Method for formulating large diameter synthetic membrane vesicles

• US 9,737,483 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): Griffin, Walter D
• Assistant Examiner(s): Howell, Marc C
• Application Number:
  US13/787,117
• Publication Number:
  US 20130177638A1
• Time in Patent Office: 1,630 Days
• Field of Search: 3661781, 3661783, 366137, 239428
• 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. A process for making an emulsion using a continuous-flow emulsification system, wherein said emulsification system comprises:

a high shear mixer, comprised of a rotor and a stator;

a recirculation loop, comprised of one or more recirculation lines and an exit line;

a heat exchanger;

one or more outlet lines, comprised of at least one nozzle feed line;

one or more continuous phase inlet lines; and

a discontinuous phase inlet line;

wherein the heat exchanger and the high shear mixer are connected together in the recirculation loop by the one or more recirculation lines, wherein an end of one of the one or more recirculation lines connects to an inlet of the high shear mixer and an end of the exit line connects to an outlet of the high shear mixer;

further wherein the one or more outlet lines and one or more continuous phase inlet lines are connected to the recirculation loop, wherein at least one of the one or more continuous phase inlet lines is directly connected to the one of the one or more recirculation lines and the at least one nozzle feed line is directly connected to the exit line;

further wherein the end of the discontinuous phase inlet line is located less than ⅓

^rd of a rotor diameter from the rotor and less than ⅓

^rd of a rotor diameter from the rotation axis of the rotor and is in fluid communication with the rotor, said process comprising;

feeding an organic discontinuous phase into the emulsification system through the discontinuous phase inlet line and feeding an aqueous continuous phase into the emulsification system through one or more continuous phase inlet lines.

2. The process of claim 1, wherein the organic discontinuous phase comprises a triglyceride.

3. The process of claim 1, wherein the emulsion comprises a triglyceride, surfactant, and water.

4. The process of claim 1 further comprising:

passing the organic discontinuous phase through a hydrophobic sterilizing filter before feeding the aqueous discontinuous phase into the emulsification system through the discontinuous phase inlet line; and

passing the aqueous continuous phase through a hydrophilic sterilizing filter before feeding the organic continuous phase into the emulsification system through the one or more continuous phase inlet lines.

5. A process for making an emulsion using a continuous-flow emulsification system, wherein said emulsification system comprises:

a high shear mixer, comprised of a rotor and a stator;

a recirculation loop, comprised of one or more recirculation lines and an exit line;

a heat exchanger;

one or more outlet lines, comprised of at least one nozzle feed line;

one or more continuous phase inlet lines; and

a discontinuous phase inlet line;

wherein the heat exchanger and the high shear mixer are connected together in the recirculation loop by the one or more recirculation lines, wherein an end of one of the one or more recirculation lines connects to an inlet of the high shear mixer and an end of the exit line connects to an outlet of the high shear mixer;

further wherein the one or more outlet lines and one or more continuous phase inlet lines are connected to the recirculation loop, wherein at least one of the one or more continuous phase inlet lines is directly connected to the one of the one or more recirculation lines and the at least one nozzle feed line is directly connected to the exit line;

further wherein the end of the discontinuous phase inlet line is located less than ⅓

^rd of a rotor diameter from the rotor and less than ⅓

^rd of a rotor diameter from the rotation axis of the rotor and is in fluid communication with the rotor, said process comprising;

feeding an aqueous discontinuous phase into the emulsification system through the discontinuous phase inlet line and feeding an organic continuous phase into the emulsification system through the one or more continuous phase inlet lines.

6. The process of claim 5, wherein the organic continuous phase comprises an organic solvent and a neutral lipid.

7. The process of claim 6, wherein the organic solvent is methylene chloride or chloroform.

8. The process of claim 5 wherein the aqueous discontinuous phase comprises an acid and a therapeutic agent.

9. The process of claim 8, wherein the acid is phosphoric acid.

10. The process of claim 8, wherein the therapeutic agent is bupivacaine.

11. The process of claim 5, wherein a portion of the emulsion is fed through the at least one nozzle feed line to a first fluid conduit of at least one atomizing nozzle apparatus, wherein said at least one atomizing nozzle apparatus comprises:

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

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

12. The process of claim 11, wherein the process further comprises applying a second aqueous phase to the second fluid conduit;

and applying a gas to the third fluid conduit.

13. The process of claim 11, wherein between 50% and 99.99% of the emulsion exiting the high shear mixer is passed through the heat exchanger.

14. The process of claim 11, wherein between 80% and 99.99% of the emulsion exiting the high shear mixer is passed through the heat exchanger.

15. The process of claim 11, wherein between 1 mL/minute and 8,000 mL/minute of the emulsion exiting the high shear mixer is fed through the at least one nozzle feed line to the first fluid conduit of the at least one atomizing nozzle apparatus.

16. The process of claim 11, wherein between 40 mL/minute and 100 mL/minute of the emulsion exiting the high shear mixer is fed through the at least one nozzle feed line to the first fluid conduit of the at least one atomizing nozzle apparatus.

17. The process of claim 11 further comprising:

providing the portion of the emulsion traveling to the at least one atomizing nozzle apparatus through the at least one nozzle feed line at a flow rate that is equal to a sum of the flow rate of the organic continuous phase through the one or more organic phase inlet lines and the flow rate of the aqueous discontinuous phase through the discontinuous phase inlet line.

18. The process of claim 5, further comprising forming emulsion droplets which are on average less than 10 microns in diameter.

19. The process of claim 5, wherein a length of one of the one or more recirculation lines annularly surrounds a length of the discontinuous phase inlet line.

20. The process of claim 5, wherein the organic continuous phase comprises a triglyceride.

21. The process of claim 5, wherein the emulsion comprises a triglyceride, surfactant, and water.

22. The process of claim 5 further comprising:

passing the aqueous discontinuous phase through a hydrophilic sterilizing filter before feeding the aqueous discontinuous phase into the emulsification system through the discontinuous phase inlet line; and

passing the organic continuous phase through a hydrophobic sterilizing filter before feeding the organic continuous phase into the emulsification system through the one or more continuous phase inlet lines.