JPH0572891B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a base composition for a bioelectrode in iontophoresis, and in particular,
It is possible to provide such compositions that can be used to administer systemic drugs. [Prior Art] Conventionally, methods for administering topical or systemic drugs through the skin include applying the drug to the skin together with a base, such as an ointment or cream, or applying a tape preparation. However, this method involves simply applying or pasting the drug onto the skin surface. Therefore, a transdermal absorption enhancer (Japanese Unexamined Patent Publication No. 1982-210026) has been proposed for transdermally absorbing external drugs. In recent years, much research has been conducted on the effects of applying voltage to biological tissues, and it has been found that changes in ion concentration are essential by-products of biological activities, that is, various factors that control biological tissues. came. From these viewpoints, the iontophoresis method (iontophoresis) is being reconsidered. This method utilizes the polar effect of ionized molecules using electrical therapy using direct current to infiltrate the drug into the skin. It's being used. On the other hand, although new formulation techniques for transdermally administering systemic drugs have been developed in recent years, no attempt has been made to administer systemic drugs using iontophoresis.
This is because it was thought that relatively high voltage, high current, and short-time treatment were required to transdermally permeate drugs into the body using iontophoresis. [Problems to be Solved by the Invention] The present inventors have conducted intensive research to achieve transdermal administration of drugs at a controlled rate using low voltage, low current, and long-time treatment. , we obtained the following findings. That is, in iontophoresis, low voltage can be achieved by blending an ionic drug into a composition made of a specific compound described later as a bioelectrode, the compound, an organic solvent, and water as necessary.
It has been found that the transdermal absorption of drugs can easily proceed at low currents. The present invention was completed based on the above findings, and its first purpose is to provide a bioelectrode base composition that enables transdermal permeation of drugs at low current density in iontophoresis. It is about providing. A second object of the present invention is to provide a method for increasing transdermal permeability of drugs at low current density in iontophoresis. [Means for solving the problem] That is, the present invention solves the general formula

[Formula] (In the formula, R ₁ represents a hydrogen atom or an aliphatic hydrocarbon group having 5 or less carbon atoms, and R ₂ represents an aliphatic hydrocarbon group having 7 to 20 carbon atoms.) )
The present invention relates to a base composition for an iontophoresis bioelectrode, which contains as an essential component. R ₁ in the general formula () is a hydrogen atom or an aliphatic hydrocarbon group having 5 or less carbon atoms, and may be a chain (straight chain, branched chain), saturated or unsaturated. Preferred are chain and saturated ones, that is, alkyl groups, such as methyl, ethyl, n-propyl,
iso-propyl, n-butyl, t-butyl, n-
Examples include amyl, iso-amyl, etc., and those having 1 to 4 carbon atoms are particularly preferred. _R2 in the general formula () is an aliphatic hydrocarbon group having 7 to 20 carbon atoms, and is a chain (straight chain, branched chain),
It may be cyclic, and may be saturated or unsaturated. Chain-like, saturated ones, that is, alkyl groups, include n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl,
n-octadecyl, 2-ethylhexyl, 3,7
-dimethyloctyl, 2-hexyldecyl, 2-
8 carbon atoms such as octyldodecyl, methyloctyl, etc.
~18 is preferred. The unsaturation in the chain-like unsaturated compound is preferably a double bond, and the number thereof is preferably 1 to 2. Preferred examples of such compounds include those having 8 to 18 carbon atoms, such as 2-octenyl, 11-dodecenyl, oleyl, and linoleyl. Cyclic ones include cyclosilethyl, cycloheptyl, cyclohexylmethyl, cyclooctyl, 4-cyclohexylbutyl, 3-cyclopetylpropyl, 5-methyl-2-isopropylcyclohexyl, cyclododecanyl, cyclohexadecanyl, Examples include cyclooctadecanyl, and those having 8 to 18 carbon atoms are particularly preferred. Examples of the pyrrolidone carboxylic acid derivative () used in the present invention include the following compounds. 1-alkylpyrrolidonecarboxylic acid methyl ester, 1-alkylpyrrolidonecarboxylic acid ethyl ester, 1-alkylpyrrolidonecarboxylic acid n
-propyl ester, 1-alkylpyrrolidonecarboxylic acid n-butyl ester, 1-alkylpyrrolidonecarboxylic acid n-heptyl ester, 1-alkylpyrrolidonecarboxylic acid n-octyl ester, 1-alkylpyrrolidonecarboxylic acid n-nonyl ester, 1- Alkylpyrrolidonecarboxylic acid n-decyl ester, 1-alkylpyrrolidonecarboxylic acid n-undecyl ester, 1-alkylpyrrolidonecarboxylic acid n-dodecyl ester, 1
-Alkylpyrrolidonecarboxylic acid n-tridecyl ester, 1-alkylpyrrolidonecarboxylic acid n
-tetradecyl ester, 1-alkylpyrrolidonecarboxylic acid n-hexadecyl ester, 1-alkylpyrrolidonecarboxylic acid n-octadecyl ester, 1-alkylpyrrolidonecarboxylic acid n-
Eicosyl ester, 1-alkylpyrrolidonecarboxylic acid iso-propyl ester, 1-alkylpyrrolidonecarboxylic acid 2-methylhexyl ester, 1-alkylpyrrolidonecarboxylic acid 2-ethylhexyl ester, 1-alkylpyrrolidonecarboxylic acid 3,7-dimethyloctyl ester ester, 1
-Alkylpyrrolidonecarboxylic acid 2-hexyldecyl ester, 1-alkylpyrrolidonecarboxylic acid 2-octyldodecyl ester, 1-alkylpyrrolidonecarboxylic acid 2,4,4-trimethyl 1
-pentane ester, 1-alkylpyrrolidonecarboxylic acid methyloctyl ester, pyrrolidonecarboxylic acid methyl ester, pyrrolidonecarboxylic acid ethyl ester, pyrrolidonecarboxylic acid n-propyl ester, pyrrolidonecarboxylic acid n-butyl ester, pyrrolidonecarboxylic acid n-heptyl ester, pyrrolidonecarboxylic acid n-octyl ester, pyrrolidonecarboxylic acid n-nonyl ester, pyrrolidonecarboxylic acid n-decyl ester,
pyrrolidonecarboxylic acid n-undecyl ester,
pyrrolidonecarboxylic acid n-dodecyl ester, pyrrolidonecarboxylic acid n-tridecyl ester, pyrrolidonecarboxylic acid n-tetradecyl ester,
Pyrrolidonecarboxylic acid n-hexadecyl ester, pyrrolidonecarboxylic acid n-octadecyl ester, pyrrolidonecarboxylic acid n-eicosyl ester, pyrrolidonecarboxylic acid iso-propyl ester, pyrrolidonecarboxylic acid 2-methylhexyl ester, pyrrolidonecarboxylic acid 2-ethylhexyl ester , 3,7-dimethyloctyl pyrrolidonecarboxylate ester, 2-hexyldecyl pyrrolidonecarboxylate ester, 2-octyldodecyl pyrrolidonecarboxylate ester, 2,4,4-trimethyl 1-pentane pyrrolidonecarboxylate ester, methyloctyl pyrrolidonecarboxylate Compounds in which R ₂ is alkyl, such as esters (however, alkyl in 1-alkyl in the above compounds is methyl, ethyl, n-propyl, iso
-propyl, n-butyl, n-amyl, iso-amyl, etc.), pyrrolidonecarboxylic acid 2-cyclohexylethyl ester, pyrrolidonecarboxylic acid cycloheptyl ester, pyrrolidonecarboxylic acid cyclohexylmethyl ester, pyrrolidonecarboxylic acid cyclooctyl ester, pyrrolidone carboxylic acid 4-cyclohexylbutyl ester,
Pyrrolidonecarboxylic acid 3-cyclopentylpropyl ester, pyrrolidonecarboxylic acid 5-methyl-
2-isopropylhexyl ester, 1-alkylpyrrolidonecarboxylic acid 2-cyclohexylethyl ester, 1-alkylpyrrolidonecarboxylic acid cycloheptyl ester, 1-alkylpyrrolidonecarboxylic acid cyclohexylmethyl ester, 1
-Alkylpyrrolidonecarboxylic acid cyclooctyl ester, 1-alkylpyrrolidonecarboxylic acid 4
- Compounds in which R ₂ is cyclic alkyl, such as cyclohexylbutyl ester, 1-alkylpyrrolidonecarboxylic acid 3-cyclopentylpropyl ester, 1-alkylpyrrolidonecarboxylic acid 5-methyl-2-isopropylcyclohexyl ester (however, 1- Alkyl in alkyl is methyl, ethyl, n-propyl,
iso-propyl, n-butyl, n-amyl, iso-
amyl), pyrrolidonecarboxylic acid-cis
-3-hexenyl ester, pyrrolidonecarboxylic acid-oleyl ester, pyrrolidonecarboxylic acid linoleyl ester, 1-alkylpyrrolidonecarboxylic acid-cis-3-hexenyl ester, 1-alkylpyrrolidonecarboxylic acid-oleyl ester, 1-alkylpyrrolidonecarboxylic acid Compounds in which R ₂ is a chain unsaturated hydrocarbon group, such as linoleyl ester and pyrrolidone carboxylic acid geranyl ester (however, the alkyl in 1-alkyl in the above compounds is methyl, ethyl, n-propyl, iso-propyl, n- butyl, n-amyl,
iso-amyl, etc.). The ionophorase bioelectrode base composition of the present invention can be used as a bioelectrode by itself by incorporating an ion-dissociative drug into it. Water can be added depending on the situation. Examples of the organic solvent include lower alcohols, cyclic ureas, alkylene glycols, lactam compounds,
Polar hydrophilic solvents such as dimethyl sulfoxide are exemplified as suitable solvents, and one or more of these solvents may be used. Examples of lower alcohols include methyl alcohol,
Ethyl alcohol, n-propyl alcohol,
Number of carbon atoms in iso-propyl alcohol, n-butyl alcohol, iso-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, n-amyl alcohol, iso-amyl alcohol, n-hexyl alcohol, cis-3-hexyl alcohol, etc. 1 to 6 chain monohydric alcohols are preferred. The cyclic urea is preferably a 5-membered ring,
It may be substituted with a lower alkyl group. especially,
general formula

[Formula] [In the formula, R ₃ and R ₄ are each a hydrogen atom or a lower alkyl group (preferably methyl, ethyl, n
A cyclic urea represented by the following formula is preferred. More specifically, N,N-dimethylethyleneurea, ethyleneurea, N,N-diethylethyleneurea and the like are listed. In alkylene glycol, alkylene preferably has 2 to 8 carbon atoms, and examples of alkylene glycol include ethylene glycol,
1,3-propanediol, 1,2-propanediol, butanediol, pentanediol, 2
-Methyl-2,4-pentanediol, 2-ethyl-1,3-hexanediol, and the like. As a lactam compound, the general formula

[Action/Effect]

The bioelectrode base composition of the present invention promotes skin permeation and transdermal absorption of ion-dissociative drugs by iontophoresis, so for example, 0.1 to 0.5 mA/cm ²
Even a moderately low current can promote skin absorption of the drug. The base composition used in the present invention promotes skin permeation of ionic drugs even when no electricity is applied;
Since energization synergistically promotes skin permeation and transdermal absorption of the drug, iontophoresis is possible even with a low current. Furthermore, since the drug can be administered over a long period of time, the drug's efficacy can be sustained. Furthermore, the skin permeation and transdermal absorption of ionically dissociative drugs are improved, making it possible to use small batteries, making them portable and electrified to allow for long-term energization for release, administration, and control. There are advantages. [Examples] Hereinafter, the present invention will be explained in more detail using Examples, Experimental Examples, etc., but the present invention is not limited by these in any way. In addition, all parts below indicate parts by weight, and PCA
means pyrrolidone carboxylic acid. Example 1 (1) 3 parts of sodium salicylate (2) 100 parts of N-methyl PCA lauryl ester A drug solution was prepared by dissolving the above (1) in (2), and the diameter
A polyester nonwoven fabric of 20 mm and 2 mm thickness was impregnated with 0.5 ml of the solution, and an aluminum current dispersion plate of the same size and 0.5 mm thickness was brought into close contact with the nonwoven fabric to form an electrode part. Comparative Example 1 (1) 3 parts of sodium salicylate (2) 100 parts of distilled water A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. Experimental Example 1 Rat exfoliated skin was installed at both ends of a glass cell with a diameter of 25 mm and a length of 50 mm and a sampling hole in the center, and the electrode part of Example 1 or Comparative Example 1 was attached to one side, and the electrode part of Example 1 was attached to the other side. Instead of the drug solution in Example 1, an electrode part impregnated with 0.9% NaCl solution similar to that in Example 1 was attached, and the drug solution side was used as a cathode.
A current of 0.25 mA/cm ² was applied for 10 minutes, and the amount of drug permeated through the skin was measured using a high performance liquid chromatograph. The results are shown in Figure 1. Examples 2 to 4 (1) Sodium salicylate 10 parts (2) N-methyl PCA lauryl ester variable (3) N-methyl-2-pyrrolidone variable Change the above (1) into (2) and (3) in Table 1 A drug solution was prepared by dissolving it in the proportion shown, and an electrode part was prepared in the same manner as in Example 1. Comparative Example 2-a (1) Sodium salicylate 10 parts (2) Distilled water 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. Comparative Example 2-b (1) Sodium salicylate 10 parts (2) N-methyl-2-pyrrolidone 100 parts A drug solution was prepared by dissolving the above (1) in (2), and the same procedure as in Example 1 was carried out. It was used as an electrode part. Experimental Example 2 Examples 2 to 4 and Comparative Examples 2-a and 2-
Regarding the electrode part b, the amount of drug permeation was measured using a high performance liquid chromatograph in the same manner as in Experimental Example 1, and the results are shown in Table 1.

[Table] Examples 5 to 7/Experimental Example 3 (1) Sodium salicylate 10 parts (2) N-methyl PCA lauryl ester 10 parts (3) N-methyl-2-pyrrolidone Variable (4) Distilled water Variable Above (1) ) was dissolved in (2), (3), and (4) in the proportions shown in Table 2 to prepare a drug solution, and an electrode part was prepared in the same manner as in Example 1. The amount of drug permeation was measured in the same manner as in Experimental Example 1, and the results are also listed in Table 2.

[Table] Examples 8 to 10/Experimental Example 4 (1) Sodium salicylate 10 parts (2) N-methyl PCA lauryl ester Variable (3) N-methyl-2-pyrrolidone 50 parts (4) Distilled water Variable above (1) ) was dissolved in (2), (3), and (4) at the ratio shown in Table 3 to prepare a drug solution, and the same procedure as in Example 1 was performed to prepare an electrode part. The amount of drug permeation was measured in the same manner as in Experimental Example 1, and the results are also listed in Table 3.

[Table] Examples 11 to 13/Experimental Example 5 (1) Sodium salicylate 10 parts (2) N-methyl PCA lauryl ester variable (3) N-methyl-2-pyrrolidone variable (4) Distilled water 10 parts Above (1) ) was dissolved in (2), (3), and (4) in the proportions shown in Table 4 to prepare a drug solution, and an electrode part was prepared in the same manner as in Example 1. The amount of drug permeation was measured in the same manner as in Experimental Example 1, and the results are also listed in Table 4.

[Table] Example 14 (1) Diclofenac sodium 1 part (2) N-amyl PCA lauryl ester 30 parts (3) t-butyl alcohol 30 parts (4) Distilled water 40 parts Add the above (1) to (2) , (3), and (4) to prepare a drug solution, and an electrode part was prepared in the same manner as in Example 1. Comparative Example 3-a (1) Diclofenac sodium 1 part (2) Distilled water 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. did. Comparative Example 3-b (1) 1 part of sodium salicylate (2) 100 parts of t-butyl alcohol A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. did. Example 15 (1) Salbutamol sulfate 1 part (2) 1-PCA octyl ester 30 parts (3) Propylene glycol 30 parts (4) Distilled water 40 parts The above (1) was replaced with (2), (3), (4) to prepare a drug solution, and an electrode part was prepared in the same manner as in Example 1. Comparative Example 4-a (1) Salbutamol sulfate 1 part (2) Distilled water 100 parts A drug solution was prepared by dissolving the above (1) in (2), and the electrode part was prepared in the same manner as in Example 1. And so. Comparative Example 4-b (1) Sodium salicylate 1 part (2) Propylene glycol 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. Example 16 (1) Terbutaline sulfate 1 part (2) 1-PCA oleyl ester 30 parts (3) N,N dimethyl sulfoxide 40 parts (4) Distilled water 30 parts The above (1) was replaced with (2) and (3) , (4) to prepare a drug solution, and an electrode part was prepared in the same manner as in Example 1. Comparative Example 5-a (1) Terbutaline sulfate 1 part (2) Distilled water 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. . Comparative Example 5-b (1) Terbutaline sulfate 1 part (2) N,N dimethyl sulfoxide 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode was prepared in the same manner as in Example 1. Department. Example 17 (1) Propranol hydrochloride 1 part (2) 1-PCA heptyl ester 30 parts (3) Dimethylethylene urea 30 parts (4) Distilled water 40 parts The above (1) was mixed with (2), (3), ( 4) to prepare a drug solution and use the same procedure as in Example 1 to prepare an electrode part. Comparative Example 6-a (1) 1 part of propranol hydrochloride (2) 100 parts of distilled water A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. . Comparative Example 6-b (1) Propranol hydrochloride 1 part (2) Dimethylethylene urea 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. did. Example 18 (1) Metoclopramide hydrochloride 1 part (2) 1-PCA dodecyl ester 50 parts (3) N-methyl-2-pyrrolidone 30 parts (4) Distilled water 20 parts The above (1) was replaced with (2) and (3) ) and (4) to prepare a drug solution, and an electrode part was prepared in the same manner as in Example 1. Comparative Example 7-a (1) Metoclopramide hydrochloride 1 part (2) Distilled water 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. Comparative Example 7-b (1) Metoclopramide hydrochloride 1 part (2) N-methyl-2-pyrrolidone 100 parts A drug solution was prepared by dissolving the above (1) in (2), and the same procedure as in Example 1 was carried out. It was used as an electrode part. Example 19 (1) Sodium salicylate 1 part (2) PCA-2-hexyldecyl ester 50 parts (3) N-methyl-2-pyrrolidone 30 parts (4) Distilled water 20 parts The above (1) was replaced with (2), A drug solution was prepared by dissolving in (3) and (4), and an electrode part was prepared in the same manner as in Example 1. Comparative Example 8-a (1) 1 part of sodium salicylate (2) 100 parts of distilled water A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 1. Comparative Example 8-b (1) 1 part of sodium salicylate (2) 100 parts of N-methyl-2-pyrrolidone A drug solution was prepared by dissolving the above (1) in (2), and the same procedure as in Example 1 was carried out. It was used as an electrode part. Experimental Example 6 Regarding Examples 14 to 19 and Comparative Examples 3 to 8, the drug permeability was measured and calculated using a high performance liquid chromatograph in the same manner as in Experimental Example 1. Drug permeation rate (%) = amount of drug permeated/total amount of drug introduced into the cell x
100 The results are shown in Table 5.

[Table] Example 20 (1) Clonidine hydrochloride 0.4 parts (2) N-methyl PCA lauryl ester 10 parts (3) Ethyl alcohol 70 parts (4) Distilled water 20 parts Add the above (1) to (2) and (3) , dissolve in (4), mix and stir.
A polyester nonwoven fabric with a diameter of 3 cmφ and a thickness of 2 mm was impregnated with 0.5 ml of this drug solution, and an aluminum sheet of the same size and a thickness of 0.2 mm was adhered to the top, and this was used as an electrode part. Comparative Example 9-a (1) Clonidine hydrochloride 0.4 parts (2) Distilled water 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 20. Comparative Example 9-b (1) Clonidine hydrochloride 0.4 parts (2) Ethyl alcohol 100 parts A drug solution was prepared by dissolving the above (1) in (2), and an electrode part was prepared in the same manner as in Example 20. Experimental Example 7 The lower abdomen of a male Wistar rat (weighing approximately 180 g) was removed, and Example 20 or Comparative Example 9 was placed on the right abdomen.
-a and 9-b were attached with adhesive tape. On the left abdomen, an electrode member having the same structure as the drug-containing solution was impregnated with 0.9% NaCl solution and attached as an electrode with adhesive tape. The drug-containing side was used as the anode, and a current of 0.25 mA/cm ² was applied for 5 minutes to measure the rat tail artery pressure. The results are shown in Figure 2.

[Brief explanation of drawings]

FIGS. 1 and 2 are graphs showing the effects of the base composition of the present invention. Figure 1-□-: Example 1,...■...: Comparative Example 1, Figure 2-○-: Example 20,...●...: Comparative Example 9-a,...▲...: Comparative example 9-b, -△-:
Control.

Claims (1)

[Claims] 1 General formula [Formula] (In the formula, R ₁ represents a hydrogen atom or an aliphatic hydrocarbon group having 5 or less carbon atoms, and R ₂ represents an aliphatic hydrocarbon group having 7 to 20 carbon atoms. ) Pyrrolidone carboxylic acid derivative ()
A base composition for an iontophoresis bioelectrode, which contains as an essential component. 2. The base composition for an iontophoresis bioelectrode according to claim 1, which contains an organic solvent. 3. The base composition for an iontophoresis bioelectrode according to claim 1 or 2, which contains water. 4. The base composition for an iontophoresis bioelectrode according to claim 2, wherein the blending ratio of the pyrrolidone carboxylic acid derivative () and the organic solvent is 1 to 99:99 to 1 (wt%). 5. The base composition for an iontophoretic bioelectrode according to claim 3, wherein the blending ratio of the pyrrolidone carboxylic acid derivative () and water is 50 to 99:50 to 1 (wt%). 6 The blending ratio of pyrrolidone carboxylic acid derivative (), organic solvent, and water is 5 to 60:25 to 95:0 to 60
(% by weight) The base composition for an iontophoresis bioelectrode according to claim 3.