Method for formulating large diameter synthetic membrane vesicles

• US 9,737,482 B2
• Filed: 03/06/2013
• Issued: 08/22/2017
• Est. Priority Date: 04/09/2010
• Status: Active Grant

• Current Assignee: Pacira Pharmaceuticals, Inc. (Pacira Biosciences, Inc.)
• Original Assignee: Pacira Pharmaceuticals, Inc. (Pacira Biosciences, Inc.)
• Inventors: Schutt, Ernest George, McGuire, Ronald Warren, Walters, Peter Andrew, Los, Kathleen D. A.
• Primary Examiner(s): Salamon, Peter A
• Application Number:
  US13/786,933
• Publication Number:
  US 20130183372A1
• Time in Patent Office: 1,630 Days
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4458 only substituted in position 2, e.g. methylphenidate
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911
• CPC Class Codes: A61K 9/1277 Processes for preparing; Proliposomes
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61M 11/00 Sprayers or atomisers specially adapted for therapeutic purposes in general B05B; aerosol containers B65D83/14
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: B01D 1/16 by spraying B01D1/22 takes precedence
• CPC Class Codes: B01F 2035/98 Cooling
• CPC Class Codes: B01F 2101/22 Mixing of ingredients for pharmaceutical or medical compositions
• CPC Class Codes: B01F 23/2132 using nozzles
• CPC Class Codes: B01F 23/41 Emulsifying
• CPC Class Codes: B01F 23/49 Mixing systems, i.e. flow charts or diagrams
• CPC Class Codes: B01F 25/52 with a rotary stirrer in the recirculation tube
• CPC Class Codes: B01F 27/27 Mixers with stator-rotor systems, e.g. with intermeshing teeth or cylinders or having orifices the stirrers having a central axial inflow and a substantially radial outflow B01F27/81
• CPC Class Codes: B01F 35/92 for heating the outside of the receptacle, e.g. heated jackets or burners
• CPC Class Codes: B01J 13/043 Drying and spraying
• CPC Class Codes: B01J 13/125 by evaporation of the solvent apparatus therefor B01J13/043

Abstract

The present invention generally relates to the field of pharmaceutical sciences. More specifically, the present invention includes apparatus and devices for the preparation of pharmaceutical formulations containing large diameter synthetic membrane vesicles, such as multivesicular liposomes, methods for preparing such formulations, and the use of specific formulations for therapeutic treatment of subjects in need thereof. Formation and use of the pharmaceutical formulations containing large diameter synthetic membrane vesicles produced by using the apparatus and devices for therapeutic treatment of subjects in need thereof is also contemplated.

Claims

1. An evaporation apparatus, comprising:

a solvent removal vessel having a top, a bottom and a circular wall;

at least one atomizing nozzle;

a carrier gas entrance orifice;

a solvent removal gas exit orifice centrally connected to the top; and

a product exit orifice connected to the bottom of the vessel,

wherein the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel, wherein the tube is fitted with a narrowing cone.

2. The apparatus of claim 1, wherein the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel, wherein the tube is fitted with a narrowing cone and an annular ring.

3. The apparatus of claim 1, wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 5:

1 and 100;

1.

4. The apparatus of claim 1, wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 20:

1 and 60;

1.

5. A process for preparing a suspension of multivesicular liposomes using the evaporation apparatus of claim 1, comprising:

introducing large diameter synthetic membrane vesicles pre-droplets to the solvent removal vessel, wherein the large diameter synthetic membrane vesicles pre-droplets comprise a first component core and an aqueous phase shell;

applying a carrier gas in a tangential direction to the circular wall through the carrier gas entrance orifice; and

removing a solvent removal gas through the solvent removal gas exit orifice to provide the suspension of multivesicular liposomes.

6. The process of claim 5, wherein the multivesicular liposomes further comprises bupivacaine.

7. The apparatus of claim 1, wherein the apparatus further comprises at least two carrier gas entrance orifices.

8. The apparatus of claim 1, wherein at least part of the solvent removal vessel is jacketed.

9. The apparatus of claim 1, wherein the atomizing nozzle is mounted to and extending through the top of the solvent removal vessel.

10. The apparatus of claim 1, wherein the top of the solvent removal vessel comprises a lid.

11. The apparatus of claim 1, further comprising a rinse nozzle mounted to and extending through the top of the solvent removal vessel.

12. The apparatus of claim 1, wherein the circular wall has a central axis and the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel residing along the central axis.

13. The apparatus of claim 12, wherein the atomizing nozzle is angled at least 5 degrees measured off the central axis of the wall and in a plane parallel to the wall nearest to it.

14. The apparatus of claim 1, wherein the tube extends from about ⅓

to about ⅘

of the way into the solvent removal vessel.

15. The apparatus of claim 1, wherein the tube extends about ⅔

of the way into the solvent removal vessel.

16. The apparatus of claim 1, wherein a bottom tip of the narrowing cone diameter is from about 1/1000 to about ⅕

of the diameter of the inside of the solvent removal vessel.

17. The apparatus of claim 1, wherein the solvent removal gas exit orifice diameter is less than 1/10 of a diameter of the inside of the solvent removal vessel.

18. The apparatus of claim 1, wherein the at least one atomizing nozzle comprises:

a first fluid conduit and a second fluid conduit each having at least one entrance orifice and at least one exit orifice;

a fluid contacting chamber having a top comprising at least one entrance orifice and having a bottom comprising at least one exit orifice and connecting to the at least one exit orifice of the first fluid conduit; and

a third fluid conduit, wherein the third fluid conduit annularly surrounds a portion of the fluid contacting chamber.

19. The apparatus of claim 1, wherein the at least one atomizing nozzle comprises:

a first fluid conduit, a second fluid conduit and a third fluid conduit each having at least one entrance orifice and at least one exit orifice;

a first fluid contacting chamber having a top comprising at least one entrance orifice and having a bottom comprising at least one exit orifice and connecting to the at least one exit orifice of the first fluid conduit, wherein the second fluid conduit annularly surrounds a portion of the first fluid contacting chamber;

a second fluid contacting chamber having a top comprising at least one entrance orifice and having a bottom comprising at least one exit orifice and connecting to the at least one exit orifice of the first fluid contacting chamber, wherein the third fluid conduit annularly surrounds a portion of the second fluid contacting chamber; and

a fourth fluid conduit, wherein the fourth fluid conduit annularly surrounds a portion of the second fluid contacting chamber.

20. The apparatus of claim 18, wherein the tube is fitted with an annular ring.

21. The apparatus of claim 18, wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 5:

1 and 100;

1.

22. The apparatus of claim 18, wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 20:

1 and 60;

1.

23. The apparatus of claim 18, wherein at least part of the solvent removal vessel is jacketed.

24. The apparatus of claim 18, wherein the atomizing nozzle is mounted to and extending through the top of the solvent removal vessel.

25. The apparatus of claim 18, wherein the top of the solvent removal vessel comprises a lid.

26. The apparatus of claim 18, further comprising a rinse nozzle mounted to and extending through the top of the solvent removal vessel.

27. The apparatus of claim 18, wherein the circular wall has a central axis and the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel residing along the central axis.

28. The apparatus of claim 27, wherein the atomizing nozzle is angled at least 5 degrees measured off the central axis of the wall and in a plane parallel to the wall nearest it.

29. The apparatus of claim 18, wherein the tube extends from about ⅓

to about ⅘

of the way into the solvent removal vessel.

30. The apparatus of claim 18, wherein the tube extends about ⅔

of the way into the solvent removal vessel.

31. The apparatus of claim 18, wherein a bottom tip of the narrowing cone diameter is from about 1/1000 to about ⅕

of the diameter of the inside of the solvent removal vessel.

32. The apparatus of claim 18, wherein the solvent removal gas exit orifice diameter is less than 1/10 of a diameter of the inside of the solvent removal vessel.

33. The apparatus of claim 19, wherein the tube is fitted with an annular ring.

34. The apparatus of claim 19, wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 5:

1 and 100;

1.

35. The apparatus of claim 19, wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 20:

1 and 60;

1.

36. The apparatus of claim 19, wherein at least part of the solvent removal vessel is jacketed.

37. The apparatus of claim 19, wherein the atomizing nozzle is mounted to and extending through the top of the solvent removal vessel.

38. The apparatus of claim 19, wherein the top of the solvent removal vessel comprises a lid.

39. The apparatus of claim 19, further comprising a rinse nozzle mounted to and extending through the top of the solvent removal vessel.

40. The apparatus of claim 19, wherein the circular wall has a central axis and the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel residing along the central axis.

41. The apparatus of claim 40, wherein the atomizing nozzle is angled at least 5 degrees measured off the central axis of the wall and in a plane parallel to the wall nearest it.

42. The apparatus of claim 19, wherein the tube extends from about 1/3 to about ⅘

of the way into the solvent removal vessel.

43. The apparatus of claim 19, wherein the tube extends about ⅔

of the way into the solvent removal vessel.

44. The apparatus of claim 19, wherein a bottom tip of the narrowing cone diameter is from about 1/1000 to about ⅕

of the diameter of the inside of the solvent removal vessel.

45. The apparatus of claim 19, wherein the solvent removal gas exit orifice diameter is less than 1/10 of a diameter of the inside of the solvent removal vessel.