Method for formulating large diameter synthetic membrane vesicles

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.

1 . An atomizing nozzle apparatus, 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 connecting to the at least one exit orifice of the first fluid conduit;   a third fluid conduit, wherein the third fluid conduit annularly surrounds a portion of the fluid contacting chamber.   
     
     
         2 . The atomizing nozzle of  claim 1 , wherein the fluid contacting chamber connects to the at least one exit orifice of the second fluid conduit. 
     
     
         3 . The atomizing nozzle of  claim 1 , wherein the at least one exit orifice of the fluid contacting chamber and the at least one exit orifice of the third fluid conduit are flush. 
     
     
         4 . The atomizing nozzle of  claim 1 , wherein the at least one exit orifice of the fluid contacting chamber is recessed within the at least one exit orifice of the third fluid conduit. 
     
     
         5 . The atomizing nozzle of  claim 1 , wherein the at least one exit orifice of the fluid contacting chamber extends beyond the at least one exit orifice of the third fluid conduit. 
     
     
         6 . The atomizing nozzle of  claim 1 , wherein the first fluid conduit and the second fluid conduit are co-axial for a first portion of the first fluid conduit length. 
     
     
         7 . The atomizing nozzle of  claim 1 , wherein the second fluid conduit annularly surrounds a second portion of the first fluid conduit. 
     
     
         8 . The atomizing nozzle of  claim 1 , wherein a diameter of the fluid contacting chamber is larger than a diameter of the first fluid conduit. 
     
     
         9 . The atomizing nozzle of  claim 1 , wherein the fluid contacting chamber conically narrows in diameter from the top of the fluid contacting chamber to the bottom of the fluid contacting chamber. 
     
     
         10 . The atomizing nozzle of  claim 1 , further comprising wherein the fluid contacting chamber conically narrows in diameter from a point below the top of the fluid contacting chamber to the bottom of the fluid contacting chamber. 
     
     
         11 . A process for preparing droplets using the atomizing nozzle apparatus of  claim 1 , comprising:
 applying a first component to the first fluid conduit;   applying a second liquid to the second fluid conduit;   applying a gas to the third fluid conduit;   wherein the gas exiting the third fluid conduit exit orifice impinges the liquid exiting the at least one exit orifice of the fluid contacting chamber, providing atomized droplets, wherein the droplets have an average diameter from about 100 nm to about 100 μM.   
     
     
         12 . The process of  claim 11 , wherein the first liquid is an emulsion comprised of:
 a first aqueous phase; and   a first organic phase comprising a first organic solvent.   
     
     
         13 . The process of  claim 12 , wherein the first organic solvent is chloroform or methylene chloride. 
     
     
         14 . The process of  claim 12 , wherein the first organic phase further comprises at least one amphipathic lipid and at least one neutral lipid. 
     
     
         15 . The process of  claim 14 , 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, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, acyl trimethylammonium propane, diacyldimethylammonium propane, stearylamine, and ethyl phosphatidylcholine. 
     
     
         16 . The process of  claim 14 , 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. 
     
     
         17 . The process of  claim 14 , 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. 
     
     
         18 . The process of  claim 14 , wherein the at least one neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaprylin, tricaproin, and tricaprin. 
     
     
         19 . The process of  claim 12 , wherein the first aqueous phase further comprises a therapeutic agent. 
     
     
         20 . The process of  claim 19 , wherein the therapeutic agent is bupivacaine. 
     
     
         21 . The process of  claim 11 , wherein the second liquid applied to the second fluid conduit is a second aqueous phase. 
     
     
         22 . The process of  claim 21 , wherein the second aqueous phase further comprises at least one from the group of dextrose and lysine or mixture thereof. 
     
     
         23 . The process of  claim 11 , wherein the droplet comprises a first component core and a second aqueous phase shell. 
     
     
         24 . The process of  claim 11 , wherein the gas is nitrogen. 
     
     
         25 . The process of  claim 11 , wherein the droplets have an average diameter from about 10 μM to about 80 μM. 
     
     
         26 . The process of  claim 11 , wherein the droplets have an average diameter from about 20 μM to about 60 μM. 
     
     
         27 . The process of  claim 11 , wherein the droplets have an average diameter from about 35 μM to about 45 μM. 
     
     
         28 . An atomized droplet comprising:
 an emulsion core, wherein the emulsion core comprises i) a first aqueous phase;   and ii) a first organic phase comprising a first organic solvent; and   an aqueous phase shell,   wherein said atomized droplet is made by a process comprising combining a first component, an aqueous phase, and a gas using the atomizing nozzle apparatus of  claim 1 , said process comprising:   applying a first component to the first fluid conduit;   applying an aqueous phase to the second fluid conduit; and   applying a gas to the third fluid conduit;   wherein the gas exiting the third fluid conduit exit orifice impinges the liquid exiting the at least one exit orifice of the fluid contacting chamber, providing atomized droplets, wherein the droplets have an average diameter from about 100 nm to about 100 μM.   
     
     
         29 . An atomizing nozzle apparatus, comprising:
 an first fluid conduit, a second fluid conduit and a third 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 connecting to the at least one exit orifice of the first fluid conduit, wherein the second fluid conduit annularly surrounds a portion 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 connecting to the at least one exit orifice of the first fluid contacting chamber, wherein the third fluid conduit annularly surrounds a portion of the second fluid contacting chamber;   a fourth fluid conduit, wherein the fourth fluid conduit annularly surrounds a portion of the second fluid contacting chamber.   
     
     
         30 . The atomizing nozzle of  claim 29 , wherein the first fluid contacting chamber connects to the at least one exit orifice of the second fluid conduit. 
     
     
         31 . The atomizing nozzle of  claim 29 , wherein the at least one exit orifice of the second fluid contacting chamber and the at least one exit orifice of the fourth fluid conduit are flush. 
     
     
         32 . The atomizing nozzle of  claim 29 , wherein the at least one exit orifice of the second fluid contacting chamber is recessed within the at least one exit orifice of the fourth fluid conduit. 
     
     
         33 . The atomizing nozzle of  claim 29 , wherein the at least one exit orifice of the second fluid contacting chamber extends beyond the at least one exit orifice of the fourth fluid conduit. 
     
     
         34 . The atomizing nozzle of  claim 29 , wherein the first fluid conduit and the second fluid conduit are co-axial for a first portion of the first fluid conduits length. 
     
     
         35 . The atomizing nozzle of  claim 29 , wherein the second fluid conduit annularly surrounds a second portion of the first fluid conduit. 
     
     
         36 . The atomizing nozzle of  claim 29 , wherein a diameter of the fluid contacting chamber is larger than a diameter of the first fluid conduit. 
     
     
         37 . The atomizing nozzle of  claim 29 , wherein the first fluid contacting, chamber conically narrows in diameter from the top of the first fluid contacting chamber to the bottom of the first fluid contacting chamber. 
     
     
         38 . The atomizing nozzle of  claim 29 , wherein the second fluid conduit and the third fluid conduit are co-axial for a first portion of the second fluid conduits length. 
     
     
         39 . The atomizing nozzle of  claim 29 , wherein the third fluid conduit annularly surrounds a second portion of the second fluid conduit. 
     
     
         40 . The atomizing nozzle of  claim 29 , wherein a diameter of the second fluid contacting chamber is larger than a diameter of the exit orifice of the second fluid contacting chamber. 
     
     
         41 . The atomizing nozzle of  claim 29 , wherein the second fluid contacting chamber conically narrows in diameter from the top of the second fluid contacting chamber to the bottom of the second fluid contacting chamber. 
     
     
         42 . A process for preparing droplets using the atomizing nozzle apparatus of  claim 29 , comprising:
 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;   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 μM.   
     
     
         43 . The process of  claim 42 , wherein:
 the first liquid is an emulsion comprised of:
 i) a first aqueous phase; and 
 ii) a first organic phase comprising a first organic solvent; 
   the second liquid is a second organic phase;   the third liquid is a second aqueous phase.   
     
     
         44 . The process of  claim 42 , wherein:
 the first liquid is an emulsion comprised of:
 i) a first aqueous phase; and 
 ii) a first organic phase comprising a first organic solvent; 
   the second liquid is a second aqueous phase;   the third liquid is a second organic phase.   
     
     
         45 . The process of  claim 43 , wherein the first organic solvent is chloroform or methylene chloride. 
     
     
         46 . The process of  claim 43 , wherein the first organic phase further comprises at least one amphipathic lipid and at least one neutral lipid. 
     
     
         47 . An evaporation apparatus, comprising at least one atomizing nozzle apparatus of  claim 1  and means for evaporating an organic solvent. 
     
     
         48 . An evaporation apparatus, comprising:
 a solvent removal vessel having a top, a bottom and a circular wall;   at least one atomizing nozzle;   a 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.   
     
     
         49 . The apparatus of  claim 48 , wherein the apparatus further comprises at least two carrier gas entrance offices. 
     
     
         50 . The apparatus of  claim 48 , wherein at least part of the solvent removal vessel is jacketed. 
     
     
         51 . The apparatus of  claim 48 , wherein the atomizing nozzle is mounted to and extending through the top of the solvent removal vessel. 
     
     
         52 . The apparatus of  claim 48 , wherein the top of the solvent removal vessel comprises a lid. 
     
     
         53 . The apparatus of  claim 48 , further comprising a rinse nozzle mounted to and extending through the top of the solvent removal vessel. 
     
     
         54 . The apparatus of  claim 48 , wherein the circular wall has a central axis and the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel residing along the central axis. 
     
     
         55 . The apparatus of  claim 54 , 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. 
     
     
         56 . The apparatus of  claim 55 , wherein the carrier gas entrance orifice is combined with the atomizing nozzle. 
     
     
         57 . The apparatus of  claim 48 , wherein the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel, wherein the tube is fitted with a narrowing cone. 
     
     
         58 . The apparatus of  claim 48 , wherein the solvent removal gas exit orifice further comprises a tube extending into the solvent removal vessel, wherein the tube is fitted with a narrowing cone and an annular ring. 
     
     
         59 . The apparatus of  claim 57 , wherein the tube extends from about ⅓ to about ⅘ of the way into the solvent removal vessel. 
     
     
         60 . The apparatus of  claim 57 , wherein the tube extends about ⅔ of the way into the solvent removal vessel. 
     
     
         61 . The apparatus of  claim 57 , 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. 
     
     
         62 . The apparatus of  claim 48 , wherein the solvent removal gas exit orifice diameter is less than 1/10 of a diameter of the inside of the solvent removal vessel. 
     
     
         63 . The apparatus of  claim 48 , wherein the at least one atomizing nozzle is the atomizing nozzle apparatus of  claim 1 . 
     
     
         64 . The apparatus of  claim 48 , wherein the at least one atomizing nozzle is the atomizing nozzle apparatus of  claim 29 . 
     
     
         65 . The apparatus of  claim 48 , wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 5:1 and 100:1. 
     
     
         66 . The apparatus of  claim 48 , wherein the ratio of the inside diameter of the solvent removal vessel to the diameter of the narrowing cone of the solvent removal gas exit orifice is between approximately 20:1 and 60:1. 
     
     
         67 . A process for preparing large diameter synthetic membrane vesicles using the evaporation apparatus of  claim 48 , comprising:
 introducing large diameter synthetic membrane vesicles pre-droplets to the solvent removal vessel, wherein the large diameter synthetic membrane vesicles pre-droplets comprise a first component core and an aqueous phase shell;   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 large diameter synthetic membrane vesicles suspension?.   
     
     
         68 . The process of  claim 67 , wherein the first component core comprises a first aqueous phase and a first organic phase. 
     
     
         69 . The process of  claim 68 , wherein the first organic phase comprises a continuous first organic solvent. 
     
     
         70 . The process of  claim 69 , wherein the first organic solvent is chloroform or methylene chloride. 
     
     
         71 . The process of  claim 68 , wherein the first organic phase further comprises at least one amphipathic lipid and at least one neutral lipid. 
     
     
         72 . The process of  claim 67 , wherein the first component core is first aqueous phase droplets as a suspension in a first organic phase. 
     
     
         73 . The process of  claim 67 , wherein the first aqueous phase droplets have an average diameter of from about 10 nm to about 10 μm, about 100 nm to about 5 μm, or about 500 nm to about 2 μm. 
     
     
         74 . The process of  claim 69 , wherein the first aqueous phase droplets have an average diameter of about 1 μm. 
     
     
         75 . The process of  claim 67 , wherein the carrier gas comprises nitrogen. 
     
     
         76 . The process of  claim 69 , wherein the solvent removal gas comprises nitrogen and organic solvent. 
     
     
         77 . The process of  claim 67 , wherein the carrier gas and the solvent removal gas travel in a vortex in the solvent removal vessel. 
     
     
         78 . The process of  claim 67 , wherein the large diameter synthetic membrane vesicles are multivesicular liposomes having a structure including multiple non-concentric chambers and comprising at least one amphipathic lipid and at least one neutral lipid. 
     
     
         79 . The process of  claim 78 , 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, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, acyl trimethylammonium propane, diacyldimethylammonium propane, stearylamine, and ethyl phosphatidylcholine. 
     
     
         80 . The process of  claim 78 , 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, and 1,2-dioleoyl-sn-glycero-3-phosphoglycerol. 
     
     
         81 . The process of  claim 78 , 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. 
     
     
         82 . The process of  claim 78 , wherein the at least one neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaprylin, tricaproin, and tricaprin. 
     
     
         83 . The process of  claim 78 , wherein the multivesicular liposomes further comprises a therapeutic agent. 
     
     
         84 . The process of  claim 83 , wherein the therapeutic agent is bupivacaine. 
     
     
         85 . An evaporation apparatus, comprising at least one atomizing nozzle apparatus of  claim 1  and means for removing an organic solvent from a droplet. 
     
     
         86 . A process for preparing large diameter synthetic membrane vesicles using the evaporation apparatus of  claim 48 , comprising:
 introducing large diameter synthetic membrane vesicles pre-droplets to the solvent removal vessel, wherein the large diameter synthetic membrane vesicles pre-droplets comprise a first component core and an aqueous phase shell;   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 pre-temperature treatment large diameter synthetic membrane vesicles;   introducing the pre-temperature treatment large diameter synthetic membrane vesicles to an outlet line;   contacting the pre-temperature treatment large diameter synthetic membrane vesicles with a hot solution in the outlet line, wherein the hot solution has a temperature ranging from about 30° C. to about 100° C. to provide post-temperature treatment large diameter synthetic membrane vesicles;   transferring the post-temperature treatment large diameter synthetic membrane vesicles to a continuous-flow particle-concentration system or continuous phase exchange system;   cooling the post-temperature treatment large diameter synthetic membrane vesicles to a second temperature to provide the large diameter synthetic membrane vesicles; and   isolating the large diameter synthetic membrane vesicles suspension.   
     
     
         87 . The process of  claim 86 , wherein the first component core comprises a first aqueous phase and a first organic phase. 
     
     
         88 . The process of  claim 87 , wherein the first organic phase comprises a continuous first organic solvent. 
     
     
         89 . The process of  claim 88 , wherein the first organic solvent is chloroform or methylene chloride. 
     
     
         90 . The process of  claim 88 , wherein the first organic phase further comprises at least one amphipathic lipid and at least one neutral lipid. 
     
     
         91 . The process of  claim 86 , wherein the first component core is a suspension of first aqueous phase droplets in a first organic phase. 
     
     
         92 . The process of  claim 86 , wherein the first aqueous phase droplets have an average diameter of from about 10 nm to about 10 μm, about 100 nm to about 5 μm, or about 500 nm to about 2 μm. 
     
     
         93 . The process of  claim 92 , wherein the first aqueous phase droplets have an average diameter of about 1 μm. 
     
     
         94 . The process of  claim 86 , wherein the carrier gas comprises nitrogen. 
     
     
         95 . The process of  claim 88 , wherein the solvent removal gas comprises nitrogen and organic solvent. 
     
     
         96 . The process of  claim 86 , wherein the carrier gas comprises nitrogen and water vapor. 
     
     
         97 . The process of  claim 86 , wherein the carrier gas and the solvent removal gas travel in a vortex in the solvent removal vessel. 
     
     
         98 . The process of  claim 86 , wherein the large diameter synthetic membrane vesicles are multivesicular liposomes having a structure including multiple non-concentric chambers and comprising at least one amphipathic lipid and at least one neutral lipid. 
     
     
         99 . The process of  claim 98 , 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, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, acyl trimethylammonium propane, diacyldimethylammonium propane, stearylamine, and ethyl phosphatidylcholine. 
     
     
         100 . The process of  claim 98 , 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. 
     
     
         101 . The process of  claim 98 , 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. 
     
     
         102 . The process of  claim 98 , wherein the at least one neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaprylin, tricaproin, and tricaprin. 
     
     
         103 . The process of  claim 98  wherein the multivesicular liposomes further comprises a therapeutic agent. 
     
     
         104 . The process of  claim 103 , wherein the therapeutic agent is bupivacaine. 
     
     
         105 . A composition comprising multivesicular liposomes having a structure including multiple non-concentric chambers and comprising at least one amphipathic lipid and at least one neutral lipid,
 wherein said multivesicular liposomes are made by a process comprising removing organic solvent from multivesicular liposomes pre-droplets using the evaporation apparatus of  claim 48 , said process comprising:   introducing multivesicular liposomes pre-droplets to the solvent removal vessel, wherein the large diameter synthetic membrane vesicles pre-droplets comprise a first component core and an aqueous phase shell;   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 large diameter synthetic membrane vesicles.   
     
     
         106 . A composition comprising large diameter synthetic membrane vesicles made by the process of  claim 67 . 
     
     
         107 . The composition of  claim 106 , wherein the large diameter synthetic membrane vesicles are multivesicular liposomes having a structure including multiple non-concentric chambers and comprising at least one amphipathic lipid and at least one neutral lipid. 
     
     
         108 . The process of  claim 107 , 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, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, acyl trimethylammonium propane, diacyldimethylammonium propane, stearylamine, and ethyl phosphatidylcholine. 
     
     
         109 . The process of  claim 107 , 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. 
     
     
         110 . The process of  claim 107 , 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. 
     
     
         111 . The process of  claim 107 , wherein the at least one neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaprylin, tricaproin, and tricaprin. 
     
     
         112 . The process of  claim 107  wherein the multivesicular liposomes further comprises a therapeutic agent. 
     
     
         113 . The process of  claim 112 , wherein the therapeutic agent is bupivacaine. 
     
     
         114 . A continuous-flow emulsification system, comprising:
 a mixer, comprised of a rotor and a stator;   a recirculation loop, comprised of one or more recirculation lines;   a heat exchanger;   one or more outlet lines;   one or more continuous phase inlet lines; and   a discontinuous phase inlet line;   wherein the heat exchanger and the mixer are connected together in the recirculation loop by one or more recirculation lines;   further wherein the one or more outlet lines and one or more continuous phase inlet lines are connected to the recirculation loop;   further wherein the end of the discontinuous phase inlet line is located within approximately ⅓ rd  of a rotor diameter from the rotor and approximately ⅓ rd  of a rotor diameter of the rotation axis of the rotor and is in fluid communication with the rotor.   
     
     
         115 . The emulsification system of  claim 114 , wherein a continuous phase entrance line is connected to the recirculation loop upstream of the mixer and downstream of the heat exchanger and an outlet line is connected to the recirculation loop downstream of the mixer and upstream of the heat exchanger. 
     
     
         116 . The emulsification system of  claim 114 , further comprising an emulsion, which emulsion recirculates through the recirculation line back to the mixer an average of at least 5 or more times. 
     
     
         117 . The emulsification system of  claim 114 , further comprising emulsion droplets produced in the mixer, which are on average less than 10 microns in diameter. 
     
     
         118 . A continuous processing system, comprising:
 one or more concentrator units, each unit comprising:
 a retentate vessel; 
 a particle suspension inlet line, connected to the retentate vessel; 
 a first outlet line, connecting the retentate vessel and a particle concentrating device; 
 a pump located along the first outlet line between the retentate vessel and the particle concentrating device; and 
 a second outlet line, leading to another concentrator unit or the final product collection vessel; and 
   means for removing or exchanging solvent.   
     
     
         119 . The system of  claim 118 , wherein the means for removing or exchanging solvent are each independently selected from the group consisting of a tangential flow filtration unit, a hydro-cyclone unit, and a centrifugal separator. 
     
     
         120 . The system of  claim 118 , further comprising a new suspending medium inlet line connected to the retentate vessel. 
     
     
         121 . The system of  claim 118 , wherein the means for removing or exchanging solvent are each a tangential flow filtration unit. 
     
     
         122 . The system of  claim 118 , wherein the means for removing or exchanging solvent are each a centrifugal separator. 
     
     
         123 . The system of  claim 118 , wherein the system comprises at least one tangential flow filtration unit and at least one centrifugal separator. 
     
     
         124 . The system of  claim 118 , wherein the continuous processing system is a continuous-flow particle-concentration system or continuous phase exchange system. 
     
     
         125 . A process for making multivesicular liposomes using the atomizing nozzle apparatus of  claim 1 , comprising:
 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.   
     
     
         126 . The process of  claim 125 , wherein the first liquid is an emulsion comprised of:
 a discontinuous aqueous phase; and   a continuous organic phase comprising the organic solvent.   
     
     
         127 . The process of  claim 126 , wherein the organic solvent is methylene chloride. 
     
     
         128 . The process of  claim 126 , wherein the discontinuous aqueous phase further comprises a therapeutic agent. 
     
     
         129 . The process of  claim 126 , wherein the continuous organic phase further comprises a therapeutic agent. 
     
     
         130 . The process of  claim 127  or  128 , wherein the therapeutic agent is bupivacaine or a salt thereof. 
     
     
         131 . The process of  claim 125 , wherein the second liquid applied to the second fluid conduit is an aqueous solution. 
     
     
         132 . The process of  claim 131 , wherein the aqueous solution further comprises dextrose and lysine. 
     
     
         133 . The process of  claim 125 , wherein the gas is a sterilized gas. 
     
     
         134 . The process of  claim 133 , wherein the gas is nitrogen. 
     
     
         135 . The process of  claim 125  further comprising:
 introducing atomized droplets to the evaporation apparatus of  claim 46 ; 
 introducing a pressurized carrier gas tangentially to the circular wall into the solvent removal vessel through the carrier gas entrance orifice; 
 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. 
 
     
     
         136 . The process of  claim 135 , wherein the carrier gas is heated and humidified. 
     
     
         137 . The process of  claim 135 , 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 on the top of the evaporation apparatus. 
     
     
         138 . The process of  claim 125 , wherein the atomized droplets contain organic solvent in the range of from about 400 ppm to about 3500 ppm. 
     
     
         139 . A process for making an emulsion using the emulsification system of  claim 114 , 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. 
     
     
         140 . A process for making an emulsion using the emulsification system of  claim 114 , comprising feeding an aqueous discontinuous phase into the emulsification system through the discontinuous phase inlet line and feeding an organic continuous phase fed into the emulsification system through the one or more continuous phase inlet lines. 
     
     
         141 . The process of  claim 140 , wherein the organic continuous phase is comprised of an organic solvent and a neutral lipid. 
     
     
         142 . The process of  claim 141 , wherein the organic solvent is methylene chloride. 
     
     
         143 . The process of  claim 140  wherein the aqueous discontinuous phase is comprised of an acid and a therapeutic agent. 
     
     
         144 . The process of  claim 143 , wherein the acid is phosphoric acid. 
     
     
         145 . The process of  claim 143 , wherein the therapeutic agent is bupivacaine. 
     
     
         146 . The process of  claim 140 , wherein a portion of the emulsion is fed through one or more outlet lines to the inner fluid conduit of the atomizing nozzle of  claim 1 . 
     
     
         147 . The process of  claim 140 , wherein a portion of the emulsion is fed through one or more outlet lines to the evaporation apparatus of  claim 48 . 
     
     
         148 . (canceled) 
     
     
         149 . (canceled) 
     
     
         150 . A composition comprising a multivesicular liposomes comprising an outer surface layer whose composition is different than the composition of the internal structure. 
     
     
         151 . A composition comprising large diameter synthetic membrane vesicles made by the process of  claim 86 . 
     
     
         152 . The composition of  claim 151 , wherein the large diameter synthetic membrane vesicles are multivesicular liposomes having a structure including multiple non-concentric chambers and comprising at least one amphipathic lipid and at least one neutral lipid. 
     
     
         153 . The process of  claim 152 , 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, phosphatidylserines, phosphatidylinositols, phosphatidic acids, cardiolipins, acyl trimethylammonium propane, diacyldimethylammonium propane, stearylamine, and ethyl phosphatidylcholine. 
     
     
         154 . The process of  claim 152 , 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. 
     
     
         155 . The process of  claim 152 , 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. 
     
     
         156 . The process of  claim 152 , wherein the at least one neutral lipid is selected from the group consisting of triolein, tripalmitolein, trimyristolein, trilinolein, tributyrin, tricaprylin, tricaproin, and tricaprin. 
     
     
         157 . The process of  claim 152 , wherein the multivesicular liposomes further comprises a therapeutic agent. 
     
     
         158 . The process of  claim 157 , wherein the therapeutic agent is bupivacaine.