Patent ID: 6077534
Filing Date: 2000-06-20
Classification: A61K

Abstract:
A method of producing a pharmaceutical formulation containing escin as a pharmaceutically active ingredient, for treatment of prophylaxis of venous circulatory disorders, venous insufficient or inflammations, edema including brain edema, or swellings, in which said formulation is prepared by a process comprising:i) milling horse chestnut seeds to a maximum particle size of 6 mm and a minimum particle size of 0.3 mm, then macerating and percolating for 1 to 2 days the milled seeds with a mixture of alcohol and water as solvent, the alcohol content being 35-65% v/v, at a temperature of 30-40.degree. C., to obtain a horse chestnut extract tincture, whereby 1500 parts by weight--2000 parts by weight is extracted by 4000 to 5000 parts by volume;ii) concentrating the thus obtained liquid horse chestnut tincture under reduced atmospheric pressure by evaporation with a temperature of 45-60.degree. C. until a content of total dry residue of 50% to 63% w/w in the liquid extract is obtained;iii) adding: a) dextrin in a ratio of 1 to 25 parts by weight per 100 parts by weight to the total dry substance calculated on the basis of the liquid extract obtained according to ii) above, optionally together with b) demineralized water in such an amount as to adjust the spray-drying solution to a total dry substance content of 38-48% w/w and a triterpene glycoside content of 15-20% w/w % in the dry extract to be made, calculated on the basis of the pharmacologically active agent escin, to prepare the liquid extract mixture for spray-drying;iv) spray-drying the preceding liquid mixture at a temperature of 40-60.degree. C., the inlet air having an O.sub.2 content of <10% and a temperature of 180-210.degree. C., the outlet air having a temperature of 75-95.degree. C.;v) addinga) dextrin tob) the free-flowing spray-dried extract obtained through iv) so that the complete mixture to be pelletized has a total standardized content of 15-19% w/w triterpene glycosides, calculated on the basis of the agent escin to form a standardized mixture;vi) blending the above standardized mixture of a) dextrin and b) spray-dried extract together withc) polyvinylpyrrolidone, selected from the group consisting of povidone and a copolymerisate of vinyl pyrrolidone and vinyl acetate andd) talcum so that the weight ratio is in w/w 0.5-10 parts a): 50-150 parts b): 1-15 parts c): 0.5-10 parts d);vii) pelletizing the mixture of a): b): c): d) by adding an alcohol for moistening the blend in a mixer/granulator apparatus or marumerizer, spheronizer or other pelletizing machine to form a moist pelletized material;viii) drying the moist pelletized material in a drier using a diverted recirculating air stream from the drier wherein the inlet temperature does not succeed 70.degree. C., the outlet end point temperature being at least 45.degree. C. to form a dried pellet material;ix) sieving the dried pellet material to obtain a specification range of 500-1700 .mu.m to obtain sieved pellets;x) coating the sieved pellets by spraying technique using a mixture of acrylates, dissolved in a mixture of organic solvents together with small amounts of a plasticizer so that the portion of the coating calculated on the basis of the total pellet weight is within the range of 2.5 to 5.0% w/w to form coated pellets and finally filling the coated pellets into hard gelatin capsule bottom parts, closing the capsules by means of the gelatin top parts or compacting the coated pellets together with usual pharmaceutically acceptable disintegrating matrix components to sustained release tablets.