JP2001131064A - Tranilast plaster composition and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a tranilast plaster composition excellent in skin permeability of tranilast. SOLUTION: This tranilast plaster composition comprises either one or a mixture of tranilast and its salt as an active ingredient. The active ingredient containing a solubilizing agent and water is included in a plaster base in an uniformly dissolved state.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a plaster composition containing tranilast as an active ingredient. More specifically, by improving the base, it is possible to obtain a stable plaster composition in a state in which a high concentration of tranilast is dissolved, the skin absorbability of the active ingredient in the preparation is excellent, and skin irritation, The present invention relates to a plaster composition having low eye irritation.

Here, the plaster is a concept including an ointment and a plaster.

[0003] In a broad sense, the skin is a “single or multi-layered tissue covering the body surface of metazoan animals” (Daishinbayashi second edition, Sanseido 1995-11-3), which constitutes the retina, cornea and other eyes. Although the concept also includes cells that perform the treatment, aspects, effects, and the like relating to the eye are separately described in this specification.

When the plaster composition of the present invention is a plaster for skin, allergic dermatitis (atopic dermatitis, contact dermatitis, etc.), keloid / hypertrophic scar, eczema / dermatitis group (progressive dermatitis) Palmar keratoderma, lichen bidard, sun dermatitis, perilip dermatitis), prurigo group, (including urticaria-like lichen, strofilus, fixed urticaria), pruritus cutaneous, insect bite, psoriasis, It is effective for treating palmoplantar pustulosis.

[0005] In the case of eye ointments, it is used as a symptomatic treatment for allergic eye diseases, inflammatory diseases of the external and anterior eye parts, a therapeutic agent for ischemic retinal diseases such as proliferative diabetes accompanied by angiogenesis, and eye surgery. Applicable. Particularly in eye surgery, specifically, a corneal therapeutic agent for promoting corneal healing and preventing corneal opacity after optical keratotomy surgery using an ultraviolet light laser, particularly an excimer laser, a pterygium It is effective in preventing recurrence as a post-operative treatment, maintaining filtration bleb after glaucoma surgery, lowering intraocular pressure, and suppressing secondary cataract after intraocular lens insertion.

Here, an ointment composition will be mainly described as an example of an ointment composition, but the invention is not limited to this.

[0007]

BACKGROUND ART Tranilast is used as a therapeutic agent for allergic diseases and keloids / hypertrophic scars.
All are oral preparations such as capsules, tablets, dry syrups and fine granules. Also, eye drops have been developed as therapeutic agents for allergic eye diseases.

[0008] On the other hand, external preparations such as ointments are directly administered locally, and therefore are less likely to cause systemic side effects than, for example, oral preparations and injections. In addition, since the increase in drug concentration is limited to the application site, it is efficient during treatment. Tranilast has been shown to have a therapeutic effect on skin diseases such as atopic dermatitis, keloids and hypertrophic scars by oral administration, and development of an ointment for topical administration is desired.
The fields of application include pharmaceuticals, quasi-drugs, and cosmetics.

[0009] As a prior publication relating to tranilast ointment, there is, for example, JP-A-6-128153.

Further, in the tranilast plaster composition produced by this production method, only the active ingredient tranilast is not dissolved in the base, and only the tranilast crystals are kneaded into the base as it is. No (desirable for skin absorption performance).

That is, since tranilast is extremely poorly soluble in water, it has been considered difficult to manufacture a preparation containing a high concentration of tranilast. Tranilast is soluble in alkali but precipitates immediately. For this reason, even if it is dissolved in an alkali and kneaded with an ointment base, crystals are precipitated in the base. The skin is a barrier to foreign foreign substances. Desirably, the permeability of the skin is contained in the ointment base in a more dissolved form than the crystalline particles.

In addition, when the eye ointment contains tranilast, it is desirable that the ophthalmic ointment is contained in the ointment base in a form dissolved from the crystal particles. When the active ingredient in the eye ointment is instilled in the conjunctival sac, it gradually moves to the interface with the tear by blinking movement, dissolves in the tear, and is absorbed into the keratoconjunctiva. Therefore, when the active ingredient is contained in a dissolved form, it can be transferred more quickly.

However, as far as the present inventors know, a tranilast ointment preparation in which tranilast is uniformly dissolved in an ointment base has not been put on the market.

[0014]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have made intensive efforts to develop them, and by using a specific solubilizing agent, 10% or more, and even 20% or more.
% Or more, it was found that tranilast was present in the base in a form dissolved stably for a long period of time, and the inventors conceived of a tranilast plaster composition having the following constitution.

The tranilast plaster composition of the present invention contains tranilast and any of its salts or a mixture thereof as an active ingredient, and the active ingredient is contained in the plaster base in a uniformly dissolved state. It is characterized by the following.

That is, the tranilast plaster composition of the present invention contains tranilast and any one of its salts or a mixture thereof as an active ingredient, and the active ingredient containing a solubilizing agent and water is uniformly dissolved. It is characterized by being contained in a plaster base.

In the above structure, when the plaster substrate is used as a plaster substrate for skin, the solubilizing agent is one or more selected from the group consisting of alcohol amines and amino acids.

Further, as the alcohol amine, N-
It is desirable to use one or more selected from methylglucamine, diisopropanolamine, monoethanolamine, diethanolamine and triethanolamine.

Preferably, the amino acid is arginine.

On the other hand, in the above structure, when the ointment base is an ointment base, the solubilizing agent is one or more selected from the group of alcohol amines.

The alcohol amine is desirably one or more selected from monoethanolamine, diethanolamine and triethanolamine.

The preparation of the tranilast plaster composition of the present invention comprises dissolving tranilast and any of its salts or a mixture thereof in an aqueous solution containing a solubilizing agent, and then, if necessary, adding a surfactant. It is manufactured by kneading with a hydrophobic base or a hydrophilic base.

[0023]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The configuration of the present invention will be described in more detail. "%" Indicating the blending amount in the following description
Means "% by weight" unless otherwise specified.

The present inventors have conducted intensive studies to complete a long-term stable preparation in which tranilast is dissolved in an ointment base (an ointment base), and as a result, a tranilast ointment having extremely excellent skin permeability is obtained. The composition could be completed. Also,
An ointment with less eye irritation could be completed. A specific solubilizer is used to dissolve tranilast, which is essentially insoluble in water, at a high concentration. By using these, it can be manufactured regardless of a hydrophobic base or a hydrophilic base.

Tranilast used as an active ingredient of the plaster composition of the present invention can be used in a free form, in a salt form, or in a mixture thereof. The content can be appropriately selected depending on the disease to be applied, but generally a higher concentration is more desirable. In the present invention, it is possible in the range of 0.1 to 20% for the skin plaster, but preferably 1 to 15%. In addition, 0.1 to 5.0%, preferably 0.3 to 5.0% in eye ointment.
It can be used in the range of 3.0%.

[0026] Tranilast used as an active ingredient in the present invention is N- (3,4-dimethoxycinnamoyl) anthranilic acid represented by the following formula.

[0027]

Embedded image

As the solubilizing agent in the plaster composition of the present invention, one or two or more selected from the group consisting of alcoholamines and amino acids can be used in the plaster composition for skin.

As the alcoholamine, N-methylglucamine (meglumine, chemical name: 1-methylamino-1)
-Deoxy-D-glycitol), one or two selected from the group consisting of diisopropanolamine, monoethanolamine, diethanolamine and triethanolamine.
It is desirable to use more than one species.

It is desirable to use arginine as the amino acid.

As the solubilizing agent in the eye ointment, one or more selected from the group of alcoholamines can be used.

As the alcohol amine, it is desirable to use one or more selected from the group consisting of monoethanolamine, diethanolamine and triethanolamine.

Tranilast is dissolved in an aqueous solution of a dissolution aid. At this time, the ratio of the aqueous solution of the solubilizing agent to the whole plaster is such that in the case of the skin plaster, when the solubilizing agent is meglumine, the water content of the hydrophobic base or the hydrophilic base is 25% or more based on the total amount. Was needed. At 20% or less, tranilast crystals were precipitated. When the dissolution aid was diisopropanolamine, a water content of more than 20% was required for both the hydrophobic base and the hydrophilic base based on the total amount of the plaster. When the water content was 15% or less, crystals of tranilast precipitated.

On the other hand, in the ophthalmic ointment, the required amount of tranilast is smaller than that of the ointment for skin, so that the required water content is relatively small. For example, when the solubilizer is monoethanolamine, 10% of the total amount is used.
When the dissolution aid is diethanolamine or triethanolamine, the water content is required to be 5% or more based on the total amount.

The upper limit is freely set in the range of the plaster for both the hydrophobic base and the hydrophilic base, but it is more preferable to set the water content to 70% or less in view of the viscosity.

The optimum concentration of the solubilizing agent in the solubilizing agent solution depends on the final desired content of tranilast. That is, Tranilast has the property of lowering the pH when dissolved in an alkaline solution. For this reason, the final pH of the formulation should be around neutral (usually pH) from the viewpoint of eye irritation.
6.5 to 8.0), the respective amounts of the solubilizer and tranilast are uniquely determined.

In the case of a tranilast plaster composition having a content of 10% in a skin plaster, tranilast shows solubility and pH at the following meglumine / diisopropanolamine concentrations (based on the total amount). The present inventors have confirmed.

The pH was 7.4 for meglumine 6%; 8.5 for 7%; and 9.2 for 8%. PH 6.0 in the case of diisopropanolamine 4%;
It was pH 7.3 at 4.2%; pH 8.4 at 5%.

In the ophthalmic ointment, in the case of the tranilast ointment composition having a content of 2.5%, from the viewpoint of solubility, 0.5% monoethanolamine (pH 7.8) based on the total amount is considered from the viewpoint of solubility.
5), 0.93% of diethanolamine based on the total amount
(PH 7.94), triethanolamine 2.7% (p
H7.96), the present inventors have confirmed that the above is necessary.

From the above, the amount of the solubilizing agent can be changed in accordance with the desired content of tranilast so that the pH of the final preparation is near neutral, which is the least irritating to the skin and eyes. It turns out that it is good.

A liquid obtained by dissolving tranilast in an aqueous solution of a solubilizing agent is kneaded as it is in the case of a hydrophilic ointment to form a uniform plaster composition.

However, in the case of a hydrophobic base material, a nonionic surfactant is used because it does not mix uniformly as it is. Generally, those having an HLB of 4 to 6 are suitably used as a water-in-oil (W / O) emulsifier. As a typical example, sorbitan monostearate; Span60 (HLB4.7)
And sorbitan monooleate; Span80 (HLB
4.3). The used amount is 2-3% of the whole amount.

As the base of the ointment for skin, the following hydrophobic bases or hydrophilic bases can be used.

Hydrophobic base: Vaseline, paraffin, plastic base, silicone, lard, wax, simple ointment, simple lead plaster, etc. Hydrophilic base: hydrophilic ointment, hydrophilic petrolatum, purified lanolin,
Aquahole, eucerin, neoserine, water-absorbing ointment, lanolin hydrolyzate, hydrophilic plastibase, macrogol, sol-base, etc.

Among those described above, examples of usable base materials for the ophthalmic ointment include a hydrophobic base: Vaseline, paraffin, plastibase, and a hydrophilic base: purified lanolin.

The plaster composition of the present invention may be used as it is in the form of an ointment or plaster as it is in actual use, or it may be prepared according to a conventional method. May be prepared.

In order to obtain a sustained action of the active ingredient, a sustained release preparation may be prepared by using a sustained release base.

In producing the plaster composition of the present invention,
Pharmaceutical excipients used for preparing ordinary plaster compositions can be appropriately selected and used. For example, a surfactant, a stabilizer, a preservative, a humectant, and other additives can be appropriately added as desired.

[0049]

EXAMPLES The present invention will be described specifically with reference to examples.
The present invention is not limited by the embodiments.

A. Formulation stability test A formulation that could be formulated was subjected to a stability test.

(1) Materials and Preparation Method 1) Raw Materials Used in Test Preparation The following raw materials were used in preparing the test preparation.

Tranilast: Meglumine manufactured by Ohara Pharmaceutical Co., Ltd .: Diisopropanolamine manufactured by SIGMA: Monoethanolamine manufactured by Wako: Diethanolamine manufactured by Wako Triethanolamine: manufactured by Wako Triethanolamine: manufactured by Wako “Span 80”: manufactured by Katayama Chemical Sorbitan monooleate White Vaseline: Maruishi Pharmaceutical Co., Ltd. Hydrophilic ointment: Maruishi Pharmaceutical Co., Ltd. 2) Preparation method of plaster composition <Examples 1 to 7, Comparative Examples 3 to 5> For each formulation shown in Tables 1 and 2, Therefore, each solubilizing agent is solubilized in water, and tranilast is further added, and the mixture is gently heated and dissolved at 60 to 70 ° C., and then added to the ointment base. (Ionic surfactant was added) and kneaded well to prepare tranilast ointment preparations for each skin and eye.

<Comparative Examples 1 and 2> Tranilast was heated and dissolved in an aqueous NaHCO ₃ solution according to the formulation shown in Table 1, and then added to an ointment base (in the case of a hydrophobic formulation, the nonionic surfactant was further increased). And kneading well, 10
% Tranilast ointment preparation (JP-A-6-128)
153, corresponding to Examples 1 and 3).

(2) Storage Conditions The above ointment preparations were stored in a high-temperature atmosphere and a low-temperature atmosphere under the following conditions, respectively.

Temperature conditions: 40 ° C. (± 1 ° C.), 75% R
H (± 5%) Equipment used: ADVANTEC Low Temperature & Humidity Chamber AGX-3
26 Temperature conditions: 10 ° C (± 1 ° C) Equipment used: Sanyo medicinal refrigerated showcase MPR-3
11D 3) Test items and test method Each ointment formulation stored under the above conditions was stored at the start at the time of storage 1.2.
-The following items were tested at a total of five points three and four weeks later.

Property test: The color tone and the like are visually observed.

Residual rate test: [Hydrophobic ointment preparation] 0.5 g of each ointment preparation was precisely weighed,
Add exactly 20 mL of hexane and shake vigorously. This solution is centrifuged (4000 rpm, 30 minutes), and the supernatant is removed. While dissolving this precipitate in absolute ethanol, make 100 mL (50 mL in Table 2) and use it as a sample stock solution. 10 mL of the sample stock solution is accurately weighed, 10 mL of the internal standard solution (5 mL in Table 2) is accurately added, and then absolute ethanol is added to make 50 mL, which is used as the sample solution. Separately, dry Tranilast standard (105 ° C, 3 hours), accurately weigh about 0.05 g, add absolute ethanol and dissolve to make exactly 100 mL. 10 mL of this solution (5 mL in Table 2) was accurately measured and 10 mL of the internal standard solution (Table 2)
5 mL), add absolute ethanol to make 50 mL, and use this solution as the standard solution.

As the internal standard solution, a 2000-fold anhydrous ethanol solution of ethyl p-nitrobenzoate was used.

5 μL of the sample solution and the standard solution (1 in Table 2
Per 0MyuL), were tested by liquid chromatography under the following operating conditions, the ratio Q _T and Q _S of the peak area of tranilast to the peak area of internal standard determined was determined tranilast residual ratio by the following equation.

Residual rate (%) = Q _T / Q _S × collected amount of standard product (g) /0.05×0.5/collected amount of ointment × 100 Chromatography operating conditions: Mobile phase: diluted glacial acetic acid (1 → 100) · acetonitrile Mixed solution (3: 2) Detector: UV absorption spectrophotometer (measurement wavelength: 255 nm) Flow rate: Adjust so that the retention time of tranilast is about 7 minutes.

Column: A stainless steel tube having an inner diameter of about 4 mm and a length of about 15 cm is filled with 5 μm octadecylsilylated silica gel for liquid chromatography.

Column temperature: 30 ° C. Sensitivity: 0.1 AUFS Sample preparation: Perform in a container protected from light and protected from direct sunlight.

Equipment used: Shimadzu LC
-10A [Hydrophilic ointment formulation] Precisely weigh 0.5 g of this product, add exactly 20 mL of hexane and 20 mL of water, and shake vigorously. This liquid is centrifuged (3000 rpm, 10 mi
n), remove the upper layer, and use the lower layer as an extract. Precisely measure 2 mL of this extract, accurately add 10 mL of the internal standard solution, and further add absolute ethanol to make 50 mL, which is used as a sample solution. The following operation methods and determination methods are the same as those for the hydrophobic ointment preparation.

(3) Stability test results and evaluation Tables 3, 4, 5, 6, and 7 show the test results for the property test and the residual ratio (40 ° C./10° C.), respectively.

A formulation prepared by solubilizing tranilast with each dissolution aid and kneading with vaseline base and hydrophilic ointment base is 4
As shown in Tables 5, 6 and 7 under storage conditions of 0 ° C., 75% RH and 10 ° C., it can be seen that the same stability as that of the comparative example is exhibited.

B. Skin Permeability Test Each ointment preparation for skin (Table 1) prepared in the same manner as the stability test described above was performed by the following method.

1) Permeation test method: An artificial skin (Aloask) was fixed to a Franz diffusion cell, and the permeation test was performed in a test tube (in vitro) under a light-shielded condition while maintaining the temperature at 37 ° C. The cell volume on the receiver side was 20 cm ^{3 and the} effective diffusion surface area was 3.8 cm ² .

The receiver side of the cell was filled with physiological saline, and the skin was placed so that the dermis side of the skin was in contact with the physiological saline. 100 mg of the preparation was applied to the stratum corneum side, and this time was regarded as time zero. Every fixed time (2, 4, 6, 8, 24
At 5 hours after the time), 1 mL was sampled from the receiver side, and the amount of tranilast in physiological saline was quantified by HPLC. After sampling, another 1 mL of drug-free saline was added to the receiver side of the cell. All the permeability experiments were repeated three times, and the average value was determined.

2) Test Results and Evaluation The test results are shown in Table 6 and FIGS.

The cumulative skin permeation amount of tranilast from the preparations of Comparative Examples 1 and 2 increased almost linearly with time, and the permeation rate was almost constant at each time.
Tranilast skin permeation rates from the 2.3.4 formulations were initially high. In addition, the tranilast skin permeation amount from the preparations of Examples 1, 2, 3, and 4 was larger than that of the preparations of Comparative Examples 1 and 2 at any time. It is presumed that the reason for this is that the preparation of each comparative example is a suspension-type preparation, whereas the preparation of each example is a dissolution-type preparation.

C. Primary eye irritation test 1) Test method According to the Draize method, administration formulation 5 in the conjunctival sac of the right eye of rabbit
0 mg (Table 2) was instilled once and the eyes were closed for about 1 second. The left eye was untreated as a control.

2) Evaluation method In accordance with the Draize criteria (Tables 8 and 9), the ophthalmic ointment was prepared using the left eye as a control and using the naked eye or a slit lamp at 1, 24, 48 and 72 hours after instillation. Eye examination (cornea, conjunctiva, iris, etc.) and 1, 2 after instillation
At 4, 48 and 72 hours, fluorescein was used to examine the presence or absence of corneal abnormalities, and the primary irritation of the ocular mucosa was evaluated.

3) Test results and evaluation The test results are shown in Tables 10, 11 and 12.

In the meglumine formulation (Comparative Example 3), the diisopropanolamine formulation (Comparative Example 4) and the L-arginine formulation (Comparative Example 5), one hour after instillation, corneal opacity, pericardial hyperemia, conjunctival redness / edema / secretion Things were found. 24 hours after the instillation, 1/3 cases of the meglumine prescription (Comparative Example 3) and the diisopropanolamine prescription (Comparative Example 4) recovered, and the L-arginine prescription (Comparative Example 5). Completely recovered.

From these facts, corneal epithelial damage was observed in the meglumine, diisopropanolamine, and L-arginine formulations of 2.5% tranilast ointment. It can be seen that it is.

On the other hand, the monoethanolamine formulation (Example 5), the diethanolamine formulation (Example 6), and the triethanolamine formulation (Example 7) have very slight irritation, but no corneal epithelial damage was observed. It was proved that it was useful as an eye ointment.

[0077]

The tranilast plaster composition according to the present invention contains tranilast and any of its salts or a mixture thereof as an active ingredient, and the active ingredient is in a uniformly dissolved state. (Active ingredient)
Is superior to the conventional example (comparative example) in skin permeability.
In addition, the eye ointment composition according to the present invention has reduced eye irritation compared to the conventional example, and the effect is more remarkable.

[0078]

[Table 1]

[0079]

[Table 2]

[0080]

[Table 3]

[0081]

[Table 4]

[0082]

[Table 5]

[0083]

[Table 6]

[0084]

[Table 7]

[0085]

[Table 8]

[0086]

[Table 9]

[0087]

[Table 10]

[0088]

[Table 11]

[0089]

[Table 12]

[Brief description of the drawings]

FIG. 1 is a graph showing the relationship between the cumulative amount of permeation of tranilast from each hydrophobic preparation and time in a skin permeability test using a Franz diffusion cell.

FIG. 2 is a graph showing the relationship between the accumulated permeation amount of tranilast from each hydrophilic preparation and time.

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Claims (11)

[Claims] 1. A tranilast plaster characterized by comprising any one of tranilast and a salt thereof or a mixture thereof as an active ingredient, and containing the active ingredient in a uniformly dissolved state in a plaster base. Composition. 2. A plaster base containing any of tranilast and a salt thereof or a mixture thereof as an active ingredient, and an active ingredient containing a solubilizing agent and water uniformly dissolved therein. A tranilast plaster composition comprising: 3. The plaster substrate is a plaster substrate for skin,
The tranilast plaster composition according to claim 2, wherein the solubilizing agent is one or more selected from the group consisting of alcoholamines and amino acids. 4. The method according to claim 3, wherein the alcohol amine is one or more selected from the group consisting of N-methylglucamine, diisopropanolamine, monoethanolamine, diethanolamine and triethanolamine. The tranilast plaster composition according to the above. 5. The tranilast plaster composition according to claim 3, wherein the amino acid is arginine. 6. The tranilast according to claim 2, wherein the plaster base is an ophthalmic ointment base, and the solubilizer is one or more selected from the group of alcoholamines. Plaster composition. 7. The tranilast plaster composition according to claim 6, wherein the alcoholamine is one or more selected from the group consisting of monoethanolamine, diethanolamine and triethanolamine. 8. Tranilast, characterized by dissolving any one or a mixture of tranilast and a salt thereof in an aqueous solution containing a solubilizing agent, adding a surfactant, and kneading the resultant with a hydrophobic base. A method for producing a plaster composition. 9. A method for preparing a tranilast plaster composition, comprising dissolving any of tranilast and a salt thereof or a mixture thereof in an aqueous solution containing a solubilizing agent, and kneading the resultant with a hydrophilic base. Method. 10. The method for producing a tranilast ointment composition according to claim 8, wherein the hydrophobic base material and the hydrophilic base material are ophthalmic ointment base materials. 11. The method for producing a tranilast plaster composition according to claim 8, wherein the hydrophobic substrate and the hydrophilic substrate are skin plaster substrates.