JPS58177916A - External drug - Google Patents

Abstract

PURPOSE:An external drug containing nifedipine or nicardipine as an active constituent, and effective for treating and preventing angina pectoris. CONSTITUTION:A remedy for angina pectoris containing a compound of the formula (the nitro group is linked to the o-position when R is methyl group, and linked to the m-position when R is N-benzyl-N-methylaminoethyl group) with a dissolution assistant, e.g. a glycol such as methyldiglycol, or an alcohol such as benzyl alcohol, and capable of keeping the concentration in blood for a long term. The dose thereof is 30-2,000mg at one time, preferably 100-1,000mg, at one time. An excipient, viscosity increasing agent, emulsifying agent, antioxidant, adhesive or perfume may be incorporated in the external drug. The concentration in blood reaches the effective value about 2hr after the administration by applying or sticking the drug to the body, preferably the breast, and the concentration thereof is kept for almost 24hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an effective external preparation for the treatment and prevention of angina pectoris. More specifically, the following general formula (1) (wherein, when R is a methyl group, the nitro group is bonded to the ortho position, and when R is an N-benzyl-N-methylaminoethyl group, the nitro group is bonded to the ortho position, The present invention relates to an external preparation containing nianidigine or nicardipine as an active ingredient.

(Summer) Nianidigine, in which R is represented by a methyl group, and nicardipine, in which R is represented by an N-benzyl-N-methylaminoethyl group, have excellent coronary vasodilation.
Widely used to treat angina pectoris.

Angina pectoris often manifests itself in the form of attacks and must be treated promptly at the time of attack. From such actual situation,
Conventionally, the compound of formula (1) has been administered orally or sublingually, taking into account its physical properties and absorption/excretion patterns.

The above-mentioned compound administered orally or sublingually is rapidly absorbed and reaches its maximum blood concentration in 0.5 to 2 hours, so it is highly effective in emergency treatment during seizures.

However, patients with angina pectoris cannot predict when their attacks will occur, and they often occur suddenly or during sleep. Therefore, if patients with angina pectoris are expected to experience fatigue or mental agitation due to their symptoms, it is necessary to pre-administer angina drugs, that is, to treat persistent angina. be. However, because the blood half-life of nifedipine and nicardipine is short at 4 to 5 hours, conventional oral or sublingual administration methods are inconvenient if you cannot take it regularly or when you are late at bedtime, and oral administration is also inconvenient. Therefore, the inventor of the present invention conducted extensive research to provide a long-lasting preparation that would overcome these drawbacks, and found that the above-mentioned compound could be absorbed transdermally. The present invention was completed based on the discovery that the drug has a medicinal effect and that when administered externally to fish, the blood concentration can be maintained for a long period of time.

Therefore, the present invention provides an external preparation containing nianidivine or nicardipine as an active ingredient.

Nianizibine is a compound that is soluble in water and alcohol, unstable to light, and hardly absorbed in crystalline form even when administered orally, so there is no idea of using it as an external preparation. It didn't exist.

The external preparation of the present invention is produced by incorporating the external use base 9ianidivine or nicardipine using a solubilizing agent.

Rigid products for external use may be prepared as long as they contain excipient compounds and can be shaken, such as ointments, creams,
Blends, liquids, tapes, poultices and the like are preferred, and any of those used in these can be used as the base.

A solubilizing agent that dissolves the compound and promotes transdermal absorption is used, such as methyl diglycol,
Glycols such as ethyl diglycol, ethyl diglycol, methyl triglycol, ethyl triglycol, butyl triglycol; Alcohols such as benzyl alcohol and phenethyl alcohol; Esters of monocarboxylic acids of 04 to 014 with alcohols of C1 to C5 ,C6
Examples include diesters of C10 dicarboxylic acids and C1 to C3 alcohols, benzyl benzoate, N-methyl vinyl, dimethylsulfoxy P1 crotamiton, propylene carbonate, and the like.

The concentration of nifedipine or nicardipine in the topical base can be selected within a wide range, with nifedipine or nicardipine in a single dose ranging from 60 to 2000 μl.
, % is preferably 100 to 100011#p.

This external preparation of Haimei may further contain commonly used excipients, thickeners, emulsifiers, antioxidants, adhesives, fragrances, and the like.

The external preparation of the present invention has an active ingredient in the above range.
The number of times is 4! Apply or paste it on the chest.K
Therefore, the dose is adjusted as appropriate depending on the disease state. In this case, the blood concentration reaches the effective concentration about 2 hours after administration, and this concentration is maintained for about 24 hours, making it extremely excellent as a long-lasting treatment and prevention agent for angina pectoris.

Next, an explanation will be given with reference to experimental examples and examples.

Experimental Example 1 Transdermal absorption experiment: After cutting the hair on the rat abdominal skin and applying the specimen in a circle with an area of 1ocIIL2, blood was collected 2.4.6.8 and 24 hours later, and was subjected to chromatography. The drug concentration in plasma was measured.

As a specimen, a book written by the next generation was used.

Specimen 1. Nihuedigin (601Rg)-benzyl benzoate (2 horse j) solution 12, l (100 instant)-diisozorobyl adipate (2sJ) solution sample 5. Nianidibin (100W) - Hensyl Alcohol (27 Nori Solution #4. I (1001v) -N-
#Lou2-pio+7)11y(2F114) solution #5. I (100*)-crotamito:/(2FIIj) age solution results are shown in FIG.

Experimental Example 2 Absorption area dependence test: Using rats treated in the same manner as Experimental Example 1, an area of 0.64
After applying 0.5~ of 2tinifedipine-diisoprobil adipate solution in the circles of 0112C specimen 1), 1.66cIrL2 (sample 2) and 10CM'' (sample 6),
The drug concentration in plasma was measured in the same manner as in Experimental Example 1.

The results are shown in Figure 2.

Example 1. Ointment Nifedipine 1.0 (parts) Methyl triglycol 5.0 Liquid paraffin 10.0 Solid paraffin 5.0 Sorbitan sesquioleate 1.0 (parts) Petrolatum Total 100.0 Example 2゜Other than changing nifedipine to nicardipine An ointment was manufactured using the same formulation as in Example 1.

Example 3. Cream nifedipine o, 5 (parts) crotamito 7
5.0 Vaseline 1&0 Liquid paraffin 6.0 Setanol 3.0 Stearyl alcohol 3.0 Polyoxyethylene cetyl ether 2.5 Purified water Total 100.0! J Example 4. Liquid nifedipine 4.0 (parts) Diisoglobil adipate Total 100.0 Example 5. Nifedipine patch 0.6 (parts) Diethyl cepatate 10.0 Polyvinyl alcohol
5.0 The above acid content is converted into ethylhexyl acrylate.
Methyl methacrylate copolymer (solids content 60%)
140 parts of the mixture was spread on cotton cloth and dried to form a film to prepare a patch.

Example 6. Padging agent Nianidibin 0.5 (part) Benzyl alcohol 4.0 Kaolin 20
．． 0 Sodium polyacrylate 2.0 Ze2ten
ZO Cal? Xypinyl polymer 1.5 glycerin
25.0 Polysorbate 80 3.0 Ammonia
Small amount of purified water total 100.0

[Brief explanation of drawings]

Figure 1 shows the blood # level over time when the topical preparation of the present invention containing nifedipine was applied to rat skin, and Figure 2 shows the relationship between the absorbed amount of the topical preparation of the present invention containing nianizipine and the applied area. . Kowa Co., Ltd.

Claims (2)

[Claims] (1) General formula (where, when R is a methyl group, the nitro group is bonded to the ortho position, and when R is a noethyl group to N-benzyl-N-methyla, the nitro group is bonded to the meta position. ) An external preparation containing nianidigine or nicardipine as an active ingredient. (2) The external preparation according to claim 1, wherein the external use base contains Nianijigin or Nicardigin using a solubilizing agent.