JPH0572890B2 - - 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 requires relatively high voltage and
This is because it was thought that high current and short time treatments were required, otherwise there was a risk of burns. Furthermore, conventional devices are large and inconvenient to carry. [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 formed by blending a specific compound described later as a bioelectrode and the compound with 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 base composition for a bioelectrode that enables transdermal permeation of drugs at low current density in iontophoresis. It's about doing. A second object of the present invention is to provide a method for increasing transdermal permeability of drugs at low current density in iontophoresis. A third object of the present invention is to provide an iontophoretic bioelectrode that can be used with a small battery. [Means for solving the problem] That is, the present invention solves the general formula

The present invention relates to a base composition for an iontophoretic bioelectrode, which contains a compound () represented by the formula: (wherein R represents an alkyl group having 6 to 20 carbon atoms) as an essential component. In the general formula (), R is an alkyl group having 6 to 20 carbon atoms, preferably 8 to 18 carbon atoms, and suitable examples include lauryl nicotinate, octyl nicotinate, stearyl nicotinate, and lauryl isonicotinate. be done. Furthermore, in the general formula (), the group represented by -COOR is substituted at the 3- or 4-position of the pyridine nucleus, that is, the group represented by -COOR is

【formula】

A compound represented by the following formula is preferable. The base composition for an iontophoretic bioelectrode of the present invention can be used as a bioelectrode by itself by incorporating an ion-dissociative drug into the base composition. It can contain an organic solvent and water. Examples of the organic solvent include lower alcohols, cyclic ureas, alkylene glycols, lactam compounds,
Preferred examples include polar hydrophilic solvents such as glycerin and dimethyl sulfoxide, 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 ₁ and R ₂ 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 are listed. As a lactam compound, the general formula

[Action/Descent]

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] The present invention will be described in more detail below using Examples, Experimental Examples, etc., but the present invention is not limited thereto. In addition, all parts below indicate parts by weight. Example 1 (1) Sodium salicylate 0.3 parts (2) Lauryl nicotinate 100 parts 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) 0.3 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) Lauryl nicotinate Variable (3) N-methyl-3-pyrrolidone Variable Add (2) and (3) to (1) above in the proportions shown in Table 1. A drug solution was prepared by dissolving it, 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 an electrode was prepared in the same manner as in Example 1. Department. 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 1 part (2) Lauryl nicotinate 1 part (3) N-methyl-2-pyrrolidone Variable (4) Distilled water Variable (1) A drug solution was prepared by dissolving 2), (3), and (4) in the proportions shown in Table 2, 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 2, and the results are also listed in Table 2.

[Table] Examples 8 to 10/Experimental Example 4 (1) Sodium salicylate 10 parts (2) Lauryl nicotinate Variable (3) N-methyl-2-pyrrolidone 10 parts (4) Distilled water Variable (1) A drug solution was prepared by dissolving 2), (3), and (4) in the proportions shown in Table 3, 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 2, and the results are also listed in Table 3.

[Table] Examples 11 to 13/Experimental Example 5 (1) Sodium salicylate 10 parts (2) Lauryl nicotinate Variable (3) N-methyl-2-pyrrolidone Variable (4) Distilled water 10 parts Above (1) 2), (3), and (4) were dissolved 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 2, and the results are also listed in Table 4.

[Table] Example 14 (1) Diclofenac sodium 1 part (2) Lauryl isonicotinate 30 parts (3) t-Butyl alcohol 30 parts (4) Distilled water 40 parts Add (2), ( A drug solution was prepared by dissolving 3) and (4), 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 diclofenac sodium (2) 100 parts of t-butyl alcohol 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 15 (1) Salbutamol sulfate 1 part (2) Octyl nicotinate 30 parts (3) Propylene glycol 30 parts (4) Distilled water 40 parts Add (2), (3), (4) to (1) above ) was dissolved 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) Salbutamol sulfate 1 part (2) Propylene glycol 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. Example 16 (1) Terbutaline sulfate 1 part (2) Lauryl nicotinic acid 30 parts (3) N,N'-dimethyl sulfoxide 40 parts (4) Distilled water 30 parts Add (2) and (3) to (1) above , (4) was dissolved 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 the same procedure as in Example 1 was carried out. This was used as the electrode part. Example 17 (1) Propranolol hydrochloride 1 part (2) Lauryl nicotinate 30 parts (3) Dimethylethylene urea 30 parts (4) Distilled water 40 parts Add (2), (3), and (4) to (1) above. A drug solution was prepared by dissolving it, and an electrode part was prepared in the same manner as in Example 1. Comparative Example 6-a (1) 1 part of propranolol 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) 1 part of propranolol hydrochloride (2) 100 parts of dimethylethylene urea 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 18 (1) Metoclopramide hydrochloride 1 part (2) Hexyl nicotinate 50 parts (3) N-methyl-2-pyrrolidone 30 parts (4) Distilled water 20 parts In addition to (1) above, (2), (3), (4) was dissolved 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) Stearyl nicotinate 50 parts (3) N-methyl-2-pyrrolidone 30 parts (4) Distilled water 20 parts In addition to (1) above, (2), (3), (4) was dissolved to prepare a drug solution, 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 In 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) Lauryl nicotinate 10 parts (3) Ethyl alcohol 70 parts (4) Distilled water 20 parts The above (1) was replaced with (2), (3), (4) ) and mix and stir.
A polyester nonwoven fabric having 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 of the fabric, which was used as an electrode part. Comparative Example 9-a (1) Clonidine hydrochloride 0.4 parts (2) Distilled water 100 parts The above (1) was dissolved 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 The above (1) was dissolved 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 liquid 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. -○-...Example 1 -□-...Comparative example 9-
a,〓○〓……Comparative example 1,〓■〓……Comparative example 9-
b,〓△〓……Control, −●−……Example
20.

Claims (1)

[Claims] 1. An iontophoretic organism characterized by containing as an essential component a compound () represented by the general formula [Formula] (wherein R represents an alkyl group having 6 to 20 carbon atoms) Base composition for electrodes. 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 blending ratio of the compound () and the organic solvent is 1 to
99:99~1 (wt%) Claim 2
The base composition for an iontophoretic bioelectrode as described in 2. 5 The blending ratio of compound () and water is 50 to 99:1
The base composition for an iontophoretic bioelectrode according to claim 3, wherein the base composition is 50 (wt%). 6. The base composition for an iontophoresis bioelectrode according to claim 3, wherein the compounding ratio of the compound (), organic solvent, and water is 5 to 95:0 to 95:0 to 95 (wt%). .