JPS61221120A - Medical material for external use - Google Patents

Abstract

PURPOSE:To provide the titled material for the continuous administration of drug through the skin or mucosa and composed of a composition obtained by clathrating a liquid transcutaneous absorbefacient in cyclodextrin or its derivative and dispersing the obtained compound in a drug-containing polymeric compound. CONSTITUTION:A liquid absorbefacient (e.g. methyloctylsulfoxide, dimethyllaurylamide, etc.) is clathrated in cyclodextrin or its derivative, and the obtained compound is dispersed in a drug-containing polymeric compound [e.g. a polymeric compound free of pressure-sensitive adhesivity under normal condition such as soft polyvinyl chloride, polyolefin, etc., or a polymeric compound having pressure-sensitive adhesivity under normal condition such as n- butyl (meth)acrylate, etc.] to obtain the objective medical material for external use. The above drug is e.g. a corticosteroid such as hydrocortisone, an analgesic and anti-inflammatory agent such as acetaminophenone, etc., a narcotic sedative such as phenobarbital, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to an external medical device for continuous administration of a drug through the skin or mucous membranes.

(b) Prior Art When administering a drug to a human or animal body, various methods have been proposed for maintaining the drug within an effective blood concentration over time by limiting the release rate of the drug.

The first method is to orally administer a microencapsulated drug and control the release of the drug by its sustained release properties.

The second method involves mixing a drug with a polymeric material such as a pressure-sensitive adhesive, molding the mixture, and applying the mixture to the skin or mucous membrane to allow the drug to be absorbed by a concentration gradient.

A third method is to disperse the transdermal absorption enhancer in the drug-containing polymeric substance in the second method.

The fourth method is an improvement on the third method, in which a transdermal absorption enhancer is added to urea to form a clathrate compound, and this clathrate compound is dispersed and blended into a drug-containing polymeric substance. It is something.

(e) Problems to be Solved by the Invention However, in oral administration using the first method, metabolism in the liver is unavoidable, and a sufficient microencapsulating agent has not been found, so sustained release cannot be achieved completely. It's hard to say that it's a thing.

In addition, in the second method, the stratum corneum on the skin surface acts as a barrier that obstructs transdermal absorption, so it may not be possible to obtain a sufficient blood concentration.

Therefore, in the third method, a transdermal absorption enhancer is dispersed in a drug-containing polymeric substance to promote transdermal absorption of the drug. However, when a transdermal absorption enhancer is dispersed in a polymeric material in this way, the polymeric material layer becomes plasticized and the cohesive force of the layer decreases. When used, problems arise such as the polymeric substance remains on the applied skin surface when peeled off after application to the skin, or the polymeric substance protrudes from the side surface of the external medicinal member when used as a patch.

In the fourth method above to solve this problem,
A transdermal absorption enhancer is added to urea to form an clathrate compound, but the crystal lattice of urea collapses as the clathrated molecules (guest molecules) form, resulting in the formation of a clathrate compound on the skin or mucosal surface. Urea is released.As a result, some patients may experience irritation symptoms, inflammation, etc. as side effects of urea.In addition, the dissociation of urea and transdermal absorption enhancer is sensitive to the amount of moisture, so sweating may occur. There are problems such as differences in medicinal efficacy due to individual differences in the amount, seasonal effects, etc., and if the amount of perspiration is large, the transdermal absorption enhancer is dissociated more than necessary and the cohesive force is reduced.

(d) Means for Solving the Problems The present invention was developed as a result of intensive research to solve the above-mentioned conventional problems.

That is, the external medicinal member of the present invention is characterized in that it consists of a composition in which an inclusion compound in which a liquid transdermal absorption enhancer is included in cyclodextrin or a derivative thereof is dispersed in a drug-containing polymer compound. It is something.

The present invention will be explained in detail below.

In the present invention, the cyclodextrin or its derivatives (hereinafter referred to as cyclodextrins) serving as the host molecule of the clathrate compound include a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or alkylated etc. Examples include treated derivatives.

In addition, the liquid transdermal absorption enhancer that serves as a guest molecule for the clathrate compound must not only be clathrated with cyclodextrins, but also be one that is released after being applied to the skin or mucous membranes. First, the function of increasing the solubility of the drug contained in the polymer compound described below, the function of promoting the movement of the drug through the substance, or the function of promoting the absorption of the drug through the skin or mucous membrane. (For example, a keratin softening function) is used.

Liquid transdermal absorption enhancers having such functions include, for example, sulfoxide-based agents such as methyloctyl sulfoxide, trimethyllaurylamide, dimethyl sulfoxide, trimethylacetamide, cumethylform 7mide, and dodecylpyrrolidone, and phosphooxide-based agents. , dimethylamide-based, alkylpyrrolidone-based, and insorbitol-based solvents M, lower alcohols such as ethyl alcohol and isopropyl alcohol, polyhydric alcohols such as ethylene glycol, polyethylene glycol, and glycerin, other animal and vegetable oils, fats and oils, and 7nan. Examples include acids, higher fatty acids, paraffins, and the like.

A clathrate compound containing a liquid transdermal absorption enhancer is dispersed in a drug-containing polymer compound.

Here, the polymer compound includes a polymer compound (A) that holds the clathrate compound in a dispersed state and does not have pressure-sensitive adhesive properties in a normal state, and a polymer compound that has pressure-sensitive adhesive properties in a normal state. (B) is preferred.

Examples of polymer compounds belonging to (A) include flexible polyvinyl chloride, flexible polyamide, polyolefin, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride resin, thermosetting or room temperature vulcanizable silicone rubber, and ethylene-
Examples include vinyl acetate copolymers.

Polymer compounds belonging to (B) include n-butyl (meth)acrylate, hexyl (meth)acrylate, tilbutyl (meth)acrylate-2, inoctyl (meth)acrylate, and actul (meth)acrylate. (Meth) such as 2-ethylhexyl acid, decyl (meth)acrylate, dodecyl (meth)acrylate, tridecyl (meth)acrylate
Acrylic esters and copolymerizable esters (
meth)acrylic acid, (anhydrous) maleic acid, (anhydrous) itaconic acid, 7-malic acid, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, (meth)acrylic 7mide, trimethyl (meth)acrylamide,
Functional monomers such as methylaminoethyl (meth)acrylate, methoxyethyl (meth)acrylate and/or vinyls such as (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinyl versatate, styrene, vinylpyrrolidone, vinyl chloride. Other examples include copolymers with monomers such as silicone rubber, polyisoprene rubber, polyisobutylene rubber, styrene-butadiene (
or isoprene) - Rubber-based adhesive substances whose main components are styrene block copolymer rubber, acrylic rubber, natural rubber, etc. Vinyl-based adhesives whose main components are polyvinyl ether, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, etc. Substances can also be used.

Furthermore, the drug to be dissolved and/or dispersed in a crystalline state in these polymeric compounds is one that has transdermal absorption properties and can be released together with the above-mentioned transdermal absorption enhancer.

Examples of such drugs include those listed below, and two or more of these drugs can also be used in combination.

(b) Flutecosteroids: For example, hydrocortisone, prednisolone, paramethacin, beclomethasone propionate, 7-lmethasone, betamethacin, betamethacin valerate, beclomethasone propionate, dexamethacin, triamcinolone, triamcinolone 7-cetonide, fluocinolone, 7-l Osinolone acetonide, 7
Luocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic and anti-inflammatory agents: For example, aceto-7 minophenone, mefenamic acid, flufenamic acid, indomethacin, nocro-7
Enac, cyclo7enac sodium, alcro7enac, oxy7enbutazone, phenylftasone, ibufuro7en, 7lurbipro7enthyl,! - Menthol, camphu T-, sulindac, tolmetin sodium, naproxen, 7-en, etc. (c) Hypnosedatives: For example, phenobarbital, 7'moparbicur, cyfrobarbicur, triazolam, nitrazepam, flunitrazepam, lorazepam, haloperidol, etc. (2) Tranquilizers: such as flu7enazine, thioridazine, diazepam, fludiazepam, flunitrazepam,
Chlorpromazine, etc. (e) Antihypertensive agents: e.g., clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, b7-ol, indenolol, nivadipine, roanidixine, nipradilol, bucumolol, nianidipine, etc. (f) antihypertensive diuretics (g) Antibiotics: For example, penicillin, tetracycline, oxytetracycline, 7-lachomycin sulfate, erythromycin, chloramphenicol, etc.

(h) Local anesthetics: e.g. ridocaine, benzicaine,
(su) Antibacterial substances: such as benzalkonium chloride, nitro-7-razone, nyscutin, acetosulfamine, clotrimazole, etc. (iii) Antifungal substances: such as pentamycin, amphotericin B1 pyrrolnidoline , Clotrimazole, etc. (Le) Autonomic nerve agents: For example, sufvoramisos, atropine, methylatropine bromide, etc.

(Te) Vitamin preparations: For example, vitamin A, vitamin E.

Vitamins such as ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate, etc. (iv) Antiepileptic drugs: e.g. nitrozepam, clonazepam, mebrobamate, etc. (power) Coronary vasodilators: e.g. nitroglycerin, nitroglycol, Insorbidononitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propatyl nitrate, sibiligmol, molysidomine, etc. (ii) Antihistamines: such as diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc. (ii) Antitussives: For example, dextromethorphan, terbutaline, ephedrine, ephedrine hydrochloride, salbutamol, isoprotenol, etc., (2) Sex hormones: For example, propsterone, estradiol, etc., (N) Stimulants: For example, doxepin, etc., (T) Cerebral circulation improving agents: For example, Videlgin, nilgot alkaloids, iaenprodil, etc., anti-emetics, anti-ulcer agents, such as metoclopramide, clevopride, donbelide, scopolamine, scopolamine hydrobromide, 5-fluorouracil, mercaptopurine, etc. Pharmaceuticals: For example, polypeptides (TRHL
HRH derivatives), prostaglandins, etc.
Others: such as 7entanyl, desmobrecin, digoxin, etc.

The mixing ratio of the polymer compound and drug varies depending on the type or amount of the percutaneous absorption enhancer in the polymer compound, drug, and clathrate compound used, but for example, 0.05 to 50+++g/
It is desirable that the amount of drug is delivered to the skin or mucous membranes for 24 hours, and it is usually preferable that the proportion of the drug in the mixture of both is 0.01 to 30% by weight.

The proportion of the above-mentioned clathrate compound dispersed in the drug-containing polymer compound is desirably selected from the range of 1 to 50% by weight based on the total amount of the compound. When the proportion of clathrate compounds is less than this range, the desired effect of promoting transdermal absorption cannot be obtained, whereas when it is more than this range, drug absorption may be increased and the drug may lack sustainability. be.

The external medicinal component of the present invention is composed of a composition in which the above-mentioned clathrate compound is dispersed in this drug-containing polymer compound, but in order to facilitate application to the skin or mucous membrane, the following measures are taken: It is desirable to apply

(2) Forming this composition into a film or sheet.

When applied to the skin or mucous membranes, this film or sheet may be fixed to the skin or mucous membranes with a plaster layer. It is also possible to apply a pressure-sensitive adhesive to the surface of this film or sheet so that it can be applied to the skin or mucous membrane.

(2) This composition is provided in a layered manner on the surface of a flexible planar carrier to form a laminated structure.

Here, the carrier may be a plastic film/sheet, metal foil, or woven fabric that is designed to have a moisture permeability level that does not substantially allow moisture to pass through, or does not cause side effects such as irritation or whitening of the skin or mucous membranes. Cloth, nonwoven fabric, metal foil, woven fabric, laminate of nonwoven fabric and plastic film, plastic film coated with metal, etc. are used.

When applying to the skin or mucous membranes, use a polymer compound that has a pressure-sensitive adhesive in its normal state or one that has pressure-sensitive adhesive properties when exposed to moisture, and when the layer of the composition itself has tackiness, The side of the composition may be applied to the skin or mucous membranes. In addition, when a polymer compound that does not have pressure-sensitive adhesive properties under normal conditions is used, and the layer of the composition does not have adhesive properties, the side of the composition is applied to the skin or mucous membrane, and the adhesive is applied from the outside of the carrier. It may be fixed to the skin or mucous membrane with adhesive tape or the like.

In the above case (2), the surface of the composition layer formed on the surface of the carrier is covered with a flexible release film such as polyethylene Tele 7 Talley F which has been subjected to release treatment to protect the surface of the layer. It is preferable to do so.

The external pharmaceutical components of the present invention are preferably stored individually or in bulk in bags made of packaging materials with excellent moisture impermeability, such as aluminum pipes and plastic film laminate films, for storage and distribution. .

(e) Effect Next, the operation of the present invention will be explained in detail, including its rocky grooves.

In the present invention, cyclodextrins are used as host molecules for the clathrate compound. Cyclodextrins exhibit the property of not collapsing their structure even after dissociating the liquid transdermal absorption enhancer, which is a guest molecule.

Cyclodextrins are C1, transdermal absorption enhancers are A, Ih
The clathrate compound included in tC is designated as A-C, and the concentrations of these in the composition are [C1%[AI, [A-
When expressed as Cl, the equilibrium relationship of C0A, -A-C is established, and the dissociation of guest molecule A from A-C is the dissociation expressed by KO=[CIX[A]/[A-CI] It is considered that it is controlled by the constant Ka.

Therefore, since the dissociation constant α is a constant that has a unique value in each system, as the dissociated A is absorbed into the body and decreases, the concentration of A in the composition [As AI decreases, the Ka value In order to keep α constant, the dissociation of A, which is in an inclusion state with C, is promoted and works to maintain dissociation equilibrium, and conversely, even if A tries to dissociate excessively, inclusion is carried out to keep α constant in the dissociation constant. It is thought that this works to increase the concentration [A-Cl in the contact state] and prevent excessive dissociation.

In addition, by increasing the concentration of C [CI], the dissociated A
concentration [AI can be kept low.

In this way, by adjusting the concentration of C [CI] and the concentration of A [AI], only the necessary amount of A is dissociated from AC, depending on the amount of A released from the composition into the skin.

By applying the external pharmaceutical component of the present invention to the skin or mucous membrane, the transdermal absorption enhancer is dissociated from the clathrate compound by moisture secreted from the skin or mucous membrane, and the drug in the drug-containing polymer compound is accordingly dissociated from the clathrate compound. penetrates into the body through the skin or mucous membranes.

(f) Examples The present invention will now be further explained with reference to Examples. Hereinafter referred to as “Department”
"" indicates parts by weight.

Example 1 97 parts of 2-ethylhexyl acrylate and 3 parts of acrylic acid
A monomer mixture consisting of 7 parts of zoisobutyronitrile and 0
．． In the presence of 2 parts, the temperature was raised to 65° C. in a toluene medium to carry out heptapolymerization to obtain an acrylic copolymer.

On the other hand, a-cyclodextrin 104 heated to 70°C
By gradually cooling a 20% (V/V) isopropyl alcohol aqueous solution containing M, an a-cyclodextrin/isopropyl alcohol conjugate compound was obtained.

50 parts of this clathrate compound and 5 parts of isosorbide nonitrate are mixed with 100 parts of the acrylic copolymer obtained above, uniformly dispersed to form a composition, and then this composition is dried on a polyester film. The composition layer was coated and dried to a thickness of 200 μm, and then a peel-treated polyethylene terephthalate film was covered over the composition layer to obtain a medicinal member for external use.

Example 2 A monomer mixture consisting of 55 parts of 2-ethylhexyl acrylate, 25 parts of 2-nodoxyethyl acrylate and 20 parts of vinyl acetate was mixed with 0 of benzoyl peroxide.

Ethyl acetate-toluene 1:1 (V
/V) Polymerization was carried out by raising the temperature to 60° C. in a mixed medium to obtain an acrylic terpolymer.

On the other hand, by gradually adding nonanoic acid equivalent to twice the mole of the cyclodextrin into an aqueous solution containing 10 M of β-cyclodextrin and leaving it for about 24 hours, β-cyclodextrin nonane r111 was obtained.

A 5:1 clathrate was obtained.

40 parts of this clathrate compound and nitrazepam o,sg are mixed with 100 parts of the acrylic terpolymer obtained above, uniformly dispersed to form a composition, and then this composition is applied to a flexible polyvinyl chloride film. The composition layer was coated and dried to a thickness of 200 μm after drying, and then a peel-treated polyethylene terephthalate film was coated on top of the composition layer to obtain a medicinal member for external use.

Example 3 Methylated β-cyclodextrin/methyloctylsulfoxide was prepared by dropping methyloctylsulfoxide little by little into an aqueous solution containing 10M of methylated β-cyclodextrin and leaving it for 24 hours. Side 1:
1 A clathrate compound was obtained.

An aqueous solution containing 50 parts of the clathrate compound obtained above, 100 parts of polyvinyl alcohol with a degree of saponification of 98 mol%, and 5 parts of scopolamine hydrobromide was cast on a glass plate, dried and peeled off to a thickness of 100 μm. A medical component for external use was obtained.

Comparative Examples 1 to 3 External pharmaceutical components were prepared in the same manner as Examples 1 to 3, except that the same amount of the transdermal absorption enhancer was used instead of the clathrate compound consisting of cyclodextrins and the transdermal absorption enhancer. Created. Comparative Example 1 corresponds to Example 1, Comparative Example 2 corresponds to Example 2, and Comparative Example 3 corresponds to Example 3.

EXPERIMENTAL EXAMPLES For the medical components obtained in Examples 1 to 3 and Comparative Examples 1 to 3. The blood concentration, retention, adhesive residue, and percutaneous absorption enhancer blooming were measured as follows. However, as for Example 3 and Comparative Example 3, it is impossible to measure the holding force and adhesive residue because the external medicinal parts do not have pressure-sensitive adhesive properties, so surgical tape is used to fix them on the skin surface. I did it.

The results are shown in Table Pl&1.

"Blood Concentration" Each external medicinal material was cut into 30I11 diameter test pieces,
It was pasted on the hat of a rat whose hair had been removed in advance, and blood was drawn from the rat after 4 hours, 8 hours, and 24 hours, and gas chromatography, high-performance liquid chromatography,
Alternatively, drug blood concentrations were measured using a gas chromatography/mass spectrometer.

"Holding force" 5 Create a 10cm long test piece in lea from a medicinal product for external use, stick it to the end of a Bakelite plate by 2c+a, apply a load of 300g to the other end of the test piece, and place it in a thermostatic chamber at 40℃. The time required for the test piece to fall from the Bakelite plate due to cohesive failure was measured.

RA Residue” Each external medical device was pasted on the side of the upper arm, and it was determined whether or not any adhesive remained on the applied skin surface when removed after 24 hours.

[Percutaneous absorption enhancer blooming] For each external medicinal member, when the release sheet was peeled off from the adhesive surface during use, it was visually determined whether or not the percutaneous absorption enhancer was blooming on the release sheet.

(The following is a blank space) Table 1 (g) Effects of the Invention The externally used pharmaceutical component of the present invention uses an inclusion compound in which a cyclodextrin or a derivative thereof is a host molecule and a liquid transdermal absorption enhancer is a guest molecule. However, since cyclodextrin or its derivatives maintain a very large molecular structure without collapsing its structure even after dissociating the guest molecule, it is difficult for the host molecule to enter the skin, such as when urea is used as the host molecule. In addition, cyclodextrin or its derivatives can include a large number of transdermal absorption enhancers, so it has the advantage of widening the selection range of usable transdermal absorption enhancers. be.

In the external pharmaceutical component of the present invention, which is composed of a composition in which this clathrate compound is dispersed in a drug-containing polymer compound, when this composition comes into contact with the skin or mucous membrane, the clathrate is encapsulated by the action of moisture due to sweating, etc. The percutaneous absorption enhancer that gradually dissociates from the contact compound reduces the barrier function of the stratum corneum,
Penetration of the drug into the skin or mucous membranes is aided.

Moreover, the dissociation of the transdermal absorption enhancer from the clathrate compound using cyclodextrin or its derivatives is considered as necessary depending on the amount of the transdermal absorption enhancer absorbed into the skin, and as a result, the drug content increases. Since the dissociation of the transdermal absorption enhancer into the molecular compound in excess of the required amount is suppressed, a decrease in the cohesive force of the composition is prevented, and when the composition is peeled off after being applied to the skin, the polymeric substance is removed from the applied skin surface. Problems such as the plasticized composition remaining on the skin or the plasticized composition protruding from the side surface of the composition during application do not occur. In addition, since the dissociation of the transdermal absorption enhancer is regulated regardless of the amount of water, it is less affected by individual differences in sweating amount, seasons, etc., the medicinal efficacy is constant, and the drug is not wasted. (It is supplied to the skin or mucous membranes.

Claims (3)

[Claims] (1) An external pharmaceutical component comprising a composition in which an inclusion compound in which a liquid transdermal absorption enhancer is included in cyclodextrin or a derivative thereof is dispersed in a drug-containing polymer compound. (2) The external pharmaceutical member according to claim 1, wherein the composition is provided in a layer on the surface of a flexible planar carrier. (3) The external pharmaceutical component according to claim 1, wherein the composition is formed into a film or sheet.