JPH0570609B2 - - Google Patents

Description

[Detailed description of the invention]

[Technical field] The present invention relates to a base composition capable of enhancing transdermal absorption of a drug, an external pharmaceutical composition using the base composition,
and a method for promoting transdermal absorption of drugs. [Prior art] Conventionally, when administering drugs to the integument, sterilization, disinfection,
They were intended to act locally on the outer skin or the subcutaneous tissue directly beneath it, such as analgesic, antipruritic, and antiinflammatory. In addition, if the purpose is to have a systemic effect,
Traditionally, it has been administered by oral tablets or injections. In the case of oral tablets, there are problems such as the fact 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, although administration by injection provides rapid absorption, there are problems such as the need for administration by a specialist such as a doctor. In recent years, transdermal administration of drugs having systemic effects has been proposed in order to improve the above-mentioned problems with oral administration and injection. When a drug is administered transdermally, its efficacy can be easily sustained, the concentration of the drug in the body can be controlled, and the drug enters the bloodstream directly through the skin tissue, making it less susceptible to primary hepatic metabolism. However, normal skin inherently has a barrier function that prevents foreign substances from entering the body, making transdermal absorption of drugs difficult. Therefore, drugs administered to the skin generally have a local pharmacological effect. It was limited to drugs that express In order to cause transdermal absorption of drugs intended for systemic action, a transdermal absorption promoting aid is generally required, and various aids have been proposed in recent years. For example, U.S. Pat. No. 3,551,544 states:
Dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, methyldecyl sulfoxide, and the like are disclosed. In addition, as an absorption promoting agent in combination with a lower alkylamide, dimethylacetamide and ethyl alcohol, isopropyl alcohol, isopropyl palmitate (US Pat. No. 3,472,431), 2-pyrrolidone and a suitable oil, straight chain fatty acid and alcohol can be used. Examples of combinations of esters (U.S. Patent No. 4017641)
However, these absorption-promoting aids are still not sufficient in terms of absorption-promoting effect, safety, and feeling of use. [Problems to be Solved by the Invention] The first object of the present invention is to provide a base composition for external preparations that can improve the percutaneous absorption of drugs. A second object of the present invention is to provide an external pharmaceutical composition with good skin permeability and transdermal absorption of drugs. A third object of the present invention is to provide a method for increasing transdermal absorption of drugs. [Structure of the Invention] To achieve the above object, the present inventors have conducted intensive research and have obtained the following knowledge. That is, the composition consisting of a sesquiterpene alcohol and a specific polar compound increases the skin permeability and transdermal absorption of drugs, and the above composition can be used as a base for drugs that can be applied to the skin. , I found out. Therefore, the present invention has been completed based on such new findings, and includes a base composition for external preparations containing at least one sesquiterpene alcohol and the following specific polar compound, and further comprising a drug in the base composition. This is an external pharmaceutical composition containing the following. A method for enhancing transdermal absorption of a drug, which comprises administering the drug transdermally in the presence of at least one sesquiterpene alcohol and the following specific polar compound. Natural essential oils have been used as fragrances since ancient times. In addition to the use of essential oils as fragrances, as described in Osamu Okuda's ``Fragrance Chemistry Overview'' (Hirokawa Shoten),
It is also known to have various pharmacological effects. It is known that some of these essential oils contain sesquiterpene alcohols. For example, falnesol is contained in essential oils such as ambrella seed, neroli, rose, cananga, lemongrass, and Peruvian balsam, or in flower essential oils such as diasmine, cyclamen, and acacia, and is used as a starting material for high-grade fragrances and vitamin synthesis. . Nerolidol is contained in Cabulba essential oil and is used as a raw material in the production of fragrances and phytol. Bisabolol is found in chamomile oil and lavender oil, and has recently been used as an anti-inflammatory agent. Santalol is present in sandalwood oil from East India and has alpha and beta forms, isolated or alpha beta.
Both mixtures are heavily used as perfume preparations and urinary tract disinfectants. Vetiverol is found in vetiver oil and is a mixture of bicyclovetivenol, veticasisole, and tricyclovetivenol, and is used in soap fragrances and oriental fragrances. However, it is completely unexpected that the combination of these sesquiterpene alcohols with certain polar compounds enhances the transdermal absorption of drugs. Sesquiterpene alcohols used in the present invention include fuarnesol, hexahydrofarnesol, nerolidol, hexahydronerollidol, sesquilabandilol, animol, bisabolol, lanceol, nuciferol, fusanol, eremol, casinol, coucinol, cousol , cimbopol, sesquicampphenol, caramendiol, cinnamonol, canoconol, agarol, caryolefin alcohol, santalol, guayol, catrol,
Examples include bicyclovetivenol, tricyclovetivenol, veticinol, vetibol, etc., and preferably linear, one-membered ring, or two-membered ring. Particularly preferred among these are filnesol, bisabolol, nerolidol, santol, and vetiverol, which have the following structures. bisabolol

[expression] or

[Formula] Fual nesor

[Formula] Nerolidol

[Formula] α-santalol

【formula】 β-santalol

[Formula] Bishikrobe Tiberol

[Formula] Tricyclo Vetiver le

[Formula] Specific polar compounds used in the present invention include lower alcohols, glycerin, glycerin esters,
Thioglycerol, lactic acid, lactic acid ester, general formula

[Formula] (In the formula, R ₁ and R ₂ each represent a hydrogen atom or a lower alkyl group.) A cyclic urea compound represented by the general formula

[Formula] (In the formula, R ₃ , R ₄ and R ₅ each represent a hydrogen atom or a lower alkyl group.) Amide compounds, alkylene glycols, monoalkyl ethers of mono- or diethylene glycol, lactones, general formula

[Formula] (In the formula, R ₆ , R ₇ , R ₈ and R ₉ are each a hydrogen atom, a lower alkyl group, a nitro group, or a carbon number 1
〜2 acyl group) and the general formula

〔effect〕

The composition of the present invention improves the transdermal absorption of drugs, and enables the formulation of drugs for external use, which have conventionally been difficult to absorb through the skin and cannot be used as external preparations. Even for drugs that can be absorbed through the skin and are used as external preparations, the transdermal absorption can be further enhanced. The present invention will be explained in more detail below using Examples and Experimental Examples, but the present invention is not limited thereto. Examples 1 to 32 Basic formulation (1) Drug 1% by weight (2) Polar compound 74% by weight (3) Sesquiterpene alcohol 25% by weight (1), (2) and (3) shown in Table 1 Using (3) and (2), respectively, the liquid composition of the above basic formulation is
The mixture was mixed with the following ingredients and further prepared by 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 6 (1) Drug 1% by weight (2) Polar compound 99% by weight Prepared by dissolving (1) in (2). Comparative Examples 7 to 11 (1) Drug 1% by weight (2) Sesquiterpene alcohol 99% by weight Prepared by dissolving or suspending (1) in (2). Example 1 The amount of drug permeation through the skin of the compositions of Examples 1 to 32, control formulations, and comparative examples 1 to 11 was measured using excised abdominal skin of rats, and the results are shown in Table 1.
It is shown in Tables 2 and 3. Note that the Q values in Tables 1, 2, and 3 mean the following. C/D=Q [C: Amount of drug permeated through the skin in Example or Comparative Example D: Amount of drug permeated through the skin in Control Formulation 1] (Measurement method) A portion corresponding to the front side of the skin is in contact with the above composition, and the skin The rat skin was attached to a glass transmission cell so that the back side of the skin 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)

[Scope of Claims] 1 At least one sesquiterpene alcohol compound, a lower alcohol, glycerin, glycerin ester, thioglycerose, lactic acid, lactic acid ester, general formula [Formula] (wherein R ₁ and R ₂ are each a cyclic urea compound represented by the general formula [formula] (in which R ₃ , R ₄ and R ₅ each represent a hydrogen atom or a lower alkyl group); Alkylene glycol, monoalkylether _of mono- or diethylene glycol, _{lactone ,} general _formula
~ ₂ acyl group), a lactam compound represented by the general formula: 1. A base composition for external preparations, comprising at least one selected polar compound. 2 The sesquiterpene alcohol is bisabolol,
The base composition according to claim 1, which is falnesol, nerolidol, santalol or vetiverol. 3. The base composition according to claim 1, wherein the amount of the sesquiterpene alcohol compound is 1 to 80% by weight based on the total amount of the sesquiterpene alcohol compound and the polar compound. 4. An external pharmaceutical composition containing the composition according to claim 1 and a drug. 5 The sesquiterpene alcohol is bisabolol,
An external pharmaceutical composition containing a drug and the base composition according to claim 1, which is farnesol, nerolidol, santalol, or vetiverol. 6. The external pharmaceutical composition according to claim 3, wherein the amount of the sesquiterpene alcohol compound is 1 to 80% by weight based on the total amount of the sesquiterpene alcohol compound and the polar compound. 7. The external pharmaceutical composition according to claim 4, wherein the drug has a molecular weight of 1000 or less.