JPS58128324A - Base composition and external pharmaceutical composition - Google Patents

Abstract

PURPOSE:A base composition consisting of a compound selected from a specific chain polydimethylsiloxane and a specific cyclic polydimethylsiloxane and a lower alcohol, and capable of enhancing the percutaneous absorbability of a chemical. CONSTITUTION:A base composition, containing at least one compound selected from a chain polydimethylsiloxane having <=3 cSt viscosity at 25 deg.C, e.g. a compound of the formula (n is an integer 0-6) and a cyclic polydimethylsiloxane having <=5 cSt viscosity at 25 deg.C, e.g. cyclooctamethyltetrasiloxane, and a lower alcohol, e.g. methyl alcohol or ethyl alcohol, and capable of enhancing the percutaneous absorbability of a chemical. The amount of the compound is 1- 50wt% based on the lower alcohol. A chemical having 0.5-5% solubility in the lower alcohol is capable of enhancing the percutaneous absorbability by the above-mentioned composition.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a base composition capable of improving transdermal absorption of a drug, and a topical medical composition using the composition.

Conventionally, drugs administered to the integument include sterilization, fumachi, and gold C →) 1
It was intended to act locally on the outer skin of plants such as No. 6 or its 1000 parts. However, in recent years, attempts have been made to administer drugs with systemic effects to the integument instead of via the route. When drugs, especially systemic drugs, are administered transdermally, it is easy to maintain the effect of the drug, and it is easy to control the absorption rate of the drug, so side effects due to overdose are less likely to occur. It is possible to effectively utilize the drug because it is not susceptible to the effects of first-pass effects caused by the liver that occur with oral administration, and it is possible to safely administer drugs that cause numbness when administered orally, such as indomethacin. It has the following advantages.

However, since normal supporting legs have a protective effect on the body, they generally have a property 1α that makes it difficult for them to absorb and permeate drugs. Therefore, drugs (especially drugs with systemic effects)
Even when administered with conventional ointments, lotions, etc., drugs that produce sufficient imaging are unlikely to be absorbed into the body.

In view of this situation, the present inventors conducted intensive research and obtained the following findings.

■ At least one compound (hereinafter referred to as A composition containing a lower alcohol (sometimes referred to as auxiliary treatment) and a lower alcohol reduces percutaneous absorption into the composition of the composition.

■ #3 solubility, especially for lower alcohols, or 0.5-5
- The transdermal absorbability of certain drugs is improved by the above-mentioned composition.

(2) The above composition can be used as a base for drugs applied to the skin.The present invention was completed by the discovery of the following.

Therefore, the first object of the present invention is to provide a base IL1 composition that enhances trans-BI absorption of drugs.

A second object of the present invention is to provide an external medical composition containing five drugs that has good transdermal absorption.

An eighth object of the present invention is to provide a method for increasing transdermal absorption of drugs.

That is, the present invention.

(1) At least one compound selected from the group consisting of linear polydimethylsiloxane with a viscosity of 3 centistokes or less at 25°C and cyclic polydimethylsiloxane with a viscosity of 6 centistokes or less at 25°C, and a lower Etsu 411 composition capable of screening transdermal absorbability of drugs containing alcohol.

(2) A medicinal composition for external use, comprising a drug blended into the above-mentioned base composition.

It is.

The lower alcohol used in the present invention is preferably a monohydric lower alcohol, specifically methyl alcohol,
Ethyl alcohol, n-propyl alcohol, 1so-
Propyl alcohol, n-butyl alcohol, 1so-
Butyl alcohol, 5ee-butyl alcohol, and t-butyl alcohol are preferred, and ethyl alcohol is particularly preferred.

Suitable examples of linear polydimethylsiloxanes having a viscosity of 3 centistokes or less at 25°C used in the present invention include, for example, the formula () % formula % (3 Specific examples thereof include hexamethyldisiloxane, decamethyltetrasiloxane, dodecamethylpentasiloxane, tetradecamethylhexasiloxane, and octadecamethyloctasiloxane. Preferred examples of the cyclic polydimethylsiloxane having a viscosity at 25°C of 6 centistokes or less (FQ) include those with 4- to 5-membered rings such as cyclooctamethyltetrasiloxane and cyclodecamethylpentasiloxane.

The base composition of the present invention is prepared by adding an additive to a lower alcohol, and the amount of additive added is 1 to 50% by weight, preferably 5 to 80% by weight based on the lower alcohol. It is a percentage. Of course, in the base composition,
Pharmaceutically acceptable additives may also be included.

In addition, the external pharmaceutical composition described in Section 1 is prepared by blending a drug with the above-mentioned base composition.

Drugs have a vulgarity level of 0.5 for the above-mentioned lower alcohols.
The content is preferably 10% to 10%, particularly 1 to 5%.

Drugs having the above-mentioned vulnerabilities will be better distributed into the skin when incorporated into the pharmaceutical composition of the present invention, and therefore will be better absorbed transdermally. In this case, the drug was dissolved in excess in lower alcohol heated to 20°C, stirred from time to time, and after 24 hours, the upper drop was collected and measured using an absorptiometer.

By the way, when it comes to drugs that aim to have a local effect on diseases of the integument or its lower tissues, conventional preparations for external use can also be somewhat effective, so the drug related to the external pharmaceutical composition of the present invention does not enter the bloodstream. It is meaningful to have something that is absorbed and exhibits its medicinal effects, that is, a flower that is intended to have a systemic effect.

The drugs specifically include benzodiazepines (e.g., diazepam, nitrasebam, flunitrazebam, lorazepam, brasebam, fludiazepam, clonazebam), antihypertensives (e.g., clonidine), anti-inflammatory agents (e.g., indomethacin, cyclofenac), Thiazide-based drugs) 4 rrl (for example, cyclopenthiazide, trichlormethiazide), drugs for treating irregularities (for example, asiarin, quinidine), mucosal nerve shaving (for example,
Haloperidol, butylscopolamine, chloropromacin), etc.

The amount of the drug to be mixed may be sufficient to achieve the desired medicinal effect, and it varies depending on the oil of the drug, the weight of the person, symptoms, etc., and should be selected appropriately according to these conditions. Bye. Generally, it is preferable for the drug to be added in an amount of 0.2% to 10% by weight, but since the amount of drug applied can be adjusted by appropriately increasing or decreasing the skin area of the pharmaceutical composition, it is not always necessary to add the drug in the above-mentioned amount. The external pharmaceutical composition according to the present invention can be used as is, or with the addition of an acceptable third ingredient, etc.
It is administered to the integument as external preparations such as bone, lotion, adhesive tape scraping, impregnating agent, and gel.

Examples of the impregnating agent include those obtained by adsorbing the external pharmaceutical composition or a composition containing a third component using a suitable adsorbent (gauze, filter paper, porous membrane, etc.).
It is generally applied to the outer shell by fixing it with adhesive tape. Further, examples of the gel agent include those made into a gel using an alcohol gelling agent (eg, Gelol (manufactured by Shinnihonsha Co., Ltd.)) and spread on a support. Examples of base materials for adhesive tapes include acrylic copolymers, polyvinyl ether compounds, and synthetic rubber adhesive mixtures. Other external preparations can also be easily prepared by means known per se.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples and Experimental Examples, but the present invention is not limited to these in any way.

Examples 1 to 6 [Basic formulation] (1) Diazepam 8 da (2) Ethanol 'l2f (8) Auxiliary agent 25F Using each of the auxiliary agents shown in Table 1, the liquid composition fik' of the above basic formulation, 'N4 was prepared by first mixing (8) with (2) and then reinterpreting (1).

Hisoft Zen n1 (1) Diazepam 3fI (2) Ethanol 9’1 A liquid composition was obtained by translating the above (1) into (2).

Comparative Example 2 (1) Diazepam 3y (2) Dimethyl sulfoxide 97F or higher (1
) was dissolved in (2) to obtain a rod-shaped composition.

Comparative Example 8 (1) Diazepam 3v (2)
Ethanol '12 (/(8) General formula (1)
Compound (referred to as compound a) 25g Comparative Example 4 (1) Diazepam 3g (2)
Ethanol 721/(4) General formula (1
), n=16 compound (viscosity: 10 centistokes) [compound name] 25v Experimental Example 1 Drug sheath I# in the liquid compositions of Examples 1 to 6 and Comparative Examples 1.8 and 4 Measurements were made using rat abdominal skin from which the transmittance was excised, and the results are shown in Table 1.

(Measurement method) A rat skin was attached to a glass transmission cell so that the front side of the skin was in contact with the above liquid composition, and the back side of the skin (1+11) was in contact with the physiological saline, and the rat skin was exposed to the physiological saline. Extract the drug that has passed through with benzene and analyze it with spectroscopic light.
It was quantified at h.

(Margins below) Table 1 Experimental Example 2 Liquid ff4t obtained in Examples 1 and 2 and Comparative Examples 1 and 2 was applied to the dehaired back of a 3.5 kg white rabbit.
A 4r4 case impregnated with an acid was applied to the blood, which was collected in a sutra-like manner, extracted using a conventional method, and quantified by gas chromatography with a 4φ detector.Table 2 shows the results. It was shown to.

Table 2 Example 7, Experimental Example 3 (1) Clonidine-base o, 5y (2
) Ethanol 75.2F (8)
Hexamethyldisiloxane 25 F (viscosity f9
-: 0.65 centistokes (2), (8) above
Dissolve (1) in a sanitary cloth, apply the above F8 paste impregnated with 0.5 d of case to the shaved abdomen of a Wistar rat, and then measure the electrical artery pressure. Table 3 also shows the tail lU1 pulse pressures of the Kasei liquid compositions of Comparative Examples 5 and 6 as a control.

Comparative Example 5 (1) Clonidine-base 0.8-(2) Ethyl alcohol 972 g Comparative Example 6 (1) Ri-o=resin 1M group 0.81(2)
Dimethyl sulfoxide 99.29 Table 8 Example 8 (1) Indomethacin 1.0 Da (2)
Ethyl alcohol 76.0f(8) Decamethyltetrasiloxane 23.Of (viscosity -1 centistoke) The above (1), (2) and (8) were mixed in the same container to obtain a liquid composition.

Comparative Example 7 (1) Indomethacin 111(2)
Ethyl alcohol 99 f (1) above (2)
dissolve in

Comparative Example 8 (1) Hibiswako-1040 (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) 1
, (1 (2) Indomethacin 1.0y (8)
Propylene glycol 12.0y (4) Ethyl alcohol 30 9 (5) Diisopropyl adipate 2゜0ff6) Diisopropyl amine 1.1f (7) Purified water Sufficient amount to make a total of 100g (5) Add the above (1) 20g water
1. (B) Substitute (2) above for (3) and (4) above.
) and (5). (0) Add (B) above to (4) above and stir until completely hydrated. (
1) Add the above (6) to 10 y of water and add it to the above (0), then add a small amount of water and stir until the whole is homogeneous.

Experimental Example 4 Rat skin permeation of indomethacin 200F Wistar type miscellaneous problems The skin of the rat's firm skin was removed using hair clippers and a Braun electric razor, and then the skin 1~ was peeled off and placed in a glass drug permeation cell. 8 Kei and Comparative Examples 5 and 6 were applied in an amount of 15 owy per 11 parts of sebum, and 6 amounts of indomethacin per 11 parts of the skin layer was applied. The results are shown in Table 4.

Patent applicant: Memushi Electric Industry Co., Ltd. Kinsha representative Patent attorney ± 1 so! After that, - Procedural amendment (
1. Indication of the case 1982 Patent Application No. 01210 da 3. Person making the amendment Relationship with 1 case Patent applicant (396) 4. Agent 〒54] 6. Number of inventions increased by the amendment N/A 7 , Truth of the "Detailed Description of the Invention" in the specification to be amended (1) All "Gluol D (manufactured by Shin Nippon Rika Co., Ltd.)" that says "Gel All (manufactured by Shin Nippon Rika Co., Ltd.)" in line 8 of No. 9 of the specification ” is corrected.

Procedural amendment (spontaneous) 1 Indication of the case 1982 Patent Application No. 012102 2 Title of the invention Base composition and external pharmaceutical composition 3 Person making the amendment Relationship with the case Patent applicant (396) 7. Column 8 of "Detailed Description of the Invention" of the specification to be amended, contents of amendment <1) Correction to "A certain meeting" in Table 2 of Specification Ip, 13 Jada 0 or more (2)

Claims (1)

[Scope of Claims] (1) Bf selected from linear polydimethylsiloxanes having a viscosity at 25°C of 8 centistokes or less and cyclic polydimethylsiloxanes having a viscosity at 25°C of 6 centistokes or less. 1. A base composition capable of improving transdermal absorption of a drug, characterized by containing at least one compound and a lower alcohol. (2) The amount of the compound is 1 to 411 alcohol
~50% by weight of the base composition according to claim box (1). (8) At least one part of linear polydimethylsiloxane having a viscosity at 25°C of 3 centistokes or less and a cyclic polymethylsiloxane having a viscosity of 6 centistokes or less at 25°C separated by Offshore compound. External medicinal products containing lower alcohol and drugs) jk, products. (4) The amount of the compound, or cut it into lower alcohol and
Claim (8) Nr2 topical medicine with 50% contribution! 1 product. (5) External medicine-M according to claim 8, 10 or 4, wherein the drug 'IN is benzocyasebins.
Japanese products. (6) ,! l/! It's something like indomethacin! 1-
1f, Ir+ ili++, item (8) or (4)
) External medical preparations described in section 2.). (7) Claim No. (8) in which the drug is clonidine
The external medical composition described in item (4) or item (4) above.