Process and apparatuses for preparing nanoparticle compositions with amphiphilic copolymers and their use

Patent metadata

Field	Value
Publication number	US-9956179-B2
Application number	US-201213368888-A
Country	US
Kind code	B2
Filing date	Feb 8, 2012
Priority date	Mar 30, 2001
Publication date	May 1, 2018
Grant date	May 1, 2018

Abstract

This invention discloses a process for making nanoparticles of amphiphilic copolymers by flash precipitation. Nanoparticles may be of amphiphilic copolymer alone or may contain an additive target molecule, preferably an organic active. The inclusion of additive target molecules in amphiphilic copolymer nanoparticles can alter their water solubility characteristics, fluid dynamics, and/or stability. Changing an additive target molecule's solubility and stability in a nanoparticle can make a water insoluble compound suitable for pharmaceutical administration as well as specifically target the molecule to a specific area of a patient's body. The process affords the production of nanoparticles at high absolute active content, at high yield, high productivity, and high processing rates while using unusually low amounts of amphiphilic copolymers. Furthermore, the resulting particles exhibit sufficient stability for post processing as desired. The invention also discloses two apparatuses for the production of nanoparticles of amphiphilic copolymers by flash precipitation.

First claim

We claim:

1. A method for preparing solid nanoparticles by flash precipitation comprising:
flash precipitating solid nanoparticles comprising at least one amphiphilic copolymer and at least one organic additive target molecule by mixing 1) an organic solvent comprising said at least one amphiphilic copolymer and said at least one organic additive target molecule and 2) water or an aqueous solution comprising a buffering agent or salt,
wherein said mixing comprises injecting the organic solvent and the water or aqueous solution as liquid streams into a confined mixing chamber,
wherein said organic solvent is soluble with said water or aqueous solution and
the mixing of said organic solvent and said water or aqueous solution results in a single product solvent that causes the precipitation of said amphiphilic copolymer and said target molecule as nanoparticles,
wherein the organic additive target molecule to amphiphilic copolymer ratio by weight is at least 1:4 in said organic solvent,
wherein the particle size of the resulting nanoparticles is a function of the temperature, the hydrophobic and hydrophilic character of at least one amphiphilic copolymer, and the mixing velocity of the process, and
wherein the mixing velocity of the organic solvent and the water or aqueous solution is at least 0.1 m/sec.

2. The method of claim 1 , wherein at least one amphiphilic copolymer comprises blocks with a minimum contour length equal to the length of at least 5 ethylene units.

3. The method of claim 1 , wherein at least one amphiphilic copolymer comprises blocks with a molecular weight of at least 300 g/mole.

4. The method of claim 1 , wherein at least one amphiphilic copolymer has a total molecular weight between about 1000 to about 50,000 g/mole.

5. The method of claim 1 , wherein at least one amphiphilic copolymer has a total molecular weight of at least 2000 g/mole.

6. The method of claim 1 , wherein at least one amphiphilic copolymer exhibits a surface tension when dissolved in water of at least 50 dynes/cm at a concentration of 0.1 weight percent at 25° C.

7. The method of claim 1 , wherein the organic solvent is capable of dissolving at least 0.1% of at least one amphiphilic copolymer by weight.

8. The method of claim 1 , wherein the organic solvent comprises an ether or an alcohol.

9. The method of claim 8 , wherein the organic solvent comprises tetrahydrofuran.

10. The method of claim 1 , wherein the concentration of at least one amphiphilic copolymer in the organic solvent is at least 0.1 wt %.

11. The method of claim 10 , wherein the concentration of at least one amphiphilic copolymer in the organic solvent is between about 0.3 wt % to about 10.0 wt %.

12. The method of claim 1 , wherein the concentration of at least one amphiphilic copolymer in the organic solvent is at least 0.05 wt %.

13. The method of claim 1 , wherein the temperature of the organic solvent and the water or aqueous solution is maintained between about 20° C. to about 50° C.

14. The method of claim 13 , wherein the temperature of the organic solvent and the water or aqueous solution is maintained at 35° C.

15. The method of claim 1 , wherein the pressure during mixing is controlled.

16. The method of claim 1 , wherein the pressure during mixing is maintained above 8 psig.

17. The method of claim 1 , wherein said at least one organic additive target molecule is continuously added to a mixer with said water or an aqueous solution comprising a buffering agent or salt such that said nanoparticles are continuously produced.

18. The method of claim 1 , wherein the organic solvent, the aqueous solution, or both is a liquefied gas.

19. The method of claim 1 , wherein at least 85% of the resulting nanoparticles are less than 1060 nm in diameter.

20. The method of claim 19 , wherein the average diameter of the resulting nanoparticles is less than about 400 nm.

21. The method of claim 1 , further comprising the step of removing the product solvent from the product solvent containing the nanoparticles.

22. The method of claim 21 , wherein the product solvent is removed by a process selected from the group consisting of filtration, distillation, evaporation, expansion, lyophilization, and extraction.

23. The method of claim 1 , wherein the organic additive target molecule to amphiphilic copolymer ratio by weight is 1:4 to about 20:1.

24. The method of claim 1 , wherein at least one organic additive target molecule make up at least 0.2% by weight of the mixture based on initial charges to the mixer.

25. The method of claim 1 , wherein at least one organic additive target molecule is selected from the group consisting of pharmaceutical organic actives, pharmaceutical organic precursor compounds, proteins, cyclosporins, immunoactive agents, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immuriological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, xanthines, anti-oxidants, preservatives, vitamins, nutrients, antioxidant, agricultural organic compounds, biocides, pesticides, herbicides, fungicides, insecticides, cosmetic products, dyes, reagents, salts, biological markers, magnetic particle precursors, radiopaque materials, β-carotene, a crystalline phase drug, and an amorphous phase drug.

26. The method of claim 25 , wherein at least one organic additive target molecule is a vitamin.

27. The method of claim 1 , further comprising adding at least one supplemental additive to the organic solvent before mixing or to the organic solvent after mixing.

28. The method of claim 27 , wherein at least one supplemental additive is selected from the group consisting of surfactants, gelatin, phospholipid, Pluronics, inert diluents, solubilizing agents, emulsifiers, suspending agents, adjuvants, wetting agents, colloidal dispersants, cellulose, dicalcium phosphate, dodecyl trimethyl ammonium bromide, glycerol, glycerol monostearate, glucose, p-isononylphenoxypolt-(glycidol), glucamides, lecithin (phosphatides), maltosides, magnesium stearate, magnesium aluminum silicate, oils, starch, polyethylene glycols, polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, poloxamers, polaxamines, silicic acid, sodium citrate, sodium dodecyl sulfate, sodium lauryl sulfate, steric acid, sucrose, tapioca starch, talc, thioglucosides, tragacanth, triethanolamine, Triton X-200®, salt, functional surface modifier, protein, sugar, fatty acid, organic pharmaceutical excipient, inorganic pharmaceutical excipient, pharmaceutically acceptable carrier, and low molecular weight oligomer.

29. The method of claim 25 , wherein at least one supplemental additi

Assignees

• Johnson Brian K
• Prudhomme Robert K
• Univ Princeton

Inventors

• Johnson Brian K
• Prud'Homme Robert K

Classifications

• A61K9/5192

  Processes · CPC title

• B01J13/0021

  containing a solid organic phase · CPC title

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title

• A61K9/5138 Primary

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K47/34

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title