Method for formulating large diameter synthetic membrane vesicles

Patent metadata

Field	Value
Publication number	US-10398648-B2
Application number	US-201715676151-A
Country	US
Kind code	B2
Filing date	Aug 14, 2017
Priority date	Apr 9, 2010
Publication date	Sep 3, 2019
Grant date	Sep 3, 2019

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.

First claim

What is claimed is:

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 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 mounted to and extending through the top of the solvent removal vessel, said 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 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; and
removing a solvent removal gas through the solvent removal gas exit orifice to provide the multivesicular liposomes and removing the suspension of formed multivesicular liposomes suspended in the suspending medium through the product exit orifice,
wherein the at least one amphipathic lipid is selected from the group consisting of phosphatidylcholines, phosphatidylserines, phosphatidylethanolamines, phosphatidylinositols, sphingomyelin, soybean lecithin (soya lecithin), egg lecithin, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylglycerols, phosphatidic acids, cardiolipins, acyl trim ethyl ammonium propane, diacyldimethylammonium propane, stearylamine, and ethyl phosphatidylcholine, and
wherein the at least one neutral lipid is selected from the group consisting of glycerol esters, glycol esters, tocopherol esters, sterol esters, hydrocarbons and squalenes.

2. The composition of claim 1 , wherein the at least one neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaprylin, tricaproin, and tricaprin.

3. The composition of claim 2 , wherein the at least one amphipathic lipid is selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-diarachidoyl-sn-glycero-3 phosphocholine, 1,2-dibehenoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine, 1,2-dieicosenoyl-sn-glycero-3-phosphocholine, 1,2-dierucoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, 1,2-dioleoyl-sn-glycero-3-phosphoglycerol.

4. The composition of claim 1 , wherein the at least one amphipathic lipid is selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dilauroyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-diarachidoyl-sn-glycero-3˜phosphocholine, 1,2-dibehenoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoleoyl-sn-glycero-3-phosphocholine, 1,2-dieicosenoyl-sn-glycero-3-phosphocholine, 1,2-dierucoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, 1,2-dioleoyl-sn-glycero-3-phosphoglycerol.

5. The composition of claim 1 , wherein the gas outlet tube resides along the central axis.

6. The composition of claim 5 , 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.

7. The composition of claim 6 , wherein the carrier gas entrance orifice is combined with the atomizing nozzle.

8. The composition of claim 1 , wherein the tube extends from about ⅓ to about ⅘ of the way into the solvent removal vessel.

9. The composition of claim 1 , wherein the tube extends about ⅔ of the way into the solvent removal vessel.

10. The composition 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.

11. The composition of claim 1 , wherein the narrowing cone tip is less than 1/10 of a diameter of the inside of the solvent removal vessel.

12. The composition of claim 1 , wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone tip is between approximately 5:1 and 100:1.

13. The composition of claim 1 , wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone tip is between approximately 20:1 and 60:1.

14. The composition of claim 1 , wherein the organic solvent is methylene chloride or chloroform.

15. The composition of claim 1 , wherein the organic solvent chloroform.

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

17. 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 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 contac

Assignees

• Pacira Pharmaceuticals Inc

Inventors

• Schutt Ernest George
• Mcguire Ronald Warren
• Walters Peter Andrew
• Los Kathleen D A

Classifications

• A61P23/02

  Local anaesthetics · CPC title

• A61P23/00

  Anaesthetics · CPC title

• A61K31/445

  Non condensed piperidines, e.g. piperocaine · CPC title

• B01J13/125

  by evaporation of the solvent (apparatus therefor B01J13/043) · CPC title

• B01J13/043

  Drying and spraying · CPC title