Method for formulating large diameter synthetic membrane vesicles

• US 9,730,892 B2
• Filed: 08/26/2016
• Issued: 08/15/2017
• 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: Los, Kathleen D. A., Schutt, Ernest George, McGuire, Ronald Warren, Walters, Peter Andrew
• Primary Examiner(s): Chorbaji, Monzer R
• Application Number:
  US15/249,195
• Publication Number:
  US 20160361260A1
• Time in Patent Office: 354 Days
• Field of Search: 422255, 422256, 422307, 422261, 210634, 210807, 210263, 210348, 424450
• 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 composition comprising a suspension of multivesicular liposomes in a suspending medium, said multivesicular liposomes having a structure including multiple non-concentric chambers and comprising at least one amphipathic lipid, at least one neutral lipid and a therapeutic agent:

wherein said multivesicular liposomes are made by a process comprising removing greater than 90% of an organic solvent from multivesicular liposome pre-droplets using an evaporation apparatus comprising;

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

a rinse nozzle mounted to and extending through the top of the solvent removal vessel;

a carrier gas entrance orifice;

a solvent removal gas exit orifice centrally connected to the top and further comprising a gas outlet tube extending into the solvent removal vessel, wherein the gas outlet tube is fitted with a narrowing cone and the narrowing cone includes a tip through which gas residing in the solvent removal vessel enters the narrowing cone;

a product exit orifice connected to the bottom of the vessel; and

a product outlet pipe connected to the product exit orifice;

at least one atomizing nozzle comprising;

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 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;

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

wherein the organic solvent removal process comprises;

introducing multivesicular liposome pre-droplets to the solvent removal vessel by the at least one atomizing nozzle, wherein the multivesicular liposome pre-droplets comprise a first component core and an aqueous phase shell, wherein the first component core comprises a suspension of first aqueous phase droplets suspended in a first organic phase;

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

removing a solvent removal gas through the solvent removal gas exit orifice to provide multivesicular liposomes in a first suspending medium and removing the formed multivesicular liposomes suspended in the first suspending medium through the product exit orifice through a product outlet pipe; and

exchanging the first suspending medium by introducing the multivesicular liposomes in the first suspending medium into a continuous processing system to form a multivesicular liposomes suspension in the suspending medium, wherein the continuous processing system, comprises;

a first concentrator unit comprising;

a first retentate vessel;

a first particle suspension inlet line, connected to the first retentate vessel and the product outlet pipe, wherein the process comprises applying the suspension of multivesicular liposomes in the first suspending medium from the product outlet pipe to the first particle suspension inlet line;

a first particle suspension outlet line, connecting the first retentate vessel and a first hollow fiber tangential flow filter;

a first solution inlet line supplying a second suspending medium;

a first sterilizing hydrophilic filter, connecting the first retentate vessel and the first solution inlet line;

a first pump located along the first particle suspension outlet line between the first retentate vessel and the first hollow fiber tangential flow filter;

a first retentate line between the first hollow fiber tangential flow filter and the first retentate vessel;

a second particle suspension outlet line, leading to a second concentrator unit,

said second concentrator unit comprising;

a second retentate vessel;

a second particle suspension inlet line, connected to the second retentate vessel and the second particle suspension outlet line;

a third particle suspension outlet line, connecting the second retentate vessel and a second hollow fiber tangential flow filter;

a second solution inlet line supplying a third suspending medium;

a second sterilizing hydrophilic filter, connecting the second retentate vessel and the second solution inlet line; and

a second pump located along the third particle suspension outlet line between the second retentate vessel and the second hollow fiber tangential flow filter;

a second retentate line between the second hollow fiber tangential flow filter and the second retentate vessel; and

optionally a fourth particle suspension outlet line.

2. The composition of claim 1, wherein the therapeutic agent is bupivacaine.

3. The composition of claim 1, wherein the continuous processing system further comprises the fourth particle suspension outlet line and a third concentrator unit, said third concentrator unit comprising:

a third retentate vessel;

a third particle suspension inlet line, connected to the third retentate vessel and the fourth particle suspension outlet line;

a fifth particle suspension outlet line, connecting the third retentate vessel and a third hollow fiber tangential flow filter;

a third solution inlet line supplying a fourth suspending medium;

a third sterilizing hydrophilic filter, connecting the third retentate vessel and the third solution inlet line;

a third pump located along the fifth particle suspension outlet line between the third retentate vessel and the third hollow fiber tangential flow filter;

a third retentate line between the third hollow fiber tangential flow filter and the third retentate vessel; and

optionally a sixth particle suspension outlet line.

4. The composition of claim 3, wherein the continuous processing system further comprises the sixth particle suspension outlet line and a fourth concentrator unit, said fourth concentrator unit comprising:

a fourth retentate vessel;

a fourth particle suspension inlet line, connected to the fourth retentate vessel and the sixth particle suspension outlet line;

a seventh particle suspension outlet line, connecting the fourth retentate vessel and a fourth hollow fiber tangential flow filter;

a fourth solution inlet line supplying a fifth suspending medium;

a fourth sterilizing hydrophilic filter, connecting the fourth retentate vessel and the fourth solution inlet line;

a fourth pump located along the seventh particle suspension outlet line between the fourth retentate vessel and the fourth hollow fiber tangential flow filter;

a fourth retentate line between the fourth hollow fiber tangential flow filter and the fourth retentate vessel; and

optionally an eighth particle suspension outlet line.

5. The composition of claim 4, wherein the continuous processing system further comprises the eighth particle suspension outlet line and a final product vessel connected to the fourth retentate vessel through the eighth particle suspension outlet line.

6. The composition of claim 4, wherein the fourth retentate vessel is a final product vessel.

7. The composition of claim 4, wherein the therapeutic agent is bupivacaine.

8. The composition of claim 3, wherein the continuous processing system further comprises the sixth particle suspension outlet line and a final product vessel connected to the third retentate vessel through the sixth particle suspension outlet line.

9. The composition of claim 3, wherein the third retentate vessel is a final product vessel.

10. The composition of claim 3, wherein the therapeutic agent is bupivacaine.

11. The composition of claim 1, wherein the continuous processing system further comprises the fourth particle suspension outlet line and a final product vessel connected to the second retentate vessel through the fourth particle suspension outlet line.

12. The composition of claim 1, wherein the second retentate vessel is a final product vessel.

13. The composition of claim 1, wherein the removing of greater than 90% of the organic solvent from the multivesicular liposome pre-droplets occurs in a few seconds.

14. The composition of claim 1, wherein the removing of greater than 90% of the organic solvent from the multivesicular liposome pre-droplets occurs in a fraction of a second.