects and has excellent storage stability. .

  (S)-(−)-1- (4-Fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof is substance P antagonistic activity, leukotriene D4 antagonistic activity and Rho kinase inhibition. It is known that the eye has an excellent intraocular pressure lowering effect in the eye and is effective as a preventive or therapeutic agent for glaucoma and ocular hypertension (Patent Document 1).

Currently, liquid eye drops are the most widely used dosage forms for ophthalmic pharmaceutical preparations. In general, liquid eye drops are administered by dropping a suitable amount of eye drops onto the eyeball. The dropped ophthalmic solution is first stored in the conjunctival sac, then penetrates into the conjunctival epithelium or corneal epithelium and moves into the eye. The drug absorbed by the conjunctival epithelium further diffuses through the sclera and reaches the eye. The drug absorbed by the corneal epithelium first passes through the corneal stroma, reaches the anterior chamber, and further reaches the iris and the lens. Further, a part of the ciliary body reaches the ciliary body and further to the optic nerve head behind by the flow of aqueous humor flowing from the iris root to the ciliary stroma and further to the choroid behind (Non-patent Document 1).
Usually, the rate of transfer of eye drops into the cornea is less than a few percent of the total dose of the drug. In addition, since the corneal epithelium has a high affinity with a fat-soluble drug, the water-soluble drug has a reduced corneal permeability as compared with the fat-soluble drug. Therefore, an eye drop containing a water-soluble drug as an active ingredient has a low drug utilization rate. After instillation, most drugs that are not used are mixed with tears and lost outside the body, or from the punctum through the nasolacrimal duct to the nasal mucosa or pharyngeal mucosa where they are absorbed and enter the systemic circulation. It has been known.

Thus, liquid eye drops, particularly water-soluble drugs such as (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or salts thereof In the case of liquid eye drops, most of the drugs are not used in the eye.
To overcome this problem, it may be possible to increase the drug concentration in liquid eye drops and enhance the intraocular transfer of the drug, but the high concentration of the drug is absorbed by the mucous membrane of the nose and throat through the nasolacrimal duct. However, when entering the systemic circulation, there is a risk that side effects may appear strongly.
In order to efficiently exert the efficacy of the drug in the eye, it is necessary to expose the drug to the target site at the target concentration for the target time. However, it is difficult to control this with normal liquid eye drops. In addition, liquid eye drops also have problems such as excessive eye drops, failure, and drug outflow due to blinking.

Therefore, in order to overcome the problems of these liquid eye drops, it has been proposed to make the eye drops into a gel, film or implant preparation.
For example, a water-soluble rebamipide-containing suspension hydrogel in which high molecular weight hydroxypropylmethylcellulose or methylcellulose is added to eye drops to prevent the drug from flowing out of the eye or to prolong the efficacy (Patent Document 2) , Paclitaxel, a water-soluble film-forming polymer and a fatty acid glyceride or fatty acid ester having a molecular weight of 150 to 4000, and a film composition suitable for drug delivery to the eye (Patent Document 3). In order to maintain the drug concentration in the drug for a required period of time, an anti-inflammatory agent or a cytostatic agent is uniformly dispersed in the polylactic acid and molded into a short rod-like sustained release intraocular implant (Patent Document) 4) Carboxyvinyl polymer is blended as a gelling agent in normal eye drops and dexamethasone dihydrogen dihydrogen phosphate Ophthalmic preparation with improved durability of Lium (Patent Document 5), levofloxacin-containing thermogelled antibacterial aqueous pharmaceutical composition prepared by blending methylcellulose and polyethylene glycol into eye drops and gelling in the body after instillation (Patent Document 6) and the like have been reported.

International Publication No. 2006/068208 Special table 2009-536940 JP-A-2005-533106 Japanese Patent Laid-Open No. 5-17370 JP-T-2001-518510 International Publication No. 2002/011734

CLINICAN'96 No. 453 80-81

The film preparation is easy to administer, can reliably administer the drug to the affected area, and has a low risk of transferring the drug to another site, so it is preferable from the viewpoint of improving the drug utilization rate and reducing side effects It is. As a result of investigation by the present inventors, a film preparation based on a water-soluble film forming agent was used as (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4. -When homopiperazine or a salt thereof is contained, (S)-(-)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or more than normal ophthalmic solution It was found that the salt was released slowly.
However, during its storage, especially when stored under high temperature conditions, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or It was found that the content of the salt decreased and there was a problem in stability.
In view of such circumstances, the present invention maintains the medicinal effects of (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof. In addition, an object of the present invention is to provide a film preparation excellent in storage stability.

  As a result of intensive studies on the above problems, the present inventor has found that (S)-(−)-1- (4-fluoroisoquinolin-5-yl) over time can be obtained by adding an antioxidant to the film preparation. (S)-(−)-1- (4-Fluoroisoquinolin-5-yl) sulfonyl-2, which is suppressed in content decrease of sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof and has excellent stability. -It discovered that it could be set as a methyl- 1, 4- homo piperazine or its salt containing formulation, and completed this invention.

That is, the present invention relates to (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof, a water-soluble film forming agent and an antioxidant. A film preparation characterized by containing an agent is provided.
The present invention also provides (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof, a water-soluble film forming agent, an antioxidant. A film preparation characterized by containing an agent and a carboxyvinyl polymer is provided.

  According to the present invention, (S)-(-)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof is sustained and stable in storage. A film preparation having excellent properties can be provided. When the film preparation of the present invention is applied to the eye, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) is continuously produced in the affected area rather than using normal liquid eye drops. The pharmacological action of sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof is exhibited, and long-term usefulness can be expected for the prevention or treatment of glaucoma and ocular hypertension.

It is a figure which shows the storage stability of a film formulation.

  (S)-(−)-1- (4-Fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof used in the present invention has substance P antagonistic activity and leukotriene D4 antagonistic activity. And a known compound having a Rho kinase inhibitory action (Japanese Patent Laid-Open No. 11-349482), and by a known method, for example, the method described in WO99 / 20620 pamphlet or WO2006 / 57397 pamphlet. Can be manufactured.

  Examples of the salt of (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine include hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, odor Salts of inorganic acids such as hydrofluoric 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, camphor Examples thereof include pharmaceutically acceptable salts such as salts of organic acids such as sulfonic acid, and hydrochloride is particularly preferable.

In addition, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof blended in the film preparation of the present invention is an unsolvent. Not only the Japanese type but also solvates thereof can be used. Examples of solvates include hydrates, alcohol solvates (for example, ethanol solvates) and the like. In the present invention, all these crystal forms are further included.
In producing the film preparation of the present invention, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate Is preferably used.

  The content of (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof in the film preparation of the present invention is not particularly limited. However, 1-20 mass% is preferable with respect to the formulation whole quantity, 3-18 mass% is more preferable, and 5-15 mass% is further more preferable.

The water-soluble film-forming agent used in the present invention has a property of forming a hydrogel by being dissolved or viscous when contacted with water, or having a property of forming a film in a dry state. Is a molecule.
Examples of the water-soluble film forming agent include alginic acid such as sodium alginate or a salt thereof, pectin, carrageenan, xanthan gum, starch, tragacanth gum, xanthan gum, collagen, gelatin, galactomannan, glycoprotein, proteoglycan, glucosaminoglycan, polyvinyl Alcohol or a water-soluble cellulose derivative is exemplified.
Examples of the water-soluble cellulose derivative include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, or salts thereof.
As the water-soluble film forming agent used in the present invention, a water-soluble cellulose derivative is preferable from the viewpoint that a transparent and uniform film can be formed, and hydroxypropyl cellulose is more preferable.
These water-soluble film forming agents can be used alone or in combination of two or more.

Hydroxypropyl cellulose may be produced by a known method, or a commercially available product may be used. Examples of commercially available products include HPC-SSL, HPC-SL, HPC-L, HPC-M, HPC-H, and HPC-SFP (above, manufactured by Nippon Soda).
The degree of substitution in hydroxypropylcellulose is not particularly limited, and those having a desired degree of substitution can be obtained, but those containing 53 to 78% of hydroxypropoxy groups are preferred. Further, the viscosity of hydroxypropylcellulose is not particularly limited, but for example, it is preferable that the kinematic viscosity (15th revised Japanese Pharmacopoeia) of a 2% aqueous solution at 20 ° C. is 1000 to 4000 mPa · s.

  Although content in particular of the water-soluble film forming agent in the film formulation of this invention does not have a restriction | limiting, 75-98.5 mass% is preferable with respect to the formulation whole quantity, 80-97.5 mass% is more preferable, 85-85 More preferred is 95% by mass.

Examples of the antioxidant used in the present invention include edetic acid, sodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, calcium disodium edetate, ascorbic acid or a derivative thereof, Organic acids such as citric acid; carotenoids such as β-carotene, lycopene, rutin, astaxanthin; α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, d-α-tocopherol acetate, dl-α-tocopherol acetate, succinic acid Tocopherols such as acid d-α-tocopherol and dl-α-tocopherol succinate; herbal extracts such as rosemary extract; or polyphenols such as catechin, saponin, flavonoid, and anthocyanin. These can be used alone or in combination of two or more.
Among these, edetic acids and citric acid are preferred in terms of stabilization of (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof. Organic acids such as, or tocopherols are preferred, sodium edetate, citric acid, d-α-tocopherol acetate, or dl-α-tocopherol acetate, more preferred, citric acid, d-α-tocopherol acetate, or dl-acetate More preferred is α-tocopherol. Citric acid may be any of a salt, an anhydride, and a hydrate, but an anhydride is preferred.

  Although the content of the antioxidant in the film preparation of the present invention varies depending on the type, it is usually preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight, based on the total amount of the preparation. More preferably, the content is 5 to 5% by mass.

The film preparation of the present invention is characterized in that (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof is improved in sustainability. From the above, it is preferable to further contain a carboxyvinyl polymer.
The carboxyvinyl polymer used in the present invention is a polymer mainly composed of acrylic acid.
Although there is no restriction | limiting in particular in the viscosity of a carboxy vinyl polymer, From the point of the persistent improvement of a medicinal effect, the thing whose kinematic viscosity of 0.2% aqueous solution in 20 degreeC is 4000-7500 mPa * s is preferable, for example.
The carboxyvinyl polymer may be produced by a known method, or a commercially available product may be used. Examples of commercially available products include Carbopol 980, Carbopol 981 (above, BF Goodrich), ETD2050, Ultretz 10 (above, NOVEON), Hibiswaco, Shintalen K, Shintalen L, or Shintalen M (above, Wako Pure Chemical Industries). ) And the like.

  In the film preparation of the present invention, the content of the carboxyvinyl polymer in the film preparation is not particularly limited, but is preferably 1 to 3% by weight, and preferably 1 to 2.7% by weight with respect to the total amount of the preparation from the viewpoint of improving the sustainability of the drug effect. % Is more preferable, and 1.3 to 2.3% by mass is more preferable.

  When the carboxyvinyl polymer is contained, the content ratio of the water-soluble film-forming agent to the carboxyvinyl polymer in the film preparation (water-soluble film-forming agent / carboxyvinyl polymer) is 28 to 98 from the viewpoint of improving the sustainability of the drug effect. Preferably, 33 to 98 are more preferable, and 40 to 75 are more preferable.

The film preparation of the present invention is (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4 as necessary, as long as the effects of the present invention are not impaired. -One or more active ingredients other than homopiperazine or a salt thereof can be blended.
Other active ingredients, e.g., sympathomimetics (nonselective stimulants such as epinephrine, alpha ₂ agonists such as apraclonidine), sympathetic nerve blockers (timolol, befunolol, carteolol, nipradilol, Betakisoru, levobunolol , beta-blockers, such as metipranolol, alpha ₁ blockers such as bunazosin hydrochloride), parasympathetic agonists (physostigmine, neostigmine, echothiophate, demecarium, carbachol, pilocarpine, etc.), carbonic anhydrase inhibitors (acetazolamide, brinzolamide , Dorzolamide, metazolamide, etc.), or prostaglandins (isopropyl unoprostone, latanoprost, travoprost, bimatoprost, etc.).

In addition, the film preparation of the present invention is blended with optional components such as a pH adjuster, a stabilizer, a preservative, a surfactant, or a refreshing agent as necessary, as long as the effects of the present invention are not impaired. Can do.
Examples of the pH adjuster include hydrochloric acid, boric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, Or potassium dihydrogen phosphate etc. are mentioned.

  Examples of the stabilizer include sodium bisulfite, benzoic acid, sodium benzoate, and the like.

  Examples of the preservative include cetylpyridinium chloride, benzalkonium chloride, benzethonium chloride, boric acid, or borax.

  Examples of the surfactant include polysorbate 80, polyoxyethylene hydrogenated castor oil, or polyethylene glycol monostearate.

  Examples of the refreshing agent include menthol, camphor, borneol, or cinnamon oil.

There is no restriction | limiting in particular in the manufacturing method of the film formulation of this invention, It can manufacture according to a well-known and usual manufacturing method. Specifically, the following production methods <Production method 1> to <Production method 4> can be mentioned, but are not limited thereto.
<Production method 1>
(S)-(−)-1- (4-Fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof, a water-soluble film forming agent, an antioxidant, and further if necessary Then, arbitrary components are uniformly mixed in an appropriate solvent to prepare a mixed solution for film preparation. This is spread with a coating machine, dried, and then cut into a desired shape and size to form a film preparation.

<Production method 2>
A silicon coat with holes formed on a flat plate such as glass is placed, and a mixed solution for film preparation prepared by the same procedure as in Production Method 1 is dropped into the holes and dried to obtain a film preparation.

<Manufacturing method 3>
A film preparation mixed solution prepared by the same procedure as in production method 1 is dropped onto a silicon coat frame placed on a flat plate such as glass, dried, and then cut out with a perforated punch of the desired size to obtain a film preparation. .

<Method 4>
An appropriate amount of the mixed solution for film preparation prepared by the same procedure as in Production Method 1 is weighed, dropped onto a flat plate such as glass and dried to obtain a film preparation.

  The solvent of the film preparation mixed solution in <Production Method 1> to <Production Method 4> is not particularly limited as long as it dissolves or uniformly disperses the components of the film preparation, and examples thereof include water, methyl alcohol, and ethyl alcohol. It is preferable to use 1 type, or 2 or more types selected from the group consisting of propyl alcohol, and isopropyl alcohol.

  In addition, in a mixed solution for film preparation, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof, a water-soluble film forming agent The total concentration of the antioxidant and the antioxidant is not particularly limited, but is preferably 0.1 to 10% by mass, more preferably 0.3 to 8% by mass with respect to the total amount of the mixed solution for film preparation, and 5-6 mass% is further more preferable.

  Moreover, you may add the pH adjuster similar to the above to this mixed solution for film preparations. The pH (25 ° C.) of the mixed solution for film preparation is preferably 4.5 to 9.5, more preferably 5 to 9, and still more preferably 5.5 to 8.5.

The film preparation of the present invention is used as a pharmaceutical preparation. Although the application site | part of a film formulation is not specifically limited, It is preferable to apply to eyes from the point which the effect of this invention is exhibited effectively.
When the film preparation of the present invention is used as an ophthalmic film preparation, it is useful as a preventive or therapeutic agent for glaucoma and 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, or malignant glaucoma. Ocular hypertension, also called ocular hypertension, refers to symptoms that show abnormally high intraocular pressure despite the absence of clear lesions in the optic nerve. High ocular pressure conditions are included.

The thickness of the film preparation of the present invention and the area and shape of one sheet are not particularly limited, but when used as an ophthalmic film preparation, a film having a thickness of 0.01 mm to 0.5 mm is finally obtained. it is preferred to preferred to the area of one Atari to 20mm ² ~35mm ^2. As the shape, for example, a square, a rectangle, a rhombus, an ellipse, a circle, a semicircle, or a crescent shape can be adopted.

  The residual rate of (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof in the film preparation of the present invention is, for example, 60 ° C. When stored under conditions for 4 weeks, it is at least 95% or more, preferably 97% or more.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

Example 1
(S)-(−)-1- (4-Fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate 0.45 g in 90 g of methanol, hydroxypropylcellulose (HPC-H, manufactured by Nippon Soda Co., Ltd.) 4.0 g, carboxyvinyl polymer (Carbopol 981, BF Goodrich) 0.075 g, and sodium edetate 0.1 g were mixed and stirred until uniform. Next, while stirring this mixed solution, an appropriate amount of sodium hydroxide was added to adjust the pH to 8.0, and methanol was further added to bring the total amount to 100 g to obtain a mixed solution for film preparation.
The obtained mixed solution for film preparation was dropped by 75 μL onto a slide glass using a micropipette, dried at 40 ° C. for 2 hours, and then the film preparation of the present invention (average drug content: 0.236 mg / sheet, n = 10) was obtained.

Example 2
A film preparation of the present invention (average drug content: 0.236 mg / sheet, n = 10) was obtained by the same procedure as in Example 1 except that sodium edetate was replaced with 0.1 g of citric anhydride.

Example 3
A film preparation of the present invention (average drug content: 0.236 mg / sheet, n = 10) was obtained by the same procedure as in Example 1 except that sodium edetate was replaced with 0.1 g of dl-α-tocopherol acetate. .

Comparative Example 1
(S)-(−)-1- (4-Fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate 0.45 g in 90 g of methanol, hydroxypropylcellulose 4.0 g of HPC-H (manufactured by Nippon Soda Co., Ltd.) and 0.075 g of carboxyvinyl polymer (Carbopol 981, BF Goodrich) were mixed and stirred until uniform. Next, while stirring this mixed solution, an appropriate amount of sodium hydroxide was added to adjust the pH to 8.0, and methanol was further added to bring the total amount to 100 g to obtain a mixed solution for film preparation.
The obtained mixed solution for film preparation is dropped by 75 μL onto a slide glass using a micropipette, dried at 40 ° C. for 2 hours, and then a film preparation (average drug content: 0.236 mg / sheet, n = 10) is obtained. Obtained.

Comparative Example 2
(S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate 0.45 g in 90 g of methanol and hydroxypropyl 4.0 g of cellulose (HPC-H, Nippon Soda Co., Ltd.) was mixed and stirred until uniform. Next, while stirring this mixed solution, an appropriate amount of sodium hydroxide was added to adjust the pH to 8.0, and methanol was further added to bring the total amount to 100 g to obtain a mixed solution for film preparation.
The obtained mixed solution for film preparation is dropped by 75 μL onto a slide glass using a micropipette, dried at 40 ° C. for 2 hours, and then a film preparation (average drug content: 0.236 mg / sheet, n = 10) is obtained. Obtained.

Comparative Example 3
(S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate 0.45 g in 90 g of methanol and hydroxypropyl 4.0 g of cellulose (HPC-H, Nippon Soda Co., Ltd.) was mixed and stirred until uniform. Next, while stirring this mixed solution, methanol was further added to make the total amount 100 g, to obtain a mixed solution for film preparation.
The obtained mixed solution for film preparation is dropped by 75 μL onto a slide glass using a micropipette, dried at 40 ° C. for 2 hours, and then a film preparation (average drug content: 0.236 mg / sheet, n = 10) is obtained. Obtained.

Test example 1 (thermal stability test)
For each of the film preparations obtained in Examples 1 to 3 and Comparative Examples 1 to 3, a content stability test under storage conditions at 60 ° C. was performed.
After storing the film preparation at 60 ° C. for 1 to 4 weeks, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride · 2 The residual rate of hydrate was determined. The residual rate of (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine hydrochloride dihydrate was measured by HPLC.

  As shown in FIG. 1, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2 is obtained even when stored at 60 ° C. for 4 weeks when an antioxidant is added to the film base. It was found that the decrease in the content of methyl-1,4-homopiperazine or a salt thereof over time can be suppressed. On the other hand, in the case of the film preparation of Comparative Example 1 containing no antioxidant, the residual rate after storage at 60 ° C. for 4 weeks was 92.5%. Moreover, from Comparative Examples 2 and 3, it was suggested that when the pH of the mixed solution for film preparations was adjusted, the residual rate was likely to decrease. However, from the viewpoint of sustained release of the active ingredient contained in the film preparation, it is preferable to use one with pH adjusted. According to the present invention, it can be seen that the storage stability is good regardless of the pH in the preparation.

Claims (7)

  (S)-(-)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof, a water-soluble film forming agent and an antioxidant. Characteristic film preparation.   The film preparation according to claim 1, wherein the water-soluble film forming agent is a water-soluble cellulose derivative.   The film preparation according to claim 2, wherein the water-soluble cellulose derivative is one or more selected from methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts thereof.   The film preparation according to any one of claims 1 to 3, wherein the antioxidant is one or more selected from sodium edetate, citric acid, d-α-tocopherol acetate and dl-α-tocopherol acetate.   Furthermore, the film formulation of any one of Claims 1-4 containing a carboxy vinyl polymer.   The film preparation according to any one of claims 1 to 4, which is an ophthalmic film preparation.   (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof, and a film preparation containing a water-soluble film forming agent, (S)-(−)-1- (4-fluoroisoquinolin-5-yl) sulfonyl-2-methyl-1,4-homopiperazine or a salt thereof in the film preparation, characterized by containing an oxidizing agent Stabilization method.

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