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.

Description

TECHNICAL FIELD[0001]The present invention relates to bisphosphonic acid derivative-containing percutaneous preparations having an excellent percutaneous permeability, which comprises bisphosphonic acid derivatives or pharmaceutically acceptable salts thereof, and solvents for the bisphosphonic acid derivatives or pharmaceutically acceptable salts thereof and amphiphilic solubilizing auxiliary agents. More particularly, the present invention relates to percutaneous preparations comprising incadronic acid or minodronic acid, or pharmaceutically acceptable salts thereof.BACKGROUND ART[0002]Certain synthetic bisphosphonate compounds having a methanebisphosphonic acid structure which are structurally analogous to pyrophosphoric acid and stable also in vivo (hereinafter referred to as bisphosphonic acid derivatives or pharmaceutically acceptable salts thereof, or sometimes merely as bisphosphonic acid derivatives) have biological actions such as an excellent bone resorption inhibitory ac...

AI Technical Summary

Benefits of technology

[0011]Under such a technical level, the present inventors made extensive studies to develop pharmaceutical preparations of incadronate, which is called the bisphosphonate of the third generation, without relying on oral administration, injections such as intravenous drip infusion, etc. As a result, it has been found that incadronate shows an excellent percutaneous permeability and targeting toward bone tissues and at the same time, excellent drug retention in bone tissues which was unexpected from conventional findings on the bisphosphonates.

[0014]The present inventors made further extensive studies to clarify causes for high permeability when using the suspension-type base. As a result, it has been demonstrated that when an amphiphilic solubilizing auxiliary agent soluble in both water and oil is formulated in the percutaneous drug system, a more excellent percutaneous permeability is exhibited than the preparations formulated with decyl methyl sulfoxide described in the British Patent No. 1,582,694 supra and known to promote a particularly excellent percutaneous permeability, and the formulation containing this amphiphilic solubilizing auxiliary agent shows effects not only on the bisphosphonates such as incadronate or minodronic acid but also on the other bisphosphonates in a similar fashion.

[0015]It has also been demonstrated that the percutaneous preparation of minodronic acid formulated with the amphiphilic solubilizing auxiliary agent shows a percutaneous permeability enhanced by several-fold, when compared to a similar percutaneous preparation of alendronate. As such, it is an unexpectedly marked effect in the art to differ in the percutaneous permeability by several times between the preparations of the same preparation materials except for the effective ingredient and among the bisphosphonates, minodronic acid, etc. were recognized to be particularly useful in providing excellent percutaneous preparations.

Problems solved by technology

It is reported that these bisphosphonates are poor in bioavailability when orally administered, should avoid alimentary effects since their absorption is suppressed especially in the presence of calcium or iron, deposit very rapidly onto bone and might cause gastrointestinal disorders by oral administration though they are mild, and further that recent studies revealed bioavailability of the bisphosphonates even when administered pernasally or percutaneously, and so on (see “Bisphosphonates and Bone Disease: Kiso-to-Rinsho (The Clinical Report)” Jul. 30, 1996, published by Ishiyaku Publishers Inc.).

However, the bisphosphonates are poor in absorbability per os and sometimes cause an undesired effect such as gastrointestinal disorders, etc. when a large dose is administered.

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