JPH0529006B2 - - Google Patents

Description

[Detailed description of the invention]

(a) Industrial Application Field The present invention relates to an externally applied pharmaceutical component for continuously administering 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 for a long period of 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. (c) 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 is not possible. It's hard to say that it's perfect. 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 order to solve this problem, in the fourth method mentioned above, a transdermal absorption enhancer is added to urea to form an inclusion compound, but the crystal lattice of urea is such that the clathrated molecules (guest molecules) As it runs out, it collapses and urea is released onto the skin or mucous membrane surface. Therefore, 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 the medicinal efficacy may vary depending on individual differences in sweating amount, season, etc., and if the amount of sweating is large, it may be necessary to use more than necessary. There are problems such as the transdermal absorption enhancer being dissociated and the cohesive force being reduced. (d) Means for Solving the Problems The present invention has been made 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 α-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 able to be included in 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, dimethyl laurylamide, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, and dodecylpyrrolidone, phosphooxide-based agents, and dimethylamide. solvents such as alkylpyrrolidone, isosorbitol, 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 higher alcohols such as nonanoic acid. Examples include fatty acids and paraffins. An inclusion compound in which a liquid transdermal absorption enhancer is included in a cyclodextrin 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, polyacrylic resin, thermosetting or room temperature vulcanizable silicone rubber, and ethylene-vinyl acetate copolymer. Examples include merging. Examples of polymer compounds belonging to (B) include n-butyl (meth)acrylate, hexyl (meth)acrylate, 2-ethylbutyl (meth)acrylate,
(meth)acrylic acid esters such as isooctyl (meth)acrylate, -2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, and tridecyl (meth)acrylate, and the esters thereof. copolymerizable with (meta)
Acrylic acid, (anhydrous) maleic acid, (anhydrous) itaconic acid, fumaric acid, hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, (meth)acrylamide, dimethyl (meth)acrylate
Functional monomers such as acrylamide, methylaminoethyl (meth)acrylate, methoxyethyl (meth)acrylate and/or (meth)acrylonitrile, vinyl acetate, vinyl propionate, vinyl versatate, styrene, vinylpyrrolidone, vinyl chloride. Examples include copolymers with vinyl monomers such as vinyl monomers. Other rubber-based sticky substances mainly composed of silicone rubber, polyisoprene rubber, polyisobutylene rubber, styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber, natural rubber, polyvinyl ether, polyvinyl alcohol, Vinyl adhesive substances containing polyvinyl acetate, polyvinylpyrrolidone, etc. as main components 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. (a) Corticosteroids: For example, hydrocortisone, prednisolone, paramethasone, beclomethasone propionate, flumethasone, betamethasone, betamethasone valerate, beclomethasone propionate, dexamethasone, triamcinolone, triamcinolone acetonide,
fluocinolone, fluocinolone acetonide,
Fluocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic and anti-inflammatory agents: e.g. acetaminophenone,
mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen,
flurbiprofen, ketoprofen, salicylic acid, methyl salicylate, l-menthol, camphor, sulindac, tolmetin sodium, naproxen, fuenbufuen, etc. (c) Hypnosedatives: e.g. phenobarbital, amobarbital, cyclobarbital, triazolam, nitrazepam , flunitrazepam, lorazepam, haloperidol, etc. (d) Tranquilizers: e.g. fluphenazine, thioridazine, diazepam, fludiazepam, flunitrazepam, chlorpromazine, etc. (e) Antihypertensive agents: e.g. clonidine, clonidine hydrochloride, pindolol, propranolol, propranolol hydrochloride, Bufranol, indenolol, nivazibine, lofedixin, nipradilol, bucumolol, nifedipine, etc. (f) Antihypertensive diuretics: for example, hydrothiazide,
(g) Antibiotics: such as penicillin, tetracycline, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. (h) Local anesthetics: e.g. lidocaine, benzocaine, ethyl aminobenzoate, etc. (li) Antibacterial substances: e.g. benzalkonium chloride,
Nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc.; (v) Antifungal substances: e.g., pentamycin, amphotericin B, pyrrolnitrine, clotrimazole, etc.; (l) Autonomic nerve agents: e.g., scopolamines, atropine. , methylatropine bromide, etc. (w) Vitamin preparations: e.g. vitamin A, vitamin E, vitamin K, ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate, etc. (w) Antiepileptic drugs: e.g. nitrozepam, clonazepam, meprobamate, etc. F) Coronary vasodilators: For example, nitroglycerin, nitroglycol, isosorbide dinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, propyl nitrate, dipyridamole, molysidomine, etc. (Y) Antihistamines: For example, diphenhydra hydrochloride Antitussives: For example, dextromethorphan, chlorpheniramine, diphenylimidazole, etc.
Terbutaline, efuedrine, efuedrine hydrochloride, salbutamol, isoprotenol, etc. (l) Sex hormones: e.g. progesterone, estradiol, etc. (g) Antidepressants: e.g. doxepin, etc. (tsu) Cerebral circulation improving agents: e.g. videlgine, ergot alkaloids, Ifenprodil, etc. (n) Antiemetics, antiulcer agents: e.g. metoclopramide, clebopride, domperid, scopolamine, scopolamine hydrobromide, 5-fluoraucil, mercaptopurine, etc. (n) Biological medicines: e.g. polypeptides (TRH,
(derivatives of LHRH), prostaglandins, etc. (La) Others: such as fuentanil, 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
The amount is preferably such that ~50mg/24hrs of drug is delivered to the skin or mucous membranes, and usually the proportion of the drug in the mixture of the two is preferably 0.01 to 30% by weight. The ratio of the above-mentioned clathrate compound dispersed in this drug-containing polymer compound is 1 to 50% of the total amount of the compound.
It is desirable to select from a range of weight %. When the proportion of clathrate compounds is less than this range, the desired effect of promoting transdermal absorption cannot be obtained, while when it is more than this range, the absorption of the drug becomes excessive and 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 membranes, the following measures are taken. This is desirable. This composition is formed 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-like material. 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. 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 whose moisture permeability is designed to be substantially impermeable to moisture or to the extent that it does not cause side effects such as irritation or whitening of the skin or mucous membranes. , non-woven fabric, metal foil, woven fabric, laminate of non-woven fabric and plastic film, metal-deposited plastic film, etc. are used. When applying to the skin or mucous membranes, use a polymer compound that normally has a pressure-sensitive adhesive, or one that has pressure-sensitive adhesive properties when exposed to moisture, and when the layer of the composition itself has tackiness. may be applied by applying the composition side to the skin or mucous membrane. In addition, the polymer compound to be used is one that does not have pressure-sensitive adhesive properties under normal conditions, and when the layer of the above composition does not have adhesive properties, the side of the composition is applied to the skin or mucous membrane, and the layer 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, it is preferable to cover the composition layer formed on the surface of the carrier with a flexible release film such as polyethylene terephthalate that has been subjected to release treatment to protect the surface of the layer. . The external pharmaceutical components of the present invention are preferably stored individually or in bulk in bags made of packaging material with excellent moisture impermeability, such as a laminate film of aluminum foil and plastic film, for storage and distribution. (e) Function Next, the function of the present invention, including its mechanism, will be explained in detail. 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 C, transdermal absorption enhancers are A, and clathrate compounds in which A is included in C are A and C, and their concentrations in the composition are [C], [A], and [A], respectively.・C], the equilibrium relationship of C+AA・C is established, and the dissociation of guest molecule A from A・C is the dissociation constant expressed as Kα=[C]×[A]/[A・C] It is thought to be controlled by Kα. Therefore, since the dissociation constant Kα is a constant that has a unique value in each system, the dissociated A
When the concentration of A in the composition [A] decreases as it is absorbed into the body, the dissociation of A in an inclusion state with C is promoted to maintain a dissociation equilibrium in order to keep the Kα value constant. On the other hand, even if A tries to dissociate excessively, it seems that in order to keep the dissociation constant Kα constant, the concentration of the clathrate state [A·C] increases and prevents excessive dissociation. Furthermore, by increasing the concentration of C [C], it is possible to keep the concentration of dissociated A [A] low. By adjusting the concentration of C [C] and the concentration of A [A] in this way, only the necessary amount of A and C can be obtained depending on the amount of A released from the composition into the skin.
more dissociated. 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-containing polymer compound is accordingly dissociated from the transdermal absorption enhancer. of drugs penetrate into the body through the skin or mucous membranes. (f) Examples Next, the present invention will be further explained with reference to Examples. Hereinafter, the term "parts" refers to parts by weight. Example 1 A monomer mixture consisting of 97 parts of 2-ethylhexyl acrylate and 3 parts of acrylic acid was prepared in a toluene medium in the presence of 0.2 parts of azoisobutyronitrile.
The temperature was raised to 65°C for polymerization to obtain an acrylic copolymer. On the other hand, α-cyclodextrin heated to 70℃
By gradually cooling a 20% (V/V) isopropyl alcohol aqueous solution containing 10 ^-2 M, α-cyclodextrin/isopropyl alcohol 1:
1 clathrate compound was obtained. After mixing 50 parts of this clathrate compound and 5 parts of isosorbide dinitrate with 100 parts of the acrylic copolymer obtained above and uniformly dispersing the mixture to form a composition,
This composition was coated on a polyester film to a dry thickness of 200 μm, dried, and then a peel-treated polyethylene terephthalate film was coated on top of the composition layer to obtain a medicinal part for external use. . Example 2 55 parts of 2-ethylhexyl acrylate, 25 parts of 2-methoxyethyl acrylate and 20 parts of vinyl acetate
A monomer mixture consisting of parts of benzoyl peroxide
1:1 ethyl acetate-toluene in the presence of 0.3 parts
(V/V) The mixture was heated to 60° C. and polymerized in a mixed medium to obtain an acrylic terpolymer. On the other hand, nonanoic acid equivalent to twice the mole of the cyclodextrin was gradually added to an aqueous solution containing 10 ^-1 M of β-cyclodextrin, and the mixture was shaken for about 24 hours.
A 1.5:1 clathrate was obtained. 40 parts of this clathrate compound and 0.5 part of nitrazepam are mixed with 100 parts of the acrylic terpolymer obtained above and uniformly dispersed to form a composition. This composition is then coated on 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 Methyl octyl sulfoxide was dropped little by little into an aqueous solution containing 10 ^-1 M of methylated β-cyclodextrin, and the mixture was shaken for 24 hours.
A 1:1 methylated β-cyclodextrin/methyloctylsulfoxide clathrate compound was obtained. 50 parts of the clathrate compound obtained above, degree of saponification 98 mol%
An aqueous solution containing 100 parts of polyvinyl alcohol and 5 parts of scopolamine hydrobromide was cast on a glass plate, dried and peeled off to obtain a 100 μm thick medicinal member for external use. 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 Example Regarding the external 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 went there. The results are shown in Table 1. "Blood Concentration" Each externally used medicinal material was cut into 3 cm diameter test pieces and pasted on the abdomen of a rat whose hair had been removed in advance. After 4 hours, 8 hours, and 24 hours, the rat's blood was drawn and a gas chromatography test was performed. Blood drug concentrations were measured using chromatography, high performance liquid chromatography, or gas chromatography/mass spectrometry. "Holding force" A test piece 1 cm wide and 10 cm long was prepared from a topical medical product, and this was pasted for 2 cm on the edge of a Bakelite board. A load of 300 g was applied to the other end of the test piece, and the test piece was heated at 40°C.
The time required for the test piece to fall from the Bakelite plate due to cohesive failure was measured in a constant temperature chamber. "Adhesive Residue" Each external medical device was pasted on the side of the upper arm, and it was determined whether or not adhesive remained on the applied skin surface when removed after 24 hours. "Blooming of transdermal absorption enhancer" For each external pharmaceutical component, when the release sheet was removed from the adhesive surface during use, it was visually determined whether or not the percutaneous absorption enhancer was blooming on the release sheet.

[Table] (g) Effects of the Invention The external pharmaceutical component of the present invention uses an inclusion compound in which cyclodextrin or its derivative is a host molecule and a liquid transdermal absorption enhancer is a guest molecule. , cyclodextrin or its derivatives do not collapse their structure even after dissociating the guest molecule and maintain a very large molecular structure, so the host molecule does not absorb into the skin like when urea is used as the host molecule. First, there is no fear of side effects, and since cyclodextrin or its derivatives can include a large number of transdermal absorption enhancers, it also has the advantage of widening the selection range of usable transdermal absorption enhancers. 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 transdermal absorption enhancer that gradually dissociates from the attached compound lowers the barrier function of the stratum corneum and helps the drug penetrate into the skin or mucous membrane. Moreover, the dissociation of the transdermal absorption enhancer from the clathrate compound using cyclodextrin or its derivatives is
The amount of transdermal absorption enhancer absorbed into the skin is considered as the necessary amount, and as a result, dissociation of more than the necessary amount of transdermal absorption enhancer into the drug-containing polymer compound is suppressed. This prevents a decrease in the cohesive force of the composition, and prevents the polymer from remaining on the applied skin surface when it is peeled off after being applied to the skin, and from causing the plasticized composition to protrude from the sides of the composition when used as a patch. No trouble will occur. In addition, since the dissociation of the transdermal absorption enhancer is regulated regardless of the amount of water, it is not affected by individual differences in sweat amount or the season, and the drug efficacy is constant, and the drug is not wasted and is absorbed into the skin. or those that are supplied to the mucous membranes.

[Claims]

1. An external preparation containing urea, phospholipids, water, and oil and fat components.