JPH0529016B2 - - 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 drugs are administered transdermally, their pharmacological effects are easily sustained, their concentration in the body can be controlled, and because they enter the bloodstream directly through the skin tissue, they are less susceptible to primary hepatic metabolism. be. However, since normal skin inherently has a barrier function to prevent foreign substances from entering the body, the purpose of administering drugs through the skin has been limited to local use. Therefore, when a systemic effect is intended, a transdermal absorption enhancer is required, 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. [Problems to be Solved by the Invention] The first object of the present invention is to provide a composition for dermal administration that can enhance the skin permeability and percutaneous absorption of drugs. 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] In order to solve the problems, the present inventors have conducted intensive research and have obtained the following knowledge.
That is, it has been found that when a water-soluble drug is administered to the outer skin in the presence of a specific nicotinic acid ester () or isonicotinic acid ester () described below, the skin permeability and percutaneous absorption of the water-soluble drug are increased. . The present invention was completed based on this new knowledge, and the general formula Or (In the formula, R and R ¹ each represent an alkyl having 1 to 4 carbon atoms.) A composition for dermal administration containing a nicotinic acid ester () or an isonicotinic acid ester () represented by the following and a water-soluble drug: Regarding. In this specification, the alkyl having 1 to 4 carbon atoms may be linear or branched, and is preferably saturated. Such alkyls include methyl, ethyl, n-propyl, iso-propyl, n-propyl,
-butyl, iso-butyl, tert-butyl and the like. In the present invention, the above nicotinic acid ester () and/or isonicotinic acid ester ()
In addition to this, it is preferable to further add a hydrophobic compound. Hydrophobic compounds include aliphatic alcohols,
Aliphatic hydrocarbons, alcohol esters, ethers, and ketones of aliphatic carboxylic acids are preferred, and specific examples thereof include the following. Alcohol having 7 to 20 carbon atoms, preferably 8 to 18 carbon atoms: The alcohol may be either a linear alcohol or a branched alcohol, and may be a saturated alcohol or an unsaturated alcohol.
Specific examples include linear alcohols such as lauryl alcohol, branched alcohols such as iso-stearyl alcohol, and unsaturated alcohols such as oleyl alcohol. 5 or more carbon atoms which may be substituted with halogen
30 Aliphatic Hydrocarbons: The aliphatic hydrocarbons may be linear, branched, or cyclic, and may be saturated or unsaturated. The halogen used as a substituent is preferably bromine or chloro. The aliphatic hydrocarbon moiety is preferably an alkyl group having 5 to 30 carbon atoms (preferably 6 to 24 carbon atoms, particularly preferably 8 to 14 carbon atoms) and having 1 or 2 unsaturated bonds when the aliphatic hydrocarbon moiety is chain-like. In the case of a cyclic ring, a monocyclic ring or a bicyclic ring is preferable. In the case of a monocyclic ring, the number of carbon atoms is preferably 6 to 10, and it is one or more methyl, the formula

[Action/Effect]

According to the composition for epidermal administration of the present invention, which comprises a nicotinic acid ester () or isonicotinic acid ester (2) and a water-soluble drug, especially a composition for epidermal administration which further contains a hydrophobic compound therein, the water-soluble drug As the skin permeability and percutaneous absorption of the drug are improved, excellent medicinal efficacy can be achieved. [Examples/Experimental Examples] Hereinafter, the present invention will be explained in more detail with reference to Examples, Experimental Examples, etc., but the present invention is not limited thereto. Examples 1 to 9 Basic formulation (1) Water-soluble drug 1% by weight (2) Nicotinic acid ester () or isonicotinic acid ester (2) 99% by weight by dissolving or suspending (1) in (2). It was prepared using As (1) and (2), those listed in Table 1 were used. Control formulation (1) Drug 1% by weight (2) Dimethyl sulfoxide 99% by weight Prepared by dissolving (1) in (2). Examples 10 to 15 (1) Water-soluble drug 1% by weight (2) Nicotinic acid ester () or isonicotinic acid ester (2) 89% by weight (3) Lauryl alcohol 10% by weight (3) mixed with (2) , and further prepared by dissolving or suspending (1). As (1) and (2), those listed in Table 2 were used. Comparative Examples 1 to 9 (1) Water-soluble drug 1% by weight (2) Polar compound 99% by weight Prepared by dissolving (1) in (2). (1) and
As for (2), those listed in Table 3 were used. Comparative Examples 10-15 (1) Hydrophobic drug 1% by weight (2) Nicotinic acid ester () or isonicotinic acid ester (2) 99% by weight Prepared by dissolving (1) in (2). As (1) and (2), those listed in Table 4 were used. Comparative Examples 16-19 (1) Hydrophobic drug 1% by weight (2) Nicotinic acid ester () or isonicotinic acid ester (2) 89% by weight (3) Lauryl alcohol 10% by weight (3) mixed with (2) , and further prepared by dissolving (1). As (1) and (2), those listed in Table 5 were used. Experimental Example 1 The amount of drug permeation through the skin in the compositions of Examples 1 to 15, the control formulation, and Comparative Examples 1 to 19 was measured using excised rat abdominal skin, and the results were
Shown in the table. In addition, the Q value in Tables 1 to 5 means the following. 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 physiological saline, and the drug that had permeated into the physiological saline was quantified using high performance liquid chromatography. Note that this experiment was conducted in a sealed container.

【table】

【table】

【table】

【table】

【table】

【table】

[Claims]

1 Catalytic hydrogenation of succinic acid dibutyl ester with incomplete conversion, butanol distilled off from the reaction mixture, and liquid distillation residue reduced to 108
℃, the upper phase resulting from phase separation consisting essentially of succinic acid dibutyl ester is returned to the hydrogenation, and the lower phase consisting essentially of 1,4-butanediol is recovered under vacuum. A method for producing 1,4-butanediol by catalytic hydrogenation of dibutyl succinate, characterized in that 1,4-butanediol is obtained by fractional distillation of succinic acid dibutyl ester. 2. Process according to claim 1, characterized in that succinic acid dibutyl ester is hydrogenated to a conversion of up to 97%. 3. Process according to claim 1, characterized in that succinic acid dibutyl ester is hydrogenated to a conversion of up to 90%. 4 Claim characterized in that succinic acid dibutyl ester is hydrogenated over a copper-containing catalyst at a temperature of 170-190°C and a pressure of 200-300 bar.