JPH05310568A - Captopril-containing percutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorption preparation having improved percutaneous absorption rate of captopril. CONSTITUTION:A percutaneous absorption preparation contains captopril in an aqueous medium comprising water as an essential component. The percutaneous absorption preparation having high safety and low skin irritation is obtained.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a transdermal patch containing captopril as an active ingredient. Captopril is N- (3-mercapto-2-D-
It is an excellent antihypertensive agent with the chemical name of methylpropionyl) -L-proline.

[0002]

2. Description of the Related Art Captopril is widely used in the field of cardiovascular medicine as an angiotensin converting enzyme inhibitor for the purpose of lowering blood pressure. Conventionally, the dosage form of this drug is an oral drug, but side effects (eg, nausea, vomiting, loss of appetite) due to intestinal wall disorders are said to be a problem. Therefore, recently, for the purpose of devising the administration method to reduce the side effects, for example, a preparation in a form of being absorbed through the skin has been studied. This transdermal administration method not only reduces the above-mentioned side effects as compared with the oral administration method, but also has many advantages. For example, when administered orally, the drug absorbed from the intestine circulates to the liver, so that a considerable amount is metabolized and decomposed by the liver before the drug effect is exerted. Since it does not pass through the liver during the first circulation of, the drug is not decomposed by the liver and the drug efficacy is not significantly reduced. Further, by controlling the transdermal absorbability of a drug, it is possible to maintain a constant blood concentration of the drug for a long time, and it is possible to reduce side effects due to a large absorption of the drug for a short time as in oral administration.

In general, when a drug is absorbed through the skin by percutaneous absorption, it is difficult for the drug to pass through the skin, and bioavailability is often low. This is because there is a stratum corneum on the skin surface, and this stratum corneum has a role of preventing foreign matter from entering the body. A preparation containing an absorption enhancer has been developed in order to lower the barrier function of the stratum corneum and promote absorption of the drug (for example, JP-A-58-52216 and JP-A-58-7991).
No. 8, JP 60-13720, and JP 60-114.
31, JP 61-24517, and JP 61-22.
1121 and Japanese Patent Laid-Open No. 2-202813).

Examples of such absorption enhancers include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, diethylene glycol, propylene glycol, propylene glycol monoacetate, ethanol, oleic acid, isopropyl myristate, gallic acid ester, glycerin, polyoxy. Various substances such as ethylene alkyl ether have been disclosed.

The transdermal absorption of captopril is described in, for example, Japanese Patent Application Laid-Open Nos. 2-202813, 3-83924 and 4-1127, and any of these known inventions is known. However, the use of a specific absorption enhancer or compounding agent is a major requirement, and captopril is only listed as an example of a large number of applied drugs, and to what extent the specifically disclosed enhancer is effective. It is unknown if there is. In addition, absorption enhancers are not used in the expectation of enhancement of the original drug effect, and there are also those having skin irritation, and it is preferable not to use them if possible. The effective blood concentration of captopril is 50
Since it is as high as ng / ml or more, it is necessary to devise a complicated method such as using a special percutaneous absorption enhancer or employing a physical acceleration method.

[0006]

DISCLOSURE OF THE INVENTION In view of the above-mentioned drawbacks of the prior art, the present inventors do not necessarily have to employ a percutaneous absorption enhancer and, in addition, contain captopril which has good absorbability of captopril into the skin. It is intended to provide a percutaneous absorption preparation.

[0007]

[Means for Solving the Problems]
As a result of diligent research on a novel and effective captopril-containing transdermal preparation that has solved the problems of the prior art, it was surprisingly found that water has a special absorption promoting effect, and the present invention has been completed. It is a thing.

[0008] That is, the present invention is a captopril-containing percutaneous absorption preparation characterized by containing 0.5 to 50% by weight of captopril in an aqueous medium containing water as an essential component.
In the present invention, captopril is easily absorbed from the skin without requiring a special absorption promoter to coexist in an aqueous medium. The aqueous medium is a solution containing water as an essential component, and water alone can be used. The water content contained in the aqueous medium is preferably 10 to 99.5% by weight, and more preferably 30 to 95% by weight. The concentration of captopril contained in the aqueous medium is preferably 0.
It is 5 to 50% by weight.

The active ingredient of the present invention, captopril, is preferably kept in a non-dissociated state in an aqueous medium containing water as an essential ingredient. For example, when water is used alone, it is preferable to keep the pka of captopril at 3.7 or less, and the range of pH 1.5 to 3.7 is more preferable from the viewpoint of skin irritation. In the case of an aqueous medium containing water, the pH range of water alone is not limited.

The present invention has a constitution as described above, but it is optionally selected from a gelling agent, a thickener, a water retention agent, an adhesive, a stabilizer, a pH adjusting agent and the like in an aqueous medium. It is free to mix one or more of the above. That is, it is possible to use a gelling agent and a thickening agent to make the aqueous medium solid. As a gelling agent, gelatin,
Agar, mannan, alginic acid, carrageenan other than 100% λ carrageenan, furceleran, carboxypolymethylene, ethylene maleic anhydride, hydroxyethyl cellulose, polyacrylamide, methyl cellulose,
Known gelling agents such as propylene glycol alginate, ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, and poly (methyl vinyl ether) -maleic anhydride may be mentioned, and the thickener may be locust bean gum, 100% λ. Carrageenan, xanthan gum, etc. can be used.
Further, these may be used in combination, and it is preferable to mix the gelling agent and / or the thickening agent so as to be 0.2 to 5% by weight.

As the water retention agent, polyhydric alcohols such as polyethylene glycol, glycerin, sorbitol, maltitol, propylene glycol, and 1,3-butylene glycol, and 1 such as ethanol and isopropanol.
The primary alcohols may be used alone or in combination of two or more. Further, the stability of the drug and the reliability of the drug associated therewith can be increased by using a known stabilizer, pH adjuster, preservative and the like.

The percutaneous absorption preparation of the present invention includes patches, poultices, ointments (including creams), plasters, tapes, lotions, solutions, suspensions, emulsions, sprays and the like. However, among them, transdermal patches (patches, poultices, plasters, tapes, etc.) are preferable. Ointments (creams) lotions, solutions, suspensions, emulsions, sprays,
Water as an aqueous medium, an antioxidant, and if necessary, a nonionic surfactant, an inorganic base, an acid and the like are mixed with an ointment base, a solvent, a suspending agent, an emulsifier or a propellant known in the field of formulation. Can be manufactured. If necessary, a preservative (eg, ethyl paraoxybenzoate, benzalkonium chloride, etc.) and an anti-inflammatory agent (eg, glycyrrhizic acid, etc.) can be added.

In addition, patches such as patches, poultices, plasters, tapes, etc. are known in the pharmaceutical field with water as an aqueous medium, an antioxidant and optionally a nonionic surfactant, an inorganic base and an acid. It can be adjusted by mixing it with the above base, adding an antiseptic, an anti-inflammatory agent, etc., if necessary, and then absorbing or adhering to a suitable support.

Examples of such a support include cellulose acetate, ethyl cellulose, polyethylene terephthalate,
Examples thereof include plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, polyurethane, polyvinylidene chloride, aluminum, non-woven fabric, woven fabric, paper and the like. As the adhesive used as required for the patch, poultice and tape, there are polyalkyl vinyl ether-based, polyalkyl acrylate-based, polyisobutylene-based, natural rubber-based and synthetic rubber-based adhesives.

Recently, regarding the evaluation of skin permeability of drugs,
T. Higuchi, R .; Konishi, Thera
p. Res. , 6 , 280-288 (1989), and Noboru Yada, Nitto Giho, 28 , 11-23 (1990).
It has been reported that the shell of a snake is useful as a model of the human stratum corneum. This is because the chemical properties of lipids and the structure of the horny layer are similar to those of the human stratum corneum, the drug permeation pattern is very similar to that of the human stratum corneum, and individual differences in drug permeability are due to human cadaver. 1/10 to 1/3 of skin and fresh animal skin,
It is stated that it can be stored for a long period of time. From the results of these documents, it was judged that at least a snake shell could be used as an experimental material as a model of human skin and chest, and was also used in the present invention.

The present invention will be described in detail below, but the present invention is not limited thereto.

[Examples 1 and 2] The experiments were carried out by placing a back shell of a tycobra (obtained from Tokai Tourism Snake Center) in a Franz cell. The receiver side of the cell was filled with physiological saline, and one of the shells of the snake was placed in contact with physiological saline. The cell temperature was kept at 37 ° C., and a certain amount of the drug solution was applied to the other shell of the snake. Then, physiological saline was sampled at regular intervals to quantify the amount of the drug that penetrated the shell of the snake. Also, physiological saline was added to the receiver side so that the shell of the snake and the saline were always in contact with each other.

A drug solution having the composition shown in Table 1 was prepared.
This solution was applied to the shell of a snake so as to have a volume of 500 μl / cm ² , and the container was sealed for the purpose of preventing evaporation of the solvent. Figure 1
The relative values of captopril integrated transmission amount over time of Examples 1 to 2 and Comparative Example 1 are shown (the 24-hour transmission amount of Example 1 is 100). It was found that when a captopril-containing transdermal preparation containing water on the donor side was used, the permeability of captopril was good. The usefulness of using water as the aqueous medium has been recognized.

[0019]

[Table 1]

[Examples 3 to 4] Experiments were conducted under the same conditions as in Example 1 with the solution compositions shown in Table 2 below.

[Table 2] FIG. 2 shows the relative values of the cumulative amount of captopril permeation in Examples 3 to 4 over time (the 24-hour permeation amount in Example 3 is 100). It was found that when water alone is used, the skin permeability of captopril changes depending on the pH.

Example 5 5 parts by weight of hydroxypropyl cellulose was added to a pH 1.9 solution consisting of 10 parts by weight of captopril and 85 parts by weight of water to give a gel-like solid, and the same conditions as in Example 1 were used. When the accumulated amount of captopril was measured, it was 2500 μg / cm ² after 24 hours.
It was confirmed that the permeability far exceeded the cumulative permeation amount of captopril 1500 μg / cm ² after 24 hours calculated from the effective blood concentration.

[0022]

EFFECTS OF THE INVENTION The percutaneous absorption preparation of the present invention can improve the skin permeability of captopril without the use of an absorption enhancer such as an organic solvent, and reduce the problems of skin irritation and odor. Can be made

[Brief description of drawings]

FIG. 1 is a graph showing the relative values of captopril integrated transmission amount in Examples 1 and 2 and Comparative Example 1.

2 is a graph showing relative values of captopril integrated transmission amount in Examples 3 and 4. FIG.

Claims (1)

[Claims] 1. A transdermal preparation containing captopril, which comprises 0.5 to 50% by weight of captopril in an aqueous medium containing water as an essential component.