JPS58172312A - Nifedipine of external use agent - Google Patents

Abstract

PURPOSE:An agent for external use useful as a remedy for attack of angina pectoris, etc., absorbable continuously from the skin, obtained by blending nifedipine as an active ingredient with one or more of an alcohol, a ketone, a polyhydric alcohol, an acid amide, a fatty acid, a surface active agent, etc. CONSTITUTION:Nifedipine useful as a remedy for attack of angina pectoris, hypertension, etc., having coronary vasodilating action, as an active ingredient is dissolved in one or more components selected from the group consisting of an alcohol, a ketone, a polyhydric alcohol, its carbonate, an acid amide, a fatty acid, and a surface active agent as a solubilizer. The amount of the solubilizer used is 0.5-50pts.wt., preferably 2-35pts.wt. based on 1pt.wt. nifedipine. In the pharmaceutical manufacturing, nifedipine is dispersed or dissolved in the solubilizer with heating, and the dispersion or the solution is blended with a base, or nifedipine is added to the base which is previously blended with the solubilizer.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external preparation containing nifedipine as an active ingredient.

The therapeutic effect of nifedipine is exerted by improving the balance of oxygen supply and demand in the myocardium by suppressing the influx of Ca, which is a substance related to muscle excitation and contraction, into myocardial and vascular smooth muscle cells, and it has a coronary vasodilator effect. It is useful as a therapeutic agent for so-called angina pectoris attacks, high blood pressure, etc.

Oral preparations (tablets, special-potency tablets, powders, and soft capsules) are known as preparations for nifedipine, but other administration methods have not yet been developed.

Nifedipine is sparingly soluble in water and polar solvents, and suitable solvents are limited, so oral administration has low bioavailability. For this reason, various efforts have been made to create orally administered drugs with good bioavailability, but the methods are complicated and
The formulation form is also limited.

The present inventors focused on external preparations as an effective method of administering nifedipine, and as a result of various studies, they kneaded powdered nifedipine into a base such as white petrolatum, which is generally used in the production of ointments. Although the transdermal absorption of nifedipine from topical preparations prepared by the method of immersion is very low, the preparation must remain in close contact with the skin for a predetermined period of time, and there must be appropriate compatibility between the base and the drug. If conditions such as the drug not crystallizing in the base and having appropriate release properties from the base to the skin are met, nifedipine will be effectively absorbed through the skin in fixed amounts and will have no pharmacological effect. The present invention was completed based on the discovery that the compound exhibits a long-lasting and excellent effect.

The present invention provides nifedipine with one or more components selected from the group consisting of alcohols, ketones, polyhydric alcohols, carbonic esters thereof, acids, amides, fatty acids, esters thereof, and surfactants. This is a compounded nifedipine topical preparation.

The formulation of the present invention satisfies the above requirements.

contains. :: The nifedipine topical preparation of the present invention is an ointment, a gel ointment,
It can be manufactured in the form of creams, patches, etc.

The preparation of the present invention can be prepared by dispersing and dissolving nifedipine in a dissolving agent while heating at the time of use, and then kneading it with a base, or by adding nifedipine to a base that has been mixed with a dissolving agent in advance and kneading it. It can be prepared. In addition to nifedipine, a solubilizer, and a base, additives such as stabilizers and absorption enhancers can be added as necessary.

The external preparation of the present invention may be applied to the skin, and if desired, the application site may be covered with parchment paper or a plastic film.

A patch can be produced by applying a drug prepared in a conventional manner by adding additives such as an adhesive, an adhesion modifier, a filler, and a softener to an aluminum, cloth, paper, or plastic film.

Examples of the dissolving agent used in the present invention include alcohols such as ethanol, inpropatol, benzyl alcohol;
Ketones such as acetone, methyl ethyl ketone; polyhydric alcohols and their carbonic esters such as polyethylene glycol 200-6000. Propylene carbonate; Acid amides such as N,N-dimethylformamide, he,N-dimethylacetamide; Fatty acids and their esters such as ethyl lactate, diethyl adipate, diethyl sebacate, isopropyl myristate, diacetin, triacetin; Surfactants such as Tween series , polyoxyethylene fatty acid ester, polyoxyethylene fatty acid ether, castor oil derivative, etc. can be used alone or as a mixture of two or more.

The amount of solubilizer used is 0.5 parts by weight of nifedipine.
~50 parts by weight, preferably 2 to 65 parts by weight. 0.5
If it is less than 50 parts by weight, the dissolution and dispersibility of Nifuezibi/ in the dissolving agent will be insufficient, and most of the drugs may not contribute to treatment, and if it is more than 50 parts by weight, the feeling of use will be poor.
It is not preferable to obtain firmness with appropriate spreadability and spreadability on the skin when applied.

As the base, ointment bases, gel ointment bases, cream bases, and liquid bases that are generally used for external preparations, such as white petrolatum, paraffin, lanolin, wax, macrogol, carboxyvinyl polymer, etc. are used. can.

Other additives include preservatives such as paraoxybenzoic acid ester, antioxidants such as butylated hydroxyanine, butylated hydroxytoluene, vitamin E, etc.
Chelating agents such as EDTA, keratolytic agents such as salicylic acid, methyl salicylate, absorption enhancers such as nicotinamide, camphor, suspending agents such as hydroxypropylcellulose, aerosol, holivinylpyrrolidone, etc., humectants such as glycerin, propylene glycol, etc. Example 1 F-1 divin 2% white petrolatum 8% microcrystalline wax 10% paraffin
20% isopropyl myristate
A solution of nifedipine in isopropyl myristate is added to a mixture of 6.0% microcrystalline wax and paraffin dissolved by heating and white petrolatum, and the mixture is crushed to obtain a nifedipine topical preparation.

Example 2 Nifedipine 2% Propylene Glycol 6Z95% Ethanol
10% carboxyvinyl polymer 1% triethanolamine
0.05% water
1. Ethanol, a propylene glycol solution of nifedipine, and triethanolamine are added to a mixture of 19% carboxyvinyl polymer and water, and the mixture is triturated to obtain a nianidipine topical preparation.

Nianidipine 5% Aerosil 7% Inglovir myristate 26% Diethyl sebacate
20% medium chain fatty acid triglyceride 20
% triacetin 20% benzyl alcohol 5% The above materials were prepared in Example 1.
Mix in the same manner as above to obtain nianidipine topical preparation. The same applies to the following examples.

Example 4 Nifedipine 2% polyethylene glycol 400 10% propylene glycol
38% ethanol
10% isopropanol 10% benzyl alcohol 5% triacetin
5% carboxyvinyl polymer
1% triethanolamine 0
．． 05% water
18.95% Example 5 °F1 Divin 2% Polyvinylpyrrolid 7 8% Ethanol
10 parts white petrolatum
70% paraffin 10% The results of a transdermal absorption test of the nifedipine topical preparation of the present invention are shown below.

Shaved rat (male, weight 550-400.9)
A topical solution of nifedipine (nifedipine) was applied to a 3 x 3 cm area at a ratio of 60 cm/9 cm, and the applied area was sealed with red cellophane.Blood was then collected over time, and plasma was collected. The amount of nifedipine was measured by gas chromatography. The results are shown in the table below. The numbers in the table are plasma concentrations (n, !ir/ml). Compared to an ointment prepared by adding 2 parts of powdered nifedipine to a base of 88 parts of petrolatum and 10 parts of lanolin, nifedipine is effectively absorbed through the skin, and the initial rise in plasma concentration is significantly faster. Maintained high concentration for a long time.

Claims (1)

[Claims] 1. Alcohol, ketone,
A nifedipine external preparation containing one or more components selected from the group consisting of polyhydric alcohols, carbonic esters thereof, acid amides, fatty acids, esters thereof, and surfactants. 2. 0.5 to 5 parts of solubilizer to 1 part by weight of nifedipine
The external preparation of nianidipine according to claim 1, which is formulated in a ratio of 0 parts by weight. ′