MICROPARTICLES AND NANOPARTICLES HAVING NEGATIVE SURFACE CHARGES

• US 20160310426A1
• Filed: 12/04/2013
• Published: 10/27/2016
• Est. Priority Date: 12/04/2012
• Status: Active Grant

• Current Assignee: Cytodigm Incorporated
• Original Assignee: Phosphorex, Inc.
• Inventors: Wu, Bin
• Granted Patent: US 11,439,594 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 47/6931 the material constituting the nanoparticle being a polymer
• CPC Class Codes: A61K 47/6933 the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol
• CPC Class Codes: A61K 47/6937 the polymer being PLGA, PLA or polyglycolic acid
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1682 Processes
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention provides methods for producing a polymer particle which contains unusually high negative charges on the surface of the particle. Preferably, the polymer is pharmaceutically acceptable. The negative charges can be conferred by chemical groups such as carboxyl, sulfonate, nitrate, fluorate, chloride, iodide, persulfate, and many others, with carboxyl group being preferred. The invention also provides polymer particle produced by the methods of the invention.

Claims

1. A method for the preparation of a composition comprising microparticles or nanoparticles having negative surface charges, said method comprising producing said microparticles or nanoparticles with a pharmaceutically acceptable polymer using either an emulsion process or a precipitation process:

(a) wherein said emulsion process or said precipitation process is carried out in an aqueous solution having a pH that promotes ionization of said pharmaceutically acceptable polymer;

(b) wherein said pharmaceutically acceptable polymer has an average molecular weight of from about 500 to about 1,000,000 Da, preferably from about 1,000 to about 50,000 Da; and

/or,

(c) wherein said pharmaceutically acceptable polymer contains multiple negatively charged terminal groups.

2. The method of claim 1, wherein said emulsion process comprises:

(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution;

(2) emulsifying the polymer solution in a solution of a second solvent to form an emulsion, wherein the first solvent is not miscible or partially miscible the second solvent, and wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent; and

,

(3) removing the first solvent to form said microparticles or nanoparticles having negative surface charges;

wherein said solution of the second solvent is optionally said aqueous solution.

3. The method of claim 1, said precipitation process comprises:

(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution;

(2) preparing a solution of a second solvent, wherein the first solvent is miscible with the second solvent, and wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent and optionally comprises a surfactant; and

,

(3) combining the polymer solution to the solution of the second solvent while mixing, thus forming said microparticles or nanoparticles having negative surface charges;

wherein said solution of the second solvent is optionally said aqueous solution.

4. The method of claim 1, wherein said emulsion process is a double emulsion process comprising:

(1) dissolving the pharmaceutically acceptable polymer in a first solvent to form a polymer solution;

(2) adding a small amount of a solution of a second solvent to the polymer solution to form a mixture, wherein the first solvent is not miscible or partially miscible with the second solvent, and wherein the solution of the second solvent optionally comprises an active pharmaceutical ingredient (API);

(3) emulsifying the mixture to form a first emulsion;

(4) emulsifying the first emulsion in the solution of the second solvent to form a second emulsion, wherein the solution of the second solvent optionally comprises a pharmaceutically acceptable negatively charged agent, and optionally further comprises a surfactant; and

,

(5) removing the first solvent to form said microparticles or nanoparticles having negative surface charges;

wherein said solution of the second solvent is optionally said aqueous solution.

5. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto said microparticles or nanoparticles to increase negative surface charges on said microparticles or nanoparticles.

6. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto said microparticles or nanoparticles to increase negative surface charge density on (e.g., the number of COOH groups on the surface of) said microparticles or nanoparticles.

11. The method of claim 1, wherein the microparticles or nanoparticles have a zeta potential of from about −

5 mV to about −

200 mV, preferably from about −

15 mV to about −

100 mV, most preferably from −

35 mV to −

85 mV.

12. The method of claim 2, wherein the first solvent is a volatile solvent.

13. The method of claim 12, wherein the polymer is a PLGA polymer, and the volatile solvent is methylene chloride, ethyl acetate, or chloroform.

14. The method of claim 2, wherein the solution of the second solvent comprises a surfactant.

16. The method of claim 14, wherein the polymer is a PLGA polymer, and the surfactant is/comprises polyvinyl alcohol, polyvinylpyrrolidone, a Tween series surfactant, Pluronic series, Poloxamer series, or Triton X-100 or a salt, derivative, copolymer, or mixture thereof.

17. The method of claim 1, wherein the emulsifying step comprises homogenization, mechanical stirring, and/or microfluidization.

18. The method of claim 1, wherein the first solvent is removed through solvent exchange and/or evaporation.

19. The method of claim 2, wherein the pharmaceutically acceptable negatively charged agent is a carboxyl-containing agent.

20. The method of claim 19, wherein the carboxyl-containing agent comprises hyaluronic acid;

gelatin;

polysaccharide;

polyacrylic acid;

polymethacrylic acid;

poly(hydroxyethylmethacrylic acid);

amino acid;

or a salt, derivative, copolymer, or mixture thereof.

21. The method of claim 1, wherein said pH that promotes ionization of said pharmaceutically acceptable polymer is between about 4-14, 6-14, 6-10, or about 8-12.

23. The method of claim 3, wherein the second solvent is water, and the first solvent miscible with water is acetone, tetrahydrofuron (THF), acetonitrile, dimethyl sulfoxide (DMSO), or dimethylformamide (DMF).

24. The method of claim 1, wherein the multiple negatively charged terminal groups are carboxyl terminal groups.

25. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by using a carboxyl-functional initiator in the preparation of the polymer.

26. The method of claim 25, wherein the carboxyl-functional initiator is an a-hydroxyl acid, preferably lactic acid or glycolic acid.

27. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by grafting a carboxyl-containing entity to the polymer.

28. The method of claim 27, wherein the carboxyl-containing entity is polyacrylic acid, polymethacrylic acid, poly(hydroxyethyl methacrylic acid), poly(maleic acid), polyanhydrides, or a salt, derivative, copolymer, or mixture thereof.

29. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by converting a functional group on the polymer to carboxyl group.

30. The method of claim 29, wherein the functional group is a hydroxyl group, and wherein the hydroxyl group is converted to the carboxyl group by reacting with an anhydride (e.g., dihydrofuran-2,5-dione).

31. The method of claim 24, wherein the polymer containing multiple negatively charged carboxyl terminal groups is produced by using an initiator that contains multiple carboxyl groups for generating hyperbranched polymer containing multiple negatively charged carboxyl terminal groups.

32. The method of claim 1, wherein the microparticles or nanoparticles have average particle sizes of from about 1 nm to about 1000 μ

m, preferably from about 10 nm to about 100 μ

m, and most preferably from about 20 nm to about 5 μ

m.

33. The method of claim 1, wherein the pharmaceutically acceptable polymer is PLGA, and wherein the microparticles or nanoparticles are PEGylated.

38. The method of claim 2, wherein an API (active pharmaceutical ingredient) is covalently attached to the surface of the microparticles or nanoparticles via covalent bonds.

39. The method of claim 2, wherein said solution of the second solvent is a mixture of the first solvent and the second solvent, and the volume ratio of the first solvent to the second solvent in said solution of the second solvent is about 0.1:

99.9, about 1;

99, about 5;

95, about 7.5;

92.5;

about 7.8;

92.2;

about 8;

92, or about 10;

90.

40. The method of claim 1, further comprising chemically conjugating a biomolecule (e.g., a peptide or a protein) to the surface of the microparticles or nanoparticles.

7-10. -10. (canceled)

15. (canceled)

22. (canceled)

34-37. -37. (canceled)

41-43. -43. (canceled)