JPS61263918A - Pharmaceutical for percutaneous absorption - Google Patents

Abstract

PURPOSE:A pharmaceutical for percutaneous absorption, containing a dihy droergot alkaloid as an active constituent, absorbable through the skin, capable of exhibiting an effective blood concentration having prolonged action and useful for treating cerebral arteriosclerosis, nerve conducting function insuffi ciency, etc. CONSTITUTION:A pharmaceutical for percutaneous absorption containing a compound expressed by the formula (R is benzyl, isopropyl, isobutyl or secondary butyl) or a salt thereof alone or in the form of a mixture as an active constituent. A mixture constituted of mesylates of compounds expressed by the formula (R is benzyl, isopropyl, isobutyl and secondary butyl) at 3:3:2:1 weight ratio, i.e. dihydroergotoxin is particularly effective. The effective blood concentration maintains for one week or more and the frequency of administration and side effect can be reduced.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a preparation for percutaneous absorption of ergot alkaloids which is useful in the pharmaceutical field and has an excellent effect on improving cerebral metabolic function.

Conventional Technology Ergot alkaloid is a general term for alkaloids contained in rye, and ergotoxin, ergotamino, ergometrine, etc. are known.

An ergot alkaloid in which the double bond at position 9 of the chemical structure of the ergot alkaloid is hydrogenated is shown by the following structural formula. Dihydroergocristine, dihydro-α-ergocributine, dihydro-β-ergocributine, and dihydroergocornine are known as compounds that have extremely similar chemical structures and are extremely useful as pharmaceuticals.

Currently being offered treatment.

Dihydroergotoxin (R-benzyl)dihydroergocornine (R-isopropyl)dihydro-
α-Ergocributine (R=isobutyl)dihydro-
β-Ergocributine (R=sec-butyl) These four dihydroergot alkaloids are used in medicine in the form of a mixture. namely, dihydroergocristine, dihydroergocornine, dihydro-α-ercoliftin.

and dihydro-β-ergocributine approximately 3:3:
The mixture in a 2:1 weight ratio is given the common name dihydroergotoxin.

Dihydroergotoxin not only relaxes the constriction of cerebral capillaries, improves blood circulation, and normalizes cerebral blood flow and oxygen consumption, but also improves neurotransmission function and improves normal brain function in the elderly. It has pharmacological effects such as improving the psychosomatic symptoms associated with dysfunction.

Therefore, clinically, dihydroergotoxin is
It is widely used as a therapeutic agent for symptoms associated with cerebral arteriosclerosis 9 after-effects of head trauma, hypertension, and peripheral circulation disorders.

[Medical practice and new medicine Vol. 21, pages '723-'730 (1984
), Geriatic Medicine Volume 11 96
5-974 (1973)) The conventional dosage form of dihydroergotoxin is.

There are only three forms: oral, sublingual, and injection.

Problems to be Solved by the Invention The disadvantage of the conventional dosage form of dihydroergotoxin is that its effective duration in the blood is short.

and gastrointestinal disorders (9) inability to promptly deal with dihydroergotoxin side effects such as anorexia, nausea, vomiting (1) and headache. In addition, since the persistence of effective blood concentration is short, 1
Since it requires administration three times a day, there is also the problem of patient non-compliance with taking the drug.

As a result of studying to improve the problems of these conventional dosage forms, the present inventor believes that if it is possible to administer the treatment through the skin, the drawbacks of the conventional dosage forms can be significantly improved. , conducted intensive research. As a result, the compound represented by general formula (I) (wherein R represents a benzyl group, isopropyl group, inbutyl group, or sec-butyl group) or a pharmaceutically acceptable salt thereof is absorbed through the skin. In addition, it has been found that when the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is administered through the skin, the effective blood concentration persists for more than one week.

The invention has been completed. That is, the present invention provides a transdermal absorption preparation containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, alone or in the form of a mixture in any combination. .

The dosage form of the transdermal absorption preparation of the present invention may be any one that can contain the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.9 For example, ointment. , plasters, liniments, lotions, tapes, poultices, etc. can all be used.

The transdermal absorption preparation of the present invention is prepared by adding the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a suitable formulation base, such as a support, in a conventional manner.

Adhesives, emulsifiers, suspending agents, softeners, fillers.

By selecting and blending solubilizing agents, preservatives, and fragrances, any of the above-mentioned dosage forms can be produced.

First, the terms used above will be explained using specific examples.

Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, as well as fumaric acid and malic acid.

Citric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, furopanesulfonic acid, butanesulfonic acid, heftanesulfonic acid, pentanesulfonic acid, tecanesulfonic acid, dodecanesulfonic acid, etc. having 01 to 0 carbon atoms. p-alkylsulfonic acid.

Examples include salts with organic acids such as alkyl-substituted benzenesulfonic acids such as benzoic acid, henzenesulfonic acid + o-toluenesulfonic acid, m-) toluenesulfonic acid, and p-) toluenesulfonic acid. Among them, the salt with methanesulfonic acid is particularly popular. As a support, for example.

Polyolefin, polyester, polyurethane.

Polyvinyl alcohol, vinylitine chloride, polyamide,
Polyacrylate, polyethylene, saponified ethylene-vinyl acetate copolymer, polypropylene, polyvinylidene chloride, cellophane.

Examples include metal foil and cotton cloth.

As the adhesive, for example, n-butyl acrylate,
Isoamyl acrylate, hexyl acrylate, 2-
Ethyl butyl acrylate.

inoctyl acrylate, 2-ethylhexyl acrylate, nonyl acrylate, iso7yl acrylate, decyl acrylate, tetrahydrofurfuryl acrylate, methoxyethyl acrylate, ethoxyethyl acrylate, butoxyethyl acrylate, polyethylene glycol acrylate, ethoxydiethylene glycol acrylate, hydroxy Globyl acrylate, vinyl acetate, vinyl propionate, vinyl methyl ether, vinyl isobutyl ether, acrylonitrile,
Acrolein.

Synthetic resins such as vinyl chloride, acrylamide, dimethylaminoethyl acrylate, diethylaminoethyl acrylate, vinylimidazole, vinylpyrrolidine, vinylpyrrolidone, methylcellulose, ethylcellulose,
Cellulose t such as hydroxyethyl cellulose, hydroxyglobil cellulose, carboxymethyl cellulose
js body, styrene-isoprene-styrene block copolymer rubber, styrene-butadiene rubber, polybutine rubber, polyisobutylene rubber.

Butyl rubber, silicone rubber, natural rubber, etc. 8
= Mu etc.

An example of a softening agent is liquid paraffin.

Examples include oils and fats of hydrocarbon low polymers such as white petrolatum, stearyl alcohol, cetanol, cetostearyl alcohol, and froprene glycol.

Examples of emulsifiers include sodium soap.

Potassium soap, calcium oleate, calcium stearate, ethanolamine oleate, funnel oil,
Sodium lauryl sulfate, sodium cetyl sulfate, sodium dioctyl sulfosuccinate, benzalkonium chloride, pensetonium chloride, phoroxyethylene glycol alkyl ether, polyoxy 7 ethylene glycol alkyl ester, polysorbate sorbate, z fatty acid ester, methylcellulose.

Surfactants such as carboxymethyl cellulose.

Plant ingredients such as gum arabic, tragacanth, agar, sodium alginate, Quillaya extract, animal ingredients such as lanolin, cholesterin, soybean lecithin, gelatin, casein, Pharmagen, kaolin, bentonite, magnesium hydroxide.

Examples include fine powder such as aluminum hydroxide.

Suspending agents include, for example, gum arabic.

Sodium alginate, karaya gum, agar, carob gum, gelatin, dextrin, starch, tragacanth,
Hydroxyethyl starch.

Carbohydrates such as pectin and Honsula extract, cellulose derivatives such as sodium carboxymethyl cellulose, hydroquine ethyl cellulose, fromalzine, and methyl cellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl alcohol, polyvinyl methyl ether.

Polyvinylpyrrolidone, Rubiscoll, Carbopol 9
Synthetic polymer compounds such as 34, Veegum.

Examples include clays such as bentonite, tex, hectorite, and surfactants such as polysorbate and polyethylene glycol monostearate.

Fillers include, for example, starch, zinc stearate, magnesium stearate, bentonite, titanium,
Examples include powders such as silica and calcium carbonate.

As a solubilizing agent, a compound of general formula (I) can be dissolved;
There are substances that promote transdermal absorption, such as liquid paraffin, vaseline, lanolin, olive oil, glycerin, benzyl alcohol, butyl benzoate,
Mi! J isopropyl stinate, octatool,]]3
-Butanediolfuropylene gelicol, ethylene glycol, polyacrylate, polymethacrylate.

Polyvinyl ether, dimethyl sulfoxide.

Dodecyl sulfoxide, methyl sulfoxide.

dimethyldecyl sulfoxide, mercaptoethanol,
Thioglycolic acid or its salts mono- or diethylacetamide, N-hydroxyethyl lactamide, dimethylacetamide, N,N-dimethyldecanamide, dimethylformamide.

Toluic acid diethylamide, ε-caprolactam, N-
Dodecyl-ε-caglolactam, tetrahydrofurfuryl alcohol, tetrahydrofuran, sorbitol, N
-dodecylpyrrolidone, N-methylpyrrolidone, urea,
Diethyl adipate, diisopropyl adipate, squalene, squalane, acetylated lanolin, cetyl lactate, dioctyl sebacate, ethoxylated stearyl alcohol, lanolin acid, lanolin alcohol, higher fatty acid alcohol, salicylic acid, amino acids, proteolytic enzymes, methyl nicotinate, T-menthol, camphor, salochol, sodium lauryl sulfate, sodium laurate, steering lyserine stearate.

Higher fatty acid triglycerides, polyoxyalkylene glycols, fatty acid mono-(alternatively) ethanolamides,
Ethylene glycol monoethyl ether, polyoxypropylene alkyl ether, higher alkyl sulfonic acid or its salt.

Examples include.

Cresol and chlorothymo are preservatives.

leuthymol, phenol, 0-phenylphenol,
Methyl p-oxybenzoate, ethyl p-oxybenzoate, propyl p-oxybenzoate, butyl p-oxybenzoate, benzyl p-oxybenzoate, p-chloro-m
-Cresol.

phenolic substances such as chlorobutanol, benzyl alcohol, and neutral substances such as formalin.

Thimerosal, phenylmercuric benzoate, acetic acid.

Organic mercury agents such as phenylmercury, phenylmercury nitrate, phenylmercury borate, benzoic acid, sodium benzoate, inverse mercury, salicylic acid, rubic acid, tehytroacetic acid, hexylene glycol.

Examples include boric acid, borax, and vitamins.

The content of the compound represented by the general formula CI) in the preparation for percutaneous absorption can be selected within a wide range, and in one dose, the content of the compound represented by the general formula ○) or its pharmaceutically acceptable amount. It is particularly preferably used in the form of a salt or a mixture in any combination in a range of 1 to 50 mg.

The percutaneous absorption preparation of the present invention is administered by applying or pasting it on the body once, so that the active ingredient is within the above-mentioned content range.

The dosage is adjusted appropriately.

Cerebral arteriosclerosis is a symptom to which dihydroergot alkaloids as shown by general formula (I) are applied.

Symptoms associated with head trauma sequelae, neurotransmission dysfunction, and psychosomatic disorders associated with geriatric chronic brain dysfunction.

For treating hypertension and peripheral (shield ring disorders).

Continuation of medication is often required, and there are associated problems such as patient non-compliance with taking the medication.
When administered with the formulation of the present invention based on the knowledge that dihydroergot alkaloids as represented by general formula (I) are absorbed through the skin and exhibit a sustained effective blood concentration, the above-mentioned It is believed that the problems can be easily resolved.

EXAMPLE The present invention will be specifically explained with reference to an example below.
These are not limited to examples only.

Example 1 55 parts of 2-ethylhexyl acrylate (L/-), 5 parts of 2-hydroxyacrylate, and 40 parts of vinyl propionate were placed in a reaction vessel, and the mixture was treated with ethyl acetate/- using 0.2 parts of benzoyl peroxide. After reacting for 8 hours at 65C in a mixed solvent of toluene (70/30), further 75-8
The reaction was carried out at 0C for 2 hours to obtain an adhesive solution. Next, dihydroergotoxin mesylate was added to the adhesive solution obtained in this manner, and the mixture was coated on the surface of a polyethylene film to a thickness of 40 μm after drying, and dried to remove dihydroergotoxin mesylate. A tape preparation was obtained. The amount of dihydroergotoxin mesylate added was 40
μ? /crl.

Example 2 2-ethylhexyl acrylate) 92i3 maleic anhydride s'':vs, 3 parts of styrene a, and 04 parts of benzo=15-yl peroxide were placed in a reaction vessel, and the mixture was heated at 80C under a nitrogen stream in ethyl acetate. The polymerization reaction was carried out for 20 hours at
Obtain adhesive solution. This was applied to the surface of a polyethylene film to a dry thickness of 70 mm, and after drying, an ethanol solution of dihydroergotoxin mesylate was added.

Is the amount added 50μ? /Ca.

A tape preparation containing dihydroergotoxin mesylate was obtained.

Example 3 The adhesive solution obtained in Example 1 was applied to a polyethylene film so that the thickness after drying would be 40 μm, and after drying, an ethanol solution of mesylate acid and doroergotoxin was soaked in. A piece of lint cloth with a diameter of 1.5 cm was attached. The amount of dihydroergotoxin mesylate added was 70 μt/cd.

Example 4 100 parts of natural rubber and 40 parts of synthetic rubber were kneaded together, 50 parts of zinc white and 50 parts of calcium carbonate were added,
We practiced. Furthermore, 100 parts of tackifying resin and fat]-
0 parts were added and kneaded to prepare a base. This base was mixed with dihydroergotoxin mesylate dissolved in methanol, then heated and spread on a subbed cloth to form a plaster containing dihydroergotoxin mesylate. Obtained. In addition, the content of dihydroergotoxin mesylate is 2
00 μf/cat.

Example 5 2ag of white petrolatum and 25 parts of cetyl alcohol were added to '75
The mixture was mixed at C and filtered through a 200 mesh sieve to obtain an oil phase component. -F, 12 parts of propylene glycol, 1 part of sodium lauryl sulfate, and 37 parts of purified water were mixed at 75C and filtered through a 200 mesh sieve to obtain a water phase component.

50 parts of the water phase component was gradually added to 50 parts of the oil phase component for 20 minutes while stirring at '75C, and then the temperature was gradually lowered to 35Ct to obtain an O7W type emulsion ointment.

To 90 parts of the obtained ointment, 10 parts of dihydroergotoxin mesylate solution (dihydroergotoxin mesylate)
A solution mixed with 90 parts of propylene glycol) was gradually added and mixed to obtain an ointment containing dihydroergotoxin temesylate.

Example 6 Dissolve 4 parts of stearyl alcohol at 80C.

Add 5 parts of sorbitan monolaurate A and 4 parts of liquid halafine, dissolve at '70C for 5 minutes, filter through a 150 mesh sieve, and add 25 parts of polyoxyethylene sorbitan monolaurate and 1 part of sodium lauryl sulfate.
Mix 1 part of dihydroergotoxin mesylate with an appropriate amount of purified water at 70°C, add the phase filtered through a 150 mesh sieve, emulsify under vacuum at 80°C, cool to 6°C, add 1 part of propylene glycol and defoamer. Add silicone
After slow mixing under vacuum at 45C, the mixture was cooled to 35C to obtain a lotion.

Example 7 The solution obtained in Example 1 was applied to a polyethylene film so that the thickness after drying was 40 μm, and then dried.
A circular lint cloth with a diameter of 1.5 cm impregnated with an ethanol solution of mesylic acid [31]]-dihydroergotoxin was attached to obtain a poultice containing mesylic acid [3I-■]-dihydroergotoxin.

The amount of mesylic acid [:”H)-dihydroergotoxin added was 125 μV (30
μOi).

Example 8 Me'sylic acid (31()-dihydroergotoxy 7100
A liniment agent was obtained by dissolving m9 in 30 ml of N-methylpyrrolidone f. In addition, the content of mesylic acid [3I]]-dihydroergotoxin in the obtained or niment agent is 1
20m9/4. It was OmOi/ml.

An example of a transdermal absorption experiment of the transdermal absorption preparation of the present invention is shown below.

Test Example 1 Transdermal Absorption Experiment The skin on the backs of four rats was removed, and the poultice of Example 3 was applied. 4 hours and 8 hours after administration.

24 hours, 48 hours, 72 hours, 96 hours, 12019
200 μt of each blood was collected at 1 hour, 144 hours, and 168 hours. The obtained blood was treated with ethanol and then centrifuged at 300 Orpm for 5 minutes. The concentration of dihydroergotoxin in the blood was determined by measuring the amount of isotope in the supernatant using a liquid scintillation counter. Figure 1 shows the average blood dihydroergotoxin concentration over time for four rats.

Test Example 2 Administrative Area Dependency Test for Percutaneous Absorption The dorsal skin of four rats was removed, and 30 μt of Nimento obtained in Example 8 was applied to the dorsal skin of each group of rats (2X 2) Coated on an area of cJ or (2×4) cd. 4 hours after administration.

8 hours, 24 hours, 48 hours, 72 hours, 96 hours.

At the elapse of 120 hours, 144 hours and 168 hours,
200 μt of each blood was collected. The obtained blood was treated with ethanol and then centrifuged at 3000 rpm for 5 minutes. The average concentration of dihydroergotoxin in each group in the blood was determined by measuring iso) 7'i of the obtained supernatant using a liquid scintillation counter. Figure 2 shows the time course of the concentration of dihydroergotoxin in each blood.

Effects of the Invention The transdermal absorption preparation of the present invention can be used to treat cerebral arteriosclerosis (9), which is an indication for dihydroergotoxine, and to treat accompanying symptoms of head trauma sequelae.
When used for neurotransmission dysfunction, psychosomatic symptoms associated with senile bisexual brain dysfunction, hypertension, and peripheral circulation disorders, the following effects are expected:

First, with the conventional technology, it was necessary to take the drug three times a day for a long period of time, but the present invention surprisingly shows a constant and sustained blood concentration for more than a week. A sufficient therapeutic effect can be expected when applied to patients.

Second, the transdermal absorption membrane Wi of the present invention does not temporarily release high concentrations of dihydroergotoxin into the body, so the blood concentration does not rise excessively. Therefore, the percutaneous absorption preparation of the present invention has the advantage that side effects are unlikely to occur.

Thirdly, unlike orally administered preparations, the percutaneous absorption preparation of the present invention can avoid the first passage through the liver; therefore, the active ingredient absorbed into the body from the percutaneous absorption preparation of the present invention is 1. Not easily metabolized 3.Fourthly: 1. The transdermal absorption preparation of the present invention continuously supplies the active ingredient into the body, making it possible to reduce the number of administrations. Therefore, problems such as patient non-compliance with taking medication can be avoided.

As described above, the transdermal preparation of the present invention is extremely useful, as it has excellent advantages that conventional dihydroergotoxin preparations cannot have.

[Brief explanation of drawings]

Figure 1 shows the change in blood concentration over time when the transdermal absorption preparation of the present invention containing dihydroergotoxin mesylate was applied to rat skin, and Figure 2 shows the change in blood concentration over time when the preparation for percutaneous absorption of the present invention containing dihydroergotoxin mesylate was applied to the skin of a rat. 2 shows the relationship between the absorption amount and application area in rats of the transdermal absorption preparation of the present invention.

Claims (4)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a benzyl group, isopropyl group, isobutyl group, or sec-butyl group.) Compounds or their A transdermal absorption preparation characterized by containing a pharmaceutically acceptable salt as an active ingredient, either alone or in the form of a mixture in any combination. (2) A compound in which R is a benzyl group in the general formula (I), R
is an isopropyl group, a compound where R is an isobutyl group, and a compound where R is a sec-butyl group are approximately 3:3:2:1
2. The transdermal absorption preparation according to claim 1, which contains as an active ingredient a mesylate in a mixture having a weight ratio of . (3) A patent claim characterized in that the compound of general formula (I) or a pharmaceutically acceptable salt thereof is contained in a pharmaceutical base alone or in the form of a mixture in any combination using a solubilizing agent. The transdermal absorption preparation according to scope 1. (4) A compound in which R is a benzyl group in the general formula (I), R
is an isopropyl group, a compound where R is an isobutyl group, and a compound where R is a sec-butyl group are approximately 3:3:2:1
2. The percutaneously absorbable preparation according to claim 1, wherein the mesylate of the mixture constituted by weight ratio is contained in the preparation base using a solubilizing agent.