JP3273506B2 - Pharmaceutical composition for transdermal administration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for transdermal administration containing a poorly water-soluble drug as an active ingredient. More specifically, the present invention provides a poorly water-soluble drug as an active ingredient, ethylene glycol salicylate and water as a medium, a polyoxyethylene chain as an emulsifier, or an average addition mole number of ethylene oxide in a polyoxyethylene glycol chain of 60 or more. The present invention relates to a pharmaceutical composition for transdermal administration comprising a hydrophilic nonionic surfactant and, as an optional component, an additive used for an external preparation.

[0001]

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for transdermal administration containing a poorly water-soluble drug as an active ingredient. More specifically, the present invention provides a poorly water-soluble drug as an active ingredient, ethylene glycol salicylate and water as a medium, a polyoxyethylene chain as an emulsifier, or an average addition mole number of ethylene oxide in a polyoxyethylene glycol chain of 100 or more. The present invention relates to a pharmaceutical composition for transdermal administration comprising a hydrophilic nonionic surfactant and, as an optional component, an additive used for an external preparation.

2. Description of the Related Art In recent years, in order to enhance the transdermal absorbability of drugs, it has recently been common to produce a pharmaceutical composition by dissolving the drug in a solvent and emulsifying the solution. Has become. However, for a poorly water-soluble drug, it is difficult to select a safe solvent that can dissolve it. For example, when producing a gel or solution of a poorly water-soluble drug, an organic solvent such as ethanol is usually used.

However, in a pharmaceutical composition for external use using an organic solvent, since the organic solvent volatilizes in a short time, drug crystals precipitate on the surface to which the external preparation is applied, and the transdermal absorbability of the drug is reduced. However, there is a disadvantage that skin irritation due to an organic solvent is recognized.

In order to improve these drawbacks, organic solvents having relatively low polarity, such as diisopropyl adipate and diethyl sebacate, are usually used as drug solvents. Drug solutions using these solvents can be further emulsified by ordinary emulsification techniques, but poorly water-soluble drugs hardly dissolve in these solvents. On the other hand, a poorly water-soluble drug can be dissolved in ethylene glycol salicylate, which is a highly polar organic solvent, but this solution cannot be emulsified by ordinary emulsification techniques.

[0004] Therefore, various methods for producing a pharmaceutical composition for transdermal administration by dissolving a poorly water-soluble drug in ethylene glycol salicylate and emulsifying the solution have been conventionally studied.

For example, since ethylene glycol salicylate itself has too high a polarity as an oil component and is difficult to emulsify, low-polar oils such as stearic acid, cetanol, isopropyl myristate, and white petrolatum are added as other oil components. To lower the polarity of the whole oil component, and as an emulsifier, polyoxyethylene sorbitan monostearate or sorbitan monostearate (JP-A-58-15909 and JP-A-63-132838).
No. 7), polyoxyl stearate 40 (JP-A-7-17 / 1990).
No. 9341) and a method of emulsification using polyoxyethylene sorbitan monostearate (JP-A-58-29706).

However, these methods have a new problem that the solubility of the poorly water-soluble drug in the mixed solution is reduced because other low-polarity oil components are mixed with ethylene glycol salicylate.

[0007]

Means for Solving the Problems The present inventor has proposed a stable pharmaceutical composition for transdermal administration by dissolving a poorly water-soluble drug in ethylene glycol salicylate and emulsifying the solution and an aqueous medium using a specific emulsifier. This invention was completed by finding that a product could be obtained.

[0008]

According to the present invention, a poorly water-soluble drug as an active ingredient, ethylene glycol salicylate and water as a medium, a polyoxyethylene chain or an average number of moles of ethylene oxide added to a polyoxyethylene glycol chain as an emulsifier are used. A hydrophilic non-ionic surfactant having a ratio of not less than 100 and an additive used for an external preparation as an optional component.

The poorly water-soluble drug in the present invention means a drug having a solubility in water of 10 mg / ml or less. For example, a drug corresponding to “very poorly soluble” and “slightly insoluble” prescribed in the 13th revised Japanese Pharmacopoeia corresponds to the poorly water-soluble drug of the present invention.

Accordingly, the poorly water-soluble drug is not particularly limited, but specifically, (S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide)- 3-methyl-1-phenyl-2,4
(1H, 3H) -pyrimidinedione, flurbiprofen, ketoprofen, indomethacin, piroxicam,
Non-steroidal anti-inflammatory agents such as flufenamic acid, steroidal anti-inflammatory agents such as betamethasone valerate and triamcinolone acetonide, antifungal agents such as miconazole, local anesthetics such as ethyl aminobenzoate, and blood circulation such as inositol hexanicotinate Accelerators.

In the present invention, the average addition mole number of ethylene oxide in the polyoxyethylene chain or polyoxyethylene glycol chain of the hydrophilic nonionic surfactant is preferably 100 or more, more preferably 150 or more.

Average number of moles of ethylene oxide added (p)
Examples of the hydrophilic nonionic surfactant having a molecular weight of 100 or more include ether type such as polyoxyethylene polyoxypropyl alkyl ether, ether ester type such as polyoxyethylene hydrogenated castor oil, and ester such as polyethylene glycol fatty acid ester. Type. Specific examples of the ether type include polyoxyethylene (p = 160) polyoxypropylene (p = 30) glycol, polyoxyethylene (p = 200) polyoxypropylene (p = 70) glycol, and ether ester type. Specific examples include polyoxyethylene (p = 100) hydrogenated castor oil. Specific examples of the ester type include polyethylene glycol monostearate (p = 150) and polyethylene glycol monostearate (p = 200). Is mentioned.

[0013] More specifically, Pluronic F68 (trade name, manufactured by Asahi Denka Kogyo KK): polyoxyethylene (p =
160) polyoxypropylene (p = 30) glycol), Yuniru Bed 70DP-950B (trade name, manufactured by NOF Corporation
Ltd.: polyoxyethylene (p = 200) polyoxypropylene (p = 30) glycol); d Marekkusu 6300M-
ST (trade name, manufactured by Nippon Emulsion Co., Ltd .: polyethylene glycol monostearate (p = 150)), Emanone 3199 (trade name, manufactured by Kao Corporation: polyethylene glycol monostearate (p = 200)), etc. Can be

Additives used as optional components include thickeners, pH adjusters, wetting agents, stabilizers, preservatives, flavoring agents, and the like.

The thickener has a molecular weight of 100,000 to 5,000,0
About 100, preferably about 1,000,000 to 3,000,000 water-soluble polymers, such as carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Specifically, Carbopol 934, 940 or 941 manufactured by BF Goodrich as a carboxyvinyl polymer, Hibiswako 103, 104 or 105 manufactured by Wako Pure Chemical Industries, Ltd., and Shin-Etsu Chemical Co., Ltd. as hydroxypropyl methylcellulose. TC-5R, Metros 90SH
Examples of hydroxypropyl cellulose include HPC-H manufactured by Nippon Soda Co., Ltd.

[0016] As the pH adjuster, for example, lactic acid, citric acid,
Phosphoric acid and the like are used, and those used for adjusting to a high pH region include sodium hydroxide, potassium hydroxide, sodium lactate, sodium citrate, monoethanolamine and diisopropanolamine. The pH can also be lowered by adding a water-soluble carboxyvinyl polymer.

As the wetting agent, propylene glycol,
Glycerin, 1,3-butylene glycol and the like can be mentioned.

Examples of the stabilizer include ascorbic acid, dibutylhydroxytoluene, sodium thiosulfate, sodium thioglycolate, sodium thiomalate, erythorbic acid, sodium erysorbate, sodium pyrosulfite, benzoic acid, sodium benzoate, sodium alginate, Sodium caprylate, L-arginine,
Examples include L-cysteine, dl-α-tocopherol, tocopherol acetate, propyl gallate, sodium edetate and the like.

As preservatives, benzethonium chloride, benzalkonium chloride, methyl paraben, ethyl paraben, propyl paraben, chlorobutanol,
Benzyl alcohol, thimerosal and the like can be mentioned.

The pharmaceutical composition of the present invention has a pH of 3 to 8 since ethylene glycol salicylate, which is a medium, is easily hydrolyzed under alkaline conditions, while a strongly acidic composition is irritating to the skin. Preferably, the pH is adjusted to 4 to 7.

The concentration of the poorly water-soluble drug in the pharmaceutical composition of the present invention is usually 0.01 to 10% by weight, preferably 0.1 to 5% by weight.
It is.

The amount of the ethylene glycol salicylate that can dissolve the drug in the pharmaceutical composition of the present invention can be used at a minimum. From that viewpoint, the concentration of ethylene glycol salicylate is 0.01 to 30% by weight, preferably 1 to 15% by weight.

The amount of the hydrophilic nonionic surfactant depends on the amount of ethylene glycol salicylate. As the amount of ethylene glycol salicylate increases, the amount of the hydrophilic nonionic surfactant increases. That is, the compounding ratio of the poorly water-soluble drug, the ethylene glycol salicylate and the hydrophilic nonionic surfactant in the pharmaceutical composition of the present invention is as follows:
Preferably, the ratio is 1: 1 to 30: 1 to 20. Specifically, the concentration of the hydrophilic nonionic surfactant in the pharmaceutical composition of the present invention is 0.01 to 20% by weight, preferably 0.5 to 10% by weight.
It is.

The pharmaceutical composition for transdermal administration of a poorly water-soluble drug of the present invention can be administered in a usual dosage form which can be administered transdermally, such as ointments, creams, gel creams, lotions and the like.
Either form may be used.

The method for producing the composition of the present invention is not particularly limited, but a conventional method in the art can be used. As a specific example, the pharmaceutical composition for transdermal administration of the present invention generally comprises first dissolving a poorly water-soluble drug in ethylene glycol salicylate, and adding water and a hydrophilic nonionic surfactant to the solution. It is manufactured by mixing. The amount of water in the composition of the present invention is used so as to constitute the poorly water-soluble drug, ethylene glycol salicylate, hydrophilic nonionic surfactant, and the balance of additives as required. For example, when the pharmaceutical composition of the present invention is a lotion, it is 60 to 99.5% by weight, preferably 70 to 95% by weight, and when it is a cream, it is 50 to 97% by weight, preferably 60 to 90% by weight. % By weight. The optional additives may be added at any stage and may be heated as needed during mixing.

Thus, according to the present invention, in one preferred pharmaceutical composition, 1-2% by weight of poorly water-soluble drug, 2-12% by weight of ethylene glycol salicylate, 76-95% by weight of water, polyoxyethylene 2 to 1 of hydrophilic nonionic surfactants having an average addition mole number of ethylene oxide of 100 or more in the chain or polyoxyethylene glycol chain
There is a pharmaceutical composition for transdermal administration containing 0% by weight.

[0027]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In addition, the compounding ratio in an Example is weight%.

Example 1 A lotion having the following composition was prepared. (S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidine − Dione 2 Ethylene glycol salicylate 10 Polyethylene glycol monostearate (p = 150) 10 Glycerin 5 Purified water Remaining amount Total 100

(S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1
(H, 3H) -pyrimidinedione, ethylene glycol salicylate, and polyethylene glycol monostearate (p = 150) were mixed and dissolved by heating at 80 ° C. Glycerin and purified water were added thereto, and the mixture was stirred well until the temperature of the mixture reached room temperature.

[0030] except that the surfactants shown in Table 1 instead of Example 2-5 monostearate polyethylene glycol (p = 0.99) were used, respectively, to prepare a lotion in the same manner as in Example 1.

Comparative Examples 1 to 10 A lotion was prepared in the same manner as in Example 1 except that the surfactants shown in Table 1 were used instead of polyethylene glycol monostearate (p = 150).

Test Example 1 The lotions prepared in Examples 1 to 5 and Comparative Examples 1 to 10 were allowed to stand at room temperature for 24 hours, and each lotion was evaluated according to the criteria shown in Table 2. Table 1 shows the test results.

[0033]

[Table 1]

[0034]

[Table 2]

As is clear from Table 1, the average number of moles of ethylene oxide added to the polyoxyethylene chain or polyoxyethylene glycol chain as an emulsifier (p)
The lotion using a hydrophilic nonionic surfactant having a ratio of 100 or more was stable without any layer separation even after standing for 24 hours.

Example 6 A cream having the following composition was prepared. (S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidine − Dione 1 Ethylene glycol salicylate 6 Polyoxyethylene (p = 100) hydrogenated castor oil 4 Glycerin 5 Carboxyvinyl polymer 1.2 Diisopropanolamine 0.48 Purified water Remaining amount Total 100

(S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1
(H, 3H) -pyrimidinedione, ethylene glycol salicylate, and polyoxyethylene (p = 100) hydrogenated castor oil were mixed and heated and dissolved at 80 ° C. Other components such as glycerin and purified water were added thereto, and the mixture was stirred well until the temperature of the mixture reached room temperature.

[0038]

Comparative Example 11 A cream was prepared in the same manner as in Example 6 , except that polyoxyethylene (p = 40) hydrogenated castor oil was used instead of polyoxyethylene (p = 100) hydrogenated castor oil.

Test Example 2 The creams prepared in Example 6 and Comparative Example 11 were
After standing at 24 ° C. for 24 hours, the state of each cream was evaluated according to the criteria in Table 4. Table 3 shows the test results.

[0041]

[Table 3]

[0042]

[Table 4]

As is apparent from Table 3, the average number of moles of ethylene oxide added to the polyoxyethylene chain or polyoxyethylene glycol chain as an emulsifier (p)
The cream using a hydrophilic nonionic surfactant having a ratio of 100 or more remained white cream-like and stable after standing at 60 ° C. for 24 hours.

Example 7 A cream having the following composition was prepared in the same manner as in Example 6 . Ketoprofen 1 Ethylene glycol salicylate 2 Emarex 6300M-ST 3 Carbopol 940 0.88 Propylene glycol 3 Diisopropanolamine Appropriate amount Remaining amount of purified water 100

[0045]

Example 8 A cream having the following composition was prepared in the same manner as in Example 6 . Clotrimazole 1 Ethylene glycol salicylate 5 Uniloop 70DP-950B 1 Hibiswako 103 1.28 Glycerin 5 Diisopropanolamine Appropriate amount Purified water Remaining amount Total 100

Test Example 3 The creams obtained in Examples 7 and 8 were placed in a refrigerator (4
C), and after storage for 6 months, the appearance and the presence of drug crystal precipitation were examined.

[Table 5]

[Table 6]

Example 9 A cream having the following composition was prepared. (S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidine − Dione 2 Ethylene glycol salicylate 12 Polyethylene glycol monostearate (p = 150) 5 Glycerin 5 Carboxyvinyl polymer 1.2 Diisopropanolamine 0.72 Sodium thiosulfate 0.10 Sodium edetate 0.02 Purified water Remaining amount 100

(S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1
(H, 3H) -pyrimidinedione, ethylene glycol salicylate, and polyethylene glycol monostearate (p = 150) were mixed and dissolved by heating at 80 ° C. Other components such as glycerin and purified water were added thereto, and the mixture was stirred well until the temperature of the mixture reached room temperature.

Stability test The cream prepared in Example 9 was stored in an aluminum tube under the conditions shown in Table 7. The concentration of the drug at the start of the test
The residual ratio of the drug at 100% was measured by liquid chromatography, and the state of the cream was also observed.
Table 7 shows the results of the drug residual ratio, and Table 8 shows the results of the state of the cream.

[0051]

[Table 7]

[0052]

[Table 8]

As is clear from Tables 7 and 8, the cream of the present invention was white cream-like even after being stored at 50 ° C. for 8 weeks, had a drug residual ratio of almost 100%, and was stable.

Example 10 A cream having the following composition was prepared in the same manner as in Example 9 . (S) -6-amino-5- (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) -3-methyl-1-phenyl-2,4 (1H, 3H) -pyrimidine − Dione 1 Ethylene glycol salicylate 6 Polyethylene glycol monostearate (p = 150) 2.5 Glycerin 5 Carboxyvinyl polymer 1.2 Diisopropanolamine 0.72 Sodium thiosulfate 0.10 Sodium edetate 0.02 Purified water Remaining amount 100

Comparative Example 12 (S) -6-amino-5- (6-hydroxy-2,5,
7,8-tetramethylchroman-2-carboxamide)
-3-Methyl-1-phenyl-2,4 (1H, 3H)-
A cream was prepared in the same manner as in Example 9 except that pyrimidinedione was not used.

Local Irritation Test Using the creams obtained in Examples 9 and 10 and Comparative Example 12 , a primary skin irritation test was performed according to the method of Draize. Six New Zealand White male rabbits were used as test animals. Table 9 shows the results.

[0057]

[Table 9]

As is clear from Table 9, the pharmaceutical composition of the present invention showed little skin irritation.

Phototoxicity Test Using the creams obtained in Examples 9 and 10 and Comparative Example 12 , a skin phototoxicity test was conducted according to the method of Morikawa et al. The test animals used were 10 male Hartley guinea pigs per group. Table 10 shows the results.

[0060]

[Table 10]

As is clear from Table 10, no phototoxicity was observed in the pharmaceutical composition of the present invention.

According to the present invention, the poorly water-soluble drug as an active ingredient, ethylene glycol salicylate and water as a medium, and the average addition mole number of ethylene oxide in water, polyoxyethylene chain or polyoxyethylene glycol chain are 100 or more. By mixing and emulsifying a hydrophilic nonionic surfactant as an emulsifier, a stable pharmaceutical composition for transdermal administration is provided.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 47/34 A61K 47/34 A61P 23/02 A61P 23/02 29/00 29/00 31/04 31/04 (72) Invention Person Kazue Kusunoki Kame, 2763 Takamiya-cho, Hikone City, Shiga Prefecture Inside the Product Research Laboratories (72) Inventor Naoki Fujisawa 3-17-35 Niisonanami, Toda City, Saitama Prefecture Japan Energy Pharmaceutical and Biotechnology Research Institute (56) Reference Document JP-A-3-161432 (JP, A) JP-A-5-331066 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/06-9/10 A61K 31 / 513 A61K 47/14-47/34

Claims (5)

(57) [Claims] (1) a poorly water-soluble drug as an active ingredient, ethylene glycol salicylate and water as a medium, a polyoxyethylene chain as an emulsifier, or a hydrophilic non-soluble polymer having an average addition mole number of ethylene oxide of 100 or more in a polyoxyethylene glycol chain; A pharmaceutical composition for transdermal administration comprising an ionic surfactant and, as an optional ingredient, an additive used in an external preparation. 2. The pharmaceutical composition according to claim 1, wherein the poorly water-soluble drug is a nonsteroidal anti-inflammatory agent, an antifungal agent or a local anesthetic. 3. The method of claim 1, wherein the nonsteroidal anti-inflammatory drug is (S) -6-
Amino-5- (6-hydroxy-2,5,7,8-tetramethyl chroman-2-carboxamido) -3-methyl-1-phenyl-2,4 (IH, 3H) - claim 2 is pyrimidinedione A pharmaceutical composition according to claim 1. 4. A pharmaceutical composition according to any one of claims 1 to 3 optional ingredient is a thickener. 5. ointments, creams or pharmaceutical composition according to to any one of claims 1 to 4 in the form of lotions.