Pharmaceutical composition of nanoparticles

• US 8,257,740 B1
• Filed: 08/15/2011
• Issued: 09/04/2012
• Est. Priority Date: 08/15/2011
• Status: Active Grant

• Current Assignee: Nanomega Medical Corporation
• Original Assignee: GP Medical, Inc., National Tsing Hua University
• Inventors: Sung, Hsing-Wen, Sonaje, Kiran, Nguyen, Ho-Ngoc, Tu, Hosheng
• Primary Examiner(s): Monshipouri, Maryam
• Application Number:
  US13/136,912
• Time in Patent Office: 386 Days
• Field of Search: 424/488
• US Class Current: 424/488
• CPC Class Codes: A61K 47/6935 the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
• CPC Class Codes: A61K 47/6939 the polymer being a polysaccharide, e.g. starch, chitosan, chitin, cellulose or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

Abstract

The invention discloses a composition of chitosan-shelled nanoparticles and methods of manufacturing. The chitosan-shelled nanoparticles are characterized with a positive surface charge and enhanced epithelial ermeability for oral drug delivery.

Claims

1. A process for manufacturing chitosan-shelled nanoparticles having a surface consisted of chitosan, the process comprising the steps of:

(a) starting with a suspension of base nanoparticles having an acidic pH;

(b) slowly adding the base nanoparticles into an aqueous solution of said chitosan;

(c) raising the solution pH such that said chitosan precipitates at the surface of the base nanoparticles, thereby forming the chitosan-shelled nanoparticles having the surface consisted of said chitosan; and

(d) collecting the chitosan-shelled nanoparticles via a solid-liquid separation process.

2. The process of claim 1, wherein the solid-liquid separation process is a centrifugation process.

3. The process of claim 1, wherein said chitosan is N-trimethyl chitosan, EDTA-chitosan, low molecular weight chitosan, mono-N-carboxymethyl chitosan, N-palmitoyl chitosan (NPCS), chitosan derivatives, or combinations thereof.

4. The process of claim 1, wherein the base nanoparticles are loaded with at least a bioactive agent.

5. The process of claim 4, wherein said bioactive agent is an anti-hemophilic factor.

6. The process of claim 4, wherein said bioactive agent is an anti-hemophilic factor selected from the group consisting of a recombinant human coagulation factor VIIa (rFVIIa) or a recombinant plasma/serum-free coagulation factor VIII.

7. The process of claim 4, wherein said bioactive agent is an anti-diabetic agent.

8. The process of claim 4, wherein said bioactive agent is an anticoagulant.

9. The process of claim 1, wherein said base nanoparticles comprise chitosan and a negatively charged substrate.

10. The process of claim 1, wherein said base nanoparticles comprise excipient or GRAS (generally regarded as safe) inactive ingredients.

11. The process of claim 1, wherein the chitosan-shelled nanoparticles have a mean particle size between about 50 and 400 nanometers.

12. The process of claim 1, wherein the chitosan-shelled nanoparticles have a positive surface zeta potential.

13. The process of claim 1, wherein the base nanoparticles are formed via a simple and mild ionic-gelation method.

14. The process of claim 4, wherein said bioactive agent is GLP-2.

15. The process of claim 4, wherein said bioactive agent is an antagonist for treating Alzheimer'"'"'s diseases selected from the group consisting of donepezile, rivastignine, galantamine, memantine hydrochloride, donepezil hydrochloride, rivastigmine tartrate, galantamine hydrochloride, and tacrine hydrochloride.

16. The process of claim 4, wherein said bioactive agent is selected from the group consisting of oxytocin, vasopressin, adrenocorticotrophic hormone, prolactin, luliberin or luteinising hormone releasing hormone, growth hormone, human growth hormone, growth hormone releasing factor, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin, calcitonin, enkephalins, endorphins, angiotensins, rerun, bradykinin, bacitracins, polymixins, colistins, tyrocidin, gramicidines, and monoclonal antibodies.

17. The process of claim 4, wherein said bioactive agent is selected from the group consisting of proteins, peptides, nucleosides, nucleotides, antiviral agents, antineoplastic agents, antibiotics, oxygen-enriching agent, oxygen-containing agent, anti-epileptic drug, and anti-inflammatory drugs.

18. The process of claim 7, wherein said anti-diabetic agent is selected from the group consisting of metformin, an insulin secretagogue, DPP-4 inhibitors, alpha-glucosidase inhibitors, amylin analogs, sodium-glucose co-transporter type 2 (SGLT2) inhibitors, benfluorex, insulin, insulin analogs, GLP-1, and GLP-1 analogs.

19. The process of claim 9, wherein the negatively charged substrate is poly(glutamic acid) (PGA).

20. The process of claim 19, wherein the PGA is selected from the group consisting of γ

-PGA, α

-PGA, derivatives of PGA, PGA-complexone conjugate, and salts of PGA.