Stealth polymeric particles for delivery of bioactive or diagnostic agents

Patent metadata

Field	Value
Publication number	US-9358211-B2
Application number	US-201414292314-A
Country	US
Kind code	B2
Filing date	May 30, 2014
Priority date	Nov 23, 2010
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

The present invention is directed to a crosslinked or non-crosslinked polymer particle, wherein the crosslinked polymer particle comprises a copolymer of poly(alkylene glycol-graft-acrylate) that is crosslinked by at least one hydrolysable monomer or crosslinking agent. The present invention is also directed to a polymer particle comprising a crosslinked polymer particle that is a product of starting materials comprising (a) a hydrophilic monomer, (b) a hydrophobic monomer, and (c) a hydrolysable crosslinking agent (the crosslinking agent may be absent in the case of non-crosslinked particles). The present invention is still further directed to a polymer particle comprising a crosslinked copolymer, where the crosslinked copolymer includes structures represented by Formulas (I), (II), and (III), as defined in the specification. Other embodiments of the present invention also include methods of manufacturing polymer particles.

First claim

The invention claimed is:

1. A method of preparing polymer particles comprising the steps of
(i) dissolving a reaction mixture of an acrylate, a poly(alkyleneglycol-graft-acrylate), an optionally hydrolysable crosslinking agent, and an initiator in a binary solvent system;
(ii) heating the reaction mixture in an oxygen free atmosphere;
(iii) leaving the reaction mixture to polymerize overnight in an oxygen free atmosphere, the polymerization being a free radical dispersion polymerization, wherein the free radical dispersion polymerization is performed at or below a temperature of about 25° C.; and,
(iv) dialyzing in water.

2. The method of claim 1 , wherein the binary solvent system is ethanol and water.

3. The method of claim 1 , wherein the acrylate is methyl methacrylate (MMA).

4. The method of claim 1 , wherein the poly(alkyleneglycol-graft-acrylate) is poly(ethyleneglycol-graft-methylmethacrylate).

5. The method of claim 3 , wherein an amount of MMA used is from 6.0 to 12.0 mmol.

6. The method of claim 3 , wherein an amount of MMA is 8.0 mmol, an amount of the hydrolysable crosslinking agent is from 4-5 mol %, and an amount of initiator is 1 mol %.

7. The method of claim 1 , wherein the initiator is selected from the group consisting of benzoyl peroxide (BPO), N-phenyl diethanolamine (NPDEA), azo-bis-isobutyronitrile (AIBN), potasium persulfate (KPS), 2,2′-azobis-2,4-dimethylvaleronitrile (ADVN), PDMS macroazoinitiator (PDMS-azo), ammonium persulfate, thermal 2,2′-azobis[N-(2-carboxyethyl)-2-2-methylpropionamidine] (VA-057), amphoteric pH sensitive initiator, N,N-dimethyl-4-toluidine (DMT), N,N-dimethylbenzyl methacrylate, N,N-dimethylbenzyl alcohol, N,N-dimethylaniline, 4-N,N-dialkyl aminophenalkanoic acids and their methyl esters, peroxides, persulfate, peroxomonosulfate, peroxidiphosphate, metal ion oxidant-reducing agent systems, 2,2-dimethoxy-2-phenylacetophenone, Quantacure ITX photosensitizer and Irgacure 907 (1-907) initiator systems, and N,N-dimethyl ethanol amine.

8. The method of claim 7 , wherein the initiator is a combination of BPO and NPDEA, used in a ratio of 50:50.

9. The method of claim 8 , wherein an amount of poly(ethylene glycol)n monomethyl ether monomethacrylate (PEG-MA) used is 0.1 mmol.

10. The method of claim 8 , wherein an amount of hydrolysable crosslinking agent used is from 0-4 mol % of a total volume of the reactants.

11. The method of claim 8 , wherein the hydrolysable crosslinking agent is N,O-dimethylacryloylhydroxylamine.

12. The method of claim 7 , wherein the initiator is azobisisobutyronitrile.

13. The method of claim 12 , wherein an amount of azobisisobutyronitrile is 1 mol % of a total volume of the reactants.

14. The method of claim 12 , further comprising a therapeutic agent in the reaction mixture.

15. The method of claim 14 , wherein the therapeutic agent is selected from the group consisting of 2-chloro-3-diacetylamino-1,4-naphthoquinone, docetaxel, doxorubicin, and paclitaxel.

16. The method of claim 15 , wherein the agent is paclitaxel.

17. The method of claim 4 , wherein a polymerizable agent for preparing the optionally hydrolysable crosslinking agent is methacryloyl chloride.

18. A method of preparing polymer particles comprising the steps of:
providing a hydrophilic monomer selected from the group consisting of alkene glycol, polyalkylene glycol and mixtures thereof;
providing a hydrophobic acrylate monomer as copolymer;
providing a hydrolysable crosslinking agent; and
initiating polymerization to form the polymer particles using the hydrophilic monomer, the hydrophobic acrylate monomer, and the hydrolysable crosslinking agent via a free radical dispersion polymerization, wherein the free radical dispersion polymerization is performed at or below a temperature of about 25° C.

19. A method of preparing polymer particles comprising the steps of:
providing a compound represented by Formula (I):

providing a compound represented by formula (II):

providing a compound represented by formula (III):

wherein R 1 -R 5 each represent a group, which may be the same or different from each other, and the group is selected from the group consisting of a hydrogen, a halogen, and an alkyl group having one to five carbon atoms, wherein R 6 represents another chain of the crosslinked polymer particle comprised of structures represented by Formulas (I), (II), and (III), wherein x, y, and z represent an integer from 1 to 100, wherein n represents an integer 1 to 10,000, wherein A 1 is an oxygen atom or a secondary amine, where A 2 is an oxygen atom or a secondary amine; and
initiating polymerization to form the polymer particles using the compounds of Formulas (I), (II), and (III) via a free radical dispersion polymerization, wherein the free radical dispersion polymerization is performed at or below a temperature of about 25° C.

20. A method of preparing a therapeutic agent encapsulated within polymer particles comprising the steps of:
(i) dissolving a reaction mixture of an acrylate, a poly(alkyleneglycol-graft-acrylate), an optionally hydrolysable crosslinking agent, and an initiator in a binary solvent system, the reaction mixture further comprising a therapeutic agent;
(ii) heating the reaction mixture in an oxygen free atmosphere;
(iii) leaving the reaction mixture to polymerize overnight in an oxygen free atmosphere, the polymerization being a free radical dispersion polymerization; and,
(iv) dialyzing in water.

Assignees

• Univ Howard

Inventors

• Akala Emmanuel Oyekanmi
• Okunola Oluyomi Modupe

Classifications

• Y10T428/2982

  Particulate matter [e.g., sphere, flake, etc.] · CPC title

• C08F290/062 Primary

  Polyethers · CPC title

• C08F222/00

  Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a carboxyl radical and containing at least one other carboxyl radical in the molecule; Salts, anhydrides, esters, amides, imides, or nitriles thereof · CPC title

• C08F8/00

  Chemical modification by after-treatment (graft polymers, block polymers, crosslinking with unsaturated monomers or with polymers C08F251/00 - C08F299/00; of conjugated diene rubbers C08C) · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title