Percutaneous preparations

Abstract

A bisphosphonic acid derivative-containing percutaneous preparation of an excellent percutaneous permeability, comprising a bisphosphonic acid derivative such as incadronic acid, minodronic acid, etc., or pharmaceutically acceptable salts thereof, a solubilizing agent for the derivative or pharmaceutically acceptable salts thereof, and an amphiphilic solubilizing auxiliary agent, which may optionally contain a suspension-type base such as a polyvalent alcohol, a higher fatty acid ester, a liquid hydrocarbon or a vegetable oil, etc. This preparation has an excellent percutaneous permeability, reduces burdens on the patient, does not deteriorate the patient's compliance even in the administration over a prolonged period of time and can achieve the therapeutic effects in a short period of time.

1 . A bisphosphonic acid derivative-containing plaster formulation, which comprises a bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof, a solubilizing agent for the derivative or a pharmaceutically acceptable salt thereof, at least one amphiphilic solubilizing auxiliary agent selected from the group consisting of a glycerine fatty acid ester, a polyglycerine fatty acid ester, a polyoxyethylene sorbitol fatty acid ester, a polyoxyethylene alkyl-formaldehyde adduct, a polyoxyethylene sterol/hydrogenated sterol, a polyethylene glycol monostearate, a polyoxyethylene alkyl ether, a polyoxyethylene polyoxypropylene alkyl ether, a polyoxyethylene polyoxypropylene glycol, a polyoxyethylene alkyl phenyl ether, a yellow beeswax derivative, a polyoxyethylene alkylamine/fatty acid amide, a polyoxyethylene alkyl ether phosphoric acid/phosphate, a monofatty acid Polyoxyethylene-hydrogenated castor oil, N-methyl-2-pyrrolidone, acetone, methyl ethyl ketone, methyl isobutyl ketone, triethyl citrate, ethyl acetate, ethyl lactate, triacetine, pantothenyl ethyl ether, ethylene glycol monobutyl ether, dimethyl ether, isopropanolamine, diisopropanolamine, 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1-propanediol, N,N-dimethylacetamide, geraniol denatured alcohol, sucrose octaacetate denatured alcohol, linalyl acetate denatured alcohol, benzyl alcohol, butanol, 2-butanol, diethylene glycol, dipropylene glycol, 1,3-butylene glycol, propylene glycol, propylene carbonate, thioglycolic acid, propionic acid, methanesulfonic acid, glacial acetic acid, lactic acid, butyric acid and ichthammol, and a styrene-isoprene-styrene block copolymer as an adhesive component. 
   
   
       2 . The plaster formulation according to  claim 1 , wherein a percutaneously effective dose of the bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof, and 0.01 to 10 parts by weight of the solubilizing agent based on 1 part by weight of the bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof and 1 to 10 parts by weight of the amphiphilic solubilizing auxiliary agent based on the whole preparation are formulated. 
   
   
       3 . The plaster formulation according to  claim 1 , which contains a suspension-type base. 
   
   
       4 . The plaster formulation according to  claim 3 , wherein the suspension-type base is a polyvalent alcohol, a higher fatty acid ester, a liquid hydrocarbon or a vegetable oil. 
   
   
       5 . The plaster formulation according to  claim 4 , wherein a compounding amount of the suspension-type base is 0.01 to 50 wt % based on the whole preparation. 
   
   
       6 . The plaster formulation according to  claim 1 , wherein the bisphosphonic acid derivative or a pharmaceutically acceptable salt is at least one selected from the group consisting of alendronic acid, ibandronic acid, incadronic acid, etidronic acid, olpadronic acid, clodronic acid, zoledronic acid, tiludronic acid, neridronic acid, pamidronic acid, risendronic acid, minodronic acid and 1-hydroxy-3-(1-pyrrolidinyl)propylidenebisphosphonic acid as well as pharmaceutically acceptable salts thereof. 
   
   
       7 . The plaster formulation according to  claim 6 , wherein the bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof is incadronate or minodronic acid. 
   
   
       8 . The plaster formulation according to  claim 7 , wherein the solubilizing agent for the bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof is water or alkaline water. 
   
   
       9 . (canceled) 
   
   
       10 . The plaster formulation according to  claim 1 , wherein a ratio of the soluble form to the insoluble form of the bisphosphonic acid derivative or a pharmaceutically acceptable salt thereof contained in the preparation is 1:0.01 to 1:0.9. 
   
   
       11 . The plaster formulation according to  claim 1 , wherein a liquid property of the solute of bisphosphonic acid and the solubilizing agent is adjusted to the pH of 4 to 7. 
   
   
       12 . A plaster formulation comprising incadronic acid or minodronic acid, or a pharmaceutically acceptable salt thereof, and a suspension-type base. 
   
   
       13 . (canceled) 
   
   
       14 . The plaster formulation according to  claim 12 , wherein the suspension-type base is a polyvalent alcohol, a higher fatty acid ester, a liquid hydrocarbon or a vegetable oil. 
   
   
       15 . The plaster formulation according to  claim 14 , wherein a compounding amount of the suspension-type base is 0.01 to 50 wt % based on the whole preparation. 
   
   
       16 - 17 . (canceled) 
   
   
       18 . The plaster formulation according to  claim 12 , wherein the preparation is in the form of a tape. 
   
   
       19 . A method for treating diseases associated with accelerated bone resorption or ectopic calcification, comprising administering an effective amount of the bisphosphonic acid derivative-containing plaster formulation according to  claim 1  to a patient in need thereof. 
   
   
       20 . A method for treating diseases associated with accelerated bone resorption or ectopic calcification, comprising administering an effective amount of the percutaneous preparation comprising incadronic acid or minodronic acid, or a pharmaceutically acceptable salt thereof according to  claim 12  to a patient in need thereof. 
   
   
       21 . A plaster formulation comprising: (a) a bisphosphonic acid derivative chosen from incadronate, incadronic acid, minodronic acid, or pharmaceutically acceptable salts thereof, (b) a solubilizing agent, (c) at least one amphiphilic solubilizing auxiliary agent chosen from a polyethylene glycol monostearate, a polyoxyethylene alkyl ether, N-methyl-2-pyrrolidone, or methyl ethyl ketone, and (d) a styrene-isoprene-styrene block copolymer as an adhesive component, wherein the amphiphilic solubilizing auxiliary agent present at from 3 to 8 weight percent and the bisphosphonic acid derivative is present at from 0.1 to 5 weight percent. 
   
   
       22 . The plaster formulation according to  claim 21 , wherein the plaster formulation is in the form of a tape. 
   
   
       23 . A method for treating diseases associated with accelerated bone resorption or ectopic calcification, comprising administering an effective amount of the bisphosphonic acid derivative-containing plaster formulation according to  claim 21  to a patient in need thereof.