JP2509585B2 - External patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a patch for external use intended for percutaneous absorption of β-blockers.

In the patch for external use of the present invention, bupranolol or its hydrochloride salt, timolol or its maleate salt, indenolol or its hydrochloride salt is used as the β-blocker, and bupranolol (or its hydrochloride salt) will be described below as a typical example. explain.

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

C ₁₄ H ₂₂ ClNO ₂ · HCl: 308.25 1-tert-butylamino-3- (2-chloro-5-methylphenoxy) -2-propanol hydrochloride In administering this drug to patients, oral administration has been conventionally used. Although it has been generally accepted, there are the following problems in oral administration.

(1) Due to low bioavailability (5%) and relatively short biological half-life (2.5hr), it is necessary to take 3 times a day, and sometimes patients forget to take it. It causes a rebound phenomenon.

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

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

Therefore, attempts have been made to change the administration route for the purpose of solving the problems associated with such oral administration. The following (A) to (C) are examples intended for transdermal absorption.

(A) Bupranolol is contained in a natural / synthetic rubber adhesive or an acrylic ester adhesive to prepare a tape preparation (patch).

(B) Bupranolol is contained in an ointment or a spray.

(C) Bupranolol is contained in the polymer matrix to prepare a patch.

[Problems to be Solved by the Invention] However, in (A), side effects such as contact dermatitis caused by an adhesive, folliculitis due to surface bacteria, and skin inflammation associated with stimulation of sweat glands are caused. I found out. Further, since the transdermal absorbability itself is not so large, bupranolol contained in the pressure-sensitive adhesive layer accumulates on the skin, which is disadvantageous in terms of drug economy and irritates the skin. In addition, it is necessary to prevent the patch from peeling off from the skin even when sweating, and it is necessary to have a considerably strong adhesive force. As a result, the stratum corneum at the site of application may be damaged during peeling, which makes continuous application as well as long-term continuous administration difficult. Next, in the case of (B) ointment and the like, in addition to the essential problem that it is difficult to administer the drug in a fixed amount, it is not welcomed by the patient because it adheres to clothes and underwear and stains them, and thus long-term continuous administration is required. The number of cases that are not fulfilled increases. In the method using the polymer matrix of (C), since the matrix itself has no adhesive force, the adhesive layer of (A) is required, and therefore the same problem as in the case of (A) occurs. .

The present invention was made in consideration of these circumstances, but since the method (A) was considered to be the most significant among the above (A) to (C), the method (A) was adopted. We considered that solving various problems in case of doing is an important issue for the time being, and conducted various studies. That is, the present invention is to solve all the above-mentioned problems in the patch, and to provide an external patch that can be safely and continuously used for a long period of time.

[Means for Solving Problems] The external patch according to the present invention includes gelatin, agar, mannan, alginic acid, polyacrylic acid, polyacrylic acid salts, carboxymethyl cellulose, methyl cellulose,
0.5 to more than one water-soluble polymer selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, tragacanth gum, locust bean gum, and metal salts thereof and those crosslinked with an organic / inorganic crosslinking agent 20% by weight, 20 to 50% by weight of water, 10 to 60% by weight of one or more moisturizers selected from the group consisting of polyethylene glycol, glycerin, sorbitol, maltitol, propylene glycol and 1,3-butylene glycol. , Starch-acrylonitrile graft product, starch-acrylic acid graft product, starch-styrene sulfonic acid graft product, starch-vinyl sulfonic acid graft product, polyvinyl alcohol cross-linked product, vinyl acetate saponified product-acrylic acid copolymer, polyethylene glycol diacrylate cross-linked product A group of bodies Selected from the group consisting of bupranolol, bupranolol hydrochloride, timolol, timolol maleate, indenolol, indenolol hydrochloride in an adhesive gel base having 0.01 to 10% by weight of one or more super-super absorbent polymers selected from The gist of the present invention is that it contains at least one of the following.

[Action] In order to solve the above problems, the present inventors intend to (a) alleviate skin irritation and (b) increase transdermal absorbability to achieve harmony with the drug release amount. 2 The present invention has been completed by establishing examination points by setting points as research goals and establishing concrete means for satisfying these points. That is, in the present invention, the adhesive gel base is composed of water-soluble polymer, water, humectant, and super-super absorbent polymer as essential components, and the β-blocker is contained in the adhesive gel base. It is characterized by the point.

The sticky gel base exerts a reliable sticking action on the skin despite having a water-retaining action, and the water-retaining action moderately softens the stratum corneum of the skin to reduce skin irritation. .

On the other hand, it is considered that the skin permeation rate of β-blockers is not so high originally. That is, the β-blocker is often stored in the application site, and causes a side effect specific to the β-blocker (for example, in the case of bupranolol, the skin irritation action occurs as described above). However, when the skin stratum corneum is softened by its water-retaining action like the patch of the present invention, the skin permeation rate of the β-blocker is increased and the storage of the β-blocker at the patch site can be reduced, which is accompanied by the storage. It is possible to eliminate side effects, and further to achieve harmony between the transdermal absorbability and the drug release amount (for example, the original action of β-blocker can be connected for a long time without causing the above side effects). be able to.

Examples of the β-blocker used in the present invention include bupranolol or its hydrochloride, timolol or its maleate, indenolol or its hydrochloride. Amount of these (the amount in the adhesive gel base, the same applies below)
Is determined in consideration of efficacy and irritation, but in the case of bupranolol or its hydrochloride, 0.5 to 6% by weight (hereinafter simply referred to as%) is preferable, and 0.5 to 4% is more preferable.
Is. 0.5 for timolol or its maleate
-8%, preferably 1-6%, in the case of indenolol or its hydrochloride 0.5-40%, preferably 1-30%
Is.

In addition, these β-blockers are β ₁ -selective, ISA, MS
Since they differ from each other in terms of their passage through A and BBB, etc., they should be selected according to their respective administration purposes.

Water-soluble polymers include gelatin, agar, mannan,
Examples include alginic acid, polyacrylic acid, polyacrylic acid salts, carboxymethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, tragacanth gum, locust bean gum, and crosslinks with these metal salts and organic / inorganic crosslinkers. Things can also be used. These water-soluble polymers are used to bring out the physical properties and other desired physical properties of the other raw materials used in the adhesive gel base. In actual use, it is used by one kind or a combination of two or more kinds, and as the blending amount in the adhesive gel base,
0.5-20% is recommended.

As the moisturizing agent, polyhydric alcohols such as polyethylene glycol, glycerin, sorbitol, maltitol, propylene glycol, and 1,3-butylene glycol may be used alone or in combination of two or more, and the compounding amount is
10-60% is recommended.

Further, starch-acrylonitrile graft product, starch-acrylic acid graft product, starch-styrene sulfonic acid graft product, starch-vinyl sulfonic acid graft product, polyvinyl alcohol cross-linked product, vinyl acetate saponification product-acrylic acid copolymer, polyethylene glycol diacrylate. An ultra-high water-absorbing polymer selected from the group consisting of cross-linked products is used, which is preferably used in the range of 0.01-10%.

 The water content in the adhesive gel base is preferably 20 to 50%.

The present invention has a configuration as described above,
If necessary, the components (1) and (2) below can be freely mixed.

(1) In order to enhance the solubility of β-blocker in the base, n-butyl stearate, benzyl alcohol, isopropyl myristate, isopropyl palmitate,
A dissolving agent such as polypropylene glycol, crotamiton, and diethyl sebacate, and a surfactant for emulsifying these with water in the base can be added.

(2) By using known stabilizers, antioxidants, pH adjusters and the like, it is possible to enhance the stability of the drug and the reliability of the drug efficacy accompanying it. It should be noted that these additives should have their respective combinations, pH values, etc. defined in consideration of drug release control, skin irritation suppression and the like. According to a study made by the present inventors, it was judged that it is preferable to adjust the composition so that the pH becomes 5.0 to 9.0 by changing various combinations.

The support used in the present invention is preferably a flexible support that easily follows the movement of the human body, and various non-woven fabrics, woven fabrics, flannel, and polyethylene films, ethylene vinyl acetate films, polyvinyl chloride films , Those laminated with a polyurethane film or the like, those perforated and the like are used. It is recommended to determine these while considering the formulation of the adhesive gel base so as to keep 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 the properties of the examples, and can be appropriately modified as necessary.

Example 1 Buplanolol hydrochloride 2.0 parts, water 36.9 parts, propyl paraoxybenzoate 0.1 part, gelatin 3.0 parts, polyvinyl alcohol 1.5 parts, carboxymethyl cellulose 3.0 parts, starch-polyacrylate (starch-acrylic acid graft body) 0.5 Parts, sodium polyacrylate 3.0 parts, glycerin 45 parts, isopropyl myristate 4.0 parts, sorbitan monooleate 1.0 parts by heating and stirring in a kneader to obtain an adhesive gel base. It is spread on a polyethylene terephthalate liner treated with silicon by the method to 200 g / m ² and then transferred to a rayon non-woven fabric laminated with an ethylene vinyl acetate film, cut into a desired size and applied for external use. I got an agent. The pH is 8.0 and 400 μg / cm ^{2 of} bupranolol hydrochloride is added.
Contained.

Example 2 2.0 parts of bupranolol hydrochloride, 29.9 parts of water, 0.1 part of methyl paraoxybenzoate, 4.0 parts of gelatin, 3.5 parts of carboxymethyl cellulose, vinyl alcohol-acrylic acid copolymer (vinyl acetate saponification-acrylic acid copolymer) 1.0
Parts, sodium polyacrylate 2.5 parts, polyacrylic acid 7 parts, glycerin 45 parts, isopropyl myristate 4.0
And 1.0 part of sorbitan monooleate were heated and stirred in a kneader to obtain a viscous gel base. Thereafter, the same operation as in Example 1 was carried out to adjust the pH of 6.0 parts to 400 μ of bupranolol hydrochloride.
An external patch containing g / cm ² was obtained.

Comparative Example 1 7.0 parts of acrylic acid, 2-ethylhexyl acrylate 68
Parts, vinyl acetate 25 parts, azobisisobutyronitrile 0.2
Parts and 150 parts of ethyl acetate are placed in a four-necked flask under a nitrogen atmosphere and heated to 65 to 70 ° C. with stirring to be polymerized to obtain an acrylic pressure-sensitive adhesive having a solid content of 40%. Next, 4% of bupranolol hydrochloride was added to and dispersed in 96% of the solid content of this pressure-sensitive adhesive, and coated on a release paper by a conventional method so that the weight after drying was 100 g / m ² , and dried. Then, it was laminated on a polyvinyl chloride film to obtain an acrylic pressure-sensitive adhesive tape agent containing 400 μg / cm ^{2 of} buplanolol hydrochloride.

Comparative Example 2 A tape preparation was obtained in the same manner as in Comparative Example 1 except that bupranolol hydrochloride was changed to bupranolol.

Experimental Example 1 A beagle dog weighing about 10 kg was pentobarbital-Na.
Insert a polyethylene catheter into the femoral artery and femoral vein under anesthesia, and apply each external patch of 5 cm x 5 cm to the abdomen 30
Isoproterenol 0.3 μg / kg was intravenously administered every 1, 2, 4, 6 hours, and changes in mean blood pressure and heart rate were measured.

Comparative Experimental Example 1 The same experiment as in Experimental Example 1 was carried out except that the external patch and tape were oral preparations (1 tablet: bupranolol hydrochloride 20 mg).

The results are shown in FIGS. 1 and 2. As is clear from these figures, the external-use patch of the present invention stably suppressed the decrease in mean blood pressure and the increase in heart rate due to isoproterenol for a long period of time.

EFFECTS OF THE INVENTION Since the present invention is configured as described above, the following excellent effects are exhibited.

(1) It can exert a reliable adhesive action on the skin and is not accompanied by skin irritation during application.

(2) The transdermal absorbability of the β-blocker can be increased, whereby the transdermal absorbability and the drug release amount can be balanced.

[Brief description of drawings]

FIG. 1 is a diagram showing the inhibitory rate of bupranolol hydrochloride on the blood pressure-increasing action of isoproterenol, and FIG. 2 is a diagram corresponding to FIG. 1 for heart rate.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 47/36 A61K 47/36 E 47/38 47/38 E (72) Inventor Larry Codewell Sanbonmatsu, Ouchi-machi, Okawa-gun, Kagawa 1989-23 (72) Keiko Yamazaki Inventor Keiko Yamazaki, 313-31, Ouchi-machi, Okawa-gun, Kagawa Prefecture (72) Ichiro Yoshimine 1646-8 Hayashi-cho, Takamatsu-shi, Kagawa (56) References JP 59-25320 (JP, A) JP 60-163811 (JP, A) Special table 58-501034 (JP, A)

Claims (1)

(57) [Claims] 1. Gelatin, agar, mannan, alginic acid,
From the group consisting of polyacrylic acid, polyacrylic acid salts, carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, gum arabic, tragacanth gum, locust bean gum, and their metal salts and those cross-linked with organic / inorganic cross-linking agents 0.5 to 20% by weight of one or more water-soluble polymers selected, 20 to 50% by weight of water, polyethylene glycol, glycerin, sorbitol,
One or more moisturizers selected from the group consisting of maltitol, propylene glycol, 1,3-butylene glycol
10-60% by weight, starch-acrylonitrile graft product, starch-acrylic acid graft product, starch-styrene sulfonic acid graft product, starch-vinyl sulfonic acid graft product, polyvinyl alcohol cross-linked product, vinyl acetate saponified product-acrylic acid copolymer, Bupranolol, bupranolol hydrochloride, timolol, timolol maleate, and indenolol were added to an adhesive gel base containing 0.01 to 10% by weight of one or more ultra-super absorbent polymers selected from the group consisting of cross-linked polyethylene glycol diacrylate. An external patch comprising at least one selected from the group consisting of indenolol hydrochloride.