Composition of docetaxel liposomal injection with high drug loading

Patent metadata

Field	Value
Publication number	US-10842771-B2
Application number	US-201816480308-A
Country	US
Kind code	B2
Filing date	Nov 26, 2018
Priority date	Nov 30, 2017
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

The present invention relates to a pharmaceutical liposomal composition comprising of about 0.8% w/w to about 1% w/w of docetaxel, about 30% w/w to about 38% w/w of Soya Phosphatidyl Choline, about 0.2% w/w to about 0.8% w/w of Sodium Cholesteryl Sulfate, about 61% w/w to about 68% w/w of Sucrose and a pH adjusting agent, wherein the pH of liposomal composition is less than 3.5 and the process for preparation thereof.

First claim

The invention claimed is:

1. A pharmaceutical liposomal composition comprising about 0.8% w/w to about 1% w/w of docetaxel, about 30% w/w to about 38% w/w of soya phosphatidyl choline, about 0.2% w/w to about 0.8% w/w of sodium cholesteryl sulfate, about 61% w/w to about 68% w/w of sucrose and a pH adjusting agent, wherein the pH of liposomal composition is less than 3.5;
wherein the method for preparing the liposomal composition comprises the steps of:
(a) dispersing soya phosphatidyl choline in solvent mixture of methanol and tertiary butyl alcohol to solubilize soya phosphatidyl choline;
(b) adding sodium cholesteryl sulfate to the solubilized soya phosphatidyl choline;
(c) adding docetaxel to contents of step (b);
(d) preparing sucrose solution by dissolving sucrose in purified water and adding the pH adjusting agent to form the sucrose solution, wherein the pH of sucrose solution is about 3;
(e) adding contents of step (c) to step (d) and mixing with high shear at 8000 RPM for 15 minutes;
(f) rota evaporation;
(g) addition of pH adjusting agent to pH of about 3;
(h) extrusion of liposomes containing docetaxel to the particle size d 90 of less than 200 nm;
(i) filtration and
(j) lyophilization.

2. A method of preparing liposomal composition comprising the steps of:
(a) dispersing soya phosphatidyl choline in solvent mixture of methanol and tertiary butyl alcohol to solubilize soya phosphatidyl choline;
(b) adding sodium cholesteryl sulfate to the solubilized soya phosphatidyl choline;
(c) adding docetaxel to contents of step (b);
(d) preparing sucrose solution by dissolving sucrose in purified water and adding the pH adjusting agent to form the sucrose solution, wherein the pH of sucrose solution is about 3;
(e) adding contents of step (c) to step (d) and mixing with high shear at 8000 RPM for 15 minutes;
(f) rota evaporation;
(g) addition of pH adjusting agent to pH of about 3;
(h) extrusion of liposomes containing docetaxel to the particle size d 90 of less than 200 nm;
(i) filtration and
(j) lyophilization.

3. The method of claim 2 , wherein the solvent mixture of methanol and tertiary butyl alcohol is in the ratio of 1:1.

4. The method of claim 2 , wherein the lyophilization of filtrate comprises the steps of freezing the filtrate at temperature ranging from about −5° C. to about −50° C. for the time duration ranging from about 10 hours to about 20 hours; drying under vacuum at a temperature ranging from about −50° C. to about 40° C. for time duration ranging from about 40 hours to about 80 hours.

5. The method of claim 2 , wherein the lyophilization cycle comprises the steps of
(a) loading the filtrate filled vials at −5° C.±2° C.;
(b) freezing the filtrate formulation at −5° C.±2° C. for 100 minutes±20 minutes;
(c) maintaining the freezing temperature for another 300 minutes±20 minutes;
(d) reducing the temperature up to −25° C.±2° C. for 50 minutes±10 minutes;
(e) maintaining the reduced temperature for another 90 minutes±10 minutes;
(f) reducing the temperature up to −50° C.±2° C. for 60 minutes±10 minutes;
(g) maintaining the reduced temperature for another 300 minutes±10 minutes;
(h) evacuating the filtrate by creating vacuum of 750 m Torr to obtain frozen formulation;
(i) drying the frozen formulation at −50° C.±2° C. by creating vacuum at 750 m Torr for 30 minutes±10 minutes;
(j) drying the frozen formulation at −35° C.±2° C. by creating vacuum at 400 m Torr for 120 minutes±10 minutes;
(k) maintaining the drying for another 1255 minutes±20 minutes at −35° C.±2° C. and 400 m Torr vacuum;
(l) drying the frozen formulation at −25° C.±2° C. by creating vacuum at 300 m Torr for 150 minutes±10 minutes;
(m) maintaining the drying for another 600 minutes±20 minutes at −25° C.±2° C. and 300 m Torr vacuum;
(n) drying the frozen formulation at −5° C.±2° C. by creating vacuum at 200 m Torr for 150 minutes±10 minutes;
(o) maintaining the drying for another 900 minutes±20 minutes at −5° C.±2° C. and 200 m Torr vacuum;
(p) drying the frozen formulation at 20° C.±2° C. by creating vacuum at 100 m Torr for 150 minutes±10 minutes; and
(q) maintaining the drying for another 300 minutes±20 minutes at 20° C.±2° C. and 100 m Torr vacuum.

Assignees

• Shilpa Medicare Ltd

Inventors

• Jadhav Kiran K
• S Prashanth
• Pradeep Shivakumar
• Reddy Sreenivasa

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/337 Primary

  having four-membered rings, e.g. taxol · CPC title

• A61K9/127 Primary

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title

• A61K47/28

  Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid · CPC title

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title