JPH1045597A - External preparation for treating hypertension and urinary disturbance - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject effective therapeutic agent not causing adverse effects such as orthostatic hypotension, high in safety, comprising a medicine having an α1 receptor blocking action such as prazosin and a specific percutaneous absorption promoter. SOLUTION: This therapeutic agent comprises (A) preferably 0.05-1wt.% of a medicine selected from prazosin, tetrazocine, tamuslosin and their hydrochlorides having an α1 receptor blocking action and (B) preferably 0.2-3wt.% of an 8-24C polyhydric alcohol fatty acid ester (preferably a monoglycerol 8-18C fatty acid ester) as a percutaneous absorption promoter. The objective external preparation can be optionally mixed with a water-soluble base such as macrogol ointment, an oily base such as vaseline and an emulsifying agent such as a polyoxyethylene alkyl ether. These bases and additives can be used in amounts of 1-80wt.%. Further, the preparation can be mixed with a proper amount of water or a buffer solution.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an external preparation, and more specifically, to a polyhydric alcohol fatty acid ester in a preparation, and if necessary, one or more kinds of bases, additives and bases usually used in pharmaceutics. using cloth for example nonwoven fabric or the like, prazosin having alpha ₁ receptor blocking action, terazosin, relates tamsulosin and external preparation for percutaneous absorption of their hydrochloride salts.

[0002]

2. Description of the Related Art Drugs having an α ₁ receptor-blocking effect have a drawback that when administered orally to hypertension, side effects such as orthostatic hypotension appear. These may be due to the highest blood concentration of the first dose, and the method of administration is often to start with a low dose and to increase or decrease as appropriate according to clinical symptoms. In addition, it is difficult to immediately lower the drug concentration in the blood when a side effect occurs.

[0003]

Even for [0006] dysuric, alpha ₁ receptor blocking often adverse reactions such as orthostatic hypotension observed a therapeutically problem due to the action.

[0004] Unlike peroral preparations, prazosin, terazosin, tamsulosin and their hydrochloride percutaneous absorbents can obtain a constant blood drug concentration for a long period of time without producing a high initial blood concentration, and are therefore clinically acceptable. Not only is it convenient for effects, but it is also possible to reduce side effects. Also,
When the occurrence of side effects is observed, the drug concentration in the blood can be rapidly reduced by exfoliation, so that the administration method is highly effective and safe.

[0005]

Means for Solving the Problems The present inventors have proposed prazosin, terazosin, tamsulosin and their hydrochlorides, polyhydric alcohol fatty acid esters, and if necessary, bases, additives, base cloths which are usually used in pharmacology. Using non-woven fabric etc.
The present invention has been found that an external preparation prepared by adding an appropriate amount of water or a buffer solution can sufficiently and promptly percutaneously absorb prazosin, terazosin, tamsulosin, and their hydrochloride.

The present invention provides (a) prazosin, terazosin,
Tamsulosin and their hydrochlorides, (b) containing polyhydric alcohol fatty acid ester, and (a) and (b) in the formulation: (a) 0.01-2w% (b) 0.1-5w% Percutaneous absorption characterized by containing one or two or more kinds of bases and additives usually used in pharmaceutics, if necessary, in a specific ratio, and adding water or a buffer solution in an appropriate amount. And a base cloth such as a nonwoven fabric, if necessary.

[0007] Prazosin, terazosin, tamsulosin and their hydrochloride salts can be contained in an amount of 0.01 to 2% by weight, preferably 0.05 to 1% by weight.

The polyhydric alcohol fatty acid ester includes glycerin fatty acid ester, propylene glycol fatty acid ester, sorbitan fatty acid ester, sucrose fatty acid ester and the like as typical substances, and preferably monoglycerin fatty acid ester.

The fatty acid of the polyhydric alcohol fatty acid ester is an unsaturated or saturated fatty acid having 8 to 24 carbon atoms, and preferably 8 to 18 carbon atoms.

The polyhydric alcohol fatty acid ester can be contained in the composition in an amount of 0.1 to 5% by weight, preferably 0.2 to 5% by weight.
3w% is desirable.

Bases and additives usually used in pharmacology are
For example, hydrophilic ointments, emulsion bases including water-absorbing ointments,
Water-soluble bases such as macrogol ointment, vaseline, isopropyl myristate, liquid paraffin, oil bases such as higher alcohols, gum arabic, gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyacrylic acid, polyvinyl alcohol, water-soluble polymers such as polyvinylpyrrolidone, polyoxyethylene alkyl ether, polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, Emulsifiers such as quaternary ammonium salts, purified hydrogenated egg yolk lecithin, purified hydrogenated soybean lecithin, lower alcohols (ethanol, isopropyl alcohol), and glycerin, propylene glycol;
One or two or more polyhydric alcohols such as 1,3-butanediol and polyethylene glycol can be blended, and they can be used as transdermal absorbents such as ointments, creams, gels, external solutions, and external suspensions. it can.

[0012]

The percutaneous absorption agent of the present invention contains prazosin, terazosin, tamsulosin and their hydrochloride salts and polyhydric alcohol fatty acid esters in a specific ratio. By using this preparation, prazosin, terazosin, tamsulosin And their hydrochlorides can be administered effectively and safely and are extremely useful clinically.

[0013]

【Example】

Examples 1-4 prazosin hydrochloride 1 w% lauric acid ester as monoglycerin fatty acid ester (C12: C ₁₂₎ or oleate (carbon number 18: C _18), ethanol,
1,3-Butanediol was mixed in the proportions shown in Table 1, and an appropriate amount of purified water was added to the transdermal absorbent of the present invention (Examples 1 to 3)
4) was prepared.

[0014]

[Table 1]

Examples 5 to 7 Terazosin hydrochloride 1% by weight as monoglycerin fatty acid ester is lauric acid ester (C12: C12) or
Oleic acid ester (18 carbon atoms: C18), ethanol, and 1,3-butanediol were mixed in the proportions shown in Table 2, and an appropriate amount of purified water was added to the transdermal absorbent of the present invention (Example 5).
To 7) were prepared.

[0016]

[Table 2]

Examples 8-13 Caprylic acid ester (C8: C8), lauric acid ester (C12: C12) or oleic acid ester (C18) as a monoglycerin fatty acid ester in tamsulosin hydrochloride 0.06% by weight. : C18), ethanol and 1,3-butanediol were mixed in the proportions shown in Table 3, and an appropriate amount of purified water was added thereto, and the transdermal absorbent of the present invention (Example 8)
~ 13) were prepared.

[0018]

[Table 3]

Example 14 The sample of Example 5 was applied to the surface of a nonwoven fabric having a drug-impermeable support on one side, which was in contact with the skin, to prepare a transdermal absorbent of the present invention (Example 14).

Example 15 The sample of Example 10 was applied to a surface of a nonwoven fabric having a drug-impermeable support on one side, which was in contact with the skin, to prepare a transdermal absorbent of the present invention (Example 15).

External preparations for percutaneous absorption (Examples 16, 17 and 18) having the following composition were prepared. (Wt%) Example 16 Example 17 Example 18 HCl Terazosin 1.0 - 2.0 Tamsulosin HCl - 0.06 - mono glycerin fatty acid ester (C ₁₂₎ 5.0 2.0 5.0 Propylene glycol 10.0 10.0 10.0 Ethanol 20.0 20.0 20.0 carboxyvinyl polymer 5% aqueous solution 10.0 10.0 10.0 Triethanolamine 2.0 2.0 2.0 Methyl paraben 0.05 0.05 0.05 Purified water 51.95 55.89 50.95

[0022]

[Reference example]

Reference Example 1 1% by weight of prazosin hydrochloride was mixed with ethanol and 1,3-butanediol at the ratios shown in Table 1, and an appropriate amount of purified water was added to prepare a transdermal absorbent (Reference Example 1).

REFERENCE EXAMPLE 2 Ethanol and 1,3-butanediol were mixed with 1% by weight of terazosin hydrochloride in the proportions shown in Table 2, and an appropriate amount of purified water was added to prepare a transdermal absorbent (Reference Example 2).

Reference Example 3 Ethanol and 1,3-butanediol were mixed with 0.06% by weight of tamsulosin hydrochloride in the proportions shown in Table 3, and an appropriate amount of purified water was added to prepare a transdermal absorbent (Reference Example 3).

Reference Example 4 The sample of Reference Example 2 was applied to the surface of a nonwoven fabric having a drug-impermeable support on one side, which was in contact with the skin, to prepare a transdermal absorbent of the present invention (Reference Example 4).

Reference Example 5 The sample of Reference Example 3 was applied to a surface of a nonwoven fabric having a drug-impermeable support on one side, which was in contact with the skin, to prepare a transdermal absorbent of the present invention (Reference Example 5).

An external preparation for transdermal absorption (Reference Examples 6 and 7) having the following composition was prepared. % By weight Reference Example 6 Reference Example 7 Terazosin hydrochloride 1.0-Tamsulosin hydrochloride-0.06 Propylene glycol 10.0 10.0 Ethanol 20.0 20.0 Carboxyvinyl polymer 5w% aqueous solution 10.0 10.0 Triethanolamine 2.0 2.0 Methyl paraben 0.05 0.05 Purified water 56.95 57.89

[0028]

【Test method】

Test Method 1 Skin Permeability Test (1) The abdominal skin of a male hairless rat was sandwiched between two chamber diffusion cells (effective diffusion area: 0.79 cm ² ), and a test sample was added to the stratum corneum and purified water was added to the dermis. The permeability of the drug in the test sample was evaluated. The permeability was evaluated by measuring the amount of drug in purified water over time using HPLC, and calculating the Flux value (μg / cm ² / hr) from the cumulative permeation amount for 24 hours.

Test Method 2 Skin Permeability Test (2) An abdominal extirpated skin of a male hairless rat was sandwiched between Franz-type diffusion cells (effective diffusion area: 3.14 cm ² ), and a test sample was purified on the stratum corneum side and purified on the dermis side Water was added to evaluate the permeability of the drug in the test sample. The permeability was evaluated by measuring the amount of drug in purified water over time using HPLC, and calculating the F
The measurement was performed by determining the lux value (μg / cm ² / hr).

The skin permeation test of the external preparation of the present invention obtained in Examples 1 to 4 and the external preparation obtained in Reference Example 1 was conducted using Test Method 1.

The skin permeation test of the external preparations of the present invention obtained in Examples 5 to 18 and the external preparations obtained in Reference Examples 2 to 7 was carried out by Test Method 2.

[0032]

【result】

(1) The results of Examples 1 to 4 and Reference Example 1 were as shown in Table 1 above. As is clear from Table 1, the external preparation of the present invention showed good skin permeability of prazosin hydrochloride.

(2) The results of Examples 5 to 7 and Reference Example 2 were as shown in Table 2 above. As is clear from Table 2,
The external preparation of the present invention showed good skin permeability of terazosin hydrochloride.

(3) The results of Examples 8 to 13 and Reference Example 3 are as shown in Table 3 above. As is clear from Table 3, the external preparation of the present invention showed good skin permeability of tamsulosin hydrochloride.

(4) Examples 14 and 15 and Reference Example 4,
The result of No. 5 was as shown in Table 4.

[0036]

[Table 4]

As apparent from Table 4, the external preparation of the present invention showed good skin permeability of terazosin hydrochloride and tamsulosin hydrochloride.

(5) Examples 16 and 17 and Reference Example 6,
The result of No. 7 was as shown in Table 5.

[0039]

[Table 5]

As is clear from Table 5, the external preparation of the present invention showed good skin permeability of terazosin hydrochloride and tamsulosin hydrochloride.

[0041]

As described above, the external preparation of the present invention is used as a percutaneous absorbent as compared with that of the conventional oral administration, and therefore has no prolonged side effects such as orthostatic hypotension. A certain amount of medicinal effect can be obtained over time.

Claims (2)

[Claims] _1. A drug selected from the group consisting of prazosin, terazosin, tamsulosin and their hydrochloride having an α1 receptor-blocking action, and a polyhydric alcohol fatty acid ester having 8 to 24 carbon atoms as a transdermal absorption enhancer. An external preparation for treating hypertension and dysuria, characterized by containing at least one species. 2. The composition contains 0.01 to 2% by weight of prazosin, terazosin, tamsulosin and their hydrochloride and 0.1 to 5% by weight of a polyhydric alcohol fatty acid ester, and optionally 1 to 80% by weight. 3. The external preparation for treating hypertension and dysuria according to claim 2, wherein an appropriate amount of water or a buffer is added using a base, an additive or the like usually used in pharmacology.