WO2003094917A1

WO2003094917A1 - Vintoperol-containing medicinal composition for transdermal administration

Info

Publication number: WO2003094917A1
Application number: PCT/JP2003/005867
Authority: WO
Inventors: Minoru Iwatsu; Isao Serizawa; Junko Yamada; Hiroki Takada; Masuo Murakami; Taku Ito
Original assignee: Takata Seiyaku Co., Ltd.
Priority date: 2002-05-13
Filing date: 2003-05-12
Publication date: 2003-11-20
Also published as: AU2003235931A1; JPWO2003094917A1

Abstract

It is intended to provide a vintoperol-containing medicinal composition characterized by exhibiting its effect over a long period of time without any side effect, being easily administered while giving no pain to patients and being free from the first-pass effect. To treat peripheral circulatory disorders, this medicinal composition is transdermally administered to mammals (including humans) having such a disease. Because of having an effect of elevating the oxygen concentration in a tissue, the composition is also usable in relieving tiredness.

Description

Description Pharmaceutical composition for transdermal administration containing binturol

Technical field

TECHNICAL FIELD The present invention relates to a pharmaceutical composition for transdermal administration, which comprises binturol. More specifically, the present invention relates to a pharmaceutical composition for percutaneous administration containing binturol having a peripheral circulation improving effect.

Background art

Focus Perono Rema, Formula (I)

It has a peripheral vasodilatory effect, an antiplatelet aggregation effect, and an erythrocyte deformability improving effect. Antagonistic action, anti-serotonin action and weak calcium antagonistic action have been confirmed as the mechanism of action (for example, see US Pat. No. 4,806,545 and Japanese Patent Publication No. 50-1518). 98). In addition, the effects of increasing arterial blood flow using anesthetized dogs, increasing the maximum mileage using mice, inhibiting platelet aggregation in mice, effecting on arterial thrombotic models, and prolonging life in pulmonary artery thrombotic occlusion models have already been published. (For example, Japanese Patent Application Laid-Open No. 61-2498986, Arzneim.-Forsch./Drug Res. 41. (1). 6. 621-625 (1991) and Arzneim.-Forsch./Drug Res. 44. (1). 1. 36-40 (1994)).

All these effects were confirmed by oral or intravenous administration (see Arzneim.-Forsch. / Drug Res. 44. (1). 1. 36-40 (1994))医薬 There was no known pharmaceutical composition for transdermal administration using a roll.

On the other hand, the general route of administration of peripheral circulation improving agents is usually oral or injection. In many cases, and the administration often takes a long time, an undesired effect may be exerted by administration by these administration methods. In addition, injections can be painful for the patient.

In recent years, the number of patients with peripheral circulatory disorders has been on the rise, and is expected to increase in the future.Therefore, administration by injection is preferable from the viewpoint of patient QOL (Quality of Life). is not.

In recent years, the development of pharmaceutical compositions for transdermal administration has been actively promoted due to the following advantages. That is, in the pharmaceutical composition for transdermal administration,

1. Because the drug absorbed in the body does not pass through the liver in the first circulation, the drug absorbed in the intestine circulates directly to the liver and undergoes metabolism as in the case of oral administration, and if its drug efficacy declines, it is likely to be lost. There are few disadvantages.

2. Patients have less mental burden and physical discomfort than injections, and do not require human resources such as doctors and nurses for administration.

3. It is easy to maintain blood or tissue concentration at the required level for a long time, and continuous administration can be performed for a long time.

4. Administration can be easily interrupted if necessary.

It has such advantages.

Based on the above, it is extremely medically beneficial to develop a formulation for percutaneous administration of binperol, a therapeutic agent for peripheral circulatory disorders. Disclosure of the invention

It is an object of the present invention to provide a vintrono erythrin characterized by its long-lasting action, no side effects, easy administration, no pain to the patient, and no first-pass effect. An object of the present invention is to provide a pharmaceutical composition for dermal administration.

The inventors of the present invention have conducted intensive studies to obtain a pintoperono-containing preparation for the purpose of solving the above problems, and as a result, have obtained an ideal preparation for transdermal administration that overcomes the drawbacks of injections and oral preparations. I found that.

In other words, the pharmaceutical composition for transdermal absorption of the present invention has no drawback that its medicinal efficacy is reduced since the vintrol is absorbed from the skin and does not receive the first-pass effect. Sa Furthermore, the pharmaceutical composition for percutaneous absorption of the present invention has a lower mental burden and physical distress to patients than injections, and can easily maintain blood levels at required levels for a long period of time. Continuous dosing is possible and can be easily interrupted if necessary. The present inventors have found that a preparation having these characteristics can be obtained, and have completed the present invention. In a first embodiment of the present invention, there is provided a pharmaceutical composition for percutaneous administration, which comprises bintrol and a carrier suitable for transdermal absorption. In a preferred embodiment, there is provided a pharmaceutical composition for transdermal administration for treating peripheral circulatory disorders. In a particularly preferred embodiment, a method for treating obstructive arteriosclerosis, Baja disease, diabetic microangiopathy, vasculitis, Reino disease, cold limbs, deep vein thrombosis and Z or intermittent claudication. A pharmaceutical composition for administration to the skin is provided.

In another embodiment of the present invention, there is provided a pharmaceutical composition for percutaneous administration containing binperol for increasing oxygen concentration in lower limb tissues of mammals (including humans). In a further embodiment, there is provided a pharmaceutical composition for percutaneous administration containing bintoperonole for increasing oxygen concentration in lower limb tissue of a mammal to treat intermittent claudication, inactive atrophy or disuse muscular atrophy. In another embodiment, there is provided a pharmaceutical composition for percutaneous administration of Vinturow / ^ for increasing oxygen concentration in lower limb tissue of a mammal to improve fatigue.

In a further aspect of the present invention there is provided a method of treating a disease comprising peripherally circulating a mammal (including a human) suffering from a peripheral circulatory disorder, comprising transdermally administering a therapeutically effective amount of a pharmaceutical composition of the present invention. In a preferred embodiment, the pharmaceutical composition of the present invention is administered in an amount of from 0.01 to: L Omg / kg, preferably from 0.01 to lmg / kg, per kg body weight of the mammal in terms of the weight of bintopelol. It is administered transdermally in an amount. Considering the rate of absorption of the pharmaceutical composition of the present invention from the skin, the pharmaceutical composition of the present invention has a skin area of about 1.1111 to ⁵ mg per bin in the weight of binperol. Is administered.

In another embodiment, there is provided a pharmaceutical composition for transdermal administration according to the present invention, wherein a blood concentration of bintrol in a mammal of 0.01 ng ZmL l μg / h is achieved. In still another aspect, the present invention provides a method for preparing a pharmaceutical composition for transdermal administration. The use of Vintrol in the construction is provided. As used herein, the term “peripheral circulatory disorder” has the same meaning as commonly used in the art. The term "peripheral circulatory disorders" as used herein includes, for example, obstructive arteriosclerosis, Baja disease; organic arterial diseases such as diabetic microangiopathy and vasculitis; Reino disease and limbs. Vascular dysfunction such as chills; disorders such as deep vein thrombosis; including, but not limited to, intermittent claudication, inactive atrophy and disuse muscular atrophy.

As used herein, the term "carrier suitable for transdermal administration" is used for transdermal administration by tape, haptic, ointment, cream, gel, lotion, spray or the like. Means a possible carrier. Intermittent claudication is unknown in Japan. The exact frequency is unknown in Japan. In Western countries, it is observed in about 5% of elderly people and the following (i) and (ii):

(i) fatigue and pain in lower limb muscles caused by walking exercise at a certain distance makes walking difficult;

(ii) Pause for a few minutes to a few + minutes alleviates the symptoms and allows walking again;

A condition in which the two symptoms are repeated. One of the causes is that the blood volume required during muscle exercise is relatively decreased due to vascular diseases such as obstructive arterial sclerosis, obstructive thromboangiitis, aortitis syndrome, Behcet's disease, and collagen disease ( That is, tissue oxygen saturation decreases), metabolites such as lactic acid accumulate, stimulating sensory nerve terminals, and pain makes it difficult to continue walking.

Conventionally, as treatments for intermittent claudication, ventoxifylline, which has the effect of improving erythrocyte deformability, and cilostazol, a phosphodiesterase III inhibitor, have been used, but they are not satisfactory. Absent. This is due to problems with drug evaluation methods, diagnostic methods, and drug efficacy. The conventional evaluation method has the drawback of poor objectivity and reproducibility because it is based on the patient's subjective appeal and the length of walking distance. In addition, as a conventional diagnostic method, blood pressure in the ankle joint using Doppler There is a method to measure the ratio of the blood pressure in the arm, but the value obtained by this method is a value at rest and is not a sufficient method to diagnose the symptoms of intermittent claudication that occurs during exercise.

As described above, it has been difficult to evaluate therapeutic drugs for intermittent claudication. Recently, however, a method for evaluating intermittent claudication by near-infrared spectrophotometry (NIRS) has been developed. Outer meeting journal 5: 5 4 1—5 48, (1996), and Kanazawa University Juzen Medical Association Journal No. 108, Vol. 3, No. 3 60—3700 (1999)). Using the methods described in these documents, the present inventors have also confirmed that the pharmaceutical composition for transdermal administration of the present invention has an effect of increasing the oxygen concentration in tissues (Example 3). 7 and Figure 1).

The peripheral vasodilatory effect of bintoperol has been known, but the fact that bintoperol is effective in treating intermittent claudication is a finding first discovered by the present inventors. It should be noted here that not all drugs with a peripheral vasodilator effect are effective in treating intermittent claudication. This means, for example, that antiplatelet drugs, vasodilators (sympathetic nervous system blockers), direct acting vasodilators, 2 agonists, calcium antagonists, angiotensin converting enzyme inhibitors) Reported as a drug with very low or no efficacy for sexual claudication (Diagnosis and treatment guidelines for arteriosclerosis obliterans in lower limbs, edited by The Japanese Vascular Society, vol. 31, No. 1, Part 2 , P. 92-98) and reports that the selective serotonin antagonist ketanserin, which has vasodilator and antiplatelet properties, was ineffective in treating intermittent claudication (Id.) Will also be understood. On the other hand, the mechanism of fatigue is explained as follows. In other words, muscle contraction occurs when myosin, which forms a thick filament, hydrolyzes adenosine triphosphate (ATP) and changes the way it interacts with actin, a thin filament. Therefore, the chemical energy of muscle contraction is supplied by ATP. Glycogen and pudose present in muscle, when supplied with sufficient oxygen, follow the glycolysis system and are oxidized in the TCA cycle to eventually become carbon dioxide and water, releasing large amounts of energy . If oxygen supply is not sufficient, only glycolysis Progresses, accumulating lactic acid, preventing further degradation of glycogen and weakening the contractile force. This is what is called muscle fatigue.

In fact, it is known that lactic acid in muscle increases significantly in response to a decrease in blood flow (Kyoto Medical Journal 104 (8), 899-913, 1995). Lactic acid produced in the body enters the blood from muscles, is reduced by being transported to the liver and converted to glycogen, and with this, fatigue is improved. Cost. In addition, conventional pharmaceuticals and health foods are not considered to have a sufficient effect on improving fatigue. Other than fatigue, illnesses such as pain from pain and functional muscle atrophy (inactive or disuse atrophy) that occur when the primary activity is restricted or stopped for other reasons. It has been reported that the muscular blood flow is clearly reduced in the target state (Kyoto Medical Journal 104 (8), 899-913, 1995). In any case, reduced blood flow is detrimental to muscle function, and maintaining high blood flow is a necessary condition for maintaining or improving muscle function.

In other words, in order to improve fatigue, it is necessary to suppress the accumulation of lactic acid in muscle by promoting the progress of glycolysis and the subsequent turnover of the TCA circuit. In addition, a short window of lactic acid accumulated due to fatigue reduces the time required to improve fatigue. Increasing blood flow in muscle tissue facilitates these improvements in fatigue. Various toxicity tests have been conducted on binperol used in the present invention. For example, the results of a single dose toxicity test by oral administration using rats (LD ₅₀ ) are 78 lmgZkg for female rats and 897 mg / kg for male rats, and these values are those of the present invention described above. It greatly exceeds the dose of the pharmaceutical composition (ie, 0.01 to 10 mg / kg, preferably 0.01 to LmgZkg). Therefore, it can be said that Vintourol is an extremely safe drug from these results. Further, as described above, since the pharmaceutical composition containing binturol of the present invention is absorbed from the skin and causes dilation of peripheral blood vessels and increase in oxygen concentration in tissues, binturol is It can be said that it is an effective drug for peripheral circulatory disorders, especially intermittent claudication. As the active ingredient of the present invention, vintrol, pharmaceutically acceptable salts, solvates and physiologically acceptable equivalents thereof can be used. In addition, the weight% of binperol based on the total amount of the preparation of the present invention was 0.01 weight ⁰ /. To 99.9% by weight, preferably 0.05% to 50.0% by weight, more preferably 0.1% to 25.0% by weight.

The formulation of the present invention may be in any form as long as it can be transdermally administered, and examples thereof include a gel, an ointment, an external solution, a tape, a patch, a spray, a cream, a lawn, a poultice and the like. The dosage form can be used for effective transdermal administration. Further, besides the above, a reservoir type preparation can be prepared. These formulations of the present invention are used for local or systemic effects.

The effective blood concentration of bintrol used in the present invention is found to be approximately 0.01 ng / mL to 1 μg ZmL from the results of various oral administration experiments. On the other hand, the blood concentration by transdermal administration in the present invention is about Olng ZmL to l / g / mL, and the blood concentration showing sufficient drug efficacy is maintained even in the administration form by transdermal absorption. It was confirmed that. Therefore, it can be seen that the use of pintoperol as a preparation for transdermal administration as in the present invention is also useful as a pharmaceutical. The formulation of the present invention is a stable and long-lasting formulation, and is administered by application or application to the arm, foot, etc., and is applied once to several times a day or once to several times a week. Or, it is expected that by applying it, it is easy to apply, high in safety, and stable drug efficacy can be obtained.

The pharmaceutical composition for transdermal administration of the present invention is manufactured by a general method known to those skilled in the art. For example, a solution for external use can be obtained by dissolving bintotrol in a solvent such as propylene glycol and then adding a transdermal absorption enhancer such as oleic acid and other additives as necessary.

As a method for producing a gel preparation, a process such as dissolving vintrol in a solvent such as ethylene glycol, adding a gelling agent such as an aqueous solution of carboxymethylcellulose sodium, and stirring the mixture until it becomes uniform is used. A formulation can be obtained. In addition, other gel manufacturing methods known in the art may be used.

In addition, tape preparations are prepared by dissolving Vintrol in solvents such as propylene glycol. After dissolving, add oleic acid and methyl atalinoleate as needed, add ethoxylate copolymer resin emulsion to allylic acid-2-ethyl ester to form a mixed solution of the adhesive, and put an appropriate amount of the above mixed solution on PET film etc. After uniformly spreading and drying, the tape can be obtained by a process such as cutting to a required size.

Further, other dosage forms can be produced by a general method known to those skilled in the art.

The formulation of the present invention may contain, if necessary, formulation additives that can be used, such as solvents, preservatives, humectants, preservatives, tackifiers, solubilizers, flavoring agents, coloring agents, pH regulators or A surfactant or the like may be added.

Examples of the solvent include, but are not limited to, water, ethanol, glycerin, propylene glycol, and isopropanol.

Examples of preservatives include phenolic substances such as paraoxybenzoate, phenol and cresol; neutral substances such as chlorobutanol, phenylethyl alcohol and propylene glycol; Inverse stones such as zezetium; acidic substances such as benzoic acid (sodium), sorbic acid, dehydroacetic acid (sodium), and salicylic acid can be used, but are not limited thereto.

The type of pH adjuster may be any as long as the preparation can be adjusted to an appropriate pH range, and is not particularly limited to the following. Inorganic salts such as hydrochloric acid, sodium hydroxide, and potassium hydroxide may be used. pH adjusters, acetic acid, lactic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, adipic acid, salicylic acid, and other organic acids or salts thereof.One or more of these may be used in combination. Alternatively, a combination having a buffering action using an acidic pH adjuster and a basic pH adjuster may be used. In addition, for the purpose of improving the usability, additives that are commonly used in external preparations such as surfactants, urea, methyl salicylate, clostamitol, and menthol may be added.

In addition, ethanolamine, diethanolamine, triethanolamine and the like can be added to increase the thermodynamic activity of the drug in the matrix and to improve the distribution-absorption to the skin. Any of these may be used as long as they are used for pharmaceutical production. In addition, a transdermal absorption enhancer can be used if necessary. As the f 圣 skin absorption enhancer, those known per se can be used. Preferably, alcohols, amides, sulfoxides, organic acids, luster esters, lower ketones, natural moisturizing factors (NMF), Azone ™, cyclodextrins, terpenes and surfactants It is at least one or more selected from, but not limited to. Furthermore, it is also within the scope of the present invention to incorporate a pore opening agent such as, but not limited to, benzyl nicotinate, as a percutaneous absorption enhancer in a broad sense.

The “alcohol” is a compound having one or more hydroxy groups, and has 1 carbon atom.

Up to 30 or more. Suitable alcohols include ethanol, isopropanolone, otatanol, laurinoleanolecole, cetinoleanorecoleno, oleinoleanoleconole, glycerin, propylene dariconeole, polyethylene glycolonele, polypropylene propylene glycol, benzyl alcohol or cholesterol 1 Not limited to these.

The “amide” may be cyclic or non-cyclic. The nitrogen atom of the amide group can be unsubstituted or substituted with an alkyl or alkaryl group of 1 to 14 or more carbon atoms. Suitable amides include dimethylformamide (D

MF), N, N-dimethylacetamide, dimethyllaurylamide, 2-pyrrolidone, 1-methyl-12-pyrrolidone (NMP), 5-methyl-12-pyrrolidone, 1,

5-dimethinolepyrrolidone, 1-ethynolei 2-pyrrolidone, 1-methinole 2-pyridone, 11- (2-hydroxyethylenole) -2-pyrrolidone, crotamiton or N, N-jetyl-m But not limited to toluamide. The “sulfoxide” is a compound in which two alkyl groups having 1 to 30 or more carbon atoms are each independently bonded to a sulfur atom. Sulfoxides include, but are not limited to, dimethylsulfoxide (DMSO), decylmethylsulfoxide or octylmethylsulfoxide. It also includes sulfoxide derivatives.

The "organic acid" is a group consisting of monocarboxylic acid, dicarboxylic acid, and alkyl sulfuric acid. Selected from Suitable monocarboxylic acids include substituted or unsubstituted salicylic acid or benzoic acid, cabronic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, isopalmitic acid, stearic acid, isostearic acid, a Laquinic acid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, eric acid, docosahexaenoic acid, tetracosenoic acid, hyaluronic acid and lactic acid, and Pharmaceutically acceptable salts include, but are not limited to. Further, thioglycolic acid or a pharmaceutically acceptable salt thereof can also be used. Suitable dicarboxylic acids include oxalic acid, maleic acid, malic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, sebacic acid, phthalic acid, isophthalenoic acid and terephthalic acid, and the like. Includes, but is not limited to, pharmaceutically acceptable salts. Also, sodium lauryl sulfate and sodium dodecyl sulfate can be used.

The “fatty acid ester” is an ester of an alcohol having 1 to 6 hydroxy groups. The fatty acid portion of the “fatty acid ester” is a straight or branched chain saturated or unsaturated mono- or dicarboxylic acid having 4 to 20 carbon atoms. "The alcohol portion of fatty acid ester J has 1 to 18 carbon atoms and is a straight or branched chain saturated or unsaturated alcohol. A preferred fatty acid ester is isopropyl myristate (IPM) Isopropyl palmitate, getyl sebacate and lecithin.

The above “lower ketone” has the general formula

R ^ OR ²

(Here, R ¹ and R ² each independently have 1 to 10 or more carbon atoms and are a linear or branched saturated or unsaturated hydrocarbon group.)

It is represented by Suitable lower ketones include, but are not limited to, acetone and methylethyl ketone.

The above-mentioned "natural moisturizing factor (NMF)" is a substance that exists in the skin and has a moisturizing action. Suitable natural moisturizing factors are urea or its derivatives (eg, thiourea, allantoin, etc.), as well as pyrrolidone carboxylic acid. The "A zone (TM) s" is unsubstituted or C E ₅ - alkyl or Putan 2-one to substituted Azashiku port at an alkenyl. Suitable A zone (TM) s, A _Z one (TM) [chemical name: 1 one Dodeshiruazashiku port heptane one 2 one On, 1 Geraniruazashiku port heptane one 2-one, 1- Fuaruneshiruaza consequent opening heptane - 2 On or 1-methylazasik heptane 2-on (N

—Also known as methylcaprolatatam).

The “cyclodextrin (CyD)” is selected from the group consisting of α, | 3 and γ-CyD, and derivatives thereof. Preferred cyclodextrins are β-CyD, dimethyl-j3-CyD, and trimethinole-CyD.

As the above “surfactant”, a nonionic surfactant, an aionic surfactant, a cationic surfactant, an amphoteric surfactant and the like can be used.

The above “terpenes” are preferably monoterpenes or triterpenes. Particularly preferred tenolepenes are limonene, menthol, cineole, perilla aldehyde and perilla alcohol, carvone, menthone, piperidone, squalane or squalene.

Any of the above-mentioned percutaneous absorption enhancers may be used as long as it is used in the production of pharmaceuticals, and two or more of these percutaneous absorption enhancers may be used in the present invention. The percutaneous absorption enhancer can be used, for example, in the range of 0.001 to 99.9% by weight of the total amount of the preparation. The base of the tape preparation used in the present invention may be any base used in a pharmaceutical composition for transdermal administration, such as silicone oil, petrolatum, plastibase, liquid paraffin, lanolin, various vegetable oils, A / coal-based, glycol-based, pressure-sensitive silicone adhesive, silicone rubber, styrene-isobutylene-styrene block copolymer rubber, polyisoprene rubber, polyisobutylene rubber, styrene-butadiene rubber, petitnole rubber, Natural rubber, poly (vinylinoleanol acrylate), poly (meth) acrylate, polyurethane, polyamide, ethylene acetate-vinyl copolymer, alkyl acrylate-acrylic acid copolymer, hydroxypropyl Cellulose or a mixture of two or more of these. Preferably, a silicone oil, a pressure-sensitive silicone adhesive, a silicone rubber, a natural rubber, a poly (meth) atalylic acid-based adhesive, or a mixture of two or more thereof are used. In the case of a tape or the like, the support (backing) is desirably a material that does not cause a decrease in the content of vinyl perforation or the like without being lost from the back surface, that is, the surface not in contact with the skin. For example, cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene monobutyl acetate copolymer, plasticized polyvinyl chloride, polyester, polypropylene, polyurethane, polyethylene, polyvinylidene chloride or Examples thereof include a single film such as a metal foil such as an anolemminium, and a laminated film thereof, but are not limited thereto, and those generally used as a tape agent can be used.

Further, as the adhesive, a rubber-based adhesive, an acrylic-based adhesive, a silicone-based adhesive, gelatin, or the like can be used. Elastomer components of the rubber-based adhesive include gum arabic, natural rubber, polyisoprene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and styrene-ethylene rubber. Tylene-styrene block copolymer and the like. One component of the elastomer of the acrylic pressure-sensitive adhesive is, for example, poly (meth) acrylate, atalylate-atalylic acid copolymer, poly (meth) atalylamide, polydimethyl (meth) acrylamide, poly-N-butyl Acrylamide, poly-N-methylol (meth) acrylamide. One elastomer component of the silicone-based pressure-sensitive adhesive is, for example, polydimethylsiloxane. Further, tackifiers such as rosin, hydrogenated rosin and esters thereof, polyterpene resin or phenol resin; softeners such as process oil, polyisobutylene, liquid paraffin, lanolin, vaseline or various vegetable oils; zinc white, titanium oxide, silica, Fillers such as aluminum hydroxide, calcium carbonate, barium sulfate or talc can also be added. In the case of gels and ointments, the base is Any pharmaceutically acceptable esters can be dissolved and pharmaceutically acceptable. For example, those known in the art as bases for ointments, creams, jellies, pastes, lotions, and the like can be used. Particularly, polymers, colloid-containing silicate metal-earth minerals, oils and fats, hydrocarbons, polyhydric alcohols, At least one selected from the group consisting of higher fatty acids (preferably having 6 to 32 carbon atoms), higher alcohols (preferably having 12 to 30 carbon atoms), lower alcohols and water; Is preferably a yarn composition containing them. For example, sodium alginate, gelatin, corn starch, tragacanth gum, methinoresenorelose, hydroxyxetinoresorenose, hydroxypropinolecellulose, carboxymethinoresenorelose, canoleboki simethinoresenorelose sodium, dextrin , Canolepoxymethyl starch, Polyvinyl alcohol, Ottatyl dodecanol (Lisonol 20SP), Polyataryl acid, Polyacrylic / relate (eg sodium salt), Methoxyethylene maleic anhydride copolymer, Polybier ether, Poly Vininolepyrrolidone, polyacrylamide, biacetate acrylate multipolymer (trade name: GEL VA 788), ethylene ■ vinylinoleate copolymer (trade name: Evaflex 45X), Styrene '' isoprene '' Colloidal hydrous aluminum silicate minerals such as styrene block polymer (trade name: Clayton D-1107CP), kaolin, bentonite, etc. Colloidal hydrous magnesium silicates such as veegum '' Aluminum minerals, beeswax, olive oil, cocoa butter , Sesame oil, soybean oil, camellia oil, laccase oil, tallow, lard, lanolin, petrolatum, paraffin, liquid paraffin; glycols such as ethylene glycol, polyethylene glycol, propylene glycol, and polypropylene glycol; capric acid, nonanoic acid , Caprinoleic acid, pendecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, oleic acid, nonadecanoic acid, arachidonic acid, linoleic acid, Saturated or unsaturated fatty acids such as henic acid, lignoceric acid, cerotic acid, heptacosanoic acid, palmitoleic acid, vaccenic acid, and linolenic acid; lauryl lanolechol, dodecyl anolenole, myristinole alcohol, pentadecinole alcohol, cetinole alcohol Alcohol, Hexadecyl alcohol, Heptadecyl alcohol, Stearyl alcohol, O Reynoreanolecole, Nonadecylanorecole, Eicosyl alcohol, Serinoleanol And alcohols such as coal and melisil alcohol.

Various variations and Z or variations may be made without departing from the scope of the invention, which are within the skill of those in the art. (Advantageous effect than before)

According to the present invention, the action is long-lasting, has no side effects, is easy to administer, does not cause pain to the patient, and is not affected by the first-pass effect, peripheral vasodilatory action, anti-platelet aggregation action, and erythrocyte deformability Provided is a pharmaceutical composition for percutaneous administration containing binperol having an improving effect. Further, as shown in FIG. 1, since the oxygen concentration in the tissue increases, it can be seen that the pharmaceutical composition of the present invention also has an effect of improving fatigue. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph comparing “recovery time” between the placebo group and the transdermal administration group. One day after administration, the “recovery time” of the dermal administration group was significantly shorter than the “recovery time” of the placebo group (P <0.05). BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be specifically described based on examples. The examples are used for illustratively explaining the present invention, and are not intended to limit the technical scope of the present invention. Formulation Example 1: Production of tape preparation

Vintperol, 1-methyl-1-pyrrolidone (NMP), Bull acetate atalyate multipolymer (trade name: GEL VA7788) and ethylene / butyl acetate copolymer (trade name: Evaflex 45) After weighing X), add toluene and stir evenly to prepare a tape preparation solution. Next, a PET film is prepared as a packing layer, a polypropylene cylinder is adhered thereto, and an appropriate amount of the above-mentioned tape agent solution is dropped therein and spread evenly. Keep in equilibrium, dry at 60 ° C for 3 hours, Prepare a preparation.

Mixing ratio (the same applies hereinafter)

Bint ぺ one mouth 30.8 parts by weight

NMP 308.2 weight parts

GE L VA 25 1.2 weight parts

409.8 weight parts

00.0 parts by weight Formulation example 2:

Bint Peronolle, NMP, Styrene / Isoprene 'Styrene block polymer (Craton D_1107CP), terpene resin, polyisobutylene (Butyl rubber (4H)), liquid paraffin and glycyrrhetinic acid. Stir to prepare a tape solution and obtain a tape in the same manner as in Formulation Example 1.

Vintroll 13.0 parts by weight

NMP 25 9.8 parts by weight

Glycyrrhetinic acid 13.0 parts by weight

Clayton 455.5 parts by weight

Terpene resin 1 29.9 parts by weight

Liquid paraffin 64.9 parts by weight

Petil rubber 64.9 parts by weight

100.0 parts by weight Formulation example 3

After weighing Vintorol, NMP, isopropyl myristinoleate, liquid paraffin, petinole gum, tenolepene resin, Clayton and glycyrrhetinic acid, add toluene and stir evenly to prepare a tape agent solution. To obtain a tape. Vintroll 12

NMP 243, 8 parts by weight Isopropyl myristylate / le 61 0 parts by weight Glycyrrhetinic acid 1 2

Clay Ton 426

Terpene resin 122.0 parts by weight 流動 Liquid paraffin 61.0 parts by weight Butyl rubber 61.0 parts by weight

000.0 parts by weight Formulation example 4

A tape is prepared according to the following formulation in the same manner as in Formulation Example 3 ₍ bintopelol 16 1 part by weight isopropyl myristylate 80 6 parts by weight glycyrrhetinic acid 16 1 part by weight Clayton 564 5 parts by weight Terpene resin 161

Liquid paraffin 80 7 parts by weight Butyl rubber 80

000.0 parts by weight Formulation example 5

Prepare a tape with the following formulation in the same manner as in Formulation Example _3.c Bint Peronore 20.9 parts by weight

NMP 261.5 parts by weight

Glycyrrhetinic acid 20, 9 parts by weight

Evaflex 435.2 parts by weight

Liquid paraffin 87.9 parts by weight

Silicon resin 1 73.6 parts by weight

100.0 parts by weight Formulation example 6

Prepare a tape with the following formulation in the same manner as in Formulation Example _3.c

Bint Peronore 40.9 parts by weight

Lisonol 20SP 409.0 parts by weight

GE L VA 208.6 parts by weight

S 341,

000.0 parts by weight Formulation example 7

A tape is prepared in the same manner as in Formulation Example 3 using the following formulation.

Vintroll 29.0 parts by weight

NMP 290.3 weight parts

Lithonol 20SP 290.3 weight parts

GE LVA 148.0 parts by weight

Evaflex _ 242.4 parts by weight

100.0 parts by weight Formulation Example 8: Production of gel

Add NMP to the specified amount of Vintrol and dissolve the Vintrol. Next, oleic acid, propylene glycol (PG) and hydroxypropyl cellulose (HPCH) are added, respectively, and the mixture is stirred until HPCH is uniformly dispersed. Sa Then, add purified water and isopropanol, stir until the mixture is evenly gelled, and prepare a gel.

Binto

HPC-H 30, 0 parts by weight

NMP 20.

Propylene dalicol 200, 0 parts by weight

Oleic acid 6.0 parts by weight

Isopropanol 600

purified water

000 Prescription example 9

Add NMP to the specified volume of Vintrol and dissolve the Vintrol. Next, each of isopropyl myristylate, concentrated glycerin, and hydrophobized hydroxypropyl methylcellulose (trade name: Sangelose 90L) is added, and the mixture is stirred until 90 L of sangelose is uniformly dispersed. Further, add purified water and disperse it, and stir until it gels uniformly to prepare a gel.

Vintroll 5.0 parts by weight

Sanjiroose 90L 20.0 parts by weight

O P 20.0 parts by weight

Isopropyl myristinoleate 10.0 parts by weight

Glycerin 10.0 parts by weight

Isopropanol 400.0 parts by weight

purified water

100.0 parts by weight Formulation example 10

Add oleic acid, polyethylene glycol monooleate (MOP EG) and 90 L of San Jellose to a predetermined amount of Vintrol, Stir until the dispersion is uniform. Further, add purified water and disopropanol and stir until gelation is uniform to prepare a gel.

5.0% by weight

Sangelose 90 L 10.0 parts by weight

10.0 parts by weight

Punoleronic F 68 10, 0 parts by weight

MOPEG 10.0 parts by weight

Isopropanol 400.0 parts by weight

purified water

000.0 parts by weight Formulation example 11

Lauryl alcohol and carboxybutyl polymer in a given amount of vinyl

After adding Carbopol # 941 (trade name), purified water and isopropanol are added with stirring, and finally, triethanoylamine is added, and the mixture is stirred until the mixture is evenly mixed to prepare a gel.

Bint ぺ mouth one hole 5.0 parts by weight

Carbo Ponore # 941 10.0 parts by weight

Lauryl alcohol 10.0 parts by weight

Triethanolamine 10.0 parts by weight

60.0 parts by weight of purified water

Isopropanol

000.0 parts by weight Formulation example 12

After adding menthol, limonene and carboponol # 941 to a predetermined amount of Vintrol, respectively, add purified water and isopropanol with stirring, and finally add triethanolamine and stir until uniform gelation. obtain. Bint ぺ mouth one hole 5.0 parts by weight

Carbo Ponore # 941 10.0 parts by weight

Limonene 5.0 parts by weight

5.0 parts by weight

Triethanolamine 10.0 parts by weight

Isopropanol 400.0 parts by weight

purified water

000

Formulation Example 13: Production of ointment

An ointment is obtained by adding isopropyl myristate and dextrin palmitate (trade name: Leopard) to a predetermined amount of bintrol and heating to about 60 ° C with stirring. Bint Peronore 10.0 weight parts

Leopard 50.0 parts by weight

Isopropyl myristylate

1000.

Formulation example 14

An ointment was obtained according to the following formulation in the same manner as in Formulation Example 13.

Vintroll 10.0 parts by weight

Leopard 50.0 parts by weight

NMP 20.0 parts by weight

Isopropyl myristylate qs

Oleic acid-12.0 parts by weight

100.0 parts by weight Formulation example 15

_T Bint Bae roll 10.0 parts by weight in the same manner as in Formulation Example 13 to obtain an ointment with the following composition

Liquid paraffin 30.0 parts by weight

Setano Nore 20.0 parts by weight

Sodium lauryl sulfate 5.0 parts by weight

NMP 20.0 parts by weight

Isopropyl myristylate 30.0 parts by weight

Oleic acid 10.0 parts by weight

purified water

000.0 parts by weight

Formulation Example 16: Liquid preparation method

By stirring NMP was added to Bint Bae roll, _c Bintopero ^ "Le 24.4 parts by weight to obtain a liquid formulation

NM P _ 975.6 parts by weight

100.0 parts by weight Formulation example 17

A liquid formulation is obtained in the same manner as in Formulation Example 16 with the following formulation.

Vintroll 47.6 parts by weight

NMP 952.4 parts by weight

000.0 parts by weight Formulation example 18

A liquid formulation is obtained in the same manner as in Formulation Example 16 with the following formulation. 5867

twenty two

Vintroll 90, 9 parts by weight

NMP 909,

000.0 parts by weight Formulation example 19

Vintroll 166.7 parts by weight

N P _ _ 833.3 weight parts

Total amount 100.0 parts by weight Formulation example 20

45.5 parts by weight

NMP 909.0 weight parts

Isopropyl myristylate 45.5 parts by weight

000.0 parts by weight Formulation example 21

A liquid formulation is obtained in the same manner as in Formulation Example 16 with the following formulation. Vintroll 45.5 parts by weight

NMP 909.0 weight parts

Oleic acid 45.5

100.0 parts by weight

Prescription example 22

_C to obtain a liquid formulation with the following formulation in the same manner as in Formulation Example 16 Bint Peronore 45.5 parts by weight Isopropinole myristylate 45.5 parts by weight Crotamiton 909.0 parts by weight

000.0 parts by weight Formulation example 23

Vintroll 45, 5 parts by weight

NMP 909.0 parts by weight Methanesulfonic acid 45.5 parts by weight _

100.0 parts by weight Formulation example 24

A liquid formulation is obtained in the same manner as in Formulation Example 16 with the following formulation. 41.5 parts by weight NMP 909.0 parts by weight

000.0 parts by weight

Formulation example 25

Vintroll 19.6 parts by weight

NMP 490.2 parts by weight

100.0 parts by weight Formulation example 26

_C to obtain a liquid formulation with the following formulation in the same manner as in Formulation Example 16 Bint ぺ mouth-19.6 parts by weight

NMP 490.2 parts by weight Diisopropyl adipate 490.2 parts by weight

100.0 parts by weight Formulation example 27

A liquid formulation is obtained in the same manner as in Formulation Example 16 with the following formulation. Bintpero ^ "Nore 36.7 parts by weight NMP 917.4 parts by weight Squalane 45.9 parts by weight

100.0 parts by weight

Prescription example 28

Vintroll 25.2 parts by weight

NMP 628.9 parts by weight Squalane 31.4 parts by weight Isopropanol-― 314.5 parts by weight Total amount 100.0 parts by weight Formulation example 29

Vintroll 41.7 parts by weight

NMP 1 25.0 parts by weight Isopropyl myristylate 333.3 parts by weight Flowing roughin 500.0 parts by weight

100.0 parts by weight Prescription example 30

Vintroll 38.5 parts by weight

NMP 961. ^^ parts by weight Total amount 1000, 0 parts by weight Formulation example 31

Vintroll 38.5 parts by weight

1-methyl-2-piperidone 961.5 parts by weight

100.0 parts by weight Formulation example 32

Vintroll 38.5 parts by weight

1-ethyl 2- 2-pyrrolidinone 961.

100.0 parts by weight Formulation example 33

Vintroll 38.5 parts by weight

2-pyrrolidinone 961.5 parts by weight Total amount 100.0 parts by weight Formulation examples 34

A liquid formulation is obtained in the same manner as in Formulation Example 16 with the following formulation. Vintroll 38.5 parts by weight

Monomethylpyrrolidine 96 1.

000.0 parts by weight

Formulation example 3 5

Vintroll 3 8, 5 parts by weight

N-methylcaprolatatam 96 1.

000.0 parts by weight Formulation example 3 6

Vintole 38, 5 parts by weight

l- (2-tK.xy-ethyl) -2-pirididone 9 61.5 parts by weight

100.0 parts by weight Based on the above Formulation Example 136, an agent of Example;! 36 is prepared as described in Tables 1, 2 and 3.

Table 1: Formulation of tape preparation (unit: mg)

Table 2 Formulation of ointment (unit: rag)

Table 3 Formulation of liquid formulation (unit: mg)

Table 3 Formulations for liquids (continued)

Example Example Example Example Example Example Example Example 24 25 26 27 28 29 Bint Peronolle 2.5 2 2 2 2 0.625

NMP 50 50 50 50 50 1.875

I PM 5 Radial alcohol 2.5

Otachildel Power Knoll 50

Disop adipate 50

Mouth pinore

Squalane 2.5 2.5

Isopropanol 25

Liquid paraffin 7.5 Total weight "¾ 55 102 102 54.5 79.5 15 Table 3 Formulations for liquids (continued)

Example 1: Skin penetration test

Yucatan minipig (five-month-old, female) cryopreserved skin is sandwiched between Franz-type diffusion cells, the temperature of the receptor layer (pH 7.0 buffered saline solution) is maintained at 37 ° C, and the skin is formulated in the donor layer. Apply the composition of Sampling in 0.5 mL portions over time for 24 hours after application, add 500 μL of the internal standard solution to L mL, and filter through a 0.45 μm pore size membrane filter. Except for the first 0.2 mL, use the next 0.8 mL as the sample solution. The sample solution is quantified by high performance liquid chromatography, and the amount of skin permeation per unit area per unit time and unit area is calculated.

In addition, the quantification of Vintrol is performed under the following conditions.

Precisely weigh approximately 5 mg of Vintrol for quantification, add methanol to dissolve, add methanol to make exactly 10 OmL, and use this solution as the standard stock solution. Accurately measure an appropriate amount of the standard solution, add 0.1 Ol / L phosphate buffer (pH 7.0), dilute accurately, and accurately transfer 500 μL of this solution and 500 μL of the internal standard solution. In addition, prepare standard solutions at concentrations of 1250, 416.7, 138.9, 46.3, and 15.4 ng / mL. You. Perform a test by liquid chromatography under the following conditions using the sample solution and standard solution 50, calculate the ratio of the peak area of Vintorol to the peak area of the internal standard substance, and quantify the amount of Vintorol.

Internal standard solution Methanol solution of butyl paraoxybenzoate (1 → 1000) Operation conditions>

Detection wavelength: 283nm

Column: Develosil ODS HG-5, inner diameter 4.6 ram, length 30 cm

Force ram temperature: constant temperature around 40 ° C

Mobile phase: Mixed solution of acetonitrile and 0.01 mol / L ammonium carbonate (55:45): 1.0 ml / min Example 2 to 36:

Using the compositions of Formulation Examples 2 to 36, quantification is performed in the same manner as in Example 1. The results of Examples 1 to 36 are shown in Table 4 below. Table 4

Table 4 (continued)

Method 1 ゥ Create a model of intermittent claudication of heron The male white heron, weighing 3.0 to 3.2 kg, purchased from Kitayama Labes Co., Ltd., was placed in a conventional breeding room A at Takada Pharmaceutical Research Institute (Temperature 23 ± 2 ° C, humidity 50 ± 10% At relative humidity (RH), ventilation rate of 15 times Zhr, lighting time of 7 to 21 o'clock), students are allowed to freely consume commercially available solid feed and water. Provide a pre-breeding period of at least one week, and only test animals that have no abnormal health condition. Under ketamine + xylazine anesthesia, an incision was made in the groin in a supine position, the femoral artery was exposed, and a balloon catheter for removal of Fogarty's arterial embolus (product number: E-0600-2F) , Size; 2 French, purchased from Baxter Co., Ltd.) 7 cm 揷, and withdraw the balloon in the iliac artery 3 times while inflating it to a diameter of 5 mm. The balloon is inserted 5 cm into the femoral artery, and the balloon is pulled out while being inflated to 5 mm in diameter. Method 2: Evaluation of recovery time after occlusion test using near infrared spectroscopy

Under ketamine and xylazine anesthesia, a proximate near-infrared spectroscopy probe (PSP—20X50, purchased from Biomedical Science Co., Ltd.) was attached directly to the back of the foot in a prone position, and an alternative evaluation method for an exercise load model A possible occlusion test (a disposable manchette for a newborn baby is worn from the stomach of the egret to the vicinity of the ankle, and degassing is performed at 180 to 22 OmmHg for 10 minutes with force tl pressure) ( Cheatle, TR et al .: Near-infrared spectroscopy in peripheral vascular disease. Br. J. Surg. 78: 405-408, 1991 and Myhre HO. Reactive hyperemia of the human lower limb. Vasa 1975; 4: 227). The recovery process of the tissue oxygen saturation that has been reduced during pressurization is measured using a near-infrared spectrometer (PSA-IIIN, purchased from Biomedical Science Co., Ltd.) to determine the recovery time of the tissue oxygen saturation.

(See Therapeutic Research, vol. 16, No. 9, (1995) p. 247-250). 1 Z 2 Recovered tissue, which is the intermediate value between tissue oxygen saturation after occlusion test (minimum tissue oxygen saturation after occlusion test) and tissue oxygen saturation after recovery (maximum tissue oxygen saturation after occlusion test) After obtaining the oxygen saturation, the time required to reach the regenerated tissue oxygen saturation 1/2 the time after the end of the occlusion test is referred to as “recovery time”. Example 3 7

ゥ Eg percutaneous administration test and evaluation of “recovery time”

A model is created by Method 1 using male Japanese white species egrets. In the placebo group (n = 4), an NMP solution containing 4% IPM is applied once daily at 26 / LZkg to the back of a rabbit that has been hair-removed with an electric clipper on the day before model creation. For the dermal administration group (n = 4), dissolve in an NMP solution containing 4% IPM to give lmgZ 26 μL / kg and apply once a day. Evaluation by Method 2 is performed on days 1, 2, 3, and 4 immediately after preparation. On the first day after the preparation, it was confirmed that the “recovery time” of the transdermal administration group was significantly faster than that of the placebo administration group (FIG. 1, P <0.05). Industrial applicability

INDUSTRIAL APPLICABILITY According to the present invention, a pharmaceutical composition for percutaneous administration of vintrol that is skin-permeable and that allows a rapid absorption of vintrol from the skin into the body and maintains an appropriate blood or tissue concentration for a long period of time. Things can be provided. The pharmaceutical composition for transdermal administration of the present invention can be used, for example, for peripheral circulatory disorders, particularly for intermittent claudication. In addition, the pharmaceutical composition for transdermal administration of the present invention has an effect of increasing oxygen concentration in lower limb tissues, and thus can be used for improving fatigue. Further, the present invention also provides a method for treating a mammal (including a human) suffering from peripheral circulatory disorders or the like, which comprises transdermally administering the pharmaceutical composition of the present invention to the mammal.

Claims

The scope of the claims

I. A pharmaceutical composition for percutaneous administration, characterized by containing a vintrol and a carrier suitable for transdermal absorption.

2. The pharmaceutical composition for transdermal administration according to claim 1, for treating a peripheral circulatory disorder.

3. The peripheral circulatory disorder is selected from the group consisting of atherosclerosis obliterans, Baja disease, diabetic microangiopathy, vasculitis, Reino disease, cold feet and feet, deep vein thrombosis and intermittent claudication. 3. The pharmaceutical composition for transdermal administration according to 2.

4. The method of increasing oxygen concentration in a lower limb tissue of a mammal.

2. The pharmaceutical composition for transdermal administration according to 1.

5. The pharmaceutical composition for transdermal administration according to claim 4, for treating intermittent claudication, inactive atrophy or disuse muscular atrophy.

6. The transdermal administration pharmaceutical composition according to claim 4, for improving fatigue.

7. The pharmaceutical composition for transdermal administration according to any one of claims 1 to 6, comprising from 0.01% to 99.9% by weight of Vintrol.

7. The pharmaceutical composition for transdermal administration according to any one of claims 1 to 6, which comprises 8.05% by weight to 50.0% by weight of bintotrol.

9. The pharmaceutical composition for transdermal administration according to any one of claims 1 to 6, wherein the pharmaceutical composition contains 0.1 to 25.0% by weight of bintrol.

10. The pharmaceutical composition according to any one of claims 1 to 9, which is a tape, a haptic, an ointment, a cream, a gel, a lotion, or a spray.

I I. The pharmaceutical composition for transdermal administration according to any one of claims 1 to 10, wherein the carrier suitable for transdermal administration is a transdermal absorption enhancer.

12. Transdermal absorption enhancers include alcohols, amides, sulfoxides, organic acids, fatty acid esters, lower ketones, natural moisturizing factors (NMF), Azone ™, cyclodextrins, terpenes and surfactants 12. The pharmaceutical composition for transdermal administration according to claim 11, which is selected from the group consisting of an agent.

13. Pinto Perot at 0.01 ng / mL to l / ig / mL in mammals The pharmaceutical composition for transdermal administration according to any one of claims 1 to 12, wherein a blood concentration of the drug is achieved.

14. A method for treating a disease comprising peripherally circulating a mammal suffering from peripheral circulatory disorder, comprising transdermally administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 13.

15. Use of Vintrol in the manufacture of a pharmaceutical composition for transdermal administration.