Process for preparing poly(glycolide-co-lactide) copolymer microparticles

Patent metadata

Field	Value
Publication number	US-10294337-B2
Application number	US-201615741995-A
Country	US
Kind code	B2
Filing date	Jun 21, 2016
Priority date	Jul 9, 2015
Publication date	May 21, 2019
Grant date	May 21, 2019

Abstract

A process for preparing poly(lactide-co-glycolide) copolymer particles with an average particle size in the range of 50-800 nm includes transferring a mixture of poly(lactide-co-glycolide) copolymer, ethanol and carbon dioxide from a first reactor into a second reactor under rapid reduction of the pressure and expansion with phase separation into a gas phase, an ethanol aerosol and an ethanolic suspension containing poly(lactide-co-glycolide) copolymer particles, removing the carbon dioxide gas and the ethanol aerosol from the second reactor, and obtaining the poly(glycolide-co-lactide) copolymer particles in the form of an ethanolic suspension or in dry form from the second reactor.

First claim

The invention claimed is:

1. A process for preparing poly(lactide-co-glycolide) copolymer particles with an average particle size in the range of 50-800 nm, the process comprising:
a) transferring ethanol and a poly(lactide-co-glycolide) copolymer with a content of polymerized monomer units of 55-80 mol % lactide and 20 to 45 mol % of glycolide and a molecular weight M w of 1,000-25,000 into a first reactor with a stirring equipment,
b) feeding carbon dioxide into the first reactor so that carbon dioxide is from 65 to 85% by weight and the ethanol is 15 to 35% by weight whereby carbon dioxide and ethanol add up to 100%,
c) mixing the poly(lactide-co-glycolide) copolymer, the ethanol, and the carbon dioxide by stirring and adjusting or maintaining the mixture in the first reactor to a temperature of at least 31 and up to 70° C. and a pressure of from 7.38 MPa to 50 MPa, where carbon dioxide enters the supercritical stage with ethanol as a co-solvent,
d) stirring the mixture from c) for 1 to 5 hours, whereby at least a part of the poly(glycolide-co-lactide) copolymer becomes dissolved in the mixture of carbon dioxide and ethanol,
e) transferring the mixture from d) into a second reactor under rapid reduction of the pressure and expansion with phase separation into a gas phase, an ethanol aerosol and an ethanolic suspension containing poly(lactide-co-glycolide) copolymer particles,
f) removing the carbon dioxide gas and the ethanol aerosol from the second reactor, and
g) obtaining the poly(glycolide-co-lactide) copolymer particles with an average particle size in the range of 50-800 nm in the form of an ethanolic suspension or in dry form from the second reactor.

2. The process according to claim 1 , wherein a polydispersity-index (PI) of the poly(lactide-co-glycolide) copolymer particles obtained in g) is 0.2 or less.

3. The process according to claim 1 , wherein the poly(lactide-co-glycolide) copolymer particles are obtained from the ethanolic suspension from step g) in dry form by evaporation of the ethanol.

4. The process according to claim 3 , wherein the evaporation of the ethanol is performed by spray drying.

5. The process according to claim 1 , wherein a yield of particles that were obtained in g) is at least 6% by weight % relative to the applied amount of poly(lactide-co-glycolide) copolymer in a).

6. The process according to claim 1 , wherein the process is performed in a semi-continuous manner wherein a part of the poly(lactide-co-glycolide) copolymer becomes dissolved in d), and, simultaneous to the transfer of the mixture from d) into the second reactor in e), a mixture of ethanol and carbon dioxide in supercritical stage is added to the first reactor, so that a part or all of the undissolved poly(lactide-co-glycolide) copolymer becomes dissolved.

7. The process according to claim 6 , wherein the addition of the mixture of ethanol and carbon dioxide in supercritical stage to the first reactor and the simultaneous transfer of the mixture from d) into the second reactor in e) is continued until the poly(lactide-co-glycolide) copolymer was dissolved to an amount of at least 98% and discharged to the second reactor in e) followed by f) and g).

8. The process according to claim 1 , wherein the process is performed in a continuous manner by continuously:
adding the poly(lactide-co-glycolide) copolymer, the carbon dioxide in supercritical stage, and the ethanol into the first reactor,
transferring the mixture into the second reactor and removing carbon dioxide and ethanol, and
obtaining the poly(lactide-co-glycolide) copolymer particles in ethanolic suspension.

9. The process according to claim 1 , wherein the poly(lactide-co-glycolide) copolymer particles obtained from g) show a storage stability of at least two months in respect to constant particle size and absence of aggregation.

10. The process according to claim 1 , wherein an active pharmaceutical ingredient is added in a).

11. The process according to claim 1 , wherein poly(lactide-co-glycolide) copolymer particles comprised in the gas phase and/or the ethanolic aerosol which is removed from the second reactor in f) are obtained by a separation technique.

12. The process according to claim 11 , wherein the poly(lactide-co-glycolide) copolymer particles are separated with an aero cyclone with electrostatical recirculation system.

13. A device for carrying out a process according to claim 1 , the device comprising:
a first reactor and a second reactor,
an apparatus operable for mixing, cooling, heating, and pressuring carbon dioxide and ethanol and feeding the same into the first reactor, and
an apparatus operable for transferring the mixture of carbon dioxide, ethanol, and poly(lactide-co-glycolide) copolymer particles into the second reactor, wherein
the second reactor comprises outlets for the gas flow, outlets for the liquid flow, and a bottom plate.

14. The device according to claim 13 , wherein the bottom plate is a double sheeted bottom plate with an upper sheet and a lower sheet, where the upper sheet is optionally in contact with the wall of the second reactor.

15. The device according to claim 13 , wherein the device further comprises an aero cyclone, and
wherein the aero cyclone is placed down-stream behind the second reactor so that the gas flow from the second reactor can be fed into the aero cyclone.

16. A device for carrying out a process according to claim 1 , the device comprising:
a first reactor and a second reactor,
an apparatus operable for mixing, cooling, heating, and pressuring carbon dioxide and ethanol and feeding the same into the first reactor, and
an apparatus operable for transferring the mixture of carbon dioxide, ethanol and poly(lactide-co-glycolide) copolymer particles into the second reactor, wherein
the second reactor is an aero cyclone.

Assignees

• Evonik Roehm Gmbh

Inventors

• Kirchner Andreas
• Lizio Rosario
• Rossmeissl Markus Rolf
• Luley Wolfgang
• Vorholz Johannes
• Grimm Silko
• Schneider Marc

Classifications

• C08G63/88 Primary

  Post-polymerisation treatment · CPC title

• C08J2367/04

  Polyesters derived from hydroxy carboxylic acids, e.g. lactones (C08J2367/06 takes precedence) · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• C08J3/12 Primary

  Powdering or granulating · CPC title

• A61K9/146

  with organic macromolecular compounds · CPC title