METHOD FOR PREPARING MICROSPHERES AND MICROSPHERES PRODUCED THEREBY

• US 20110217341A1
• Filed: 05/12/2011
• Published: 09/08/2011
• Est. Priority Date: 11/14/2008
• Status: Active Grant

• Current Assignee: EWHA University-Industry Collaboration Foundation (Ewha Womans University), SK Chemicals Co Ltd (SK Discovery Co. Ltd.)
• Original Assignee: EWHA University-Industry Collaboration Foundation (Ewha Womans University), SK Chemicals Co Ltd (SK Discovery Co. Ltd.)
• Inventors: SAH, Hong Kee
• Granted Patent: US 8,697,127 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• 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 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

The present invention relates to a method for preparing microspheres and microspheres prepared thereby, more particularly to a method for preparing a polymeric microsphere, including preparing an emulsion including a polymer compound, a drug, a water-insoluble organic solvent and a dispersion solvent and adding to the prepared emulsion a base or an acid to remove the water-insoluble organic solvent from the emulsion, a polymeric microsphere prepared thereby, and a composition for drug delivery including the microsphere. According to the present invention, a drug-containing polymer microsphere may be prepared quickly and simply without the solvent evaporation or solvent extraction process, thereby reducing water consumption and minimizing wastewater generation.

Claims

1. A method for preparing a polymeric microsphere, including:

(a) preparing an oil-in-water (O/W), oil-in-oil (O/O) or water-in-oil-in-water (W/O/W) emulsion including a polymer compound, a drug, a water-insoluble organic solvent and a dispersion solvent and

(b) adding to the emulsion prepared in (a) a base solution or an acid solution to remove the water-insoluble organic solvent from the emulsion.

2. The method of claim 1, wherein the polymer compound is one selected from the group consisting of polylactic acid, polylactide, polylactic-co-glycolic acid, polylactide-co-glycolide(PLGA), polyphosphazine, polyiminocarbonate, polyphosphoester, polyanhydride, polyorthoester, a copolymer of lactic acid and caprolactone, polycaprolactone, polyhydroxyvalerate, polyhydroxybutyrate, polyamino acid, a copolymer of lactic acid and amino acid, and a mixture thereof.

3. The method of claim 1, wherein the drug is one or more selected from the group consisting of progesterone, haloperidol, thiothixene, olanzapine, clozapine, bromperidol, pimozide, risperidone, ziprasidone, diazepam, ethyl loflazepate, alprazolam, nemonapride, fluoxetine, sertraline, venlafaxine, donepezil, tacrine, galantamine, rivastigmine, selegiline, ropinirole, pergolide, trihexyphenidyl, bromocriptine, benztropine, colchicine, nordazepam, etizolam, bromazepam, clotiazepam, mexazolum, buspirone, goserelin acetate, somatotropin, leuprolide acetate, octreotide, cetrorelix, sandostatin acetate, gonadotropin, fluconazole, itraconazole, mizoribine, cyclosporin, tacrolimus, naloxone, naltrexone, cladribine, chlorambucil, tretinoin, carmustine, anagrelide, doxorubicin, anastrozole, idarubicin, cisplatin, dactinomycin, docetaxel, paclitaxel, raltitrexed, epirubicin, letrozole, mefloquine, primaquine, oxybutynin, tolterodine, allylestrenol, lovostatin, simvastatin, provastatin, atrovastatin, alendronate, salcatonin, raloxifene, oxadrolone, conjugated estrogen, estradiol, estradiol valerate, estradiol benzoate, ethinyl estradiol, etonogestrel, levonorgestrel, tibolone, norethisterone and piroxicam.

4. The method of claim 1, wherein the water-insoluble organic solvent is water-insoluble compound having one backbone selected from the group consisting of acid halogen, anhydride, phosphoric anhydride, ester, carboxylic esters, phosphoric esters compound, sulfuric acid esters compound, nitric esters compound, boric acid esters, amide and carboxylic amides.

5. The method of claim 1, wherein the water-insoluble organic solvent is one selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl formate, ethyl formate, isopropyl formate, propyl formate, butyl formate, methyl dichloroacetate, methyl chloroacetate, ethyl chloroacetate, ethyl dichloroacetate, methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, ethyl difluoroacetate, maleic anhydride, acetic anhydride, propionic anhydride, phosphoric anhydride, acetamide, propionamide, butylamide and carboxyl amide

6. The method of claim 1, wherein the dispersion solvent is aqueous dispersion solvent which is selected from the group consisting of polyvinyl alcohol aqueous solution, aqueous solution of polysorbates or co-solvent thereof, or non-aqueous dispersion solvent which is selected from the group consisting of vegetable oil, toluene, xylene and silicon oil containing emulsifier such as glycerin esters of fatty acids or lecithin.

7. The method of claim 1, wherein the base is selected from the group consisting of NaOH, LiOH, KOH, NH₄OH, Cu(OH)₂ and Fe(OH)₃.

8. The method of claim 1, wherein the acid is HCl, HNO₃, H₂SO₄, CH₃COOH, H₃BO₃ and H₂CO₃.

9. A polymer microsphere prepared by the method of anyone of selected from the group consisting of claim 1.

10. A composition for drug delivery comprising the polymer microsphere of claim 9 as an effective ingredient.