A method for producing a cationic liposomal preparation comprising a lipophilic active compound with physical and chemical stability during manufacturing, storing and reconstituting, and further a cationic liposomal preparation obtainable by this method as well as specific cationic liposomal prepara
A method for producing a cationic liposomal preparation comprising a lipophilic active compound with physical and chemical stability during manufacturing, storing and reconstituting, and further a cationic liposomal preparation obtainable by this method as well as specific cationic liposomal preparations as well as pharmaceutical compositions are disclosed.
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1. A method for producing a cationic liposomal preparation comprising: (a) mixing an organic solvent with a lipophilic active compound and a cationic lipid to form an organic solution;(b) mixing the organic solution of step (a) with an aqueous solution comprising a stabilizing agent to form a disper
1. A method for producing a cationic liposomal preparation comprising: (a) mixing an organic solvent with a lipophilic active compound and a cationic lipid to form an organic solution;(b) mixing the organic solution of step (a) with an aqueous solution comprising a stabilizing agent to form a dispersion of cationic liposomes, wherein the dispersion comprises cationic liposomes in an aqueous medium;(c) optionally homogenising the dispersion of step (b) at least once;(d) optionally sterile filtrating the dispersion obtained in step (c); and(e) optionally dehydrating the dispersion of cationic liposomes of step (d) to form a cationic liposomal preparation;wherein the cationic liposomes in the dispersion of step (b) comprise at least one cationic lipid in an amount of at least about 30 mol % and a lipophilic active compound in an amount of at least about 0.1 mol %; and wherein the stabilizing agent in the dispersion of step (b) is present in an amount of about 0.1% (m/v) to about 20% (m/v); and,wherein the pH value of the aqueous medium in any one of steps (b), (c), or (d) is between about 3.0 and 7.0. 2. The method of claim 1, wherein the pH value of the aqueous medium in any one of steps (b), (c), or (d) is between about 3.0 and about 6.5 between about 4.0 and about 6.5, between about 4.0 and about 6.0, or between about 4.5 and about 5.5. 3. The method of claim 1, wherein the pH value of the aqueous medium in step (b) is between about 3.0 and about 6.5, between about 4.0 and about 6.5, between about 4.0 and about 6.0, or between about 4.5 and about 5.5. 4. The method of claim 1, wherein the cationic liposomes comprise a further amphiphile in an amount of up to about 69.9 mol %. 5. The method of claim 1, wherein the method further comprises reconstituting the cationic liposomal preparation of step (c) in an aqueous solution. 6. The method of claim 1, wherein the method further comprises ultra filtrating the dispersion before step (c) and/or (d). 7. The method of claim 1, wherein the liposomal preparation comprising the active compound is physically and chemically stable in any one of the steps (b), (c), or (d) for at least about 12 hours at about 2° C. to about 8° C. or at least about 4 hours at ambient temperature. 8. The method of claim 1, wherein at least one of the steps (b), (c), or (d) is performed at a temperature between about −1° C. and about 15′C. between about 1° C. and about 10° C., or between about 2° C. and about 8° C. 9. The method of claim 4, wherein the further amphiphile is non-cationic. 10. The method of claim 1, wherein the lipophilic active compound is selected from the group consisting of a taxane, a camptothecin, an epothilone, a statin, a depsipeptide, thalidomide, other agents interacting with microtubuli such as discodermolide, laulimalide, isolaulimalide, eleutherobin, Sarcodictyin A, and Sarcodictyin B. 11. The method of claim 1, wherein the taxane is paclitaxel, docetaxel, or any lipophilic derivative thereof. 12. The method of claim 10, wherein the liposomal preparation comprising the taxane is physically and chemically stable in any one of the steps (b), (c), or (d) for at least about 12 hours at about 2° C. to about 8° C. and at least about 4 hours at ambient temperature. 13. The method of claim 1, wherein the liposomal preparation comprises liposomes with an average particle size of about 50 nm to about 400 nm or about 100 nm to about 300 nm. 14. The method of claim 9, wherein the non-cationic amphiphile is a sterol, a phospholipid, a lysolipid, a lysophospholipid, a sphingolipid, as pegylated lipid, or a combination thereof. 15. The method of claim 14, wherein the sterol is cholesterol. 16. The method of claim 14, wherein the phospholipid is diacylphosphatidylcholine. 17. The method of claim 1, wherein step (c) is performed by freeze drying. 18. The method of claim 1, wherein step (c) comprises removing water under vacuum. 19. The method of claim 1, wherein the cationic liposomal preparation comprises a non-volatile organic acid and/or the aqueous solution. 20. The method of claim 19, wherein the non-volatile organic acid is citric acid. 21. The method of claim 5, wherein reconstitution of the cationic liposomal preparation is performed at a temperature between about −1° C. and about 15° C., between about 1° C. and about 10° C., or between about 2° C. and about 8° C. 22. The method of claim 5, wherein the pH value of the aqueous solution is between about 3.0 and about 6.5, between about 4.0 and about 6.5, between about 4.0 and about 6.0, or between about 4.5 and about 5.5.
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이 특허에 인용된 특허 (17)
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