JPS62228018A - Member for external use - Google Patents

Abstract

PURPOSE:A base for external use, containing a specific dihydropyridine based calcium antagonistic agent, having a very low available concentration in blood and improved rapid-acting drug effect, capable of sustaining the drug effect for a long period and useful for preventing and treating angina pectoris, caridiac insufficiency and hypertension. CONSTITUTION:A member for external use containing isopropyl 4-(2,1,3- benzoxadiazol-4-yl)-1, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarbo xylate expressed by the formula as an active ingredient. The above-mentioned compound is contained in a base consisting essentially of a high polymer, prefer ably having tackiness and the resultant base is then applied directly or indirectly applied through an undercoating member to a flexible carrier. An acrylic high polymer having -70--10 deg.C, particularly -55--25 deg.C glass transition tempera ture is preferred for the tacky high polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION (1) Industrial Application Field The present invention is directed to a novel dihydropyridine calcium antagonist, isopropyl 4-(2,1,3-benzoxadiazol-4-yl)'-1. The present invention relates to external products such as poultices, tapes, and gels containing 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate as an active ingredient.

(b) Prior art Calcium antagonists reduce myocardial contractility by suppressing the influx of calcium into myocardial and vascular smooth muscle cells, and increase coronary blood flow through coronary vasodilatation. It improves the enzyme supply and demand balance, and these effects are used to treat and prevent angina pectoris, heart failure, and hypertension.

In recent years, the number of patients suffering from angina pectoris and hypertension has increased, and since it is difficult to predict when these types of diseases will develop, there is a particular desire for a formulation with a long acting time.

As conventional therapeutic drugs, dosage forms such as tablets, fine granules, and soft capsules have been developed for drugs such as nitroglycerin, insorbito nitrate, and diphenobine.

(c) Problems to be Solved by the Invention However, although attempts have been made to improve the durability of the medicinal efficacy of conventional formulations, no satisfactory results have been obtained so far.

Therefore, topical preparations of nitroglycerin and insorbito nitrate, which have vasodilatory effects, have recently been released.

This type of topical preparation allows the highly effective calcium channel blocker to be absorbed into the body through the outer skin, and although it exhibits excellent medicinal efficacy over a long period of time compared to oral administration, it Fundamental problems still remain, such as solubility in materials and transdermal absorption of drugs.

(d) Means for solving the problems The inventors have solved the above r! As a result of extensive research in order to solve the J3M point, we have discovered isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4, which has a calcium antagonistic effect and is represented by the following structural formula. - Novidrow 5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate (hereinafter referred to as PN-200) is stable in the base material of external use materials such as poultices, tapes, and gels, and has medicinal properties. It has immediate effect, low effective blood concentration, high bioavailability, and remarkable persistence, making it effective for patients with angina pectoris and hypertension for a long time. We have discovered that this is the case, and have completed the present invention.

That is, the present invention provides isopropyl 4-(2,1,3-bentuxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl which is represented by the following structural formula and is a dihydropyridine calcium antagonist. This is an externally used member containing -2,6-nomethyl-3-pyridinecarboxylate as an active ingredient.

PN-200 used in the present invention has the above structural formula,
It is more stable against light than dihydropyridine calcium antagonists such as diphenobine, and its effective blood concentration is about 1/7 of that of nianizibine, making it suitable for external use.

The external member of the present invention is formed by incorporating the above-mentioned PN-200 into a base material whose main component is a polymeric substance (including cases where only a polymeric substance is used), and is used as a poultice, tape, gel, etc. used.

A preferred embodiment of the external member of the present invention is that the PN-200 described in 1. is contained in a polymeric substance, and the PN-200 is contained in a polymeric substance.
The contained polymeric substance is formed directly on a flexible carrier or indirectly via an undercoating member.

A polymeric substance (A) that does not have adhesion to the polymeric substance mentioned above.
and an adhesive polymeric substance (B), of which (B) is particularly preferred from the viewpoint of ease of handling during application.

Examples of polymeric substances belonging to the above (A>) include flexible polyvinyl chloride, flexible polyamide, polyolefin, polyvinyl alcohol, polyacrylic resin, thermosetting or room temperature vulcanizable silicone rubber, ethylene-vinyl acetate copolymer, etc. is exemplified.

Further, as the polymeric substance belonging to the above (B), various adhesive polymeric substances can be used, and a typical preferred example is an acrylic polymeric substance.

Among the above acrylic polymer substances, those having a glass transition temperature (Tg) of -70 to -10°C are preferable, and those having a Tg of -55 to -25°C are more preferable. When Tg is within the above range, the shape retention of the base material and the diffusion mobility of PN-200 in the acrylic polymer material are excellent, so the release properties of PN-200 are good, and the adhesion is also good. It is also preferable because it has the advantage that it causes less physical irritation when peeled off from the skin surface.

It is also optional to adjust the Tg by adding generally known compounding agents such as a liquid softening component with good compatibility such as liquid paraffin or various softeners to the above-mentioned acrylic polymer material.

Examples of the acrylic polymer include homopolymers of (meth)acrylic acid alkyl esters in which the alkyl group has 4 or more carbon atoms, or copolymers containing at least 50% by weight of (meth)acrylic acid alkyl esters. be able to.

Examples of the (meth)acrylic acid alkyl ester include n-butyl acrylate, n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, inoctyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, and Examples include decyl acrylate, dodecyl acrylate, tridecyl acrylate 1, and tridecyl methacrylate.

Examples of other monomers copolymerized with the (meth)acrylic acid alkyl ester include carboxyl group-containing monomers such as (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, and hexamaric acid; styrene sulfonic acid,
Sulfoxyl group-containing single fA such as allylsulfonic acid, sulfopropyl acrylate, (meth)acryloyloxynaphthalenesulfonic acid, acrylamidemethylpropanesulfonic acid, and acryloyloxybenzenesulfonic acid.
body, (meth)acrylic acid hydroxyethyl ester, (
Hydroxyl group-containing monomers such as meth)acrylic acid hydroxypropyl ester, amide group-containing acrylics such as (meth)acrylamide, dimethyl (meth)acrylamide, N-butylacrylamide, tetramethylbutylacrylamide, and N-methylol(meth)acrylamide. System monomer, (meth)acrylic acid aminoethyl ester, (meth)acrylic acid dimethylaminoethyl ester,
(meth)acrylic acid diethylaminoethyl ester, (
Alkylaminoalkyl group-containing acrylic monomers such as meth)acrylic acid tert-butylaminoethyl ester, (meth)acrylic acid methoxyethyl ester, (meth)acrylic acid ethoxyethyl ester, (meth)acrylic acid butoxyethyl ester, (meth)acrylic acid tetrahydrofurfuryl ester, (meth)acrylic acid me)oxyethylene glycol ester, (meth)acrylic acid methoxydiethylene glycol ester, (meth)acrylic acid methoxypolyethylene glycol ester, (
ivy) Alkoxy group (or ether bond in side chain) such as acrylic acid methoxypolypropylene glycol ester
Containing monomers include vinyl-based monomers such as N-(meth)acryloyl amino acids! 41 i-form, urethane of acrylic acid, urea,
Functional monomers such as acrylic monomers such as incyanate esters, and (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, vinylpyridine, vinylpyrazine, vinylbiperanone, vinylpiperidone, vinylbiperanone, vinylvirol, vinylimidazole , vinyl caprolactam, vinyl oxazole, vinyl thiazole, vinyl morpholine, styrene, α-methylstyrene, and bis(N,N''-dimethylaminoethyl) maleate.

In the present invention, the (meth)acrylic acid alkyl ester and the copolymerizable monomer include various isomers in which the alkyl moiety is linear or branched, as well as various isomers and derivatives in which the position of the substituent group is different. It is something to do.

Examples of other adhesive polymer substances include rubbers such as silicone rubber, polyisoprene rubber, polyisobutylene rubber, polybutanoene, styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber, and natural rubber. examples include synthetic resins such as polyurethane, polyester, polyamide, and ethylene-vinyl acetate copolymer; examples of these tackifying components include rosin and modified rosin, petroleum-based resins, coumaron indene resin, and methyl indene. Cottonwood, polyterpene resin, polystyrene wax, polybutene, liquid polyisobutylene, and examples of plasticizers include machine oil, transformer oil, rosin oil, and various liquid paraffins.

Polymeric substances with adhesive properties other than those mentioned above that can be used in the present invention include polyvinyl alkyl ether, polyvinyl acetate, partially saponified polyvinyl acetate, polyvinyl alcohol, vinyl-based polymeric substances such as polyvinylpyrrolidone, methylcellulose, carboxylic acid, etc. Cellulose derivatives such as methylcellulose and hydroxypropylcellulose,
Polysaccharides such as pullulan, dextrin, and agar, polyurethane elastomers, polyester elastomers, and water-soluble acrylics such as polyacrylic acid (or salts thereof), polymethacrylic acid (or salts thereof), and carboxyvinyl polymers. A water-containing gel-like product containing a polymer, a polyhydric alcohol such as glycerin, a crosslinking agent such as triglycity isocyanate, and water may also be used.

In addition, when using the above-mentioned polymeric substances, if there is a risk that adhesive may remain on the skin surface after application due to insufficient cohesive force and contaminate the skin surface, the skin adhesion may be impaired. It is preferable to subject the polymeric substance to appropriate chemical crosslinking treatment or physical crosslinking treatment to the extent that it does not.

The drug (PN-2) can be efficiently obtained from the external member of the present invention.
It is also possible to add various transdermal absorption promoting agents to release 00).

The above-mentioned transdermal absorption promoting aid can be simply defined as one that promotes the release of the drug (PN-200) to the body surface, but this includes the solubility of the drug (PN-200) within the polymeric substance. and those that have the function of improving diffusion, as well as those that have the function of keratin water retention, keratin softening, keratin permeability (loosening), penetration aids and pore opening agents, and functions that change the skin interface condition. PN-200 has the function of improving transdermal absorption, and also has the above functions, or in addition to these functions, also has the function of enhancing the pharmacological effect of the drug (PN-200). This includes things such as

Examples of this type of percutaneous absorption promoting aid include lower alcohols such as methanol and ethanol, ethylene glycol, propylene glycol, polyethylene glycol,
Glycols such as polypropylene glycol (mainly to improve drug solubility), oils and fats such as olive oil, squalene, and lanolin (mainly to improve drug diffusivity), urea derivatives such as urea and allantoin (mainly to improve water retention in the stratum corneum) , dimethyldecyl phosphooxide, methyl octyl sulfoxide, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, dimethyl laurylamide, dodecyl pyrrolidone, polar solvents such as insorbitol (mainly to improve keratin permeability), salicylic acid (mainly to improve keratin softening property) ,
Examples include amino acids (mainly to improve stratum corneum permeability), nicotinic acid benzyl ester (mainly as a hand pore opening agent), and sodium lauryl sulfate (mainly to change the skin interface state). Other plasticizers such as diisopropyl adipate, 7-talic acid ester, noethyl sebacate, nidoxylated stearyl alcohol, N-methylpyrrolidone, glycerin ester, 1-dodecyl-azacyclohebutan-2-one, isopropyl myristate, ethyl laurate. etc. can be mentioned. One or more of these can be added as necessary.

The amount of the above-mentioned transdermal absorption promoting aid is determined by considering the balance between skin adhesion and cohesive force, and the total weight of the drug (PN-200), the above-mentioned polymeric substance, and the transdermal absorption promoting aid added as desired. It is desirable that the weight range be 0°1 to 30% by weight; if the amount added is less than 0.1% by weight, the effect will be poor, and if it exceeds 30% by weight, skin adhesion and cohesive force will deteriorate. This is not preferable because it may happen.

The blending ratio of the above PN-200 (D) to the base material (C) containing the above polymer substance as a main component may vary depending on the polymer substance used and the form of the external member, such as a poultice, tape, or del agent. Generally 0.1 to 30% by weight, preferably 0.2% by weight based on the total weight of (C) and (D), although it varies.
It is best to adjust the amount within the range of ~20% by weight; if it is less than 0.1% by weight, the therapeutic effect will be poor, while if it exceeds 30% by weight, there will be a limit to the therapeutic effect and it will be economically disadvantageous.

Furthermore, in the present invention, as the undercoat member, a primer having a strong affinity with the carrier, the above-mentioned polymeric substance, or the like can be formed in advance on the carrier.

The external members of the present invention, such as poultices, tapes, and gels, are manufactured by known methods.

For example, a drug (PN-200)-containing base material is created by emulsion polymerization, solution polymerization, etc., and directly placed on a carrier.
Alternatively, various methods can be used, such as applying and drying indirectly through an undercoating member, or coating and drying a drug (PN-200)-containing base material on a release liner in advance to form a film, and transferring this onto a carrier. method can be adopted.

In the external member of the present invention, the exposed surface of the drug (PN-200)-containing base material layer formed on the surface of the carrier is made of a flexible material such as polyethylene terephthalate that has been subjected to a release treatment such as silicone treatment. Preferably, it is protected by covering with a release film.

The external components of the present invention are preferably stored individually or in bulk in bags made of packaging material with excellent moisture impermeability, such as a laminate film of aluminum foil and plastic film, for storage and distribution. .

(e) Action The external member of the present invention has the most significant feature in that it uses PN-200 shown by the following structural formula as its active ingredient. do,
It has high polarity, excellent solubility in substrates mainly composed of polymeric substances, and has a low effective blood concentration and has a mild effect on living organisms.

(f) Examples Examples of the present invention will be shown below, and the contents will be explained in more detail, but the present invention is not limited thereto.

In addition, in Examples and Comparative Examples, parts or % indicate parts by weight or % by weight.

Example 1 In an inert gas atmosphere, 93 parts of acrylic acid iso/nyl ester, 7 parts of methacrylic acid, and 42.8 parts of ethyl acetate were charged into a fourth 7-rasf, and 0.0 parts of azobisisobutyronitrile was added as a polymerization initiator. 2 parts of the solution were added to initiate polymerization. Polymerization was carried out for 8 hours while controlling the internal temperature to 62 to 65 °C by adjusting the stirring speed and external temperature and dropping ethyl acetate, and adding 100 parts of ethyl acetate dropwise.
The temperature was raised to 0°C and aged for 10 hours to obtain a solution of a polymeric substance (substrate) (polymerization rate 94%, viscosity of a 30% solids solution was 168 poise at a temperature of 30°C).

Solid content of the obtained polymer substance (base material) solution: 95 parts = 16
- Dissolve 5 parts of PN-200 in water and apply it on an aluminum vapor-deposited polyester film to a dry thickness of 60 μm, and dry at a temperature of 100"C for 6 minutes to prepare a type of external member of the present invention. A tape preparation was obtained (PN-200
Content 300 ug/cm2).

Example 2 85 parts of 2-ethylhexyl acrylate, 15 parts of N-vinylpyrrolidone, and 150 parts of ethyl acetate were placed in a four-bottle flask under an inert gas atmosphere, and 0.2 parts of benzoyl peroxide was added as a polymerization initiator. Polymerization started.

Ethyl acetate 83 was added while controlling the internal phase temperature to 62 to 65°C by adjusting the stirring speed and outer temperature and dropping ethyl acetate.
．． Polymerize for 6 hours while dropping 3 parts, and then add 75 to 80
The temperature was raised to °C and aged for 5 hours to obtain a solution of a polymeric substance (substrate) (polymerization rate 98%, viscosity of a 30% solids solution was 210 poise at a temperature of 30 °C).

10 parts of PN-200 and 5 parts of dimethyl sulfoxide were dissolved in 85 parts of the solid content of the obtained polymeric substance (base material) solution and applied onto an aluminized polyester film to a thickness of 50/l' after drying. llT and dried at a temperature of 100°C for 6 minutes to obtain a tape agent, which is a type of external member of the present invention (P N -200 content 600μ
g/Cl02).

Example 3 Styrene-isoprene-or styrene block copolymer 28
A poultice base material consisting of 18 parts of liquid paraffin, 5 parts of polybutene, 32 parts of petroleum resin, and 17 parts of titanium was obtained by a known method.

10 parts of PN-2 for 85 parts of the resulting poultice base material
00 and 5 parts of sodium polyoxyethylene lauryl ether phosphate were blended to form a layer of 100μ thick aluminum-deposited ethylene vinyl acetate film/paper laminated film.
0 to obtain a pumping agent, which is a type of external use member of the present invention (PN-200 content 1000 μg/
Cm2).

Example 4 11 parts of sodium polyacrylate, 3 parts of polyacrylic acid, 50 parts of water, 50 parts of glycerin, 0.5 parts of potassium alum
A gel base material was obtained by mixing g.

2 parts of PN-200 for 17 parts of the gel patch obtained;
One part of N-methylpyrrolidone was blended and pressed onto an aluminum vapor-deposited nonwoven fabric to a thickness of 400 μm to obtain a gel agent, which is a type of external use member of the present invention (including PN-200, 41° g/g). c+n.

Table 1 shows the results of skin adhesion and drug stability for each of the above Examples (hereinafter referred to as samples), and Table 2 shows the results showing changes in blood concentration over time.

(Leaves below) -19 = Table 1 Table 2 = 20 - 1) Skin adhesion Various samples were cut into 5 cm squares, and the test pieces were pasted on the inside of the arm. I saw the match.

100% adhesion ◎ 85% or more” 202) Drug stability Various samples were stored at room temperature and 40°C, and the content of the drug (PN-200) after 6 months storage was compared to the initial value. It is expressed in weight%.

3) Blood concentration The hair on the back of a rabbit (weight 2 kg) was shaved and
' After pasting each sample, 4 hours, 8 hours, 12 hours
After 24 hours, blood was collected from the ear vein, and the blood concentration was measured by gas chromatography.

From Tables 1 and 2, it was confirmed that the Example products had good drug stability, and the blood concentration of the drug remained in the effective range for a long period of time.

(g) Effects of the invention As described above, the external member of the present invention contains PN-200, which is a calcium antagonist, as an active ingredient. However, since the effective blood concentration of PN-200 is extremely low, it has excellent fast-acting efficacy and can maintain its efficacy over a long period of time. It has extremely excellent pharmacological effects in preventing high blood pressure and curing the disease.

Claims (3)

[Claims] (1) Isopropyl 4-(2,1,3-benzoxacyazol-4-yl)-1,4, which is shown by the following structural formula ▲ Numerical formula, chemical formula, table, etc. ▼ and is a dihydropyridine calcium antagonist. - An external member containing dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate as an active ingredient. (2) A patent claim in which a dihydropyridine calcium antagonist is contained in a base material mainly composed of a polymeric substance, and the drug-containing base material is formed directly on a flexible carrier or indirectly through an undercoat member. 1. The external member according to item 1. (3) The external member according to claim 2, wherein the polymeric substance is adhesive.