Process for preparing microparticles having a low residual solvent volume

• US 8,728,528 B2
• Filed: 12/18/2008
• Issued: 05/20/2014
• Est. Priority Date: 12/20/2007
• Status: Active Grant

• Current Assignee: Evonik Corporation
• Original Assignee: Evonik Corporation
• Inventors: Biggs, Danielle, Nettles, Heather
• Primary Examiner(s): BARHAM, BETHANY P
• Application Number:
  US12/338,488
• Publication Number:
  US 20090162407A1
• Time in Patent Office: 1,979 Days
• Field of Search: None
• US Class Current: 424/489
• CPC Class Codes: A01N 25/12 Powders or granules A01N25/26 takes precedence
• CPC Class Codes: A01N 25/28 Microcapsules or nanocapsules
• CPC Class Codes: A61K 2800/412 Microsized, i.e. having sizes between 0.1 and 100 microns
• CPC Class Codes: A61K 2800/654 The particulate/core comprising macromolecular material
• CPC Class Codes: A61K 8/0241 Containing particulates characterized by their shape and/or structure see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes
• CPC Class Codes: A61K 8/06 Emulsions
• CPC Class Codes: A61K 8/90 Block copolymers A61K8/89 takes precedence
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• 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: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50
• CPC Class Codes: C11D 17/0039 Coated compositions or coated components in the compositions, (micro)capsules
• CPC Class Codes: C11D 3/505 encapsulated or adsorbed on a carrier, e.g. zeolite or clay

Abstract

The disclosed processes for forming microparticles utilize low volumes of processing water while still providing microparticles having low residual solvent levels. The processes are adaptable to both continuous and batch processes using oil/water or water/oil or water/oil/water or oil/water/oil emulsions.

Claims

1. A process for preparing low residual solvent level microparticles, comprising:

(a) providing a dispersed phase comprising a polymer excipient in a weight amount of a dispersed phase solvent, W_{DP solvent}, wherein the polymer excipient comprises;

i) a non-water soluble block copolymer comprising a polyethylene glycol (PEG) hydrophilic block or blocks and a hydrophobic block or blocks;

or

ii) an admixture of non-water soluble block copolymers comprising a PEG hydrophilic block or blocks and a hydrophobic block or blocks;

or

iii) an admixture of a PEG hydrophilic, water soluble biocompatible polymer; and

a non-water soluble, biocompatible and/or biodegradable polymer;

(b) combining the dispersed phase with a continuous phase processing medium to form an emulsion wherein the dispersed phase is a discontinuous phase in the continuous phase;

(c) combining the emulsion formed in (b) with a weight amount of an extraction phase solvent, W_{EP solvent}, thereby forming microparticles;

wherein the W_EP solvent comprises water or a mixture of water and a fully water-miscible solvent, and

(d) isolating the microparticles;

wherein the amount of residual dispersed phase solvent present in the isolated microparticles is less than or equal to about 3 wt %, and is less than the amount of residual dispersed phase solvent present in microparticles produced by said process in the absence of PEG;

the total amount of extraction phase solvent is W_{EP solvent, total} defined by the formula;

2. The process according to claim 1, wherein the Extraction Ratio is less than or equal to about 9.

3. The process according to claim 1, wherein the Extraction Ratio is less than or equal to about 8.

4. The process according to claim 1, wherein the Extraction Ratio is less than or equal to about 7.

5. The process according to claim 1, wherein the Extraction Ratio is less than or equal to about 6.

6. The process according to claim 1, wherein the dispersed phase of Step (a) comprises a non-water soluble block copolymer comprising:

i) one or more hydrophobic components or blocks of a biocompatible polymer; and

ii) one or more PEG hydrophilic components or blocks of a hydrophilic (water soluble) biocompatible polymer;

wherein the non-water soluble block copolymer has a molecular weight of from about 1,000 to about 2,000,000 daltons.

7. The process according to claim 1, wherein the dispersed phase of Step (a) comprises a block copolymer comprising:

i) one or more hydrophobic components (blocks) comprising biocompatible and biodegradable polymer chemistries comprising polyesters, polyanhydrides, polyorthoesters, polyphosphazenes, polyphosphates, polyphosphoesters, polyphosphonates, polydioxanones, polyhydroxyalkanoates, polycarbonates, polyalkylcarbonates, polyorthocarbonates, polyesteramides, polyamides, polyamines, polypeptides, polyurethanes, polyetheresters, or combinations thereof;

the hydrophobic component having a molecular weight from about 500 daltons to about 2,000,000 daltons; and

ii) one or more hydrophilic components (blocks) comprising PEG;

the hydrophilic component having a molecular weight of from about 100 daltons to about 100,000 daltons;

wherein the copolymer is non-water soluble and has a molecular weight of from about 1,000 daltons to about 2,000,000 daltons.

8. The process according to claim 1, wherein the dispersed phase of Step (a) comprises a block copolymer comprising:

i) a hydrophobic component comprising lactide, glycolide, caprolactone, hydroxybutyrate, or hydroxyvalerate or a combination thereof, the hydrophobic component having a molecular weight from about 500 daltons to about 2,000,000 daltons; and

ii) a hydrophilic component comprising a polyethylene glycol having a molecular weight of from about 100 daltons to about 100,000 daltons;

wherein the copolymer is non-water soluble and has a molecular weight of from about 1,000 daltons to about 2,000,000 daltons.

9. The process according to claim 1, wherein the polymer excipient of Step (a) comprises:

iii) a non-water soluble block copolymer having a molecular weight from about 500 to 2,000,000 daltons; and

iv) a biocompatible and/or biodegradable polymer having a molecular weight from about 500 to 2,000,000 daltons;

wherein the polymer excipient contains from about 10% by weight up to less than about 100% by weight of the non-water soluble block copolymer.

10. The process according to claim 1, wherein the polymer excipient of Step (a) comprises:

i) a non-water soluble block copolymer having a molecular weight from about 500 daltons to about 2,000,000 daltons; and

ii) a biocompatible or biodegradable polymer having a molecular weight from about 500 daltons to about 2,000,000 daltons, comprising a polyester, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyphosphoester, polyphosphonate, polydioxanone, polyhydroxyalkanoate, polycarbonate, polyalkylcarbonate, polyorthocarbonate, polyesteramide, polyamide, polyamine, polypeptide, polyurethane, polyetherester, or a combination thereof; and

wherein the polymer excipient contains from about 10% by weight up to less than about 100% by weight of the non-water soluble block copolymer.

11. The process according to claim 1, wherein the polymer excipient of Step (a) comprises:

i) a non-water soluble block copolymer having a molecular weight from about 500 daltons to about 2,000,000 daltons; and

,

ii) a biocompatible or biodegradable polymer comprising lactide, glycolide, caprolactone, hydroxybutyrate, or hydroxyvalerate or a combination thereof;

having a molecular weight from about 500 daltons to about 2,000,000 daltons;

wherein the polymer excipient contains from about 10% by weight up to less than about 100% by weight of the non-water soluble block copolymer.

12. The process according to claim 1, wherein the polymer excipient of Step (a) comprises comprising:

iii) a PEG hydrophilic, water soluble biocompatible polymer having a Molecular weight from about 100 daltons to about 100,000 daltons; and

,

iv) a non-water soluble, biocompatible and/or biodegradable polymer having a molecular weight from about 500 to 2,000,000 daltons;

wherein the polymer excipient contains from about 1% by weight up to less than about 20% by weight of the water soluble biocompatible polymer.

13. The process according to claim 1, wherein the polymer excipient of Step (a) comprises comprising:

iii) a hydrophilic, water soluble biocompatible polymer comprising a PEG having a molecular weight from about 100 daltons to about 100,000 daltons; and

,

iv) a non-water soluble, biocompatible and/or biodegradable polymer comprising a polyester, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyphosphoester, polyphosphonate, polydioxanone, polyhydroxyalkanoate, polycarbonate, polyalkylcarbonate, polyorthocarbonate, polyesteramide, polyamide, polyamine, polypeptide, polyurethane, polyetherester, or a combination thereof;

the biocompatible polymer having a molecular weight from about 500 daltons to about 2,000,000 daltons;

wherein, the polymer excipient from about 1% by weight up to less than about 20% by weight of the water soluble biocompatible polymer.

14. The process according to claim 1, wherein the polymer excipient of Step (a) comprises:

i) a hydrophilic, water soluble biocompatible polymer comprising a polyethylene glycol having a molecular weight from about 100 daltons to about 100,000 daltons ; and

,

ii) a non-water soluble, biocompatible and/or biodegradable polymer comprising lactide, glycolide, caprolactone, hydroxybutyrate, hydroxyvalerate, or a combination thereof, the biocompatible polymer having a molecular weight from about 500 daltons to about 2,000,000 daltons;

wherein, the polymer excipient contains from about 1% by weight up to less than about 20% by weight of the water soluble biocompatible polymer.

15. The process according to claim 1, wherein the polymer excipient of Step (a) comprises:

i) a hydrophilic, water soluble biocompatible polymer comprising polyethylene glycol having a molecular weight of from about 100 daltons to about 100,000 daltons; and

ii) a non-water soluble, biocompatible and/or biodegradable polymer comprising lactide, glycolide, caprolactone, hydroxybutyrate, hydroxyvalerate, or a combination thereof, the biocompatible polymer having a molecular weight from about 500 daltons to about 2,000,000 daltons;

wherein, the polymer excipient contains from about 1% by weight up to less than about 20% by weight of the water soluble biocompatible polymer.

16. The process according to claim 1, wherein the dispersed phase of Step (a) comprises a non-water soluble block copolymer that is an AB block copolymer, an ABA block copolymer, or a BAB block copolymer, wherein the A block represents the hydrophilic component and the B block represents the hydrophobic component of the composition.

17. The process according to claim 1, wherein the dispersed phase of Step (a) comprises a non-water soluble block copolymer that is a regular or a random configuration of two or more A blocks and two or more B blocks, wherein the A block represents the hydrophilic component and the B block represents the hydrophobic component of the composition.

18. The process according to claim 1, wherein the dispersed phase solvent of Step (a) is a non-halogenated solvent.

19. The process according to claim 1, wherein the dispersed phase solvent of Step (a) is a non-halogenated solvent comprising acetone, methyl ethyl ketone, methanol, ethanol, n-propanol, iso-propanol, benzyl alcohol, glycerol, diethyl ether, tetrahydrofuran, glyme, diglyme, methyl acetate, ethyl acetate, n-pentane, iso-pentane, hexane, heptane, isooctane, benzene, toluene, or xylene.

20. The process according to claim 1, wherein the dispersed phase solvent of Step (a) is ethyl acetate.

21. The process according to claim 1, wherein the dispersed phase solvent of Step (a) is a halogenated solvent comprising carbon tetrachloride, chloroform, methylene chloride, chloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, or 1,2-dichloroethane.

22. The process according to claim 1, wherein the dispersed phase solvent of Step (a) is methylene chloride.

23. The process according to claim 1, wherein the microparticles are nanoparticles, microspheres, nanospheres, microcapsules, or nanocapsules having a size from about 10 nanometers to 2 millimeters.

24. The process according to claim 1, wherein the residual solvent level is less than or equal to 1.75%.

25. The process according to claim 1, wherein the residual solvent level is less than or equal to 1.5%.

26. The process according to claim 1, wherein the residual solvent level is less than or equal to 1.25%.

27. The process according to claim 1, wherein the residual solvent level is less than or equal to 1%.

28. The process according to claim 1, wherein further the residual moisture level is less than of equal to 1.75%.

29. The process according to claim 1, wherein the residual moisture level is less than or equal to 1.5%.

30. The process according to claim 1, wherein the residual moisture level is less than or equal to 1.25%.

31. The process according to claim 1, wherein the residual moisture level is less than or equal to 1%.

32. The process according to claim 1, wherein the continuous processing medium comprises one or more processing aids.

33. The process according to claim 32, wherein the processing aid comprises poly(vinyl alcohol).

34. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises one or more agents.

35. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises a bioactive agent, the bioactive agent comprising at least one member of peptides, proteins, antibodies, antibody fragments, monoclonal antibodies, monoclonal antibody fragments, nucleic acids, antisense nucleic acids, anabolic agents, antacids, anti-asthmatic agents, analeptic agents, anti-cholesterolemic, anti-lipid and antihyperlipidemic agents, anticholinergic agents, anti-coagulants, anti-convulsants, antidiabetic agents;

anti-diarrheals, anti-edema agents;

anti-emetics, antihelminthic agents;

anti-infective agents, antibacterial agents, antimicrobial agents, anti-inflammatory agents, anti-manic agents, antimetabolite agents, anti-migrane agents;

anti-nauseants, anti-neoplastic agents, anti-obesity agents, anorexic agents;

antipruritic agents;

anti-pyretic agents, analgesic agents, anti-smoking agents, anti-alcohol agents;

anti-spasmodic agents, anti-thrombotic agents, antitubercular agents;

anti-tussive agents, anti-uricemic agents, anti-anginal agents, antihistamines, anxiolytic agents;

appetite suppressants, attention deficit disorder agents, attention deficit hyperactivity disorder drugs, biologicals, cerebral dilators, coronary dilators, bronchiodilators, cytotoxic agents, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, central nervous system agents, central nervous system stimulants, antipsychotics, atypical antipsychotics, dopamine agonists, iron chelators, hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulating agents, immunosuppressive agents, muscle relaxants, nicotine, parasympatholytics, sialagogues, ion-exchange resins, laxatives, mineral supplements, mucolytic agents, neuromuscular drugs, vasodialators, peripheral vasodilators, beta-agonists;

tocolytic agents;

psychotropics, psychostimulants, sedatives, stimulants, thyroid and anti-thyroid agents, tissue growth agents, uterine relaxants, vitamins, or antigenic agents.

36. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises a bioactive agent, the bioactive agent comprising at least one member of hormones, enzymes, antibodies, aptamers, siRNA'"'"'s, DNA'"'"'s, RNA'"'"'s, or antisense nucleic acids.

37. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an inhibitor, the inhibitor comprising at least one member of polysaccharide, growth factor, VEGF, anti-VEGF, bone morphogenetic proteins (BMPs), hormone, hormonolytic, anti-angiogenesis factor, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, chlophedianol hydrochloride, chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral supplements, cholestryramine, N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenyl propanolamine hydrochloride, caffeine, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptide, polypeptide, protein, amino acid, hormone, interferon, cytokines, carbonic anhydrase inhibitors, adrenergic receptor agonists, adrenergic receptor antagonists, protein kinase inhibitors, or vaccines.

38. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an antibiotic, the antibiotic comprising at least one member of an antimicrobial agent, antiviral, antibacterial, antiparasitic, antifungal substance and combination thereof, antiallergenic, steroid, androgenic steroid, decongestant, hypnotic, steroidal anti-inflammatory agent, anti-cholinergic, sympathomimetic, sedative, miotic, psychic energizer, tranquilizer, vaccine, estrogen, progestational agent, humoral agent, prostaglandin, analgesic, antispasmodic, antimalarial, antihistamine, cardioactive agent, nonsteroidal anti-inflammatory agent, antiparkinsonian agent, anti-alzheimers agent, antihypertensive agent, beta-adrenergic blocking agent, alpha-adrenergic blocking agent, nutritional agent, or the benzophenanthridine alkaloid.

39. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises at least one member of a compound capable of acting as a stimulant, a compound capable of acting as a sedative, a compound capable of acting as a hypnotic, a compound capable of acting as an analgesic, or a compound capable of acting as an anticonvulsant.

40. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, the agent comprising at least one member of anorexic, antiarthritic, antiasthmatic, antibiotic, antifungal, antiviral, anticancer agent, anticoagulant, anticonvulsant, antidepressant, antihistamine, hormone, tranquilizer, antispasmodic, vitamins and mineral, cardiovascular agent, calcium channel blocker, peptides and protein, prostaglandin, nucleic acid, carbohydrate, fat, narcotic, narcotic antagonist, narcotic partial-agonists psychotherapeutic, anti-malarial, L-dopa, diuretic, or antiulcer drugs.

41. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, the agent comprising at least one member of lidocaine, xylocaine, dexadrine, phendimetrazine tartrate, methylprednisolone, ibuprofen, terbutaline sulfate, theophylline, ephedrine, sulfisoxazole, penicillin G, ampicillin, cephalosporin, amikacin, gentamicin, tetracycline, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, amphotericin B, nystatin, ketoconazole, acyclovir, amantadine, cyclophosphamide, methotrexate, etretinate, heparin, warfarin, phenytoin sodium, diazepam, isocarboxazid, amoxapine, diphenhydramine HCl, chlorpheniramine maleate, insulin, progestin, estrogen, corticoid, glucocorticoid, androgen, steroids, corticosteroids, prostaglandins, thorazine, diazepam, chlorpromazine HCl, reserpine, chlordiazepoxide HCl, belladonna alkaloid, dicyclomine hydrochloride, essential amino acid, calcium, iron, potassium, zinc, vitamin B₁₂, prazosin HCl, nitroglycerin, propranolol HCl, hydralazine HCl, pancrelipase, succinic acid dehydrogenase, LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptides including glucagon, GLP-1, GLP-2, IP-1, IP-2;

growth releasing factor, angiotensin, FSH, EGF, vasopressin, ACTH, human serum albumin, gamma globulin, toxins including botulinum toxin;

morphine, codeine, furosemide, spironolactone, rantidine HCl, or cimetidine HCl.

42. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, the agent comprising at least one member of an immunological agent, an allergen, or an antigen of a fungus, protozoa, or parasite.

43. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, the agent comprising at least one member of cytokines, interleukins, interferon, colony stimulating factor, granulocyte-colony stimulating factors, granulocyte macrophage colony-stimulating factors, tumor necrosis factor, cat dander, birch pollen, house dust mite, or grass pollen.

44. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, the agent comprising at least one member of antigens to cush bacterial organisms chosen from Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphteriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptspirosis interrogans, Borrelia burgddorferi, or Campylobacter jejun.

45. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, wherein the agent is an antigen of a virus comprising at least one member of smallpox, influenza A, influenza B, respiratory synctial, parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex 1 and 2, cytomeglavirus, Epstein-Barr, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps, rabies, rubella, coxsackieviruses, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocytic choriomeningitis, or hepatitis B.

46. The process according to claim 1, wherein the dispersed phase of Step (a) further comprises an agent, wherein the agent is an antigen of a fungus, protozoa, or parasite comprising at least one member of Cryptococcuc neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroids, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamyda psittaci, Chlamydia trachomatis, Plasmodium falciparum, Trypanasoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas Vaginalis, or Schistosoma manson.

47. The process according to claim 1, wherein the microparticles further comprise an excipient comprising at least one member of an adhesive, a pesticide, a fragrance, an antifoulant, a dye, a salt, an oil, an ink, a cosmetic, a catalyst, a detergent, a curing agent, a flavor, a fuel, a herbicide, a metal, a paint, a photographic agent, a biocide, a pigment, a plasticizer, a propellant, a stabilizer, or a polymer additive.

48. The process according to claim 1, wherein the microparticles further comprise a pharmaceutically acceptable agent comprising at least one member of preservatives, lipids, fatty acids, waxes, surfactants, plasticizers, porosigens, antioxidants, bulking agents, buffering agents, chelating agents, cosolvents, water-soluble agents, insoluble agents, metal cations, anions, salts, osmotic agents, synthetic polymers, biological polymers, hydrophilic polymers, polysaccharides, sugars, hydrophobic polymers, hydrophilic block copolymers, hydrophobic block copolymers, block copolymers containing hydrophilic or hydrophobic blocks.

49. The process according to claim 1, wherein the composition of step (a) further comprises at least one member of a poly(vinyl pyrrolidone), a copolymer containing one or more blocks of poly(vinyl pyrrolidone) or one or more biocompatible polymers.