Method for formulating large diameter synthetic membrane vesicles

• US 9,757,336 B2
• Filed: 03/06/2013
• Issued: 09/12/2017
• 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): Zemel, Irina S
• Application Number:
  US13/786,945
• Publication Number:
  US 20130183373A1
• Time in Patent Office: 1,651 Days
• Field of Search: 264 43, 264 46, 264 432, 264 41, 264 42, 264 433, 264 44, 264 47, 42721331, 427212, 4272133, 427 214, 427 231, 427 8, 4273855, 4273899, 4283215, 4283211, 428403, 428402, 428404, 42840224, 424450, 424489, 424491, 424497, 424 60
• 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 multivesicular liposomes using an atomizing nozzle apparatus, wherein the apparatus 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, wherein the fluid contacting chamber conically narrows in diameter from the top of the fluid contacting chamber to the exit orifice of the fluid contacting chamber; and

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

wherein the process for making multivesicular liposomes comprises;

applying a first liquid to the first fluid conduit, wherein the first liquid comprises an organic solvent;

applying a second liquid to the second fluid conduit;

applying a pressurized gas to the third fluid conduit to provide atomized droplets, wherein the pressurized gas exiting the third fluid conduit exit orifice impinges the liquid exiting the fluid contacting chamber exit orifice; and

removing the organic solvent from the atomized droplets, wherein less than 4000 ppm of the organic solvent remains in the atomized droplets, resulting in formation of multivesicular liposomes.

2. The process of claim 1, wherein the first liquid is an emulsion comprised of:

a discontinuous aqueous phase; and

a continuous organic phase comprising the organic solvent.

3. The process of claim 2, wherein the organic solvent is methylene chloride or chloroform.

4. The process of claim 2, wherein the discontinuous aqueous phase further comprises a therapeutic agent.

5. The process of claim 2, wherein the continuous organic phase further comprises a therapeutic agent.

6. The process of claim 5, wherein the therapeutic agent is bupivacaine or a salt thereof.

7. The process of claim 1, wherein the second liquid applied to the second fluid conduit is an aqueous solution.

8. The process of claim 7, wherein the aqueous solution further comprises either dextrose or lysine, or a mixture thereof.

9. The process of claim 1, wherein the gas is a sterilized gas.

10. The process of claim 9, wherein the sterilized gas is nitrogen.

11. The process of claim 1, wherein the atomized droplets contain organic solvent in the range of from about 400 ppm to about 3500 ppm after solvent removal.

12. The process of claim 4, wherein the therapeutic agent is bupivacaine or a salt thereof.

13. A process for making multivesicular liposomes using an evaporation apparatus comprising,

wherein the evaporation apparatus comprises:

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

at least one atomizing nozzle,

at least one 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 at least one atomizing nozzle comprises;

a first fluid conduit 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, wherein the fluid contacting chamber conically narrows in diameter from the top of the fluid contacting chamber to the exit orifice of the fluid contacting chamber; and

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

wherein the process for making multivesicular liposomes comprises;

applying a first liquid to the first fluid conduit, wherein the first liquid comprises an organic solvent;

applying a second liquid to the second fluid conduit;

applying a pressurized gas to the third fluid conduit to provide atomized droplets, wherein the pressurized gas exiting the third fluid conduit exit orifice impinges the liquid exiting the fluid contacting chamber exit orifice; and

removing the organic solvent from the atomized droplets wherein the step of removing the organic solvent from the atomized droplets comprises;

introducing atomized droplets from the at least one atomizing nozzle into the evaporation apparatus,

introducing a pressurized carrier gas tangentially to the circular wall into the solvent removal vessel through one of the at least one carrier gas entrance orifices; and

removing a solvent removal gas wherein the solvent removal gas removes greater than 90% of the organic solvent in the atomized droplets resulting in formation of multivesicular liposomes.

14. The process of claim 13, wherein the carrier gas is heated and humidified.

15. The process of claim 13, further comprising spraying a wall rinse solution into the solvent removal vessel using a rinse nozzle, wherein the wall rinse solution prevents build-up of particles in the evaporation apparatus.