JPS58164520A - Base composition and drug composition for external use - Google Patents

Abstract

PURPOSE:The titled composition having raised endermic absorption, containing a compound selected from a specific saturated hydrocarbon, a fatty carboxylic acid alcohol ester, etc., dimethylpolysiloxanes having a given viscosity range, and an imidazolidinone derivative. CONSTITUTION:A base containing at least one compound selected from 5-20C saturated hydrocarbon which may be replaced with a halogen, 12-18C fatty carboxylic acid alcohol ester (e.g., hexyl laurate), an ether (e.g., dibutyl ether), dimethylpolysiloxane having <=6 centistoke viscosity at 25 deg.C, and cyclic polydimethylsiloxane having <=6 centistoke viscosity at 25 deg.C and an imidazolidinone derivative shown by the formula (R<1> and R<2> are lower alkyl). The amount of the compound blended is preferably 1-50wt% based on the imidazolidinone derivative, and a benzodiazepine, indomethacin, etc. are used as a drug.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides Mj, a cutting composition, and
and an external pharmaceutical composition using the base composition.

Conventionally, drugs administered to the integument have been intended to act locally on the integument or its underlying tissues, such as sterilization, disinfection, and disinfection. However, in recent years, attempts have been made to administer drugs with systemic effects to the outer skin in addition to orally or by injection. When drugs, especially systemic drugs, are administered transdermally,
It is easy to maintain drug efficacy, and the absorption rate of the drug is improved by wM.
Since it is easy to administer, it is possible to reduce the effect of the drug by administering a dose, and it is possible to effectively utilize the drug due to the first-pass effect on the liver that is associated with oral administration. It has the advantage that even drugs that cause gastrointestinal disorders when administered orally, such as indomethacin, can be administered safely.

However, since normal skin has a protective effect on the body, it generally has a property that it is difficult to absorb and permeate drugs. Therefore, even if a drug (particularly a drug intended for systemic action) is administered in the form of a conventional ointment, lotion, etc., the drug will not be absorbed into the body in an amount sufficient to produce a sufficient medicinal effect.

In view of this situation, the inventors of the present invention conducted a series of researches and obtained the following findings.

■ 5 to 20 carbon atoms that may be substituted with /%Q poppy
saturated hydrocarbon, alcohol ester of aliphatic carboxylic acid having 12 to 18 carbon atoms, ether, viscosity at 25 °C is 6
At least one compound selected from the group consisting of dimethylpolysiloxane having a viscosity of 6 centistokes or less and V polydimethylsiloxane having a viscosity of 6 centistokes or less at 25°C (hereinafter sometimes collectively referred to as auxiliary agent), and the general formula ( (1) The composition containing the imidazolidino/derivative represented by the following formula (wherein R1 and R8 each represent a lower alkyl group) increases transdermal absorption of the drug into the blood; (1) The above composition is applied to the integument; The present invention was completed by discovering scales that can be used as a base for drugs.

Therefore, the first object of the present invention is to provide a base composition that enhances transdermal absorption of drugs.

A second object of the present invention is to provide a composition for external medicine 1 in which the drug has good percutaneous absorption.

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

That is, the present invention provides: (1) A base composition capable of enhancing transdermal absorption of a drug, which contains at least one auxiliary agent and an imidazolidinone derivative (1).

(2) An external pharmaceutical composition in which a drug is blended into the above base composition.

It is.

Regarding the general formula (1), the lower alkyl groups represented by R1 and R8 each have a carbon number of 1, such as methyl, ethyl, n-propyl, 110-propyl, n-butyl, etc.
-4 is exemplified, and among the dark ones, particularly preferred are methyl and ethyl (among others).

methyl).

The saturated hydrocarbon having 5 to 20 carbon atoms which may be substituted with halogen used in the present invention may be linear, branched, or cyclic.
- Pentane, n-hexane, n-hebutane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tetradecane, n-hexadecane, n-octadecane, n-eicosane, etc. Among these, preferred are those having 6 to 16 carbon atoms.

As branched ones, for example, 2-methylpenotane,
2,8 dimethylhexane, 2,2,4,4,6°8.8
Examples include 1-heptamethylnonane, limonene, etc.
Among these, those having 6 to 16 carbon atoms are preferred. Examples of cyclic compounds include those having 6 to 12 carbon atoms, such as cyclohexane, cyclododecane, and decalin. Examples of halogens used as t&substituents include chlorine, bromine, etc., and examples of those having halogen substitution include octyl bromide, dodecyl bromide, hexadecyl bromide, dobusil bromide, etc. with an R prime number of 8 to 16. Examples include saturated direct halogenated hydrocarbons.

The carboxylic acid moiety in the alcohol ester of aliphatic carboxylic acid of FIHI5 [12 to 18] includes fatty acid (
Among them, R prime numbers 12 to 18) are preferred, and the mata alcohol moiety is methyl alcohol, ethyl alcohol, n-furobyl alcohol, 1so-propyl alcohol, n-butyl alcohol, 1so-phthyl alcohol% n-pentyl Preferred examples include m-alcohols having numbers 1 to 6. Preferred alcohol esters of carboxylic acids include hexyl laurate, isopropyl myristate, isopropyl palmitate, butyl stearate, and the like.

Ethers include those with 8 to 16 carbon atoms and one ether bond per molecule, such as dibutyl ether,
Examples include dioctyl ether, dioctyl ether, methoxydodecane, ethoxydodecane, and 1.8 cineole.

The base composition of the present invention comprises an imidazolidinone derivative (1)
It is prepared by adding an auxiliary agent to the imidazolidinone derivative (1) and dissolving it uniformly.
iii%. Of course, pharmaceutically acceptable additives may be added to the base composition.

Preferred examples of the linear polydimethylsiloxane having a viscosity of 6 centistokes or less at 25°C used in the present invention include compounds represented by the formula (where n is an integer from θ to 6). Specific examples thereof include hexamethyldisiloxane, decamethyltetrasiloxane, dodecamethylpentasiloxane, tetradecamethylhexasiloxane, and octadecamethyloctasiloxane. In addition, examples of cyclic polydimethylsiloxanes having a viscosity of 6 centistokes or less at 25°C include cyclooctamethyltetrasiloxane, cyclodecamethylpentasiloxane, etc.
Preferred examples include membered rings.

Further, the external pharmaceutical composition of the present invention is split by adding a drug to the base composition and uniformly mixing or dissolving the drug.

By the way, for drugs intended for local action on diseases of the integument or its underlying tissues, a certain effect can be obtained by conventional external preparation, so the drug related to the external pharmaceutical composition of the present invention does not enter the bloodstream. It is meaningful that the drug be absorbed and exhibit its medicinal effects, that is, it should be a drug that aims to have a systemic effect.

Drugs include specifically benzodiazepines (e.g., diazepam, nitrazebam, flunitrazebam, lorazepam, prazepam, fludiacepam, clonazepam), antihypertensive agents (e.g., clonidine), anti-inflammatory agents (e.g., indomethacin, cyclofenac), thiazides. Examples include diuretics (for example, cyclopenthiazide, trichlormethiazide), antiarrhythmia agents (for example, asiarin, quinidine, and neuropsychiatric M (for example, haloperidol, butylscopolamine, chloropromacine), etc.).

The amount of the drug to be mixed is sufficient as long as it is sufficient to achieve the desired medicinal effect, and it varies depending on the type of drug, patient's weight, symptoms, etc., and should be selected appropriately according to these conditions. Generally speaking, drugs are 0.2 volume% to 10ffi.
Although the amount added is preferably % by weight, the amount added can be adjusted by appropriately increasing or decreasing the skin area of the pharmaceutical composition, so it is not necessarily limited to the amount added above.

The external pharmaceutical composition according to the present invention can be used as it is or with the addition of a pharmaceutically acceptable third component to form an ointment, a plaster, a lotion, an adhesive tape scraper, or an impregnating agent.

It is administered to the skin as an external preparation such as a gel.

Examples of impregnating agents include those made by absorbing the external pharmaceutical composition or a composition containing a third component onto a suitable adsorbent (gauze, P paper, porous membrane, etc.),
This is applied to the outer skin by fixing with a general number and adhesive tape. In addition, as a gel agent, for example, an alcohol gelling agent [eg, Gel All D (manufactured by Shin Nippon Rika Co., Ltd.)]
] can be used to form a gel and spread it on a support. Acrylic copolymers and polyvinyl ether compounds were the beginnings of adhesive tapes.

Examples include synthetic rubber adhesive mixtures. Other external preparations can also be easily prepared by means known per se.

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

Example 1-19 [Basic prescription] (1) Diazepam 8g (2) 1,8-dimethyl-2-imidazolidinone 2f (8) Auxiliary agent 25F Using each of the auxiliary agents shown in Table 1, the above First, mix (8) with (2) and then (
Ill was prepared by dissolving 1).

Comparative example 1 (1) Diacepam 8F (2) 1,8-dimethyl-2-imidazolidinone 7F A liquid composition was obtained by dissolving (1) in (2).

Comparative Example 2 (1) Diazepam 8f (2) Dimethyl sulfoxide 911 or more (1
) was dissolved in (2) to obtain a liquid composition. - Experimental Example 1 The amount of drug permeation through the skin in the liquid compositions of Examples 1 to 19 and Comparative Example 1 was measured using excised rat abdominal retractions, and the results are shown in Table 1.

(Measurement method) The rat skin was attached to a glass transmission cell so that the part corresponding to the front side of the skin was in contact with the above liquid composition, and the part corresponding to the back side of the skin was in contact with the physiological saline, and the saline was allowed to pass through the rat skin. The resulting drug was extracted with benzene and quantified using a spectrophotometer.

(Margins below) Table 1 Experimental Example 2 A 4-d gauze impregnated with Example 2 and IO and Comparative Examples 1 and 2 was pasted on the dehaired back of a white rabbit weighing 8.6 kti, and blood was collected over time. 1 The usual one.

Table 2 Example 20. Experimental Example 8 (1) Clonidine-base 0.8v (2)
IJ-dimethyl-2-imidazolidinone' 15.2 g (8) Isopropyl myristate 26 f Above (
2) and (8) were mixed, and (1) was further dissolved, and the above solution impregnated with gauze of 0.5 d was pasted on the abdominal hair removal area of a Wistar rat to measure the caudal artery pressure. The results are shown in Table 8, and as a control, the caudal artery pressures of the dispersion compositions of Comparative Examples 8 and 4 are also shown.

Comparative Example 8 (1) Clonidine-base 0.81(2) 1
．． 8-Dimethyl-2-imidazolidinone 97,2F Comparative Example 4 (1) Clonidine-base 0.81 (2) Dimethyl sulfoxide 99.2F Example 21 (1) Indomethacin 1.0f (2)
1.8-dimethyl-2-imidazolidinone'16.0
f (8) n-dodecane 2B, Of (1) above,
(2) and (8) were mixed and dissolved in the same container to obtain a liquid composition.

Comparative Example 5 (1) Indomethacin If(2) 1
．． 8-dimethyl-2-imidazolidinone 9 g Dissolve the above (1) in (2).

Comparative Example 6 (1) Hibis Wako 104■ (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) 1
．． 0f <2) Indomethacin 1.0f (8) Propylenegutucol 12.0f (4) Ethyl alcohol 80 f (5) Diisopropyladipate 2. Og (6) Diisopropanolamine 1.1F (7) Purified water Enough to make a total of 1001 - (4) Swell the above (1) in 209 of water.

CB) Replace (2) above with (8), (4) and (5) above.
dissolve in Add phantom) above to (4) above and stir until completely hydrated. (2) Dissolve the above (6) in 10F water and add it to the above U, then add the remaining amount of water and stir until the whole is homogeneous.

Experimental Example 4 Indomethacin rat skin dander permeator MA 200 f The abdominal skin of a male Wistar rat was hair-removed using hair clippers and an electric razor manufactured by Braun, and the skin legs were peeled off and placed in a glass drug-permeable cell.

The above Example 21 and Comparative Examples 5 and 6 were applied at a rate of 150"f per ld of skin, and the skin permeation range of indomethacin was determined. The results are shown in Table 1.

Procedural amendment (voluntary) 1982 Patent Application No. 046642 2 Title of the invention Base composition and external pharmaceutical composition - 3 Relationship with the case of the person making the amendment Patent applicant's residence!・11 Mr. I'+ ('t'+ S・) Nitto Electric Kogyo Co., Ltd. (396) 7 Subject of amendment (1) In Table 2 on page 15 of Specification 11, ``+n'' is corrected.

that's all

Claims (1)

[Claims] (1) Carbon 5Xi which may be substituted with halogen! 5～
20 saturated hydrocarbons, alcohol esters and ethers of aliphatic carboxylic acids having 12 to 18 carbon atoms, dimethylpolysiloxane with a viscosity of 60 centistokes or less at 25°C, and cyclic polysiloxanes with a viscosity of 6 centistokes or less at 25°C. At least one compound selected from dimethylsiloxane and the general formula (wherein R1 and R8 each represent a lower alkyl group,
vinegar. ) A base composition capable of enhancing transdermal absorption of a drug, characterized by containing an imidazolidinone derivative represented by: (2) The base composition according to claim (1), wherein the amount of the compound is 1 to 50% by weight based on the imidazolidinone derivative. (8) 1 with halogen! ! Saturated hydrocarbons having 5 to 20 carbon atoms which may be substituted, alcohol esters of fatty acids and carboxylic acids having 12 to 18 carbon atoms, ethers, dimethylpolysiloxanes having a viscosity of 6 centistokes or less at 25°C, and 25°C At least one compound selected from cyclic polydimethylsiloxanes having a viscosity of 6 centistokes or less, an imidazolidinone derivative represented by the general formula (wherein Ll and R8 each represent a lower alkyl group), and a drug. An external pharmaceutical composition comprising: (4) Claim No. 1, wherein the amount of the compound blended is 1 to 601 L'% based on the imidazolidinone derivative.
The external pharmaceutical composition according to item 8). (6) The external pharmaceutical composition according to claim (8) or (4), wherein the drug is a benzodiazepine. (6) Claim m in which the drug is indomethacin (
8) Shelf or the external pharmaceutical composition described in item (4). (7) Claim No. (8) in which the drug is clonidine
The external pharmaceutical composition according to item or item (4).