Residual solvent extraction method and microparticles produced thereby

1. A method for preparing microparticles, comprising:

preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent;

combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;

extracting the halogenated solvent from the combined phase with an extraction medium, that is a non-solvent for the polymer and a solvent for the halogentated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;

rinsing the precipitated microparticles to form finished microparticles; and

after said rinsing step, washing the finished microparticles in a non-aquesous washing system comprising 100% heptane to thereby reduce the level of residual halogenated solvent.

2. The method of claim 1 , wherein the halogenated solvent is methylene chloride.

3. The method of claim 1 , wherein a temperature of the washing is between about 10° and about 26° C.

4. The method of claim 1 , wherein the coacervating agent is silicone oil.

5. The method of claim 1 , wherein the extraction medium is a 1:9 ratio of ethanol to heptane.

6. The method of claim 1 , wherein the biodegradable, biocompatible polymer is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.

7. The method of claim 1 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.

8. The method of claim 1 , further comprising after said washing step:

final drying of the washed microparticles.

9. A method for preparing microparticles, comprising:

contacting rinsed finished microparticles comprising a biodegradable, biocompatible polymer matrix comprising a peptide and a halogenated solvent with a non-aqueous washing system to thereby reduce a level of residual halogentated solvent with a non-aqueous washing system to thereby reduce a level of residual halogenated solvent in the rinsed, finished microparticles to formed washed microparticles, wherein the washing system comprises 100% heptane; and recovering the washed microparticles from the washing system.

10. The method of claim 9 , wherein the halogenated solvent is methylene chloride.

11. The method of claim 9 , wherein a temperature of the washing is between about 10° and about 26° C.

12. The method of claim 9 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.

13. Microparticles prepared by the method of claim 1 .

14. A method for preparing microparticles, comprising:

preparing a first phase comprising a biodegradable, biocompatible polymer and a halogenated solvent;

preparing an aqueous second phase comprising a peptide;

combining the first phase and the second phase under the influence of a mixer to form an emulsion;

combining the emulsion with a coacervating agent that is free from solvent for the polymer to form a combined phase;

extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;

rinsing the precipitated microparticle to form finished microparticles; and

after said rinsing step washing the finished microparticles in a non-aqueous washing system that comprises 100% heptane to thereby reduce a level of residual halogenated solvent.

15. The method of claim 14 , wherein the mixer is a static mixer.

16. The method of claim 14 , wherein the halogenated solvent is methylene chloride.

17. The method of claim 14 , wherein a temperature of the washing is between about 10° and about 26° C.

18. The method of claim 14 , wherein the coacervating agent is silicone oil.

19. The method of claim 14 , wherein the extraction medium is a 1:9 ratio of ethanol to heptane.

20. The method of claim 14 , wherein the biodegradable, biocompatible polymer is selected from the group consisting of poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers of the foregoing.

21. The method of claim 14 , wherein the washing step is carried out until the level of residual halogenated solvent in the washed microparticles is less than about 0.06% by weight.

22. A method for preparing microparticles, comprising:

preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a halogenated solvent;

combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;

extracting the halogenated solvent from the combined phase with an extraction medium that is a non-solvent for the polymer and a solvent for the halogenated solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;

rinsing the precipitated microparticles to form finished microparticles; and

after said rinsing step, washing the finished microparticles in a non-aqueous washing system that comprises heptane.

23. A method for preparing microparticles, comprising:

preparing an emulsion comprising an aqueous peptide solution and a biodegradable, biocompatible polymer dissolved in a solvent;

combining the emulsion with a coacervating agent that is free from solvents for the polymer to form a combined phase;

extracting the solvent from the combined phase in an extraction medium that is a non-solvent for the polymer and a solvent and the coacervating agent, whereby microparticles precipitate out of the extraction medium;

rinsing the precipitated microparticles to form finished microparticles; and

after said rinsing step, washing the finished microparticles in 100% heptane.