Method for formulating large diameter synthetic membrane vesicles

• US 10,045,941 B2
• Filed: 03/06/2013
• Issued: 08/14/2018
• 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:
  US13/786,873
• Publication Number:
  US 20130177636A1
• Time in Patent Office: 1,987 Days
• Field of Search: 428402-40224, 428403, 428404, 428407, 4283211, 4284744, 427331, 4273899, 427212, 427213-21336, 427483, 427256, 427 5, 427 41, 427 4- 47, 264534, 424400, 424408, 424450, 424451, 424455, 424 937, 4241841, 424497, 424489, 424501, 424490, 424491, 424492, 424493, 424494, 424495, 204451, 204453, 204601, 204604, 204450, 436 52, 436180
• 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 preparing droplets using an atomizing nozzle apparatus, wherein the apparatus comprises:

a first fluid conduit, a second fluid conduit, a third fluid conduit, and a fourth 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 said at least one entrance orifice connecting to the at least one exit orifice of the first fluid conduit and the at least one exit orifice of the second fluid conduit, wherein the second fluid conduit annularly surrounds a portion of the first fluid conduit, wherein the first fluid contacting chamber conically tapers from the top of the first fluid contacting chamber to the bottom 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 said at least one entrance orifice connecting to the at least one exit orifice of the first fluid contacting chamber and the at least one exit orifice of the third fluid conduit, wherein the third fluid conduit annularly surrounds a portion of the first fluid contacting chamber and wherein the diameter of the second fluid contacting chamber conically tapers from its top to its bottom, wherein the first and second fluid contacting chambers are hydraulic extrusion cones; and

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

wherein the process for preparing droplets comprises;

applying a first liquid to the first fluid conduit;

applying a second liquid to the second fluid conduit;

applying a third liquid to the third fluid conduit; and

applying a gas to the fourth fluid conduit,

wherein the gas exiting the fourth fluid conduit exit orifice impinges the liquid exiting the at least one exit orifice of the second fluid contacting chamber, providing atomized droplets, wherein the droplets have an average diameter from about 100 nm to about 100 μ

M.

2. The process of claim 1, wherein:

the first liquid is an emulsion comprised of;

i) a discontinuous first aqueous phase; and

ii) a continuous first organic phase comprising a first organic solvent;

the second liquid is a second organic phase;

the third liquid is a second aqueous phase.

3. The process of claim 1, wherein:

the first liquid is an emulsion comprised of;

i) a discontinuous first aqueous phase; and

ii) a continuous first organic phase comprising a first organic solvent;

the second liquid is a second aqueous phase;

the third liquid is a second organic phase.

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

5. The process of claim 2, wherein the first organic phase further comprises at least one amphipathic lipid and at least one neutral lipid.

6. The process of claim 1, wherein the second liquid forms a sheath around the first liquid, the first liquid forming a first liquid core.

7. The process of claim 6, wherein the second liquid sheath comprises a composition that is different from a composition of the first organic phase.

8. The process of claim 6, wherein the first fluid contacting chamber decreases the diameter of the first liquid core and the second liquid.

9. The process of claim 6, wherein the diameter of the second fluid contacting chamber conically tapers from its top to its bottom and the third liquid is constricted by the second fluid contacting chamber to create a concentric annular sheath around the first liquid core and the second liquid sheath.

10. The process of claim 2, wherein the second organic phase comprises a charged lipid solution.

11. The process of claim 2, wherein the atomized droplets comprise an outer layer and an internal membrane, the outer layer comprising a charged lipid and the internal membrane comprising a lipid.

12. The process of claim 2, wherein the first organic phase further comprises a first lipid and the second organic phase comprises a second lipid and a second organic solvent.

13. The process of claim 12, wherein the second lipid is the same type of lipid as the first lipid.

14. The process of claim 12, wherein the second lipid is a different type of lipid than the first lipid.

15. The process of claim 12, wherein the second organic solvent is the same type of solvent as the first organic solvent.

16. The process of claim 12, wherein the second organic solvent is a different type of solvent than the first organic solvent.

17. The process of claim 2, wherein the second organic phase comprises a polymer and an organic solvent.

18. The process of claim 2, wherein the second organic phase comprises a polymer.

19. The process of claim 1, wherein the third liquid is a buffer solution.

20. The process of claim 1, wherein the first fluid travels at a first volumetric flow rate through the first fluid conduit, the second fluid travels at a second volumetric flow rate through the second fluid conduit, and the third fluid travels at a third volumetric flow rate through the third fluid conduit.

21. The process of claim 20, wherein each of the first volumetric flow rate, second volumetric flow rate, and third volumetric flow rate is between 2 mL/minute and 1,000 mL/minute.

22. The process of claim 20, wherein each of the first volumetric flow rate, second volumetric flow rate, and third volumetric flow rate is between 10 mL/minute and 500 mL/minute.

23. The process of claim 20, wherein each of the first volumetric flow rate, second volumetric flow rate, and third volumetric flow rate is between 10 mL/minute and 100 mL/minute.

24. The process of claim 20, wherein each of the first volumetric flow rate, second volumetric flow rate, and third volumetric flow rate is between 50 mL/minute and 100 mL/minute.

25. The process of claim 1, wherein:

the first liquid is an aqueous phase comprising an active agent;

the second liquid is an organic phase comprising a lipid solution; and

the third liquid is a buffer solution.

26. The process of claim 1, wherein:

the first liquid is a first aqueous phase;

the second liquid is an organic phase comprising phospholipids, a polymer, or a combination of phospholipids and a polymer in an organic solvent; and

the third liquid is a second aqueous phase.