JPS63104913A - Plaster for external use - Google Patents

Abstract

PURPOSE:To produce a plaster for external use, alleviating skin irritation, increasing percutaneous absorption ability of beta-blocker, by blending a tacky gel base comprising a water-soluble high polymer, water and a water retaining agent with a specific beta-blocker such as bupranolol, etc. CONSTITUTION:(A) One or more beta-blockers selected from bupranolol, bupranolol hydrochloride (remedy and preventive for hypertension, arrhythmia, angina pectoris, extrasystole, etc.) shown by the formula, timolol, timolol maleate, indenolol and indenolol hydrochloride is added to a tacky gel base comprising (B) a water-soluble high polymer such as gelatin, etc., (C) a water retaining agent such as polyhydric alcohol, e.g. glycerin, etc., or extremely higher aqueous high polymer such as starch-acrylic acid graft material, etc., and (D) water as essential components to give a plaster for external use which can be surely attached to the skin, does not cause skin irritation in the plaster and regulates balance of a percutaneous absorption amount of the drug A and a release amount of the drug.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an external patch for transdermal absorption of β-blockers.

In the topical patch of the present invention, bupranolol or its hydrochloride, timolol or its maleate, and indenolol or its hydrochloride are used as β-blockers, and below, bupranolol (or its hydrochloride) is listed as a representative example. I will explain.

[Prior Art] Bupranolol hydrochloride is a β-blocker having the following structural formula, and is used as a therapeutic and preventive drug for hypertension, arrhythmia, premature 9th contraction of angina pectoris, and the like.

C+dh2CINOx ・HCI: 308.2
51-Tertiary-butylamino-3-(2-chloro-5-methylphenoxy)-2-propatol hydrochlorideIt has traditionally been said that oral administration is the most common method of administering this drug to patients. However, oral administration has the following problems.

(1) Because the bioavailability is low (5%) and the biological half-life is relatively short (2.5 hr), it is necessary to take the drug three times a day, and patients sometimes forget to take it. This causes rebound phenomena.

(2) It may not be possible to prevent angina pectoris attacks when waking up early in the morning.

(3) As side effects of the drug itself, hypersensitivity, hypotension, 1 headache, nausea, 1 loss of appetite, etc. have been pointed out.

Therefore, attempts have been made to change the route of administration in order to solve the problems associated with oral administration. The following (^) to (C) are examples intended for transdermal absorption.

(^) Bupranolol is incorporated into a natural/synthetic rubber adhesive or an acrylic ester adhesive to form a tape (patch).

(B) Bupranolol is included in an ointment or spray.

(C) Bupranolol is contained in a polymer matrix, and this is made into a patch.

[Problems to be solved by the invention] However, (^) causes side effects such as contact dermatitis caused by adhesives, folliculitis caused by epidermal bacteria, and skin inflammation due to stimulation of sweat glands. That's what I found out. Furthermore, since the transdermal absorption capacity itself is not very large, bupranolol contained in the adhesive layer accumulates on the skin, which is disadvantageous in terms of pharmacoeconomics and irritates the skin. Naoki patches need to be made so that they do not peel off from the skin even when sweating, and they must have fairly strong adhesive strength. Therefore, when peeled off, the stratum corneum at the application site may be damaged, making continuous application and long-term continuous administration difficult. Next, in (B) ointments, etc., in addition to the woody problem that it is difficult to administer the drug in a fixed amount,
Since it adheres to clothes and underwear and stains them, it is not welcomed by patients, and there are many cases where long-term continuous administration is not carried out.

In the method (C) using a polymer matrix,
Since the matrix itself has no adhesive strength, the adhesive layer (A) is necessary, and therefore the same problem as in (A) arises.

The present invention was made in consideration of these circumstances, but among the above (A) to (C), method (A) was considered to be the most meaningful, so method (^) was adopted. We considered that solving the various problems that arise when doing so is an important issue at hand, and we have considered various issues. That is, the present invention aims to provide an external patch that can be safely used for a long period of time by solving all of the above-mentioned problems with the patch.

[Means for solving problems] The external patch according to the present invention is a water-soluble polymer.

1 f1 or more selected from the group consisting of bupranolol, bupranolol hydrochloride, timolol, timolol maleate, indenolol, and indenolol hydrochloride in a sticky gel base containing water and a water-retaining agent as essential components; It has a gist.

[Function] In order to solve the above-mentioned problems, the present inventors have proposed two methods: (a) alleviating skin irritation, and (b) harmonizing the amount of drug released by increasing transdermal absorption capacity. After repeated studies with these points as research goals, we established specific means to satisfy these points and completed the present invention. That is, the present invention relates to a water-soluble polymer.

The adhesive gel base is composed of water and a water retention agent as essential components, and the β-blocker is contained in the adhesive gel base.

The above-mentioned adhesive gel base exhibits a reliable adhesive effect on the skin despite having a water-retaining effect, and
Its water-retaining action moderately softens the stratum corneum of the skin and alleviates skin irritation.

On the other hand, it is believed that the skin permeation rate of β-blockers is originally not very high, so β-blockers often accumulate at the application site, and side effects specific to β-blockers (for example, bupranool) However, when the patch of the present invention softens the stratum corneum of the skin through its water-retaining effect, the skin permeation rate of the β-blocker increases. It is possible to alleviate the accumulation of β-blocker at the application site and eliminate the side effects associated with accumulation,
Furthermore, it is possible to achieve a balance between transdermal absorption capacity and drug release amount (for example, the original action of the β-blocker can be maintained for a long time without causing the above-mentioned side effects).

Examples of the β-blocker used in the present invention include bupranolol or its hydrochloride, timolol or its maleate, and indenolol or its hydrochloride. The amount of these compounds (in the adhesive gel base, the same hereinafter) is determined by taking into consideration efficacy and irritation, etc., but in the case of bupranolol or its hydrochloride, it is 0.5 to 61i% (hereinafter the same). %) is preferable, more preferably 0.5~
It is 4%. In the case of timolol or its maleate salt it is (1.5-8%, preferably 1-6%) and in the case of indenolol or its hydrochloride it is 0.5-40%, preferably 1-30%.

These β-blockers are β1-selective.

Since they are different in terms of ISA, MSA, BBB permeability, etc., they should be selected depending on the purpose of administration.

Water-soluble polymers include gelatin, agar, mannan, alginic acid, polyacrylic acid, polyacrylates, carboxymethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic,
Gum tragacanth.

Examples include locust bean gum, and those crosslinked with metal salts thereof and organic/inorganic crosslinking agents can also be used. These water-soluble polymers are used to impart desired physical properties to other raw materials used in the adhesive gel base. In actual use, they are used singly or in combination of two or more kinds, and the amount blended in the adhesive gel base is recommended to be 0 to 40%, and more preferably 0 to 20%.

As the water retention agent, one or a combination of two or more polyhydric alcohols such as polyethylene glycol, glycerin, sorbitol, maltitol, propylene glycol, and 1,3-butylene glycol are used, and the blending amount is 0.
-70% is preferable, and 10-60% is more preferable. Also, starch-acrylonitrile graft, starch-acrylic acid graft, starch-styrene sulfonic acid graft, starch-vinyl sulfonic acid graft, and polyvinyl alcohol crosslinked product.

Ultrahigh water absorbency polymers such as saponified acrylic acid-vinyl acetate and crosslinked polyethylene glycol diacrylate can also be used, and in these cases, 0 to 20% is preferable.
More preferably, it is used in a range of 0.01 to 10%.

The water content in the adhesive gel base is preferably 10 to 70%, more preferably 20 to 50%.

Although the present invention has the structure as described above, the following components (1) and (2) may be added as necessary.

(1) In order to increase the solubility of the β-blocker in the base, solubilizers such as n-butyl stearate, benzyl alcohol, isopropyl myristate, isopropyl balmitate, polypropylene glycol, crotamiton, diethyl sebacate, etc. In addition, a surfactant may be added to emulsify these and the water in the base.

(2) By using known stabilizers, antioxidants, pH adjusters, etc., it is possible to increase the stability of the drug and the reliability of its associated drug efficacy. The combination, pH, etc. of these additives should be determined in consideration of drug release control, suppression of skin irritation, etc. According to the studies conducted by the present inventors, it was determined that it is preferable to adjust the composition so that the pH is 5.0 to 9.0 by making various changes in combination.

The support used in the present invention is preferably a flexible support that can easily follow the movements of the human body, such as various nonwoven fabrics, woven fabrics, flannelette, and polyethylene films, ethylene vinyl acetate films, and polyvinyl chloride films. ,
Those laminated with polyurethane film, etc., and those with holes processed are used. It is recommended that these be determined while considering the formulation of the adhesive gel base in order to maintain the water content in the base within the above range.

Examples will be described below in comparison with comparative examples, but the present invention is not limited to these examples and can be modified as necessary.

[Example] 2.0 parts of bupranolol hydrochloride, 37.4 parts of water, 0.1 part of methyl hydroxybenzoate, 4.0 parts of gelatin, 3.5 parts of carboxymethylcellulose, 3.0 parts of sodium polyacrylate 1 part, 45 parts of glycerin, 4.0 parts of isopropyl myristate, and 1.0 part of sorbitan monooleate were heated and stirred in a kneader to obtain a sticky gel base. It was spread on a silicone-treated polyethylene terephthalate liner to a weight of 200 g and 7 m2, then transferred to a rayon family nonwoven fabric laminated with an ethylene vinyl acetate film, and cut into desired large grains to obtain an external patch. Ta. The pH is 9.
0 and contained 400 parts g/cm'' of bupranolol hydrochloride.

KA-riyu 2.0 parts of bupranolol hydrochloride, 36.9 parts of water, 0.1 part of propyl hydroxybenzoate, and 3.0 parts of gelatin.

1.5 parts of polyvinyl alcohol, 3.0 parts of carboxymethyl cellulose, 0.5 parts of starch-polyacrylate, 3.0 parts of sodium polyacrylate, 45 parts of glycerin
1 part, isopropyl myristate, 4.0 parts, and sorbitan monooleate 1.0 parts were heated and stirred in a kneader to obtain an adhesive gel base, and then the same operation as in Example 1 was carried out to obtain a pH of 8, 400 parts g/c of bupranolol hydrochloride at 0
A topical patch containing m'' was obtained.

East A group: 2.0 parts of bupranolol hydrochloride, 29.9 parts of water, 0.1 part of methyl hydroxybenzoate, 4.0 parts of gelatin, 3.5 parts of carboxymethyl cellulose, 1.0 parts of vinyl alcohol-acrylic acid copolymer. 1 part, 2.5 parts of sodium polyacrylate, 7 parts of polyacrylic acid, 45 parts of glycerin, 4.0 parts of isopropyl myristate, and 1.0 part of sorbitan monooleate were heated and stirred in a Niguu to form a sticky gel group. After that, perform the same operation as in Example 1 to adjust the pH.
400 parts g/c+++ of bupranolol hydrochloride in 6.0 parts
``A topical patch containing the following was obtained.

K1riA A topical patch was obtained in the same manner as in Example 1 except that bupranool hydrochloride was changed to bupranool.

Specific JUI: 7.0 parts of acrylic acid, 6 parts of 2-ethylhexyl acrylate
8 parts of vinyl acetate, 25 parts of azobisisobutyronitrile, and 150 parts of ethyl acetate were put into 4 flasks under nitrogen gas, and heated to 65-70°C while stirring to polymerize and form a solid. To obtain an acrylic adhesive with a weight of 40%, 4% of bupranolol hydrochloride was added and dispersed to 96% of the solid content of this adhesive, and the weight after drying was 1.
00 g/m', and after drying, it was laminated on a polyvinyl chloride film to obtain an acrylic pressure-sensitive adhesive tape containing 400 parts g/cm' of bupranorol hydrochloride.

A tape preparation was obtained in the same manner as in Comparative Example 1 except that bupranool hydrochloride was replaced with bupranool.

east! ■ A Peagle-sized body weighing approximately 1110 kg was anesthetized with ventoparvitar-Na, a polyethylene catheter was inserted into the femoral artery and vein, and 30 minutes after each topical patch of 5CIIIX5CI11 was applied to the abdomen, 1.2.4.6 Isoproterenol (0.3 μs/kg) was administered intravenously every hour, and changes in mean blood pressure and heart rate were measured.

An experiment was carried out in the same manner as in Experimental Example 1, except that the oral patch (1 tablet: bupranolol hydrochloride zomg) was used instead of the external patch and tape.

These results are shown in FIGS. 1 and 2. As is clear from these figures, the external patch of the present invention suppressed the decrease in mean blood pressure and increase in heart rate caused by isoproterenol in a long-term and stable manner.

Fire A■1 Timolol maleate 2.0 parts, water 38.9 parts, ethylenediaminetetraacetate 0.1 part, carboxymethyl cellulose 3.0 parts, polyacrylic acid 4.0 parts, d-sorbitol (70% liquid) 20.0 parts of glycerin, 30.0 parts of zinc oxide, and 0.5 parts of dihydroxyaluminum aminoacetate were stirred in a kneader to obtain a sticky gel base. 20 on a polyethylene terephthalate liner siliconized by
After spreading it to 0 g/m2, it was transferred to a nylon group nonwoven fabric laminated with a polyurethane film and cut into a desired size to prepare a topical patch containing 400 μg/cm'' of timolol maleate at pH 8.5. I got it.

2.0 parts of timolol maleate, 37.0 parts of water, 5.0 parts of polyvinyl alcohol, 23 parts of glycerin, 1.0 parts of crosslinked polyacrylic acid, 23 parts of triethanolamine,
A sticky gel base was obtained by heating and stirring 8.0 parts of isopropyl myristate and 1.0 parts of sorbitan monooleate in a kneader.
8.5 to obtain an external patch containing 400 μg/cm'' of timolol maleate.

Using a Peagle-sized animal weighing approximately 1110 kg per body, polyethylene catheters were inserted into the femoral arteries and veins under ventoparvital-Na anesthesia, and the femoral artery side was connected to a heart rate monitor and a blood pressure monitor. Furthermore, 0.3 μg/kg of isoproterenol was administered through the femoral vein, and changes in heart rate and blood pressure were measured.
30 minutes after applying each formulation.

Isoproterenol was administered at 1.2 and 4.6 hours, and the inhibition rate against the initial changes was determined.

At the same time, before administering isoproterenol, blood was collected, plasma was separated, and the blood concentration was measured using N1ECD-GC.

An experiment was conducted in the same manner as in Experimental Example 2, except that the external patch and tape were used as oral preparations (2 tablets: timolol maleate 10 mg).

These results are shown in Figures 3 to 5. The external patch of the present invention stably suppressed the decrease in mean blood pressure and increase in heart rate caused by isoproterenol over a long period of time. Incidentally, the blood concentration dynamics in FIG. 5 confirms that the duration of action is long.

8.0 parts of indenolol hydrochloride, 38.95 parts of water, 3.0 parts of gelatin, 1.0 part of polyvinyl alcohol, 0.05 part of propyl hydroxybenzoate, 3.0 parts of carboxymethylcellulose, sodium polyacrylate 4.0 copies,
40 parts of glycerin, 1.0 part of sorbitan monooleate, and 1.0 part of n-butyl stearate were stirred and dissolved in a kneader to obtain a sticky gel base.

Next, aluminum was vapor-deposited on polyethylene terephthalate, and the liner obtained by silicone processing was spread on a liner obtained by a conventional method to a thickness of 200 gets, and then transferred to a nylon group nonwoven fabric laminated with a polyurethane film. It was cut to the desired size.

This adhesive gel base had a pH of 9.0 and contained 1.8 mg/c+o' of indenolol hydrochloride. Said Example 1
．． 2. Comparative Experiment Example 1. When the same study as that conducted in 2 was conducted, the superiority of the adhesive patch of the present invention was confirmed.

[Effects of the Invention] Since the present invention is configured as described above, the following excellent effects are exhibited.

(1) It can exhibit reliable adhesion to the skin, and does not cause skin irritation during application.

(2) The transdermal absorption capacity of the β-blocker can be increased, thereby achieving a balance between the transdermal absorption capacity and the amount of drug released.

[Brief explanation of the drawing]

Figure 1 is a diagram showing the inhibition rate of bupranolol hydrochloride against the blood pressure increasing effect of isoproterenol, Figure 2 is a diagram corresponding to Figure 1 regarding heart rate, and Figure 3 is a diagram 2 in the case of timolol maleate. Figure 's4 is a diagram corresponding to Figure 1 in the case of timolol maleate, and Figure 5 is a diagram showing changes in blood concentration of timolol maleate over time. Oo o o mouth oLI'I
- Hejunichi Q Bukisho (Yu) ・ΩNenso C, Jinshomochi (Yu) ・■Ken 4Q Sha Notificationsho (Law) @ DeQ Jinkisho ([Has])

Claims (1)

[Claims] A sticky gel base containing a water-soluble polymer, water, and a water retention agent as essential components contains one or more selected from the group consisting of bupranolol, bupranolol hydrochloride, timolol, timolol maleate, indenolol, and indenolol hydrochloride. A patch for external use that is characterized by: