CN1669554A - Liposome vitality conazole preparation - Google Patents

Abstract

The invention relates to an externally use medicinal preparation, which mainly comprises (by weight ratio), (1) 0.08-0.8% voriconazole, (2) 10-32% phosphatides or their derivatives, (3) 0.3-10% cholestrins or their derivatives, (4) acid liquor 10-40% capable of dissolving voriconazole, phosphatides or their derivatives, cholestrins or their derivatives, (5) alkaline solution 10-40%, (6) bracket agent 1-5%.

Description

Liposome vivocon azoles preparation

Technical field

The present invention relates to a kind of external pharmaceutical preparation, especially a kind of local skin drug-delivery preparation with antifungic action.

Background technology

Chinese patent application 93101514.6 discloses a kind of " Liposomal itraconazole formulations ", this invention provides and has comprised according to Taikan azoles (itraconazole), phospholipid, for the part Liposomal formulation of the dicyandiamide solution of using according to Taikan azoles and described phospholipid, water and conventional auxiliary formulation, it is characterized in that described compositions comprises DIMETHYLISOSORBIDE (dimethylisosorbide) and tetraethylene glycol (TEG) as dicyandiamide solution.All is new in the part with the application in the Liposomal formulation according to the Liposomal formulation of Taikan azoles and described dicyandiamide solution.Chinese patent application 97199420.X discloses a kind of " antifungal combination therapy ", and this article is described antifungal combination therapy and comprised that known antifungal medicine such as pyroles or polyenoid class and the deutero-antifungal of Pneumocandin unite use.More particularly, this invention relates to antifungal combination therapy, comprises pyroles such as fluconazol, Voriconazole, itraconazole, ketoconazole, miconazole, ER30346, SCH56592; Polyenoid class such as amphotericin B, nystatin or its liposome and lipid form such as Abelcet, AmBisome and Amphocil; Purine or pyrimidine nucleoside acid inhibitor such as 5-flurocytosine; Or polyoxin such as fumanomycin, particularly fumanomycin Z or other chitin inhibitor, elongation factor inhibitor such as sordarin and analog thereof, mannan inhibitor such as Predamycin, germ-resistant/permeability induce (BPI) protein such as XMP.97 or XMP.127 or complex carbohydrate antifungal such as CAN-296 and Pneumocandin derivant described herein to unite use.

Summary of the invention

Purpose of the present invention aims to provide a kind of local skin drug-delivery preparation with antifungic action---liposome vivocon azoles preparation.

Liposome vivocon azoles preparation of the present invention mainly comprises following components in weight percentage:

(a), 0.08-0.8% vivocon azoles;

(b), 10-32% phospholipid or derivatives thereof;

(c), 0.3-10% cholesterol or derivatives thereof;

(d), can dissolve the acid solution 10-40% of vivocon azoles, phospholipid or derivatives thereof, cholesterol or derivatives thereof;

(e), alkaline solution 10-40%;

(f), caffolding agent 1-5%.

Except that said components, also can comprise the thickening agent that percentage by weight is 0.5-1.5%; Antiseptic is an amount of; Described thickening agent and antiseptic are liposome kind commonly used.

Above-mentioned vivocon azoles voriconazole, UK109406 are a kind of state-of-the art second filial generation triazole antifungal agents; Above-mentioned phospholipid or derivatives thereof is meant that those can be dissolved in phospholipid in nontoxic, the pharmaceutically useful organic solvent with the vivocon azoles, as: lecithin, phosphatidylcholine, ethanolamine and serine, sphingomyelins, cuorin, plasmalogen, phosphatidic acid or cerebroside; Above-mentioned cholesterol or derivatives thereof can be cholesterol, cholesterol acetonyl ester or Cholesteryl hemisuccinate etc.; Above-mentioned acid solution for can dissolve vivocon azoles, phospholipid or derivatives thereof, cholesterol or derivatives thereof and can with the acid solution of alkali generation neutralization reaction, as formic acid, acetic acid, propanoic acid etc.; The alkaline solution of neutralization reaction be for taking place with acid in above-mentioned alkaline solution, as: sodium carbonate, phosphoric acid are received, phosphoric acid hydrogen two is received, strong aqua ammonia etc.; Above-mentioned caffolding agent is caffolding agent commonly used, as: mannitol, glucose, alginic acid etc.

The present invention is single lipid bilayer bodily form formula, and the dosage form that the present invention makes can be various external preparation.

Liposome of the present invention is specially adapted to local skin treatment local fungal and infects.

Pharmacodynamic study:

Vivocon azoles voriconazole, 10～500 times of the antifungal activities of UK109406 are to fluconazol, the then similar itraconazole itraconazole of its antimicrobial spectrum comprises that to some condition pathomycetes such as aspergillus, Cryptococcus and Candida drug-fast Candida krusei of fluconazol and Candida glabrata (the MIC scope can reach 0.001～0.5g/ml person) are all had antibacterial activity.

The vivocon azoles is to the bactericidal action of aspergillosis kind tool, and its MIC (minimum bactericidal concentration) is 2 times of minimum inhibitory concentration.External, the vivocon azoles is to some endemicity funguses such as Blastomyces dermatitidis, Blastomyces coccidioides, Paracoccidioides brasiliensis and Histoplasma capsulatum, even some contaminants such as Fusarium spp., crin plug prop up top spore, the many spores of flat match, trichosporon bacteria kind and Podbielniak and match many spores and also have antibacterial activity, and these are insensitive to fluconazol, itraconazole and amphotericin B etc.Be that in the Cavia porcellus body in the experimental infection, the vivocon azoles also has obvious curative effects and prevents that pathomycete from invading the effect of tissue with these experiment in vitro parallel.When the Cavia porcellus systemic infection similar to human infection causes pulmonary aspergillosis, use vivocon azoles 10mg/kg and 8mg/kg respectively, po, bid, all obtain healing, can make in the tissue aseptic, its effect no matter the animal immune state how all than with itraconazole and 4mg/kg the next day effect of intraperitoneal injection amphotericin B more obvious.With vivocon azoles 10mg/kg, po, bid also can cure the aspergillosis endocarditis, and than the itraconazole effect of same dose for good.

The aggressive candidiasis that immunologic function animal Candida albicans normal or immune dysfunction causes, with vivocon azoles 5mg/kg, po, bid treats, and can obtain the fluconazol effect same; And to the caused aggressive infection of fluconazol resistant Candida albicans, Candida krusei and Candida glabrata, the vivocon azoles is than the better efficacy of fluconazol.Vivocon azoles 2.5～20mg/kg, po, bid also has the same curative effect of fluconazol to lung and intracranial cryptococcosis.Material proof vivocon azoles is arranged recently to induced lung aspergillosis (30mg/ (kg.And rabbit aggressive aspergillosis (15mg/ (kg d)).D)) respectively with amphotericin B (4,1mg/ (kg.D)) compare research, its curative effect height, pharmacokinetics shows that its metabolism is faster.

The specific embodiment

Embodiment:

Get 0.1 part of vivocon azoles, 25 parts of soybean phospholipids, 4 parts in cholesterol, 30 parts of formic acid solutions, vivocon azoles, soybean phospholipid, cholesterol are dissolved in the formic acid, under stirring, add the sodium carbonate neutralizing acid, make pH value between 4-10, add 4 parts in mannitol, stir, packing promptly.

Claims (2)

1, a kind of liposome vivocon azoles preparation is characterized in that mainly comprising following components in weight percentage:

(a), 0.08-0.8% vivocon azoles;

(b), 10-32% phospholipid or derivatives thereof;

(c), 0.3-10% cholesterol or derivatives thereof;

(d), can dissolve the acid solution 10-40% of vivocon azoles, phospholipid or derivatives thereof, cholesterol or derivatives thereof;

(e), alkaline solution 10-40%;

(f), caffolding agent 1-5%.

2, according to the described liposome vivocon of claim 1 azoles preparation, it is characterized in that comprising the thickening agent that percentage by weight is 0.5-1.5%.