JPH05946A - Ketotifen-containing percutaneous absorption preparation - Google Patents

Abstract

PURPOSE:To provide the subject preparation produced by compounding ketotifen with a 8-12C fatty acid, an aliphatic alcohol or their mixture as an absorbefacient to remarkably increase the skin permeability of ketotifen and a >=2-hydric alcohol. CONSTITUTION:The objective ketotifen-containing transcutaneous absorption preparation is produced by compounding (A) ketotifen {4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]-thiophen-10(9H)-one} and its pharmacologically allowable salt with (B) a 8-12C fatty acid (e.g. caprylic acid, capric acid and lauric acid, especially lauric acid) or an aliphatic alcohol (e.g. octyl alcohol, decyl alcohol or lauryl alcohol, preferably lauryl alcohol) and (C) >=2-hydric alcohol (e.g. propylene glycol, glycerol or polyethylene glycol, preferably propylene glycol). It exhibits broad antiallergic action such as excellent anti-SRS-A action and antihistaminic action.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a ketotifen-containing percutaneous absorption preparation showing a wide range of antiallergic effects such as excellent anti-SRS-A effect and antihistamine effect.

[0002]

2. Description of the Related Art Ketotifen is converted into S by the antigen-antibody reaction.
It has a strong inhibitory effect on the release of chemical mediators such as RS-A and histamine, and is used as an oral preparation such as capsules and syrups for the treatment of bronchial asthma, allergic rhinitis, eczema, dermatitis, urticaria, etc. Widely used.

However, oral preparations have many drawbacks such as side effects such as gastrointestinal disorders, lower utilization rate due to hepatic first-pass effect, and lower administration compliance for patients.

Recently, as means for solving these problems, transdermal or transmucosal administration by external preparation has been attracting attention.

Administration by external preparation transfers the drug from the skin to the systemic circulatory system, so that it does not have the above-mentioned drawbacks of the oral preparation and has a long-lasting drug effect. There is an advantage that the administration of can be promptly stopped.

[0006] However, when a drug is transdermally transferred into the body, it is difficult to transfer a drug sufficient to exert a drug effect by only dissolving or suspending the drug in a base. Yes, it is necessary to somehow enhance the skin permeability of the drug.

[0007] As a method for promoting skin permeability, there is a heat method, iontophoresis for promoting permeation of an ionic drug by applying electricity, phonophoresis using ultrasonic waves, and use of a transdermal absorption enhancer. It has been known. Of these, the use of absorption enhancers is easy to apply and can be expected to have a great effect.

As the absorption enhancer, alcohols such as ethanol and isopropanol, propylene glycol,
Polyhydric alcohols such as glycerin, fatty acids, fatty acid esters, pyrrolidones such as N-methyl-2-pyrrolidone,
Urea derivatives, aprotic solvents such as dimethylformamide and dimethylsulfoxide, surfactants such as sodium lauryl sulfate, Azone, cyclic urea and the like are known.

However, the above-mentioned ketotifen cannot obtain a sufficient absorption promoting effect even if these absorption promoters are used alone.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to provide a ketotifen-containing transdermal preparation having extremely good skin permeability.

[0011]

The present inventors have found an absorption enhancer which significantly increases the skin permeability of ketotifen and arrived at the present invention.

That is, the present invention is a ketotifen-containing percutaneous absorption preparation in which ketotifen is blended with a fatty acid or an aliphatic alcohol having 8 to 12 carbon atoms or a mixture thereof, and a divalent or higher alcohol.

The ketotifen referred to in the present invention is ketotifen (generic name) [chemical name: 4- (1-methyl-4-piperidylidene) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene-10. (9H) -one] and pharmaceutically acceptable salts thereof.

Examples of the fatty acid having 8 to 12 carbon atoms used in the present invention include caprylic acid, capric acid and lauric acid.

Examples of the aliphatic alcohol having 8 to 12 carbon atoms used in the present invention include octyl alcohol, decyl alcohol and lauryl alcohol.

Examples of the dihydric or higher alcohol used in the present invention include propylene glycol, butanediol, glycerin, polyethylene glycol and the like.

The content of ketotifen in the transdermal preparation of the present invention is 0.1 to 50% by weight, preferably 10 to 50% by weight.

The amount of fatty acid or aliphatic alcohol having 8 to 12 carbon atoms is 0.1 to 50% by weight, preferably 1
10 to 10% by weight.

The amount of dihydric or higher alcohol is 0.1
˜99% by weight, preferably 1 to 50% by weight.

Further, the percutaneous absorption preparation of the present invention includes known bases used for external preparations such as hydrophobic bases such as petrolatum, paraffin, silicone, vegetable oil and wax, and other than the alcohol. Alcohols, hydrophilic bases such as water-soluble polymers, and known bases used for patch preparations, such as rubber-based, acrylic-based or silicone-based adhesives and tackifiers, for transdermal absorption preparations. Surfactants, stabilizers, preservatives, preservatives, emulsifiers, suspending agents and the like used can be added.

The dosage form of the transdermal preparation of the present invention is not particularly limited, and examples thereof include ointments, plasters, creams, lotions, poultices, sprays, tapes, patches and suppositories.

[0022]

The present invention has the following effects. (1) The skin permeability of ketotifen is extremely good. (2) There is no liver first permeation effect and the bioavailability is high. (3) No gastrointestinal disorders. (4) A sustained effect can be obtained by single administration. (5) If side effects occur, administration can be stopped immediately.

[0023]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Examples 1 to 3 Ketotifen fumarate was added to a solution of each composition shown in the column of Examples in Table 1 until it was suspended to prepare a ketotifen-containing transdermal preparation.

With respect to the obtained transdermal preparation containing ketotifen, skin permeability was evaluated by the following in vitro test. The results are shown in Table 2.

In vitro test The skin of the abdomen extracted from an anesthetized male hairless rat (body weight: about 150 g) was fixed in a diffusion cell (permeation area: 0.9 cm ² ) in which water at 37 ° C. was circulated, and the stratum corneum was fixed. In the side cell,
2.5 ml of the prepared ketotifen-containing percutaneous absorption preparation was added to 2.5 ml of distilled water in the dermis side cell, and stirred with a stirrer.

Next, the solution in the dermis side cell was sampled with time, the amount of ketotifen fumarate contained in the solution was measured by high performance liquid chromatography to determine the cumulative permeation amount (mg) at 10 hours, and the cell permeation amount was determined. The skin permeability was evaluated by calculating the cumulative amount of permeation (mg / cm ² ) per unit area of the surface.

Comparative Examples 1 to 6 Ketotifen was prepared in the same manner as in Example 1 except that the solutions shown in the Comparative Examples column in Table 1 were replaced with the solutions having the respective compositions shown in Table 1. The contained percutaneous absorption preparation was prepared and the skin permeability was evaluated. The results are shown in Table 2.

[0029]

[Table 1]

[0030]

[Table 2]

Examples 4 to 7 Ketotifen was prepared in the same manner as in Example 1 except that the solutions shown in the Example column of Table 1 were replaced with the solutions of the respective compositions shown in Table 3 below. The contained percutaneous absorption preparation was prepared and the skin permeability was evaluated. The results are shown in Table 4.

Comparative Examples 7 to 10 Ketotifen was carried out in the same manner as in Example 1 except that the solutions shown in Table 3 in the column of Comparative Example were used in place of the solutions shown in Table 1 in the column of Example. The contained percutaneous absorption preparation was prepared and the skin permeability was evaluated. The results are shown in Table 4.

[0033]

[Table 3]

[0034]

[Table 4]

Evaluation As is clear from Tables 2 and 4, a ketotifen-containing transdermal preparation using capric acid, lauric acid, octyl alcohol, decyl alcohol or lauryl alcohol together with propylene glycol and water was prepared. The skin permeability of ketotifen fumarate was particularly excellent.

Claims (5)

[Claims] 1. Ketotifen, a fatty acid or aliphatic alcohol having 8 to 12 carbon atoms, or a mixture thereof,
A transdermal preparation containing ketotifen mixed with a divalent or higher alcohol. 2. The transdermal preparation containing ketotifen according to claim 1, further comprising water. 3. The percutaneous absorption preparation according to claim 1, wherein the fatty acid having 8 to 12 carbon atoms is lauric acid. 4. The percutaneous absorption preparation according to claim 1 or 2, wherein the aliphatic alcohol having 8 to 12 carbon atoms is lauryl alcohol. 5. The transdermal preparation according to claim 1, wherein the divalent or higher alcohol is propylene glycol.