Coacervation Process
Methods of forming compositions for the sustained release of water soluble active agents, including biologically active polypeptides and products produced by the process are described. Improved product characteristics and ease of scale-up can be achieved using a novel coacervation process wherein at least one coacervation agent is added to the mixture comprising the active agent and the polymer in at least two distinct stages.
1 . A method for preparing microparticles comprising
(a) providing a first phase comprising an active agent, a biocompatible polymer and a solvent;
(b) forming a coacervate; and
(c) combining the coacervate with a quench liquid, thereby forming microparticles containing the active agent;
wherein step (b) comprises
(i) adding a first coacervation agent to the first phase; and subsequently
(ii) adding a second coacervation agent.
2 . The method of claim 1 , wherein the average particle size of the microparticles is between about 1 um and about 250 um.
3 . (canceled)
4 . The method of claim 1 , wherein the active agent is a water soluble drug.
5 . The method of claim 1 , wherein the active agent is a biologically active polypeptide.
6 . (canceled)
7 . The method of claim 5 , wherein the biologically active polypeptide is a glucoregulatory peptide.
8 . (canceled)
9 . The method of claim 7 , wherein the glucoregulatory peptide is exendin-4.
10 . (canceled)
11 . The method of claim 5 , wherein the polypeptide is present from about 1% w/w to about 5% w/w of the total dry weight of the microparticles.
12 - 13 . (canceled)
14 . The method of claim 1 , wherein said polymer comprises poly(lactide-co-glycolide).
15 . (canceled)
16 . The method of claim 14 , wherein said polymer has an inherent viscosity of between about 0.3 and 0.5 dL/g.
17 . The method of claim 16 , wherein the polymer comprises a poly(lactide-co-glycolide) having an uncapped free carboxyl group.
18 . (canceled)
19 . The method of claim 1 , wherein the solvent is methylene chloride.
20 . (canceled)
21 . The method of claim 1 , wherein the first phase is a water-in-oil emulsion comprising the active agent dissolved in the aqueous dispersed phase of the emulsion.
22 . (canceled)
23 . The method of claim 21 , wherein the water-in-oil emulsion has a dispersed phase droplet size of 0.2 μm to 0.4 μm.
24 . (canceled)
25 . The method of claim 21 , wherein the concentration of active agent in the aqueous phase of the water-in-oil emulsion is 50 mg/g to 100 mg/g.
26 . The method of claim 1 , wherein the first phase is a suspension of particles comprising the active agent in a solution comprising the polymer and solvent.
27 . (canceled)
28 . The method of claim 26 , wherein the average diameter of the suspended particles is less than about 1 μm.
29 . The method of claim 1 , wherein the first phase comprises the active agent dissolved in the aqueous phase.
30 . The method of claim 1 , wherein the first phase further comprises an excipient selected from the group consisting of salts, sugars, carbohydrates, buffers and surfactants.
31 - 33 . (canceled)
34 . The method of claim 30 , wherein the excipient is sucrose.
35 . (canceled)
36 . The method of claim 30 , wherein the excipient and the active agent are dispersed together in the first phase.
37 . The method of claim 34 , wherein the amount of sugar in the microparticles is 1% to 5% of the total dry weight of the microparticles.
38 . The method of claim 37 , wherein the amount of sugar in the microparticles is about 2% of the total dry weight of the microparticles.
39 . (canceled)
40 . The method of claim 30 , wherein the total amount of drug and excipient in the microparticles is between 3% and 8% of the total dry weight of the microparticles.
41 . (canceled)
42 . The method of claim 1 , wherein the ratio of polymer to solvent in the first phase is about 20% or less.
43 . The method of claim 42 , wherein the ratio of polymer to solvent in the first phase is about 10% or less.
44 - 45 . (canceled)
46 . The method of claim 1 , wherein the first coacervaton agent comprises silicone oil.
47 . The method of claim 46 , wherein the first coacervation agent and the second coacervation agent are the same.
48 . (canceled)
49 . The method of claim 1 , wherein the weight ratio of coacervation agent to solvent in step (b) is about 0.75:1 to about 2:1.
50 . The method of claim 49 , wherein the weight ratio of coacervation agent to solvent is about 1.3:1.
51 . The method of claim 1 , wherein the weight ratio of the first coacervation agent to the solvent is about 0.5:1 or less.
52 . The method of claim 1 , wherein the first coacervation agent is gradually added to the first phase over a period of at least 3 minutes.
53 . The method of claim 1 , wherein the quench liquid comprises heptane.
54 - 56 . (canceled)
57 . The method of claim 1 , wherein the quench liquid comprises a mixture of heptane and ethanol.
58 . (canceled)
59 . The method of claim 1 , wherein step (b) further comprises (iii) adding at least one additional coacervation agent; wherein the additional coacervation agent is the same or different from the first or second coacervation agents.
60 . The method of claim 1 , wherein step (i) is performed in a stirred tank and the first coacervation agent is added through at least two addition ports.
61 . (canceled)
62 . The method of claim 60 , wherein the first coacervation agent is added through at least one spray nozzle.
63 . The method of claim 1 , wherein the first coacervation agent and the first phase are made to flow simultaneously through a static mixer.
64 . The method of claim 1 , wherein the second coacervation agent and a mixture comprising the first phase and the first coacervation agent are made to flow simultaneously through a static mixer.
65 . The method of claim 1 , wherein the coacervate and a quench liquid are made to flow simultaneously through a static mixer.
66 . The method of claim 1 , wherein at least one coacervation agent and a mixture comprising the first phase and the first coacervation agent are made to flow simultaneously through a static mixer.
67 . A method for preparing microparticles comprising
(a) preparing a first phase comprising an active agent, a biocompatible polymer and a solvent;
(b) forming a coacervate; and
(c) combining the coacervate with a quench liquid, thereby forming microparticles containing the active agent;
wherein step (b) comprises addition of a coacervation agent through at least two inlets of a continuous flow mixing apparatus.
68 . The method of claim 67 , wherein the continuous flow mixing apparatus is an agitated plug flow reactor with multiple coacervation agent addition ports.
69 . The method of claim 67 , wherein the continuous flow mixing apparatus is a static mixer assembly with multiple coacervation agent addition ports.
70 . The method of claim 67 , wherein the continuous flow mixing apparatus is a static mixer with a porous wall through which the coacervation agent is made to flow.
71 . (canceled)
72 . Microparticles prepared by the method of claim 1 .