JPH08310946A - Percutaneous absorbable pharmaceutical preparation - Google Patents

Abstract

PURPOSE: To obtain a percutaneously absorbable pharmaceutical preparation useful as a therapeutic agent for hypertension, angina pectoris and arrhythmia and capable of administering atenolol through the skin into the body. CONSTITUTION: This percutaneously absorbable pharmaceutical preparation contains 2-60wt.% atenolol having β1 blocking actions and 1-30wt.% nonionic surfactant and/or compound of terpenes as an absorbefacient. For example, a tacky agent base ingredient (e.g. an acrylic copolymer) is thermally melted and atenolol and an absorbefacient [e.g. polyoxyethylene (4) lauryl ether and 1-menthol] are then added to provide the percutaneously absorbable preparation. The obtained plaster is spread on a support and covered with a liner to form a polymer layer containing the atenolol. The resultant polymer layer is spread on an ethylene film undergoing the surface oxidation treatment, regulated to an area corresponding to about 10-100mg and applied for 12-48hr for use.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel dosage form of atenolol known as a therapeutic drug for hypertension, angina, arrhythmia, etc. More specifically, by applying it to the skin, applying it, etc. The present invention relates to a percutaneous absorption preparation used for administering atenolol into the body through the skin.

[0002]

2. Description of the Related Art Atenolol (chemical name: 2- [p- [2
-Hydroxy-3- (isopropylamino) propoxy] phenyl] acetamide) is a compound used as a therapeutic agent for essential hypertension, angina, and tachyarrhythmia. Atenolol is administered in appropriately adjusted doses depending on age and symptoms. Generally, atenolol is usually administered orally 5 times a day.
0 mg, the maximum amount is 100 mg orally once a day. Orally administered atenolol is rapidly absorbed, the blood concentration reaches its maximum about 3 hours after administration, and the elimination half-life is said to be about 10 hours.

By the way, generally, in drug therapy for cardiovascular diseases such as hypertension, angina and arrhythmia, it is ideal to keep the blood concentration of the drug at a constant level.
However, in the case of oral administration, it is known that the state of gastrointestinal tract such as stomach or intestines or contents greatly influence the absorption amount of the drug, and it is difficult to keep the blood concentration constant. Is. In addition, if the drug is taken inadvertently and the blood concentration in the body rises sharply even if the effective dose that was taken last time remains in the body, or if side effects occur, the drug should be promptly removed from the body. It is difficult to remove. Furthermore, oral administration can be painful for the elderly and bedridden patients, and if external administration is possible and administration is possible transdermally, patients can greatly benefit from the treatment.

Under these circumstances, in recent years, circulation of hypertension, angina, arrhythmia, etc., which are widely used as oral agents, such as renin-angiotensin converting enzyme inhibitors, β blockers, diuretics or calcium antagonists. With respect to drugs for treating systemic diseases, attempts have been made to absorb the drug through the skin to improve the therapeutic effect.

For example, JP-A-54-20129 and JP-A-5-20129.
7-150614, 60-28917, 61-
83118, 63-203615, 63-20
3616, JP-A-1-287024 and 5-27.
No. 9254 discloses a transdermal preparation containing clonidine. Further, Japanese Patent Application Laid-Open Nos. 61-40215 and 64-70415 disclose moxonidine,
1-501324 describes a bopin roll, JP-A-5-3.
Nos. 10568 and 5-310569 describe transdermal preparations containing captopril, respectively.
Furthermore, JP-A-61-133128 and JP-A-62-1272.
No. 5 and No. 62-228018 disclose a transdermal patch containing a calcium antagonist.

Although a transdermal drug has been developed in this way, since the skin originally has a barrier property, the drug cannot easily pass through the skin simply by mixing with the base,
The therapeutically effective concentration is not reached in body blood. The physicochemical properties of the drug itself, the physical properties of the adhesive base itself, and the interaction with the drug greatly affect the transdermal absorption of the drug. In the past, attempts have been made to reduce the barrier function of the stratum corneum by incorporating an absorption promoter or the like in order to increase the transdermal absorption rate of the drug.

As absorption enhancers for increasing the transdermal absorption rate of drugs, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, diethylene glycol, propylene glycol, propylene glycol monoacetate, ethanol, oleic acid, isopropyl myristate, gallic acid Various substances such as acid esters and glycerin are known.

As described above, a transdermal absorption enhancer is used as a method for promoting the absorption of a drug. As described above, the transdermal absorption of a drug is accompanied by its own physicochemical properties and adhesive group. Many factors are involved, such as the physical properties of the agent, the interaction with the drug, and the selection of an appropriate absorption enhancer.Furthermore, it is necessary to consider the safety of the adhesive base and absorption enhancer used, As a percutaneous absorption preparation, especially as an adhesive patch, there are still few that can satisfy the quality, efficacy and safety.

[0009] For atenolol, a transdermal agent is required like other drugs, but since human skin is hydrophobic and has a high barrier property against a hydrophilic compound, atenolol, which is hydrophilic, is used. Percutaneous absorption is particularly difficult, and despite the above studies, the fact is that no transdermal preparation of hydrophilic drug has been provided.

[0010]

[Problems to be Solved by the Invention] Under these circumstances,
There is a demand for the development of a new technique capable of converting a hydrophilic drug, atenolol, into a percutaneous absorption preparation, and an object of the present invention is to provide such a technique.

[0011]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that at least one non-adsorption enhancer is used as an absorption enhancer in order to promote the absorption of atenolol in the preparation through the skin. The inventors have found that a good absorption promoting effect can be obtained by using an ionic surfactant, terpenes, or a combination thereof, and completed the present invention.

That is, the present invention provides an atenolol percutaneous absorption preparation containing atenolol and a nonionic surfactant and / or a terpene compound as an absorption promoter.

In the atenolol transdermal preparation of the present invention (hereinafter referred to as "transdermal preparation"), atenolol used as an active ingredient has already been used as a β1 blocker.
What is used for the treatment of hypertension, angina, arrhythmia, etc. may be used, and particularly, JP-A-3-77856.
It is preferable to utilize the S-form atenolol disclosed in the publication.

On the other hand, as the nonionic surfactant used as the absorption promoter, polyoxyethylene sorbitan fatty acid ester (eg, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), polyoxyethylene Sorbit fatty acid ester (eg, monooleic acid polyoxyethylene sorbite, monostearic acid polyoxyethylene sorbite, etc.), polyoxyethylene alkyl ether (eg, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, etc.), sorbitan fatty acid ester ( (Eg, sorbitan monooleate, sorbitan sesquioleate, etc.), glycerin fatty acid ester (eg, glyceryl monostearate, glyceryl monooleate), etc. . Among these, polyoxyethylene alkyl ether and sorbitan fatty acid ester are more preferable.

The above nonionic surfactant has a higher absorption-promoting effect when the number of added polyoxyethylene is smaller, but the irritation tends to increase, and conversely, when the number of added moles is larger, the irritation is increased. Although it is low, the absorption promoting effect also decreases, so that it is necessary to select an appropriate number of added moles, and preferably 2 to 10 added moles. The oleyl group is more preferable as the fatty acid group of the fatty acid ester.

Among the absorption enhancers, limonene, menthol, geraniol and the like are used as terpenes.

The absorption enhancer may be either a nonionic surfactant or a terpene, or a combination of both, but preferably one kind from the nonionic surfactants. It is preferable to select one or more of the above and the terpenes and combine them. When the nonionic surfactant and the terpene are used in combination, the ratio of both may be about 1: 0.1 to 1:10, particularly 1:
It is desirable to set it to 1.

The percutaneously absorbable preparation of the present invention can be used in the form of various external preparations, for example, gel, cream, etc. However, the drug can be accurately administered and can be removed after administration. From the viewpoint of difficulty and the like, it is particularly preferable to take the form of a transdermal patch.

The above-mentioned transdermal patch (hereinafter referred to as "patch")
In addition to the above-mentioned atenolol and absorption enhancer, an adhesive base for imparting adhesive strength and a support for applying a transdermal absorption composition obtained by mixing these are used in the production of It

The adhesive base is not particularly limited as long as it can contain and retain atenolol which is a medicinal component and is a layer formed of an adhesive that adheres to the skin surface. Considering the adhesiveness and irritation to the skin, an acrylic adhesive base and a polystyrene-polyisoprene-polystyrene block copolymer adhesive are preferable, but a rubber adhesive base and a silicone adhesive base can also be used.

Of these, the acrylic pressure-sensitive adhesive base is, for example, a homopolymer of an alkyl (meth) acrylic acid alkyl ester having 4 or more carbon atoms in the alkyl group as a main monomer, or another copolymerizable monomer. Mention may be made of copolymers with the body and mixtures of these polymers. More specific (meth) acrylic acid alkyl ester monomers include (meth) acrylic acid butyl ester, (meth) acrylic acid pentyl ester, (meth) acrylic acid hexyl ester, (meth) acrylic acid peptyl ester, ( (Meth) acrylic acid octyl ester, (meth) acrylic acid nonyl ester, (meth) acrylic acid decyl ester, (meth) acrylic acid dodecyl ester, (meth) acrylic acid stearyl ester, etc., and the monomer is alkyl. The group includes linear or branched groups, and two or more groups may be used in combination.

Examples of the monomer copolymerizable with the above-mentioned monomer include carboxyl group-containing monomers such as (meth) acrylic acid, maleic acid, maleic anhydride, crotonic acid, and hydroxy (meth) acrylate. Ethyl ester,
Hydroxyl group-containing monomers such as (meth) acrylic acid hydroxypropyl ester, (meth) acrylamide,
Functional monomers such as amide group- or amino group-containing monomers such as (meth) acrylic acid dimethylaminoethyl ester, nitrile group-containing monomers such as acetonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine , Vinylimidazole, (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid butoxyethyl ester, and the like.

On the other hand, polystyrene-polyisoprene-polystyrene block copolymers, polystyrene-polybutadiene copolymers, polystyrene-polyisoprene copolymers are also excellent in sticking properties and are suitable as an adhesive base for the present drug. Other adhesive bases include natural rubber (cis-1,4-isoprene) and synthetic rubber (trans-1,4).
-Isoprene), polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, ethylene-vinyl acetate copolymer, silicone rubber (polydimethylsiloxane etc.) etc. as rubber elastic body, and tackifier resin, modifier such as softening agent, etc. Can also be used by appropriately adding a suitable amount thereof.

Further, the support used in the present invention is not particularly limited as long as it is flexible and does not give a feeling of strangeness when attached to the skin. Specific examples of the support include films or sheets of polyolefin, polyester, polyurethane, polyvinyl alcohol, polyvinylidene chloride, polyamide, etc., rubber and / or synthetic resin foam sheet / film, non-woven fabric,
Examples include cotton cloth, paper, metal foil, and laminated films and sheets thereof.

In order to produce the adhesive patch of the present invention using each of the above-mentioned materials, first, the adhesive base component is heated and melted,
Then, atenolol and an absorption enhancer are added to prepare a transdermal absorption composition, and finally, a support is covered with a plaster and a liner,
The product may be cut into a desired shape.

As another method, the above-mentioned percutaneous absorption composition is once spread on a release-treated film, then transferred to a suitable support and pressure-bonded to obtain a product, and a pressure-sensitive adhesive base. Hexane as the agent component, atenolol and absorption promoter,
Dissolve and disperse in a solvent such as heptane, ethyl acetate, toluene, spread on a support, dry, cover with a liner, cut into a desired shape to make a product, or a film that has been once subjected to peeling treatment. After the plaster is applied, it may be transferred to an appropriate support and pressure-bonded to obtain a product.

The amount of atenolol used in the production of the patch of the present invention is 2 to 60% by weight in the transdermal absorption composition.
(Hereinafter, simply indicated by "%") (about 1 to 30% when S-atenolol is used) is preferable. Further, the amount of the absorption promoter blended is preferably about 1 to 30%. If the content of the absorption promoter is less than 1%, its effect is poor, and if it exceeds 30%, the skin adhesiveness or cohesive force may be deteriorated, which is not desirable.

Although the patch of the present invention thus obtained varies depending on the medical condition and age of the patient, a target therapeutic effect can be obtained by applying a patch having an area corresponding to about 10 to 100 mg for 12 to 48 hours. You can

[0029]

In the percutaneous absorption preparation of the present invention, the mechanism of absorption promotion of atenolol is not clear, but it is speculated that the absorption promoter is involved in dissolving atenolol or changing the skin condition. ing. The percutaneous absorption preparation of the present invention effectively and continuously absorbs atenolol, which is an active ingredient, through the skin, and can maintain the blood concentration at a constant level. Therefore, hypertension, angina pectoris and arrhythmia It can be effectively used for long-term treatment of cardiovascular diseases such as.

[0030]

【Example】

Example 1 Transdermal formulation for atenolol (1): Acrylic copolymer (trade name: Primal N-580) at 70.0%, atenolol at 10.0%, and polyoxyethylene (4) lauryl as an absorption promoter Ether 10.0% and 1-menthol 10.0% were added and mixed. This mixture was spread on a release liner (polyethylene resin processed paper) so that the thickness after drying was 100 μm, and the atenolol-containing polymer layer (Athenolol 50) was applied onto the release liner.
0 μg / cm ² ) was formed. The surface of this polymer layer was spread on the treated surface of a polyethylene film which had been subjected to a surface oxidation treatment to obtain a transdermal preparation.

Example 2 Transdermal formulation for atenolol (2): A transdermal formulation was prepared in the same manner as in Example 1 with the following components and blending amounts. (Component) (Blend amount) S-Athenolol 10% Acrylic copolymer 70% (Brand name: Nisetsu PE-300) Polyoxyethylene (2) lauryl 10% Ether sorbitan trioleate 10%

Example 3 Atenolol Transdermal Preparation (3): A transdermal preparation was prepared according to Example 1 with the following components and blending amounts. (Component) (Blend amount) S-Athenolol 10% Acrylic copolymer 80% (Brand name: Nicazole TS-620) Polyoxyethylene (2) Stearyl 5% Ether Glyceryl monostearate 5%

Example 4 Atenolol Transdermal Preparation (4): A transdermal preparation was prepared in the same manner as in Example 1 with the following components and blending amounts. (Component) (Blend amount) Atenolol 10% Acrylic copolymer 80% (Brand name: Primal N-580) Polyoxyethylene (6) tetra 5% Sorbit oleate Glyceryl monomyristate 5%

Example 5 Transdermal formulation for atenolol (5): A transdermal formulation was prepared in the same manner as in Example 1 with the following components and blending amounts. (Component) (Amount of compounding) Atenolol 10% Acrylic copolymer 80% (Brand name: Nicazole TS-620) Polyoxyethylene monooleate 5% (20) Sorbitan Glyceryl monostearate 5%

Example 6 Atenolol Transdermal Preparation (6): A transdermal preparation was prepared according to Example 1 with the following components and blending amounts. (Component) (Blend amount) Atenolol 10% Acrylic copolymer 70% (Brand name: Nicazole TS-620) Limonene 20%

Example 7 Transdermal formulation for atenolol (7): A transdermal formulation was prepared in the same manner as in Example 1 with the following components and blending amounts. (Component) (Compounding amount) S-Athenolol 10% Styrene-isoprene-styrene block copolymer 25% (Brand name: Califlex) Liquid paraffin 30% Saturated alicyclic hydrocarbon 25% (Brand name: Alcon-P) ) Polyoxyethylene (7) cetyl 5% ether sorbitan sesquioleate 5%

Comparative Example 1 Atenolol Comparative Transdermal Preparation (1): A transdermal preparation was prepared according to Example 1 with the following components and blending amounts. (Component) (Blend amount) Atenolol 10% Acrylic copolymer 90% (Brand name: Nicazole TS-620)

Comparative Example 2 Atenolol Comparative Transdermal Preparation (2): A transdermal preparation was prepared according to Example 1 with the following components and blending amounts. (Component) (Compounding amount) S-Athenolol 10% Acrylic copolymer 50% (Brand name: N-580) Polyoxyethylene (2) Stearyl 20% Ether Trioleic acid sorbitan 20%

Test Example 1 Skin Adhesion Test and Skin Irritation Test: For each transdermal absorption patch obtained in Examples 1 to 7 and Comparative Examples 1 and 2, test agents for rabbit skin by the following method. Adhesion test was conducted. That is, the back of a rabbit is hair-removed with a hair clipper and a shaver.
A patch having a circular shape of mm (area: 3.14 cm ² ) was applied for 24 hours. With respect to this patch, the adhesiveness at the time of application and after 24 hours and the skin irritation after 1 hour from peeling were observed. This experiment was conducted in three cases for each patch. Table 1 shows the evaluation criteria for skin adhesion, and Table 2 shows the evaluation criteria for skin irritation.
The evaluation results are shown in Table 3.

[0040]

[0041]

[0042]

As shown in Table 3, the invention products of Examples 1 to 7 and the product of Comparative Example 1 had no problem in skin tackiness and skin irritation, but the products of Comparative Example 2 had no problem. Adhesive residue was seen. This adhesive residue is a fatal defect as a patch preparation, and it is shown that when the content of the absorption promoter exceeds 30%, it is unsuitable as a preparation.

Test Example 2 Skin permeation test: Hairless mice were sacrificed by cervical dislocation, and immediately the back skin was peeled off to remove subcutaneous fat. A vertical diffusion cell (effective area: 1c
m ² ), and a phosphate buffer (pH 7.4) in the dermis side cell
2.8 ml was added and stirred at 37 ° C. The patches of Compositions 1, 2 and 4 of the present invention and the patch of Comparative Example 1 were applied to the keratinous side, and the amount of drug transferred to the dermis side with time was measured. The result is shown in FIG.

As shown in FIG. 1, when the patches of Examples 1, 2 and 4 were used, the amount of permeation of atenolol was obviously higher than that when the patches of Comparative Example 1 were used. It was

Test Example 3 Measurement of drug concentration in rat plasma: After removing hair from the back of the rat under light ether anesthesia, the patch prepared in Examples 1, 2 and 4 and Comparative Example 1 was applied and taped. Supported and fixed. Blood was collected from the orbital vein at each measurement time, and the concentration of atenolol in plasma was measured. The result is shown in FIG.

As shown in FIG. 2, when the patches of Examples 1, 2 and 4 were used, the plasma drug concentration of atenolol was obviously higher than that when the patches of Comparative Example 1 were used. Was high.

Test Example 4 Effect of the product of the present invention on blood pressure and heart rate of SHR: Blood pressure of male SHR (22 weeks old, Charles River Japan) was measured once weekly from 4 months before drug administration and stabilized. 4 rats showing blood pressure and heart rate were selected, 2 per group
The experiment was conducted as an animal.

In the experimental group, the product of the present invention prepared in Example 1 (30 mg / kg as S-atenolol) was administered twice a week.
The left and right hairs were affixed to the left flank alternately for 6 weeks. One application was for 3 or 4 days, and the application was continued until the next application. On the other hand, to the control group, only the base was similarly applied. Blood pressure and heart rate of the rats of the experimental group and the control group were measured once a week by non-invasive measurement by the tail-cuff method after heating the rats at 35 ° C. for 20 minutes on the day after application. went. This result is shown in FIG. 3 and FIG.
Shown in

The effect on blood pressure is as shown in FIG.
From the 4th week to the 6th week, a tendency of lowering blood pressure was observed.
Moreover, the level was increased to the level of the base patch group after the administration was discontinued.

As for the action on the heart rate, as shown in FIG. 4, a clear decrease in the heart rate was recognized from the start of application, and the effect was maintained during the administration period. This effect also disappeared after the administration was discontinued.

[0052]

EFFECTS OF THE INVENTION The percutaneous absorption preparation and the percutaneous absorption patch of the present invention allow atenolol, which is a β1 blocker, to be absorbed from the skin, maintain an effective blood concentration for a long time, and have no skin irritation. Since it is few and has excellent safety, it can be advantageously used for treatment of diseases such as hypertension, angina, and arrhythmia.

[Brief description of drawings]

FIG. 1 shows the results of a permeation test on hairless mouse skin. In the figure, the horizontal axis shows the elapsed time and the vertical axis shows the transmittance of atenolol from each preparation.

FIG. 2 shows the results of absorption tests in rats. In the figure, the horizontal axis represents the elapsed time and the vertical axis represents the plasma concentration.

FIG. 3 shows the effect of SHR on blood pressure. In the figure,
The horizontal axis indicates elapsed time (weeks), and the vertical axis indicates blood pressure (mmHg)
Indicates.

FIG. 4 shows the effect of SHR on heart rate. In the figure, the horizontal axis indicates elapsed time (weeks), and the vertical axis indicates heart rate (times /
Minutes). that's all

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 9/70 363 A61K 9/70 363 365 365 47/10 47/10 E 47/34 47/34 E (72) Inventor Chizuko Noda 1510 Takatsuhara Eijoji-ji, Kashima City, Saga Prefecture No. 2 Shigeshita Apartment No. 2 (72) Inventor Shinji Uchida 33-113 Mihara-cho, Nagasaki-shi, Nagasaki Prefecture

Claims (10)

[Claims] 1. A percutaneous absorption preparation of atenolol, which comprises atenolol and a nonionic surfactant and / or a terpene compound as an absorption promoter. 2. The percutaneous absorption preparation according to claim 1, wherein the atenolol is S-form atenolol. 3. The absorption promoter is a nonionic surfactant and / or menthol selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene alkyl ether, sorbitan fatty acid ester or glycerin fatty acid ester. The percutaneous absorption preparation according to claim 1, which is a terpene selected from limonene and geraniol. 4. The percutaneous absorption preparation according to any one of claims 1 to 3, wherein the content of the absorption enhancer is 1 to 30% by weight. 5. A percutaneous absorption patch obtained by coating a support with a percutaneous absorption composition containing atenolol, a nonionic surfactant as an absorption promoter and / or a terpene compound and an adhesive base. Agent. 6. The transdermal patch according to claim 5, wherein the adhesive base is an acrylic adhesive base. 7. The transdermal patch according to claim 5, wherein the adhesive base is a polystyrene-polyisoprene-polystyrene block copolymer. 8. The transdermal absorption patch according to claim 5, wherein the atenolol is S-form atenolol. 9. The absorption promoter is a nonionic surfactant selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitol fatty acid ester, polyoxyethylene alkyl ether, sorbitan fatty acid ester or glycerin fatty acid ester, and / or The transdermal patch according to claim 5, which is a terpene selected from menthol, limonene or geraniol. 10. The percutaneous absorption patch according to claim 5, wherein the content of the absorption enhancer in the percutaneous absorption composition is 1 to 30% by weight.