JPS61178915A - Endermic absorption agent for lowering blood pressure - Google Patents

Abstract

PURPOSE:An endermic absorption agent for lowering blood pressure, capable of being administered independently health condition of a taker, preventing occurrence of side effects such as orthostatic hypotension, etc., maintaining successively fixed medicinal effects for a given period, containing prazosin hydrochloride as an active ingredient. CONSTITUTION:Prazosin hydrochloride usually orally administered as a remedy for hypertension as an active ingredient in a given concentration, 0.5-10wt%, is optionally blended with about 1-10wt% absorption promoter such as propylene glycol and/or about 0.5-5wt% absorption regulator such as carboxyvynyl polymer, etc., to give an endermic adsorption agent for lowering blood pressure such as external solution preparation, ointment, cream, gel ointment, plaster, etc. The endermic absorption agent is different from an oral drug, can be administered independently of health condition of patient, conditions of digestive organs such as the stomach and intestines, and liver function, or influence of foods, and the drug can be fed successively independently of half- life.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a blood pressure lowering transdermal absorbent that exerts a blood pressure lowering effect by directly absorbing a drug into the body through the skin surface, In particular, it relates to those containing brazosin hydrochloride as an active ingredient.

[Prior Art] Brazosin hydrochloride has a blood pressure lowering effect based on the adrenaline alpha receptor blocking effect, is widely used as a therapeutic agent for hypertension, and is usually administered as an oral preparation.

[Problems to be Solved] Brazosin hydrochloride has the disadvantage that when administered orally, its medicinal effects are rapid and side effects such as orthostatic hypotension occur. Additionally, in general, the absorption rate of orally administered drugs varies depending on the health condition of the user, the state of the gastrointestinal tract, or the influence of food, making it difficult to maintain a constant blood concentration. In order to compensate for these drawbacks of oral preparations, research has recently been carried out on transdermal absorption preparations. However, at present, a transdermal absorption agent containing brazosin hydrochloride as an active ingredient has not yet been realized.

[Solution Means] The present inventors have proposed a solution that avoids the above-mentioned drawbacks of brazosin hydrochloride as an oral preparation, prevents the occurrence of side effects such as orthostatic hypotension, and maintains the sustainability of the medicinal efficacy. It is a product of transdermal absorption agents such as ointments, creams, gel ointments, and patches. That is, the gist of the present invention is a transdermal absorption agent containing brazosin hydrochloride as an active ingredient. This will be explained in detail below.

Specifically, the percutaneous absorption agent for lowering blood pressure of the present application includes a liquid preparation for external use,
It is realized as an ointment, cream, gel ointment or patch. These transdermal absorption agents can be manufactured using commonly used methods, such as using a solvent that is not irritating to the skin, an ointment base, a cream base, or forming them on a support such as a flexible plastic film. This is achieved by incorporating brazosin hydrochloride in a predetermined concentration, for example 0.5 to 10%, in an adhesive polymer layer. At this time, a substance that promotes or regulates the transdermal absorption of Brazosin hydrochloride is used in combination. Among these absorption modifiers, those that mainly promote the absorption of the active ingredients of the powder include propylene glycol, polyethylene glycol, lecithin,
Urea, amino acid, 1-dodecylhexahydro-2H
-Azepine-2-one (for example, Eishin (trade name)) or the like can be used in an amount of about 1 to 10%. In addition, carboxyvinyl polymer (
In a row, Carbopol 934, Hipiswako 104
(both trade names)) can be blended in an amount of about 0.5 to 5%. These absorption modifiers may be used alone or as a mixture of several.

In particular, when the transdermal absorption agent of the present application is implemented as a patch, the most basic structure is one in which a single layer of adhesive polymer containing brazosin hydrochloride is formed on a support made of a flexible film or sheet. However, this support can be made of polyethylene, polypropylene, ethylene-
Flexible films or sheets such as acrylic acid copolymer, ethylene-vinyl acetate copolymer, polyester, and nylon can be used. Further, as the polymer layer having adhesion to the skin, a commonly used copolymer of acrylic ester or the like is used as it forms an adhesion that is less irritating to the skin. At this time, brazosin hydrochloride is added before the start of polymerization of the acrylic ester.
In addition, a suitable polymerization initiator such as lauroyl peroxide or azobisisobutyronitrile may be added in advance to produce a single layer of adhesive polymer from a suitable polymerization solution. Furthermore, a crosslinking agent may be added to the resulting adhesive polymer for the purpose of adjusting the adhesiveness, retention of active ingredients, release properties, etc. As the crosslinking agent in this case, an epoxy compound or the like is suitable, and for example, polyethylene glycol glycidyl ether, ethylene glycol glycidyl ether, etc. are used. Furthermore, the fact that propylene glycol, polyethylene glycol, lecithin, urea, amino acids, or alcohol esters can be used as a modifier for promoting absorption of the active ingredient in the powder is no different from other drug layers such as ointments and creams. There isn't.

[Efficacy] Unlike oral administration, the transdermal antihypertensive agent of the present application can be administered regardless of the patient's health condition, the state of the gastrointestinal tract or liver function, the influence of food, etc. can be,
In addition, it is possible to continuously supply the drug regardless of its half-life, avoid side effects such as orthostatic hypotension that are characteristic of brazosin hydrochloride, and maintain a predetermined concentration continuously for a certain period of time. The following are pharmacological tests and manufacturing examples of the transdermal absorption agent of the present application.

[Pharmacological test example] Antihypertensive effects: Rats with abdominal hair removed were anesthetized with urethane (246 mg/mQ, 5
mj2/kg, i, p, )L, was fixed on a fixing table with the abdomen facing up. A cannula connected to a transducer was inserted into the femoral artery, and the mean blood pressure was measured using a polygraph (manufactured by Nihon Koden 1), and recorded on a recorder (manufactured by Nihon Kohden) to measure the mean blood pressure. The results are shown in the table below.

In the table, the numbers on the implementation side each refer to the drugs produced in the corresponding examples shown below.

Examples are shown below.

[Example 1 Topical solution Brazosin hydrochloride 0.5g Propylene glycol 86.5g Distilled water
10.0g Eishin
3.0 g of Brazosin hydrochloride was placed in a mortar, and a mixed solution of propylene glycol, eisin and distilled water was added little by little and stirred. This liquid was heated in a water bath at about 40°C and stirred to obtain a clear solution.

[Example 2] External liquid Brazosin hydrochloride 0.5g Propylene glycol 79.5g Distilled water
10.0g urea 1
0.0 g It was prepared in the same manner as in Example 1.

[Example 3 Co-cream agent Brazosin hydrochloride 0.5g Eishin
5.0g distilled water
63.5g Sorbitan monostearate 2
．． 0g polyoxyethylene sorbitan monostearate 1.5g whale wax
3. Og cetostearyl alcohol 10.0g (cetyl alcohol) 2-octyldodecanol (oitanol G) Benzyl alcohol 1.0g oil layer (sperm wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol heated to about 60℃) Dissolve the aqueous layer (sorbitan monostearate, polyoxyethylene sorbitan monostearate, distilled water) at about 60°
It was heated to C and melted. The two components were mixed together and thoroughly mixed at room temperature.

This base and Brazosin hydrochloride were thoroughly mixed and prepared.

[Example 4 Co-gel ointment Brazosin hydrochloride 0.5g Eisin
4.0g lecithin
1.0g propylene glycol 8
2. 5g distilled water 10.0g
Power-Bopole 934 1. 0g diisopropanolamine 1.1g brazosin hydrochloride,
Eishin, lecithin, propylene glycol 65-7
After heating and melting at 5°C, Carbopol 934 was added and dissolved. Separately, a solution of diisopropanolamine added to distilled water was added and mixed at 75°C.

[Example 5 First step of adhesive patch Synthesis of adhesive base (polymerization agent) Dodecyl methacrylate 43g Vinyl acetate
5g acrylic acid 2gn
-Hexane 28g toluene
6g lauroyl peroxide/n-hexane 0. 6g/4. 4m Qn-hexane
While bubbling nitrogen into a 36g, 200ml, 4-diameter flask, add 43g of dodecyl methacrylate, 5gs of vinyl acetate, 28g of acrylic m2gb, 28g of n-hexane, and 6g of toluene and heat to about 70°C, then add 0.6g of lauroyl peroxide to n-hexane. 4.4m
Add the solution dissolved in 100ml over 1 hour, and then continue the reaction for 7 hours. After the polymerization was completed, 36 g of n-hexane was further added to obtain a white translucent sticky liquid.

Second step 10g of the sticky liquid obtained in the first step was added with 0% of brazosin hydrochloride.
．． A solution of 1 g dissolved in 5 mff1 of ethyl acetate was added and stirred, and then Brazosin hydrochloride was applied to a silicone-treated polypropylene film at a concentration of 10 mg/loocm, and the solvent was evaporated to obtain a sheet adhesive. The adhesive side of this sheet is used as a support for ethylene.
By bonding to a casting film made of acrylic acid copolymer, the sheet-like adhesive is transferred to the support to obtain a patch.

[Example 6 Patch Brazosin hydrochloride 0.5g Sodium polyacrylate 6.0g Glycerin
13.0g urea 2.
0g glycerin diglycidyl ether 2.0g polyethylene glycol 15.0g water
61.5g sodium polyacrylate (degree of polymerization 20.000 > 6.0g glycerin 1
3.0 g, dissolved in 2.0 g of urea and 44.5 g of water.

Separately, add 2.0 g of glycerin diglycidyl ether to 10 g of water.
Dissolve in g. Furthermore, 7.0 g of water, 15 g of polyethylene glycol, and 0.5 g of Brazosin hydrochloride are dissolved.

These solutions are stirred and mixed, and applied as a support to a casting film made of vinyl-acrylic acid copolymer in an amount of 10 mg of brazosin hydrochloride (7100 cm) to obtain a patch.

Claims (1)

[Claims] A transdermal antihypertensive agent containing brazosin hydrochloride as an active ingredient.