Hazard-free microencapsulation for structurally delicate agents, an application of stable aqueous-aqueous emulsion

• US 20060121121A1
• Filed: 06/03/2003
• Published: 06/08/2006
• Est. Priority Date: 06/03/2002
• Status: Abandoned Application

• Current Assignee: BioPharm Solutions, Inc.
• Original Assignee: BioPharm Solutions, Inc.
• Inventors: Jin, Tuo, Zhu, Hua, Zhu, Jiahao
• Application Number:
  US10/517,122
• Publication Number:
  US 20060121121A1
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/113 Multiple emulsions, e.g. oil-in-water-in-oil A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• 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 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5036 Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings

Abstract

This invention provides method for sustained release delivery of structurally delicate agents such as proteins and peptides. Using unique emulsion system (Stable polymer aqueous-aqueous emulsion), proteins and peptides can be microencapsulated in polysacchride glassy particles under a condition free of any chemical or physical hazard such as organic solvents, strong interfacial tension, strong shears, elevated temperature, large amount of surfactants, and cross-linking agents. Proteins loaded in these glassy particles showed strong resistance to organic solvents, prolonged activity in hydrated state, and an excellent sustained release profile with minimal burst and incomplete release when being further loaded in degradable polymer microspheres. This invention provides a simple yet effective approach to address all the technical challenges raised in sustained release delivery of proteins.

Claims

1. A method for encapsulating agents into particles through stable aqueous-aqueous emulsification comprising:

a. selecting polysaccharides as the dispersed phase for aqueous-aqueous emulsification, selecting aqueous polymers as the continuous phase, and selecting an stabilizing agent and its concentration for aqueous-aqueous emulsification, to provide a stable polymer aqueous-aqueous emulsion which is capable of encapsulating an agent into the polysaccharide dispersed phase;

b. providing at least one agent;

c. controlling the size and shape of the agent-loaded polysaccharide particles into appropriate size range;

d. drying the emulsion; and

e. removing the continuous phase after drying by washing the sample with solvent(s) which do not penetrate into the dried dispersed phase nor affect the loaded delicate agent(s).

2. A composition used in the method of claim 1, including an aqueous dispersed phase, an aqueous continuous phase and an aqueous surface modifier, capable to form a stable aqueous-aqueous emulsion.

3. The composition of claim 2, comprising sufficient amount of polysaccharides or derivatives thereof capable of forming the dispersed phase of the aqueous-aqueous emulsion and protecting agents encapsulated.

4. The composition of claim 3, wherein the polysaccharide is selected from the group consisting of dextran, starch, cellulose and its derivatives, and agarose and all type of poly- or oligo-sugars, which possess similar structure.

5. The composition of claim 4, wherein the average molecular weight of the polysaccharides is ranged from 2,000 to 2,000,000.

6. The composition of claim 3, wherein the agent is a biologically active agent.

7. The composition of claim 6, wherein the agent is selected from the group consisting of proteins, peptides, DNA/RNA, liposomes, and live viruses.

8. The composition of claim 7, wherein the protein or peptide is selected from the group consisting of erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), interferon and β

, growth hormone, calcitonin, tissue-type plasminogen activator (TPA), factor VIII, factor IX, hirudin, dornabe, and other therapeutic proteins or peptides.

9. The composition of claim 3, further comprising a small molecular sugar as complimentary agents for better protection of agents encapsulated in the polysaccharide dispersed phase during successive steps.

10. The composition of claim 9, wherein the small molecular sugar is selected from trehalose, manitol, sucrose, lactose or glycerin.

11. The composition of claim 2, comprising an aqueous polymer, which is immiscible with the polysaccharides, to form the continuous phase of the aqueous-aqueous emulsion.

12. The composition of claim 11, wherein the aqueous polymer in the continuous phase is polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinyl pyrrolidone (PVP), or polyvinyl alcohol (PVA).

13. The composition of claim 12, wherein the average molecular weight of the polymer is ranged from 2,000 to 2,000,000.

14. The composition of claim 2, comprising an aqueous polymer as the surface modifier of the dispersed phase.

15. The composition of claim 14, wherein the polymeric surface modifier is selected from sodium alginate, hyaluronate, carboxymethyl cellulose, carboxymethyl dextran, dextran sulfate, and other dextran or starch devertives, or other polymers that possess negatively charged backbone and positively charged counter ions.

16. The method of claim 1, wherein the emulsion is dried through lyophilization, spray drying or a conventional drying process to solidify the agent-encapsulated polysaccharide dispersed phase.

17. Dried polysaccharide dispersed phase prepared by the method of claim 16, possessing an average diameter of 1-5 μ

m for inhalation and for double microencapsulation, and of 1-50 μ

m for other applications.

22. A composition of any one of claims 2-15 for or acceptable for pharmaceutical applications.

18. A method of encapsulating dried polysaccharide dispersed phase into biodegradable polymer microspheres for controlled release of bioactive agent(s) comprising:

a) utilizing a solid-in-oil-in-water (S-O-W) emulsification process or a solid-in-oil-in-oil process with the dried polysaccharide dispersed phase as the solid phase;

b) selecting a biodegradable polymer, dissolving the polymer in an organic solvent and suspending the dried polysaccharide dispersed phase in the polymer solution;

c) selecting polymeric surfactant(s) for dispersing the solution of the biodegradable polymers in a water solution of a small molecular salt;

d) the concentration of the slat solution ranges from 0.5% to 50%;

e) removing the organic solvent by extraction or evaporation.

19. The method of claim 18, wherein the biodegradable polymer is PLGA, poly-pseudo CBZ-serine or other polymers.

20. Particulates of degradable polymers prepared using the method of claim 18, wherein dried polysaccharide dispersed phase is distributed in the matrix.

21. Particulates of claim 20, wherein the ratio of dried polysaccharide dispersed phase to the degradable polymer is within the range of 1:

2 to 1;

40.