JPH0240645B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a drug-containing tape preparation containing a compound in which a drug is packaged with an inclusion agent. More specifically, drug-containing tape preparations intended to continuously and transdermally administer coronary vasodilators such as nitroglycerin, anti-inflammatory analgesics such as indomethacin, etc. into the circulatory system through predetermined areas of the skin. It provides: For example, compounds having a nitrite ester in the molecule, such as nitroglycerin and isosorbide dinitrate, are known as anti-anginal drugs having excellent coronary vasodilatory effects. Drugs consisting of these compounds are widely used as sublingual tablets to treat angina pectoris attacks, and have been shown to be highly effective. However, their effects are short-lived, and at their peak blood concentrations, they can cause headaches, headaches, etc. There is a problem with side effects such as nausea. Another problem is that since nitroglycerin has strong volatility, the content of nitroglycerin in sublingual tablets decreases over time, and the expected medicinal effects are not exhibited when used. To solve these problems, nitroglycerin ointments have been developed and are used not only for treatment but also for the prevention of angina attacks, but the duration of action is longer than that of sublingual tablets. At present, the drug supply amount cannot be controlled and the problem of side effects still remains unsolved. Moreover, in the case of ointment type, nitroglycerin is unlikely to volatilize during storage because it can be stored in a closed system, but after application to the body, it volatilizes into the atmosphere faster than it absorbs into the skin, so This requires a complicated operation of sealing with plastic film or the like. It is also conceivable to mix nitroglycerin into the adhesive layer and form it on the tape support surface, as in normal medical adhesive tapes, but nitroglycerin may permeate the tape support or diffuse to the sides of the tape. There is a problem in that it evaporates and does not provide sufficient medicinal efficacy during use. In view of the state of the prior art, the inventors of the present invention have realized that the duration of drug efficacy is longer, the amount of drug supplied can be controlled, and most of the drug is absorbed into the skin without volatilization over time or during use. As a result of intensive research into a drug-containing tape preparation that satisfies all conditions, such as being easy to handle and requiring no skill, we found that the drug was clathrated with an inclusion agent and then incorporated into a polymeric material. Find a tape formulation that satisfies the above conditions by blending the inclusion agent in an amount that does not exceed a predetermined amount,
This led to the present invention. That is, the present invention comprises a substantially anhydrous molded mixture in which a powdery clathrate compound, in which a drug is clathrated with an clathrate, is blended with a polymeric substance, and the clathrate is contained in a large amount in the mixture. The formulation is adjusted so that the drug content does not exceed 90% by weight, and the drug content is 50 to 2000μg/
The present invention provides a drug-containing tape preparation characterized in that the drug is contained in a range of cm ² . One specific example of the present invention is a tape, sheet, or strip-shaped preparation formed by molding a mixture of a compound formed by including a drug with an inclusion agent (hereinafter referred to as an inclusion compound) and a polymeric substance. When this preparation is brought into close contact with the body surface, the clathrate is softened and dissolved by the moisture supplied from the body, and the unclathrated drug diffuses and moves toward the body surface, allowing the body to continuously absorb the drug. make it possible to absorb it. Another embodiment of the present invention is a formulation in which a coating film consisting of a mixture of an clathrate compound and a viscous material that normally has pressure-sensitive adhesive properties is formed on a film-like support material. This preparation is used by being applied directly to the body surface. The drug-containing tape preparation of the present invention is made to satisfy the above-mentioned conditions by skillfully utilizing the properties, functions, and materials of the clathrate used to prepare the clathrate. This will be understood from the explanation. For example, the drug-containing tape preparation of the present invention constitutes a system in which drug volatilization does not occur under normal conditions, but when a large amount of moisture is supplied, the drug is unclasped by the clathrating agent and the drug is released. are doing. Therefore, if the drug is placed in close contact with the body surface and moisture is supplied from the body surface, most of the drug will be released toward the body surface.
Therefore, drugs can be supplied to the body without waste. As an inclusion agent that exhibits such a function, cyclodextrin consisting of a cyclic oligosaccharide homologue also called Schjardinger dextrin or cycloamylose is useful. Typical examples of cyclodextrins are α-cyclodextrin, in which 6 D-glucoses are cyclically linked with α-1,4 bonds, and β-cyclodextrin, in which 7 D-glucoses are cyclically linked in α-1,4 bonds. Can be mentioned. Other inclusion agents include γ-cyclodextrin and crown ether. Drugs included in these inclusion agents include:
Coronary vasodilators containing nitrite esters in the molecule such as nitroglycerin, isosorbide, dinitrate, erythritol tetranitrate, pentaerythritose tetranitrate, mannitol hexanitrate, anti-inflammatory analgesics such as indomethacin, etc. can be exemplified. There are various methods for including drugs with inclusion agents, but the following two methods are useful. (1) Add 8 to 50 times the weight of water to an appropriate amount of cyclodextrin and heat to 30 to 90°C to prepare a completely dissolved aqueous solution. The liquid drug is left as it is, and the powdered drug is dissolved in a solvent such as methanol, ethanol, acetone, or ether to form a solution, and the mixture is gradually added to the solution while stirring the aqueous solution, and after stirring for 2 to 10 hours, it is left to cool. The deposited precipitate is filtered and dried to obtain a powdery clathrate compound. (2) Add 2 to 5 times the weight of water to an appropriate amount of cyclodextrin to make a paste, add a drug solution dissolved in a small amount of solvent to this, mix for 2 to 6 hours, dry it, and then The mixture is washed with an appropriate solvent and dried to obtain a powdery clathrate compound. The powdered clathrate compound obtained by such a method is blended with a polymeric substance to grow a mixture.
Depending on the type of polymeric substance, the resulting mixture is either a drug-containing tape preparation in which the mixture itself has a predetermined shape, or a drug-containing tape preparation that maintains a predetermined shape with the help of a film-like support material. Ru. In each tape formulation, the clathrate that makes up the clathrate is used to disperse the mixture and prevent it from being deformed or remaining on the body surface due to the plasticization of the mixture by the drug. The filling and viscosity-increasing effects of this function effectively prevent this from occurring. One group of the above-mentioned polymeric substances is a group consisting of substances that maintain clathrate compounds in a dispersed state and do not have pressure-sensitive adhesive properties under normal conditions, and this group includes flexible polyvinyl chloride, flexible polyamide, polyolefin, polyvinyl Alcohol, polyacrylic resin, thermosetting or room temperature vulcanizable silicone rubber, ethylene.
Composed of vinyl acetate copolymer, etc. Tape formulations using these substances can be made by simply molding a mixture of the clathrate compound and the substance, and the resulting tape formulation is superior to that of the polymeric substance alone due to the action of the clathrate. It has sufficient moisture permeability and has a structure that reduces the amount of drug contained in the tape formulation. Another group of polymeric substances are viscous substances that hold clathrate compounds in a dispersed state and have appropriate moisture permeability and pressure-sensitive adhesive properties in normal state, and one such group includes (meth)acrylic acid n -Butyl, (meth)
Hexyl acrylate, 2-ethylbutyl (meth)acrylate, isooctyl (meth)acrylate,
(meth)acrylic acid 2-ethylhexyl, (meth)
(meth)acrylic acid esters such as decyl acrylate, dodecyl (meth)acrylate, and tridecyl (meth)acrylate; (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, which can be copolymerized with the esters; with functional monomers such as hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, methylaminoethyl methacrylate, methoxyethyl (meth)acrylate and/or vinyl monomers such as acrylonitrile, vinyl acetate, vinyl propionate. An example is an acrylic composition that is a copolymer. Other examples include rubbers such as silicone rubber,
Rubber-based viscous materials containing polyisoprene rubber, polyisobutylene rubber, styrene-butadiene (or isoprene)-styrene block copolymer rubber, acrylic rubber, natural rubber, etc., vinyl polymers such as polyvinyl ether, polyvinyl alcohol, Examples include vinyl-based viscous materials whose main component is vinyl acetate. When using a tape formulation using these viscous substances as a supporting matrix for an clathrate compound, when using a viscous substance that exhibits good properties by adding a crosslinking component in the process of manufacturing the viscous substance, The inclusion agent constituting the clathrate compound functions to stabilize the drug, that is, to effectively prevent the drug from being modified by reacting with any of the materials constituting the viscous substance. In this way, the inclusion agent that constitutes the clathrate compound has the function of preventing the volatilization of the drug under normal conditions, and also to supply the drug to the body surface accurately and without waste, as mentioned above. It exerts a remarkable effect on preventing plasticization of the polymeric substance as a supporting matrix due to the influence of the drug, and also on stabilizing the drug. This is obtained by adjusting the amount of inclusion agent contained therein so that it does not exceed 90% by weight at most. Even if the content of the inclusion agent exceeds 90% by weight, it will not inhibit the control of the drug supply amount, prevent plasticization, and stabilize the drug, but on the contrary, it will reduce the physical strength of the molding mixture. , is undesirable because it reduces the pressure-sensitive adhesive properties of viscous materials and lacks uniform dispersibility in polymeric materials, and is preferably 70
The content is preferably 3% to 50% by weight, more preferably 5% to 30% by weight. Mixed systems of clathrate compounds and polymeric substances can promote the release of unclathrated drugs such as propylene glycol, diethylene glycol, diisopropyl adipate, ethyl laurate, dimethylacetamide, and diethyl sepacate, and can also be used to promote the release of drugs into the skin. Appropriate amounts of adjuvants can be added that function to promote absorption into the body. In this way, the mixture consisting of the clathrate compound, the polymeric substance, and the auxiliary agent added as necessary can be made into a tape preparation formed by the mixture alone into a predetermined tape, sheet, or piece, or A mixture layer is formed on one or both sides of a film-like support material made of non-woven fabric, woven fabric, knitted fabric, leather, foamed film, metal foil, plastic film or sheet, etc. using means such as coating or bonding. It is considered to be a tape formulation. The above film-like support material is selected or processed so that sufficient moisture is supplied to the tape preparation from the body surface and does not cause rashes on the skin due to irritation, and the film-like support material and the mixture layer are It is desirable to design the composite system to have a moisture permeability of 150 to 1900 g/m ² /24 hr. The thickness of the tape formulation is not very important and is usually 30~
500 μg/cm 2 , but it is desirable to adjust the thickness or the amount of the clathrate compound added to the polymer material so that the drug content per unit area is 50 to 2000 μg/cm ² . The drug-containing tape preparation of the present invention configured in this way has almost no loss due to volatilization of the drug under normal conditions, and most of the drug is supplied to the body surface after application, so it can be used accurately. The blood concentration of 2 to 15 ng/ml plasma can be reduced to 6.
It is something that can be maintained for ~24 hours. Furthermore, since it is a tape formulation, it is convenient to handle by simply applying it directly to the skin surface or using other auxiliary means. The fact that the drug-containing tape preparation of the present invention is stable even during long-term storage and continuously and transdermally supplies the drug to the circulatory system through the predetermined area without waste is demonstrated by the following examples. Illustrated concretely. The words "part of the text" indicate parts by weight. Example 1 Inclusion compound 40 g of β-cyclodextrin and 700 ml of water
The solution was heated to 0.degree. C. to form a completely dissolved aqueous solution, and a solution obtained by dissolving 6 g of nitroglycerin in 12 ml of acetone was gradually added dropwise to this solution. After the addition was completed, the mixture was further stirred for 1 hour and allowed to stand for about 4 hours, and a white clathrate compound was precipitated. This is filtered and dried to obtain 35 g of a powdered clathrate compound having a nitroglycerin content of 12.3% by weight. Drug-containing tape preparation 75 parts of ethylene-vinyl acetate copolymer with a vinyl acetate content of 28% by weight is dissolved in chloroform, 25 parts of the above clathrate compound is added thereto, and the thickness is measured after drying on a release liner. It is casted to a thickness of 80μ and dried at 80°C for 15 minutes to obtain a drug-containing tape formulation with a nitroglycerin content of 190μg/cm ² . Example 2 75 parts of isooctyl acrylate 20 parts of methoxyethyl acrylate Stir at a heating temperature of 68°C, control the reaction time while dropping 125 parts of ethyl acetate, and let the mixture react for 10 hours.
The polymerization rate was determined by aging for 2 hours under heating conditions of 75-80℃.
A copolymer solution of 99.5% and 40% solution viscosity of 470 poise is obtained. Prepare 320 parts of this solution diluted with ethyl acetate to give a 25% base, and 20 parts of the clathrate compound used in Example 1 are mixed therein and dispersed and dissolved. The mixture solution prepared in this way is applied to the surface of a polyethylene film to a dry thickness of 60 μm and dried at 80° C. for 5 minutes to obtain a drug-containing tape preparation with a nitroglycerin content of 150 μg/cm ² . Example 3 2-Ethylhexyl acrylate 65 parts Vinyl acetate 33 parts 2-hydroxyethyl acrylate 2 parts Azobisisobutyronitrile 0.2 parts The above formulation was treated in the same manner as in Example 2 to obtain a 40% solution with a polymerization rate of 93%. A copolymer solution with a viscosity of 780 poise is obtained. Prepare 340 parts of this solution diluted with ethyl acetate to give a base of 25%, and 15 parts of the clathrate compound used in Example 1 are mixed therein and dispersed and dissolved. Using the mixture solution thus prepared, a drug-containing tape preparation having a nitroglycerin content of 110 μg/cm ² is obtained in the same manner as in Example 2. Example 4 77 parts of isooctyl acrylate 20 parts of hexyl acrylate 3 parts of acrylic acid 5 parts of nonylphenyl polyethylene glycol The above mixture was placed in a four-necked flask, thoroughly stirred, and then 200 parts of ion-exchanged water was added and stirred. ,
The internal temperature was raised to 60°C under an inert gas atmosphere, and a polymerization reaction was carried out for 3 hours using 0.2 parts of ammonium persulfate based on the mixture, followed by aging at 80-85°C for 2 hours, resulting in a polymerization rate of 99.8. % and a viscosity (4 rpm) of 38 poise. 20 parts of the clathrate compound used in Example 1 is mixed with 240 parts of the copolymer liquid and sufficiently dispersed and dissolved. This is made into a polyethylene film with a thickness of 60 μm after drying.
The drug was applied and dried at 80°C for 10 minutes to obtain a drug-containing tape preparation with a nitroglycerin content of 150 μg/cm ² . Comparative Examples 1 to 3 Nitroglycerin is added to the copolymer solution (25% base) or liquid used in Examples 2 to 4 to obtain a drug-containing tape formulation having the same nitroglycerin content as in each of the following Examples. . Table 1 shows the test results of Examples 1 to 4 and Comparative Examples 1 to 3.

[Table] Blood concentration measurement method 2ml of plasma obtained by directly centrifuging the collected blood
8 ng of isosorbide dinitrate as internal standard
(Add 10 μl of isosorbide dinitrate solution containing 0.8 μg/ml n-hexane) and shake for a few seconds. Add 5.5 ml of n-heptane to this and shake for 40 seconds. Immediately after shaking, transfer the organic solvent layer to a Spitz tube and evaporate the solvent with washed inert gas. After adding 100 μl of n-hexane to the residue and shaking, the sample is separated using a gas chromatograph equipped with an electron capture detector. Setting conditions for gas chromatograph with electron capture detector Radiation source: 10 mCi of ⁶³ Ni Carrier gas: Nitrogen gas 20 ml/mm (flow rate) Column temperature: 130°C Injection temperature: 165°C Tedector temperature: 180°C Column: Internal diameter 2.4 mm, 1.2 m long glass column (silane treated) Packing material: Silicon OV-101 (80 to 100 mesh) As is clear from the above example, nitroglycerin as a drug was encapsulated using cyclodextrin as an encapsulating agent. It is remarkable that a drug-containing tape preparation made by blending a compound in contact with a polymeric substance has less loss of drug due to volatilization and a longer duration.

Claims (1)

[Scope of Claims] 1. Consists of a substantially anhydrous molded mixture formed by blending a powdered clathrate compound in which a drug is clathrated with an clathrate agent into a polymeric substance, wherein the clathrate is present in the mixture. 1. A drug-containing tape preparation, characterized in that the drug content is adjusted so that the drug content does not exceed 90% by weight at most, and the drug content is in the range of 50 to 2000 μg/cm ² . 2. The drug-containing tape preparation according to claim 1, wherein the drug is a coronary vasodilator having a nitrite ester in the molecule. 3. The drug-containing tape preparation according to claim 2, wherein the coronary vasodilator is nitroglycerin. 4. The drug-containing tape preparation according to claim 1, wherein the inclusion agent is cyclodextrin. 5. The drug-containing tape preparation according to claim 1, wherein the polymeric substance is a viscous substance that exhibits pressure-sensitive adhesive properties in its normal state. 6 Inclusion agent content in the molding mixture is 3 to 50% by weight
The drug-containing tape preparation according to claim 1. 7. The drug-containing tape preparation according to any one of claims 1 to 6, in which a film-like support material is fixed to or interposed on the surface and/or inside of the preparation.