JPS63203630A - Percutaneous absorption-promoting agent - Google Patents

Abstract

PURPOSE:To obtain the titled promoting agent containing a specific cyclohexane derivative as an active ingredient. CONSTITUTION:Percutaneous absorption-promoting agent containing at least one compound (e.g. 2-tert. butylcyclohexanone, 2-hexylcyclohexanone, 2- heptylcyclohexanone, etc.) selected from cyclohexanone derivatives having at least one hydrogen atom in 2 and 6 position substituted by a hydrocarbon group as an active ingredient. The promoting agent is added in an amount of 0.1-10wt.% to a base for external medicine such as ointment, poultice, plaster, adhesive tape agent, lotion, gelling agent, etc. The medicine (e.g. local anesthetic such as lidocaine, antibiotic such as tetracycline hydrochloride, antifungal agent such as gluceofrubin, etc.) which is a main agent is blended in an amount of 0.01-20wt.% based on the total weight.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a transdermal absorption enhancer that is added to the base of various external preparations for the purpose of promoting transdermal absorption of pharmaceuticals.

BACKGROUND OF THE INVENTION Regarding the administration of drugs, there are various methods depending on the characteristics of the drug itself, the presence or absence of side effects, the purpose of administration, etc., and one of these methods is transdermal administration.

Formulations suitable for transdermal administration include ointments, poultices, plasters, adhesive tapes, lotions, gels, and the like.

Each of these external preparations contains a drug that exhibits a desired therapeutic effect in a variety of bases, and is used by being applied or pasted onto a target body part. Pharmaceutical products in formulations are absorbed through the skin, permeate to the site of action, or are transported to each site of action by the blood to exert their unique pharmacological effects.

However, since the skin originally has a barrier function to prevent foreign substances from entering the body, there are cases where the drug is not absorbed sufficiently and the blood concentration cannot be raised to the extent that the desired therapeutic effect can be achieved. This is one of the obstacles to transdermal administration of drugs.

Therefore, especially when the drug is intended for systemic action, it is necessary to add a transdermal absorption enhancer to the external preparation in order to eliminate such disorders.

In recent years, various types of transdermal absorption enhancers have been developed. For example, amide compounds such as dimethyl sulfoxide and dimethylacetamide, azacycloalkan-2-one derivatives such as 1-dodecyl azacyclohebuta/-2-one, and combinations of alcohols and carboxylic acids such as isopropyl myristate and isopropyl palmitate. Ester, urea, pyrrolidone derivatives, etc. are known.

Problems to be Solved by the Invention As mentioned above, various transdermal absorption enhancers are known, but their absorption promoting effects are still not sufficient. Furthermore, even though they have a fairly high absorption promoting effect, there are some that are highly irritating to the skin (e.g. dimethyl sulfoxide, pyrrolidone derivatives, etc.). Since external preparations are intended for use on humans, the use of compounds with strong skin irritation effects must be avoided.

Means for Solving the Problems The present invention was made for the purpose of developing a transdermal absorption enhancer that does not have an irritating effect on the skin and can exhibit a sufficient transdermal absorption promoting effect.

As a result of extensive research into transdermal absorption enhancers for drugs, the inventors discovered that in derivatives with cyclohexanone as the core, at least one hydrogen atom at the 2- and 6-positions is substituted with another hydrocarbon group. The present inventors have discovered that this product has a strong transdermal absorption promoting effect and is superior to known transdermal absorption enhancers, leading to the present invention.

That is, an object of the present invention is to provide a transdermal absorption enhancer comprising at least one compound selected from cyclohexanone derivatives in which at least one hydrogen atom at the 2nd and 6th positions is substituted with a hydrocarbon group.

Effects Cyclohexanone derivatives are compounds that are widely used as starting materials in the synthesis of various compounds in the field of organic synthetic chemistry, but it was never predicted that they would have the effect of promoting transdermal absorption of drugs. moreover,
The transdermal absorption promoting effect related to the present invention is specifically observed only in cyclohexanone derivatives in which at least one hydrogen atom at the 2- and 6-positions is substituted with a hydrocarbon group; Even if the isomer is bonded to a site other than the 2nd or 6th position, no transdermal absorption promoting effect is observed.

The substituents at the 2- and 6-positions of the cyclohexanone derivative constituting the transdermal absorption enhancer of the present invention may be either saturated hydrocarbon groups or unsaturated hydrocarbon groups, and the arrangement may be linear, branched, It may be any ring shape. Note that even if a plurality of these molecular groups are included in the same side chain, the effect is exhibited.

Specifically, saturated hydrocarbon groups include, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t,-butyl, n-pentyl, n-hebutyl, n-octyl, n-decyl. Examples include groups, and those having 1 to 20 carbon atoms are preferred. Examples of unsaturated hydrocarbon groups include propenyl, n-butenyl, 2-pentenyl, 4
-hexenyl, 3-octenyl, etc., and those having 1 to 20 carbon atoms are preferred.

In particular, the cyclohexanone derivatives constituting the transdermal absorption enhancer according to the present invention include, for example, 2-t. -Butylcyclohexanone, 2-hexylcyclohexanone, 2
-heptylcyclohexanone, 2-(3-octene)cyclohexamine, 2-succilcyclohexane, 2-t6
-butyl-6-octylcyclohexanone, 2.6-dioctylcyclohexanone, 2-butyl-6-decanecyclohexanone, 2.6-dibutylcyclohexanone,
2-octyl-6-heptylcyclohexanone and the like are effectively used.

According to the present invention, the above-mentioned compounds are used alone or in a mixture as transdermal absorption enhancers, and the amount of these transdermal absorption enhancers is determined by the type of preparation used and the purpose of use (slow-acting, quick-acting). (e.g.), the type and chemistry of the base for the formulation, the type of main drug (locally acting drug, systemically acting drug), chemistry (interaction with transdermal absorption enhancers, etc.), etc. However, in general, it is determined by the weight of the formulation base.
．． The amount is selected from 1 to 10% by weight.

The drug to be mixed with the transdermal absorption enhancer of the present invention is not particularly limited as long as it can be administered transdermally, and various drugs can be used for the purpose of local action and systemic action. By using the transdermal absorption enhancer of the present invention, for drugs intended for local action, the drug penetrates deep into the site of action, and for drugs intended for systemic action, the drug quickly moves into the bloodstream. , an effective blood concentration is obtained.

Specifically, locally acting drugs include local anesthetics (e.g., lidocaine, propylene hydrochloride, tetrahydrohydrochloride, dypcaine hydrochloride, etc.), antibiotics (e.g., tetracycline hydrochloride, penicillin G1 erythromycin, lincomycin, kanamycin, oxychloride, etc.). tetracycline, chloramphenicol, nyscutin, gramicidin hydrochloride, etc.), antifungal agents (e.g., gluceofulvin,
N-methyl-N-(3-tolyl)thiocarbamic acid-2
-naphthyl esters, oleothricin, siametazole hydrochloride, pyrrolnitrile, etc.), and antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, diphenylimidazole, etc.).

Systemically acting drugs include specifically nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ketoprofen,
ibuprofen, mefenamic acid, flurbiprofen,
diclofenac, etc.), antihypertensive agents (e.g., clonidine, bunitrol, propranolol, captopril, etc.), anticancer agents (e.g., ethosuximide, phenytoin, brimidone, etc.), antiarrhythmic agents (e.g., ajmaline, pindolol, propranolol, quinidine, Brush, etc.) (Marin, etc.), neuropsychiatric agents (Tatoeba, Haloperil, Moperone, Clofluperilol, etc.), benzodiazepines (e.g., diazepam, nitrazebam, lorazepam, fludiazepam, fludiazepam, etc.), diuretics ( For example, polythiazide, methyclothiazide, pendroflumethiazide, hydrochlorothiazide, diphenhydramine, curbinoxamine, fenbenzamine, chlorpheniramine, etc.)
Antitussive and expectorant agents (e.g. codine phosphate, ephedrine, noscapine, dextromethorphan, salbutamol sulfate, tulobuterol hydrochloride, bromhexine hydrochloride, theophylline, sodium chromglyphate, etc.), anticancer agents (e.g. 5-)l orouracil, 1-(2- vasodilators (e.g., nitroglycerin, isosorbitcinitrate, diphenyl, etc.), antibiotics (e.g., tetracyclines, chloramphenicols, erythromycins, etc.).

The amount of the main drug to be blended is sufficient as long as it has a therapeutic effect, and depends on the type of drug, patient's weight, symptoms, etc., and is appropriately selected depending on these conditions. Generally, the amount is preferably in the range of 0.01 to 20% by weight based on the total weight of the transdermal absorption enhancer according to the present invention and the base. In addition, since the amount of drug used can be adjusted by increasing or decreasing the skin application area, it is not necessarily limited to the above-mentioned amount.

The external pharmaceutical composition containing the transdermal absorption enhancer according to the present invention can be used as it is or with the addition of a known pharmaceutically acceptable third component to form ointments, poultices, plasters, adhesive tapes, and lotions. It is administered to the skin as an external preparation such as a gel.

The transdermal absorption enhancer of the present invention has no irritating effect on the skin, and this property is also advantageous as a transdermal absorption enhancer.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Synthesis Example 2 - Synthesis of octylcyclohexanone (C112) 7 H3 Cyclohexanone (2.24 mol) was refluxed with sodium amide (2.05 mol) using anhydrous ether (10 mol) as a catalyst under a Nt stream for 3 hours. Made me react.

After cooling, 1-octyl bromide (2.03 mol) was quickly added together with anhydrous ether and refluxed for a further 3 hours.

After completion, the target product was purified by silica gel 60 column liquid chromatography. The purified target product was confirmed by NMR, elemental analysis, and MS.

Purity was 98%.

The other cyclohexanone derivatives mentioned above can also be synthesized according to the above synthesis examples with some modifications by changing the reaction starting materials and reactants.

Example 1-IO Transdermal absorption enhancers made of various 2-substituted and 2.6-substituted cyclohexanone derivatives according to the present invention were used in various external preparations, and the promotion of transdermal absorption of the main drug was tested. did.

Table 1 shows the type and blending machine of the drug, the form and base of the formulation, the type and amount of the transdermal absorption enhancer used, and the experimental method and results.

In addition, in the table, A shown in the experimental method column is in vitro.

This is a drug permeation test using pig skin in an experiment, and 1 after drug addition.
The amount of drug permeation up to the 0th hour was measured. B: In an in vitro experiment, the abdomen of a rat was dehaired, and if ointment was applied to the site, a sample t. 59 was applied, and 3 x 3 am samples were applied to the others, and the blood concentration of each drug at the time of C wax was measured. C, like B, is an in vitro experiment using rabbits, in which the sample amounts were 5 g and 5 x 5 cm, respectively.

Furthermore, the effect value F is expressed by the following formula.

X: Amount of drug permeated or blood concentration when no transdermal absorption enhancer is added Y: Amount of drug permeated or blood concentration when various transdermal absorption enhancers are added as shown in Table 1 Furthermore, it is understood that the transdermal absorption enhancer of the present invention exhibits an excellent transdermal absorption promoting effect.

Examples 11-13 These examples demonstrate that cyclohexanone derivatives substituted at the 2- or 6-position are more effective than substituted derivatives at other positions.

Each data is shown in Table 2. In the table, the experimental methods and effect values are the same as in Table 1.

Table 2 From the results shown in Table 2, the transdermal absorption promoting effect related to the present invention is unique to cyclohexanone derivatives in which at least one hydrogen atom at the 2- and 6-positions is substituted with a hydrocarbon group. It is clear that this is an effect.

In addition, as a result of conducting local irritation tests (skin secondary irritation, skin cumulative irritation) on various cyclohexanone derivatives according to the present invention using rabbits according to the Draize method, no irritation was observed□ .

Effects of the Invention As described above, cyclohexanone derivatives in which at least one hydrogen atom at the 2- and 6-positions is substituted with a hydrocarbon group exhibit the effect of promoting good transdermal absorption of various drugs, and are moreover effective in promoting good transdermal absorption of various drugs. Because there is no stimulatory effect on
It is advantageously used as a transdermal absorption enhancer in external preparations.

Claims (1)

[Scope of Claims] 1. A transdermal absorption enhancer comprising at least one compound selected from cyclohexanone derivatives in which at least one hydrogen atom at the 2nd and 6th positions is substituted with a hydrocarbon group. 2. The product according to claim 1, wherein the hydrocarbon substituent is a linear chain having 1 to 20 carbon atoms,
A transdermal absorption enhancer that is a branched or cyclic saturated or unsaturated hydrocarbon group. 3. The product according to claim 2, wherein the saturated hydrocarbon group is methyl, ethyl, n-propyl, iso-propyl, n-butyl, t. - A percutaneous absorption enhancer which is a butyl, n-pentyl, n-heptyl, n-octyl or n-decyl group. 4. The transdermal absorption enhancer according to claim 2, wherein the unsaturated hydrocarbon group is a propenyl, n-butenyl, 2-pentenyl, 4-hexenyl or 3-octenyl group. 5. The compound according to claim 1, wherein the compound is 2-t. -butylcyclohexanone, 2-hexylcyclohexanone, 2-heptylcyclohexanone, 2-(3-octene)cyclohexanone, 2-octylcyclohexanone, 2-t. -Butyl-6-octylcyclohexanone, 2,6-dioctylcyclohexanone, 2-butyl-6-decanecyclohexanone, 2,6
- A transdermal absorption enhancer selected from dibutylcyclohexanone and 2-octyl-6-heptylcyclohexanone. 6. In the product described in claim 1, ointment,
A transdermal absorption enhancer that is added in an amount of 0.1 to 10% by weight to a base for external preparations such as poultices, plasters, adhesive tapes, lotions, and gels.