JPH0479328B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a composition for dermal administration that can enhance transdermal absorption of drugs, and a method for promoting transdermal absorption of drugs. [Prior Art] Conventionally, when drugs were administered to the integument, the aim was to have a local effect on the integument or the subcutaneous tissue immediately below it, such as sterilization, disinfection, analgesia, antipruritic, and antiinflammatory effects. Furthermore, when a systemic effect is desired, administration has conventionally been carried out through oral tablets or injections. In the case of oral tablets, they have the disadvantage that they are easily subjected to primary hepatic metabolism after absorption, and that the concentration in the body becomes higher than necessary in order to maintain the effect. In addition, some drugs, such as indomethacin, cause gastrointestinal disorders when administered orally. On the other hand, administration by injection allows rapid absorption, but requires a specialist such as a doctor. In recent years, transdermal administration methods aiming at systemic effects have been proposed in order to improve the above-mentioned side effects and drawbacks. When a drug is administered transdermally, it is easy to sustain the drug, making it possible to control the concentration of the drug in the body, and because it enters the bloodstream directly from the skin tissue, it has the advantage of being less susceptible to primary hepatic metabolism. . However, since normal skin inherently has a barrier function to prevent foreign substances from entering the body, the purpose of administering medicines through the skin has been limited to local use. For this reason, when the purpose is to have a systemic effect, a transdermal absorption promoting agent is necessary, and various kinds of agents have been proposed in recent years. For example, U.S. Pat.
No. 3551554 contains dimethyl sulfoxide,
dimethylacetamide, dimethylformamide,
Methyldecyl sulfoxide and the like are disclosed. In addition, absorption promoting aids in combination with lower alkylamide include dimethylacetamide and ethyl alcohol, isopropyl alcohol, isopropyl palmitate (US Pat. No. 3,472,431), 2-pyrrolidone and a suitable oil, and esters of straight chain fatty acids and alcohols. Example of combining (U.S. Patent No. 4017641)
No.), etc., but these absorption promoting aids have no effect,
It is still not sufficient in terms of safety and usability. Under these circumstances, the present inventors have conducted intensive research and have obtained the following knowledge. In other words, the specific isonicotinic acid ester () mentioned below increases the skin permeability and transdermal absorption of the drug, and furthermore, the effect can be further enhanced by using the isonicotinic acid ester () in combination with a specific compound. I found that it can be improved. [Problems to be solved by the invention] The present invention was completed based on the above new findings, and its first purpose is to improve skin permeability of drugs,
The object of the present invention is to provide a composition for dermal administration that can enhance percutaneous absorption. A second object of the present invention is to provide a method for increasing skin permeability and percutaneous absorption of drugs. [Means for Solving the Problems] The present invention provides the general formula (In the formula, R represents a saturated, unsaturated or cyclic alkyl having 5 or more carbon atoms.) A composition for dermal administration comprising an isonicotinate ester () represented by: In addition to the isonicotinate ester () Skin permeation of a drug, characterized in that the drug is administered dermally in the presence of an external preparation base composition and an isonicotinic acid ester (2), further containing the following specific polar compound, and preferably in the presence of the following specific polar compound. The present invention relates to a method for increasing transdermal permeability, transdermal permeability, and transdermal absorption. In the present invention, lower alkyl includes methyl, ethyl, n-propyl, iso-propyl,
Examples include those having 1 to 4 carbon atoms such as n-butyl and iso-butyl. Regarding the general formula (), the alkyl having 5 or more carbon atoms represented by R may be saturated, unsaturated, chain, or cyclic. The alkyl preferably has 6 to 24 carbon atoms. The saturated chain alkyl preferably has 5 to 20 carbon atoms, such as n-pentyl,
n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n
- Straight chain ones such as hexadecyl, n-octadecyl, n-eicosyl, 2-methylhexyl, 2
-ethylhexyl, 2-octyldodecyl, 2,
Branched ones such as 4,4-trimethyl-1-pentyl and 1-methyloctyl are mentioned. The number of carbon atoms in the unsaturated chain alkyl is preferably 6 to 24, for example
Examples include cis-3-hexenyl, oleyl, linoleyl, and the like. The total number of carbon atoms in the cyclic alkyl is 6 to
12 is preferable, and examples include ring-containing alkyl such as 2-cyclohexylethyl, cycloheptyl, cyclohexylmethyl, cyclooctyl, 4-cyclohexylbutyl, isopropylcyclohexyl, and the number of carbon atoms forming the cyclic portion is 6 to 6.
8, ie 6- to 8-membered rings are preferred. Specific polar compounds used in the present invention include lower alcohols, glycerin, glycerin esters,
Thioglycerol, lactic acid, lactic acid ester, general formula [In the formula, R ₁ and R ₂ are each hydrogen or lower alkyl (preferably one having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl)
Cyclic urea represented by the general formula [In the formula, R ₃ , R ₄ and R ₅ each represent a hydrogen atom or lower alkyl (preferably one having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl)] Amide compounds, alkylene glycols, monoalkyl ethers of mono- or diethylene glycol, lactones, general formula [In the formula, R ₆ , R ₇ , R ₈ and R ₉ are each a hydrogen atom or lower alkyl (preferably methyl,
ethyl, n-propyl, iso-propyl, n-butyl, etc.), nitro or acyl having 1 to 2 carbon atoms. [In the formula, _R10 is a hydrogen atom, lower alkyl (preferably methyl, ethyl, n-propyl, iso-
1-3 carbon atoms such as propyl), n is 3-3
represents an integer of 5], and specific examples of such polar compounds are as follows. Lower alcohols: methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol,
n-butyl alcohol, iso-butyl alcohol,
sec-butyl alcohol, t-butyl alcohol,
n-amyl alcohol, iso-amyl alcohol,
Preferred examples include monohydric alcohols having 1 to 6 carbon atoms, such as n-hexyl alcohol and cis-3-hexenol. Glycerin, its ester: The ester may be mono-, di- or triester, and the acid component may have 2 to 6 carbon atoms.
Preferred are fatty acids, especially acetic acid. Specifically, glycerin monoacetate, glycerin diacetate, etc. are listed. Thioglycerol: Any of mono-, di-, or triglycerol may be used. For example, α-monothioglycerol is exemplified. Lactic acid, its ester: The alcohol-derived moiety in the ester is preferably an aliphatic monohydric alcohol having 1 to 4 carbon atoms. Specific examples include methyl lactate, ethyl lactate, butyl lactate, and the like. Cyclic urea (): Specifically, N,N'-dimethylethylene urea,
Ethylene urea, N,N'-diethylethylene urea, etc. are listed. Amide compound (): Specifically, formamide, N-methylformamide, N,N-dimethylformamide, N,N
-diethylformamide, thiacetamide, N-
Methylacetamide, N,N-dimethylacetamide, N,N-diethylacetamide, propionamide, N-methylpropionamide, N,N
-dimethylpropionamide, N,N-diethylpropionamide, and the like. Alkylene glycol: Alkylene preferably has 2 to 8 carbon atoms, specifically ethylene glycol, 1,3
-Propanediol, 1,2-propanediol, butanediol, pentanediol, 2-methyl-2,4-pentanediol, 2-ethyl-
1,3-hexanediol and the like are listed. Monoalkyl ether of mono- or diethylene glycol: The alkyl in the monoalkyl ether preferably has 1 to 2 carbon atoms. Specific examples include ethylene glycol monomethyl ether and ethylene glycol monoethyl ether. Lactone: A 4-membered ring or a 5-membered ring is preferred, and specific examples include propiolactone and butyrolactone. Urea compound (): Specifically, urea, N-methylurea, N-ethylurea, N-butylurea, 1,1-dimethylurea, 1,3-dimethylurea, 1,1-diethylurea, 1, Examples include 3-diethylurea, 1,1,3,3-tetramethylurea, N-acetyl-N'-methylurea, and nitrourea. Lactam compounds (): Specifically, 2-pyrrolidone, N-methylpyrrolidone, N-methylpiperidone, caprolactam,
N-methyl caprolactam and the like are listed. The isonicotinic acid ester () is preferably 0.5 to 07% by weight, preferably 1 to 25% by weight, based on the total amount of the polar compound and the isonicotinic acid ester ().
It is blended in a proportion of % by weight. Further, the composition for dermal administration of the present invention increases the skin permeability and transdermal absorption of a drug, and the drug may be administered dermally in the presence of the composition.
Preferably, a drug is mixed in the composition of the present invention in advance. There are no particular restrictions on the drug that can be incorporated into the composition for dermal administration of the present invention, as long as it can be administered dermatically. If the drug is intended for , the drug will quickly enter the bloodstream. Specifically, local drugs include local anesthetics (e.g., procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, piperocaine acetate), antihistamines (e.g., diphenhydramine hydrochloride, chlorphene maleate), niramine, brompheniramine maleate, diphenylimidazole, clemizole hydrochloride), antibiotics (e.g., lincomycin, penicillin G, erythromycin, tetracycline hydrochloride, clindamycin, kanamycin, oxytetracycline,
chloramphenicol, fradiomycin, nystatin, gramicidin hydrochloride, bacitracin),
Antifungal agents [e.g. griseofulvin, N-methyl-
N-(3-tolyl)thiocarbamic acid-2-naphthyl ester, diamethazole hydrochloride, oleothricin, trichomycin, pyrrolenitrile, 5-
Fluorocytosine] etc. Specific examples of systemic drugs include benzodiazepines (e.g. diazepam, nitrazepam, flunitrazepam, lorazepam, prazepam, fludiazepam, clonazepam), diuretics [e.g. thiazides (e.g. bendroflumethiazide, polythiazide, methyclothiazide) , trichlormethiazide, cyclopenthiazide, benzylhydrochlorothiazide, hydrochlorothiazide, bumetanide),
Antihypertensive drugs (e.g., clonidine), antihistamines [e.g.,
aminoethers (e.g., diphenhydramine, carbinoxamine, diphenylpyraline), ethylenediamines (e.g., phebenzamine), monoamines (e.g., chlorpheniramine)], nonsteroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, ibufuenats, alclofenats, diclofenats, mefenams, flurbiprofen, flufenams, ketoprofen), antineoplastic agents [e.g., 5-fluorouracin, 1-(2)
-tetrahydrofuryl)-5-fluorouracil,
cytarabine, broxuridine], steroidal anti-inflammatory agents (e.g., cortisone, hydrocortisone, prednisolone, prednisone, triamcinolone, dexamethasone, betamethasone), antiepileptic agents (e.g., ethosuximide), antiarrhythmia agents (e.g.,
ajmaline, pradimarine, pindolol, propranolol, quinidine), psychotropic agents [e.g.
clofluperiol, trifluperidol, haloperidol, moperon), scopolamines (e.g.
methylscopolamine, butylscopolamine), chloropromazine, atropines (e.g., methylatropine bromide, methylanisotropine bromide)], vasodilators (e.g., isosorbide dinitrate, nitroglycerin, pentaerythritol tetranitrate, propanil) nitrate, dipyridamole), antibiotics [e.g., tetracyclines (e.g., tetracycline, oxytetracycline, methacycline, doxycycline, minocycline), chloramphenicols, erythromycins], etc. The amount of the drug to be mixed may be an amount sufficient to achieve the desired medicinal effect, and the amount varies depending on the type of drug, patient's weight, symptoms, etc., and may be appropriately selected depending on these conditions. In general,
It is preferably 0.01 to 20% by weight, particularly 0.2 to 10% by weight, based on the total amount of the isonicotinic acid ester () and the polar compound. Note that the amount of the drug to be used can be adjusted by increasing or decreasing the area of the pharmaceutical composition applied to the skin, so it is not necessarily limited to the above-mentioned amount. The external pharmaceutical composition according to the present invention can be used as it is or with the addition of a known pharmaceutically acceptable third component to ointments, plasters, lotions, adhesive tapes, etc.
It is administered to the skin as an external preparation such as an impregnation agent or gel. Examples of impregnating agents include those prepared by adsorbing the topical pharmaceutical composition or a composition containing a known third component onto a suitable adsorbent (gauze, filter paper, porous membrane, etc.); Applied to the skin by fixing with adhesive tape. Examples of the gel agent include those made into a gel using dipendylidene sorbitol (eg, Gelol D (manufactured by Shin Nihon Rika Co., Ltd.)) and spread on a support. Further, examples of bases for adhesive tapes include known ones such as acrylic copolymers, polyvinyl ether compounds, and rubber adhesive mixtures. Other external preparations can also be easily prepared by known means. The present invention will be explained in more detail below using Examples and Experimental Examples, but the present invention is not limited thereto. Production example 1 Production of isonicotinic acid n-decyl ester in the general formula (), where R=-(CH ₂ ) ₉ CH ₃ Dissolve 4.9 g (0.04 mol) of isonicotinic acid in 100 ml of hexamethylphosphoramide to give 25% The mixture was added to an aqueous solution of sodium hydroxide (0.06 mol) and stirred with a magnetic stirrer at room temperature for 1 hour. Next, add 26.5g (0.12mol) of decyl bromide and further
Stirred for 24 hours. After that, the reaction solution was dissolved in 5% hydrochloric acid solution.
200 ml, extracted with ether, washed with water, dried over sodium sulfate, distilled off the solvent, and purified by column chromography to obtain 6.7 g of isonicotinic acid n-decyl ester. Yield is 63.7
% (from isonicotinic acid). Production Examples 2 to 6 Isonicotinic acid esters having the following ester groups were produced in Production Examples 2 to 6 in the same manner as Production Example 1. Production example R of general formula () 2 - (CH ₂ ) ₅ CH ₃ isonicotinic acid n-hexyl ester 3 - (CH ₂ ) ₁₁ CH ₃ isonicotinic acid n-dodecyl ester 4 - (CH ₂ ) ₁₇ CH ₃ iso Nicotinic acid n-octadecyl ester 5

[Formula] Isonicotinic acid 2-ethylhexyl ester 6

[Formula] Isonicotinic acid 4-cyclohexylbutyl ester Examples 1 to 30 Basic formulations 1 to 30 (1) Drug 1% by weight (2) Polar compound 89% by weight (3) Isonicotinic acid ester () 10% by weight (1 ), (2) and (3) shown in Table 1, the liquid composition of the above basic formulation was prepared by mixing (3) with (2).
It was prepared by mixing (1) and further dissolving (1). Control formulation (1) Drug 1% by weight (2) Dimethyl sulfoxide 99% by weight Prepared by dissolving (1) in (2). Comparative Examples 1 to 10 (1) Drug 1% by weight (2) Polar compound 99% by weight Prepared by dissolving (1) in (2). (1) and
As (2), those listed in Table 2 were used. Comparative Examples 11-21 (1) Drug 1% by weight (2) Polar compound 89% by weight (3) Ethyl isonicotinate 10% by weight (3) by mixing with (2) and further dissolving (1) Prepared. As (1) and (2), those listed in Table 3 were used. Comparative Examples 22-34 (1) Drug 1% by weight (2) Polar compound 89% by weight (3) Butyl isonicotinate 10% by weight (3) by mixing with (2) and further dissolving (1) Prepared. As (1) and (2), those listed in Table 4 were used. Experimental Example The amount of drug permeation through the skin of the compositions of Examples 1 to 30, control formulations, and comparative examples 1 to 34 was measured using excised abdominal skin of rats, and the results are shown in Tables 1, 2, and 3. It is shown in Table 3 and Table 4. Note that the Q values in Tables 1, 2, 3, and 4 have the following meanings. Q=C/D C: Amount of drug permeated through the skin in Examples or Comparative Examples D: Amount of drug permeated through the skin in the control formulation (Measurement method) The rat skin was attached to a glass transmission cell so that the corresponding part was in contact with the saline, and the drug that had permeated into the saline was quantified using high performance liquid chromatography. Note that this experiment was conducted in a sealed container.

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Claims (1)

[Claims] 1. General formula (In the formula, R represents an alkyl having 5 or more carbon atoms.) A composition for dermal administration comprising an isonicotinic acid ester () represented by the following formula. 2 In addition to isonicotinic acid ester (), lower alcohol, glycerin, glycerin ester, thioglycerol, lactic acid, lactic acid ester,
general formula (In the formula, R ₁ and R ₂ each represent hydrogen or lower alkyl.) A cyclic urea represented by the general formula (In the formula, R ₃ , R ₄ and R ₅ each represent a hydrogen atom or lower alkyl.) Amide compounds, alkylene glycols, monoalkyl ethers of mono- or diethylene glycol, lactones, general formula (In the formula, R ₆ , R ₇ , R ₈ and R ₉ are each hydrogen atom, lower alkyl, nitro, or has 1 to 2 carbon atoms.
urea compound represented by the general formula (In the formula, R ₁₀ is a hydrogen atom or lower alkyl,
The composition for dermal administration according to claim 1, characterized in that it contains at least one polar compound selected from lactam compounds represented by the formula (n is an integer of 3 to 5). 3. The composition for dermal administration according to claim 2, wherein the amount of the isonicotinate ester () is 0.5 to 0.7% by weight based on the total amount of the isonicotinate ester () and the polar compound. 4. The composition for dermal administration according to any one of claims 1 to 3, which further contains a drug. 5. Integumentary administration according to claim 4, characterized in that the amount of isonicotinate ester () is 0.5 to 0.7% by weight based on the total amount of isonicotinate ester () and polar compound. Composition for use.