JPS63152316A - Preparation of percutaneous absorption - Google Patents

Abstract

PURPOSE:To obtain a preparation of percutaneous absorption having excellent stability, absorbing characteristics, drug release and alleviating action on angina pectoris, containing nicoradil and 1-dodecylazacycloheptan-2-one. CONSTITUTION:Nicorandil and/or a salt thereof in a crystallite state is uniformly dispersed into a hydrophobic base for exodermis and further blended with 1-dodecylazacycloheptan-2-one. The blend is further mixed with an organic acid such as fumaric acid, oxalic acid, salicylic acid, to give a preparation of percutaneous absorption. The amount of 1-dodecylazabicycloheptan-2-one is 1-10wt% based on sum of the preparation and that of the organic acid is >=0.1wt%.

Description

Detailed Description of the Invention The present invention provides nicorandil [chemical name:
The present invention relates to a transdermal absorption preparation with excellent absorption and stability of N-(2-hydro≧noethyl)nicotinamide nitrate] and/or its salts.

More specifically, the present invention relates to a transdermal preparation that contains nicorandil and/or its salts and 1-dodecyl azacycloheptan-2-one in a base and is stable and has good transdermal absorption.

Conventional technology Nicorandil has a coronary vasodilatory effect and a coronary artery spasm suppressing effect, and is an effective drug for treating various types of angina pectoris with little effect on cardiovascular dynamics and cardiac function.
No. 8-17463). Nitroglycerin ointment is also known as an ointment as a transdermal absorption agent (coronary vasodilator) for angina pectoris. In addition, as a patch, a tape preparation (Japanese Unexamined Patent Application Publication No. 1989-1999
6-1 Roro No. 681, Roro No. 57-116011), etc. are folded. Furthermore, a tape formulation has been proposed in which nicorandil is blended with a polymer that has pressure-sensitive adhesive properties at room temperature and whose glass transition temperature (TP) is adjusted to -70 to 1D'C, and a support is laminated with this blend ( Japanese Patent Publication No. 59-1051
No. 3).

1-Dodecyl azacycloheptan-2-one is a known compound commercially available under the trade name AZONE (Nelson, Ikechi & Development Company, USA). This compound is used as a transdermal absorption enhancer for drugs such as anti-inflammatory agents and antifungal agents (
JP-A No. 52-1065, No. 57-142918, No. 58-210026, No. 58-208216, No. 6
1-27966, etc.), and is also well known as a transmucosal absorption enhancer for these drugs (Japanese Patent Application Laid-open No. 109738/1982), and various transdermal or transmucosal absorbable pharmaceutical compositions containing the same are well known. has been developed.

However, none of these publications related to Eisin discloses a transdermal or transmucosal absorbable pharmaceutical composition containing nicorandil or its salts, which are the active ingredients of the present invention.

Problems to be Solved by the Invention In general, when administering drugs orally, it is difficult to obtain a constant absorption of the drug depending on conditions such as the pH content in the stomach or intestines, so it is difficult to administer the drug gradually over a long period of time. difficult. Oral administration of nicorandil may sometimes cause side effects such as orthostatic anemia and headache due to a sudden increase in blood concentration.

Therefore, it is desired to develop a transdermal absorption preparation as a dosage form that can maintain a constant blood concentration for a long time, reduce the above-mentioned side effects, and be expected to improve convenience and functionality. The conditions include having appropriate compatibility between the base and the drug and having appropriate release properties from the base to the skin.

However, it is known that nicorandil drug substance is relatively unstable when stored at high temperature and high humidity or in a solution state (Pharmaceutical Research, Vol. 14, No. 6).

(pp. 968-979, 1983), nicorandil is in an extremely unstable state in transdermal absorption preparations that satisfy the above conditions, and long-term storage stability of 2 tatami is hardly ensured as a transdermal absorption preparation. It has the following drawbacks. Therefore, the present inventors conducted conceptual research on a transdermal absorption preparation that is stable, well-absorbed, and has little skin irritation, and found that by combining nicorandil and/or its salts with 1-dodecyl azacycloheptan-2-one, We have now invented a transdermal preparation that has good transdermal absorption and is stable.

For a composition comprising nicorandil and/or its salts and a pharmaceutical carrier such as an ointment base or a patch base,
Contains 1-dodecyl azacycloheptan-2-one,
Desired transdermal absorption preparations, ie, ointments, patches, etc., can be prepared by conventional methods.

Nicorandil and/or its salts have antianginal effects. Normally, crystalline substances should be uniformly dispersed in the base to ensure the necessary long-term storage stability of the drug and to ensure that the drug is released from the base to the skin at an appropriate rate. preferable. The method of containing the two drugs in a fine crystalline state is carried out by directly mixing the jet-pulverized drugs.

Nicorandil salts are usually pharmaceutically acceptable organic and inorganic salts such as hydrochloride and oxalic acid! , p-toluenesulfonate, fumarate.

Maleate and the like are used.

In the case of an ointment, the base is composed of one or a mixture of two or more of Plastibase, white petrolatum, liquid paraffin, isopropyl myristate, medium chain fatty acid triglyceride, etc.; Stabilizers, preservatives, dispersants, etc. are added as necessary.

In the case of a patch, any general adhesive composition that has pressure-sensitive adhesive properties at room temperature may be used, including, but not limited to, polyvinyl alkyl ether, poly(meth), etc.
Acrylate, polyurethane, polyamide, ethylene-
Vinyl acetate copolymer.

Alkyl acrylate, ester-acrylic acid copolymer,
Is it composed only of one type or a mixture of two or more of polyisoprene rubber, 5IS (styrene-y, norene-styrene block copolymer comb), styrene-butadiene rubber, polyisobutylene rubber, butyl rubber, natural rubber, etc. Alternatively, tackifiers, softeners, fillers, anti-aging agents, etc. may be added as necessary.

From the viewpoints of adhesion to the skin, drug release properties from the base, and drug stability, these bases are preferably hydrophobic bases that do not contain water.

1-Dodecyl azacycloheptan-2-one is known as a transdermal absorption enhancer as described above. Various other surfactants such as polyoxyethylene alkyl ether and polyoxyethylene sorbitan fatty acid ester lauroyl jetanolamide are also used as transdermal absorption enhancers, but in the case of transdermal absorption preparations containing nicorandil or its salts. In particular, by using 1-dodecyl azacycloheptan-2-one, the absorption of the drug into the body, the release of the drug from the base, and the stability of the drug in the preparation are greatly improved. The amount added to the 1-dotecylazacyclohecyclohebutane-2-onno preparation is preferably 1 to 10% by weight, particularly preferably 2 to 6% by weight, based on the total weight of the preparation.

In addition, especially when using nicorandil, fumaric acid,
A stable transdermal absorption preparation can be obtained by mixing one or more organic acids selected from the group consisting of oxalic acid, salicylic acid, tartaric acid, and glutaric acid into the base. The amount of the above organic acid added to the formulation is 0.1% by weight of the total weight of the formulation.
The above is preferable.

Effect The transdermal absorption preparation obtained by the present invention has stability, AUG
48 and 1/100 of the survival rate (%) after storage for 1 or 2 weeks at 50°C as an indicator of stability (here,
It has a very large stability parameter (referred to as "stability parameter"), which means that it has good absorbency and is very stable.The following will explain it with examples, but the present invention is not limited to these. Not.

Example 1 (Ointment) 2 parts by weight of nicorandil AZONE 5 tt 9 parts by weight of Plastibase 〃 2 parts by weight of nicorandil and 5 parts by weight of AZONE were put into a vacuum crusher and kneaded while gradually adding Plastibase base, and tonight they were evenly mixed to make an ointment. obtained the drug.

For comparison, an ointment was prepared under the same conditions in which the same amount of polyoxy/ethylene (9) lauryl ether was substituted for AZONE in the formulation of the example.

Example 2 (Ointment) Nicorandil 2 weight -) 3.1 Weight mAZON
E 8 11 Plastibase
88.9Il nicorandil fumarate 3.1 parts by weight, AZONE8
The weight part was put into a vacuum masher and mixed while gradually adding Plastibase base to give an ointment.

For comparison, the same amount of polyoxyethylene (6) Sorvita! was used instead of AZONE in the example formulation. An ointment in which monooleate was substituted was prepared under the same conditions.

Example 6 (Ointment) Nicorandil 2 parts by weight AZONE 5 u Fumaric acid 2 〃 Plastibase 91〃 2 parts by weight of nicorandil, 5 parts by weight of AZONE, and 2 parts by weight of fumaric acid were placed in a vacuum kneader and kneaded while gradually adding Plastibase. Tonight I made it evenly and got the ointment. For comparison, an ointment was prepared under the same conditions in which AZONE in the formulation of the example was replaced with the same amount of lauroylgetanolamide.

In Examples 1 to 3, the ointments were placed in a plastic airtight container and a stability test was conducted for 50'02 weeks. In addition, the back of a rat (4 x 4
cm2) for 48 hours and the area of the drug in the blood is AU.
C43 (ng, -hr/ml) was determined and calculated as "More". The results are shown in Table 1.

Table 1 Example 4 Polyvinyl isobutyl ether 70 parts by weight Polyvinyl ethyl ether 30 parts by weight nicorandil
5 parts by weight A Z ON E
5.56 parts by weight Polyvinyl isobutyl ether [Product name Lutonal Cl25: manufactured by BASF:) 70M parts Polyvinyl ethyl ether [Product name
Lutonal A5Q: manufactured by BASF] 50 parts by weight 1
5 parts of nicorandil (average particle size 1 filtration, um) suspended in 7 chlorohexane in a 5% cyclohexane solution and A Z
Add 556 parts by weight of ON E and stir with a disilver to prepare a coating solution in which nicorandil is almost uniformly dispersed.

This was coated on a polyethylene terephthalate release paper liner so that the thickness after drying was 100/jm, and dried.
A polyethylene support was laminated on this to make the average particle size 16 μm.
The amount of chorandil is 0.45 when nicorandil is uniformly dispersed.
A tape formulation of m97α2 was obtained. For comparison, a tape preparation was produced under the same conditions in which AZONE in the Example formulation was replaced with the same amount of oleoylsarcosine.

Example 5 Polyvinyl isobutyl ether 70 parts by weight Polyvinylethyl ether 30 parts by weight Nicolandyl fumaley) 7.75 parts by weight AZONE
5.53 parts by weight of nicorandil 5M part of Example 4 was substituted with 775 parts by weight (average particle diameter: 12 μm) of nicorandil fumarais) The amount of corandil was 0.44 m97 cm2). A tape formulation was obtained.

For comparison, a tape preparation was produced under the same conditions in which AZONE in the Example formulation was replaced with the same amount of lauroylgetanolamide.

The tape formulations in Examples 4 and 5 were placed in an aluminum bag, and a stability test was conducted at 50° C. for 1 week when a desiccant was added. In addition, the tape preparation was applied for 48 hours to the back of a rat (3 x 3 twr2) whose hair had been removed using a shaver, and the blood drug m
Area under the 1 degree curve AUC4s (ng, hr/ml)
I asked for The results are shown in Table 2.

Table 2

Claims (4)

[Claims] (1) A stable transdermal absorption preparation that contains nicorandil and/or its salts and 1-dodecyl azacycloheptan-2-one in a base and has good transdermal absorption. (2) The transdermal absorption agent according to claim 1, wherein the base is a hydrophobic skin base. (3) The transdermal absorption preparation according to claim 2, which contains nicorandil and/or its salts in a fine crystalline state. (4) The method according to claim 2 or 3 further contains one or more organic acids selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid, and glutaric acid. Dermal absorption preparation.