CN103370057A - Method for removing residual organic solvent from microparticles - Google Patents
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- CN103370057A CN103370057A CN2011800471235A CN201180047123A CN103370057A CN 103370057 A CN103370057 A CN 103370057A CN 2011800471235 A CN2011800471235 A CN 2011800471235A CN 201180047123 A CN201180047123 A CN 201180047123A CN 103370057 A CN103370057 A CN 103370057A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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Abstract
Disclosed herein are methods comprising suspending microparticles in a surfactant/non-polar alkane solution to remove residual solvent that is present in the microparticle.
Description
Background of invention
Usually the polymer with dissolution with solvents formation matrix of microparticles prepares microgranule.Typical solvent for polyester such as lactide and/or Acetic acid, hydroxy-, bimol. cyclic ester type polymer comprises various ICH I classes and II kind solvent, such as the chlorinated solvent class.This kind solvent there is regulation, can not be higher than the existence of specified quantitative ground in the preparation for being applied in the body.Yet residual solvent is difficult to remove in a lot of microgranule production processes.Therefore, need to solve the method for residual solvent problem.
Summary of the invention
The invention discloses the method that solves the residual solvent problem, comprising: (a) in nonpolar alkane, microgranule and surfactant are mixed to get dispersion liquid; Wherein microgranule comprises the residual organic solvent of at least 2% weight; (b) stir this dispersion liquid; (c) collect microgranule; (d) rinsing microgranule; (e) dry particles.
Detailed Description Of The Invention
In present specification and in claims subsequently, relate to many terms, it is defined as having following implication:
In present specification, unless context has regulation in addition, word " comprises/comprise (comprise) " or version is appreciated that as finger comprises the set of described integer or step or integer or step such as " comprises " or " comprising ", but does not get rid of the set of any other integer or step or integer or step.
Singulative " a kind of (a) ", " a kind of (an) " and " being somebody's turn to do (the) " comprise the indicant of plural number, unless context has clear and definite regulation in addition.Therefore, for example, address the mixture that " a kind of bioactivator " comprises two or more this type of bioactivator, etc.
" biodegradable " refer to corrode into solable matter or under physiological condition, be degraded to itself to experimenter nontoxic (biocompatible) and can by experimenter's metabolism, elimination or drain the material than junior unit or chemical substance.
The term " microgranule " that uses in this article refers to have the various structures of about 10nm to 2000 micron of granularity (2 millimeters) in general manner, comprises microcapsule, microsphere, nanoparticle, nanocapsule, nanosphere and usually less than the granule of about 2000 microns (2 millimeters).
" bioactivator " refers to have the reagent of biologic activity.Biological agent can be used for treating, diagnoses, cures, relaxes, prevents (i.e. prevention), improves, regulates disease, disorder, infection etc., or disease, disorder, infection etc. are had other advantageous effect.Bioactivator comprises that also those affect the material of experimenter's structure or function, or becomes biological activity or the stronger prodrug of biological activity are arranged after in inserting predetermined physiological environment.
On the one hand, the invention discloses the method that solves the residual solvent problem, comprising: (a) in nonpolar alkane, microgranule and surfactant are mixed to get dispersion liquid; Wherein microgranule comprises the residual organic solvent of at least 2% weight; (b) stir this dispersion liquid; (c) collect microgranule; (d) rinsing microgranule; (e) dry particles.
Method disclosed herein comprises microgranule is suspended in the nonpolar alkane surfactant solution to remove the residual organic solvent on the microgranule.The organic solvent that is present among the microgranule may be residual by microgranule preparation method (such as emulsion process), and wherein organic solvent can be used as the solvent of polymer and/or bioactivator or other excipient.Nonpolar alkane can be miscible with residual organic solvent, but the polymer in the soluble particles not.Yet nonpolar alkane plays plasticizer and infiltrates through in the microgranule, and this allows residual organic solvent, such as chlorinated solvent or ethyl acetate, is diffused in the n-heptane solution.Then use the nonpolar alkane of surfactant-free such as the heptane wash of surfactant-free.Microgranule is available water or water and nonpolar alkane such as heptane (heptane that comprises surfactant-free) rinsing also, and dry.
Residual organic solvent can comprise C1-C4 halogenated alkane (such as, for example, C1-C4 chloralkane), ethyl acetate or their compositions.Residual organic solvent can be any suitable solvent, comprises without limitation dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, vinyl chloride, 2,2,2-trichloroethane or their mixture.
When microgranule comprised lactide and/or Acetic acid, hydroxy-, bimol. cyclic ester, nonpolar alkane solution had the effect of plasticizing to microgranule.When the microgranule of lactide or Acetic acid, hydroxy-, bimol. cyclic ester class was suspended in the water (after the preparation microgranule), polymer had the tissue of tension force to produce large microparticle pores structure and increases material outside microgranule and the diffusibility in the microgranule.Thereby cause initial the breaking of capsule compound matter.Yet therefore the internal stress of nonpolar alkane solution release polymers reduces entering of water and initial breaking.Nonpolar alkane such as heptane, can be used for increasing or reducing the release (adjustment release) of reagent in the microgranule, also reduces simultaneously the level of residual organic solvent.In some instances, bioactivator has microsolubility or being partly dissolved property in nonpolar alkane, for example, and the dissolubility of 0.1mg/mL or 0.1mg/mL to 0.5mg/mL.In these cases, bioactivator breaking or discharging from microgranule can be accelerated.
Opposite with present phase detachment technique, disclosed method does not relate to oil such as the use of silicone oil.Silicone oil is used in the microgranule phase separation usually.Yet silicone oil may be difficult to remove fully, contaminated surface, and may be difficult to remove.Disclosed method also allows can be with ICH II kind solvent (such as dichloromethane or ethyl acetate) and III kind solvent (such as heptane) exchange.Residual nonpolar alkane (such as heptane) may be present among the microgranule after implementing the method, receives great concern unlike residual dichloromethane or ethyl acetate.
Such as above concise and to the point discussion, disclosed method comprises at first mixes to obtain the dispersion liquid of microgranule in nonpolar alkane solution with microgranule and surfactant solution in nonpolar alkane.Before adding microgranule, surfactant can be joined in the nonpolar alkane.The function of surfactant-dispersed microgranule is so that nonpolar alkane can soak and/or penetrate matrix of microparticles effectively.
Can use various surfactants.The example of surfactant comprises sorbitol monostearate (also claiming SPAN), sorbitan monostearate (also claiming SPAN60), dehydrated sorbitol mono-fatty acid ester (SPAN80), Polysorbate 80 (tween 80), all these all are commercially available.Should understand and consider that in the present invention surfactant mixture can comprise the combination of any surfactant or two kinds, three kinds, four kinds or more kinds of surfactants.For example, surfactant mixture can comprise sorbitol monostearate and sorbitan monostearate, sorbitol monostearate and dehydrated sorbitol mono-fatty acid ester; Sorbitol monostearate and Polysorbate 80, sorbitan monostearate and dehydrated sorbitol mono-fatty acid ester, sorbitan monostearate and Polysorbate 80, dehydrated sorbitol mono-fatty acid ester and Polysorbate 80, sorbitol monostearate, sorbitan monostearate, and dehydrated sorbitol mono-fatty acid ester, sorbitol monostearate, sorbitan monostearate, and Polysorbate 80, or other combination of the surfactant of any above-mentioned affirmation.Nonpolar alkane solution can comprise at least 0.5% surfactant, and for example 0.5% to 10%, 0.5% to 8%, 0.5% to 6%, 0.5% to 5% or 0.5% to 2%.
Nonpolar alkane can be the various alkane with 1 to 24 carbon.Alkane can be that side chain arranged or unbranched, ring or acyclic.Example comprises pentane, Pentamethylene., hexane, cyclohexane extraction and heptane without limitation." hexane class " refers to commercially available hexane, comprises that the various isomers of hexane (have formula C
6H
14All hexanes), thereby claim " hexane class ", and do not claim " hexane ".
Before adding nonpolar alkane solution, microgranule comprises a certain amount of residual solvent that is stayed by production method such as emulsion process.On the one hand, disclosed method can be used for comprising the microgranule of at least 2% weight residual organic solvent (for example 2% to 5%).Residual organic solvent may be the solvent that is used as the solvent of polymer in the microgranule production process.On the contrary, nonpolar alkane is not the solvent that forms the polymer of microgranule.Nonpolar alkane neither be present in any bioactivator in the microgranule or the solvent of excipient.After implementing disclosed method, can reduce the amount of residual solvent.
After adding nonpolar alkane solution, the dispersion liquid of microgranule can be stirred a period of time, be generally 5 minutes to 4 hours, for example, 30 minutes to 2 hours.After dispersed with stirring liquid, can be by filtering or logical sieving separating collection microgranule.In case the collection microgranule, the nonpolar alkane (such as heptane) of available surfactant-free, water or their compositions rinsing microgranule, and dry.Drying steps can use methods known in the art to carry out, such as spray drying, air-dry, vacuum filtration etc.
Various microgranule production methods all use one or more to be used for forming the solvent of the polymer of microgranule.These class methods usually comprise without limitation film casting (film casting), molded (molding), spray drying and extrude or emulsion process or multi-emulsion method.On the one hand, disclosed method can be particularly useful for the microgranule that utilizes the preparation of emulsifying or emulsion technology.The emulsion process of preparation microgranule is people such as Jeffery, " The preparation and characterisation of poly (lactide-co-glycolide) microparticles.I:Oil-In-water emulsion solvent evaporation, " Int.J.Pharm.77 (2-3): 169-175 (1991); The people such as Jeffery, among " The Preparation and Characterization of Poly (lactide-co-glycolide) Microparticles.II.The Entrapment of a Model Protein using a (Water-in-Oil)-in-Water Emulsion Solvent Evaporation Technique, " Pharm.Res.10 (3): 362-368 (1993) discussion is arranged.Solvent evaporated method is at Wichert, and B.and Rohdewald has discussion among P. (1993) J.Microencapsul.10:195.Solvent extraction method is described at U.S. Patent number 5,407, and in 609, which is hereby incorporated by reference.
Microgranule can comprise various biocompatibility or biodegradable polymer.Biocompatible polymer also can be biodegradable polymer.On the one hand, biocompatible polymer can be one or more polyester, PHA, poly butyric ester, polydioxanone, poly-hydroxyl valerate, polyanhydrides, poe (polyorthoesters), polyphosphazene, Quadrafos, poly phosphate (polyphosphoesters), polydioxanone, poly phosphate (polyphosphoesters), Quadrafos, polyphosphonates, Quadrafos, PHA, Merlon, poly-alkyl carbonate, poly-orthocarbonic ester, polyesteramide, polyamide, polyamine class, polypeptide, polyurethane, polyalkylene alkylates, polyalkylene oxalate, the polyalkylene succinate, poly-hydroxy fatty acid, polyacetals, polybutylcyanoacrylate, polyketals (polyketals), polyether ester, polyethers, poly alkylene glycol, polyoxygenated alkene, Polyethylene Glycol, poly(ethylene oxide), polypeptide, polysaccharide, or polyvinyl pyrrolidone.Other non-biodegradable but durable and biocompatible polymer comprises ethylene-vinyl acetate copolymer without limitation, politef, and polypropylene, polyethylene, etc.Equally, other suitable non-biodegradable polymer comprises silicone and polyurethane without limitation.
Biocompatible and/or biodegradable polymer can be PLA, poly-(Acetic acid, hydroxy-, bimol. cyclic ester), PLGA, poly-(caprolactone), poly-(ortho esters), poly-(phosphonitrile), poly-(butyric ester) or contain the copolymer of poly-(butyric ester), lactide caprolactone copolymer, Merlon, polyesteramide, polyanhydride, poly-(dioxane ketone), poly-(alkylidene alkylates), the copolymer of Polyethylene Glycol and poe, biodegradable polyurethane, poly-(aminoacid), polyamide, polyesteramide, polyether ester, polyacetals, polybutylcyanoacrylate, poly-(oxygen ethylene)/poly-(oxypropylene) copolymer, polyacetals, polyketals, poly phosphate gathers hydroxyl valerate or contains the copolymer that gathers hydroxyl valerate, the polyalkylene oxalate, the polyalkylene succinate, poly-(maleic acid), and they and copolymer, trimer, compositions or mixture.
Biocompatible or biodegradable polymer can comprise any lactide residue, comprises the lactide of all racemes and stereospecificity form, includes but not limited to L-lactide, D-lactide and D, L-lactide or their mixture.The useful polymer that contains lactide includes but not limited to gather (L-lactide), PDLA and poly-(DL-lactide); And PLGA, comprise L-PLGA, D-PLGA and DL-PLGA; Or their copolymer, trimer, compositions or mixture.The lactide/glycolides polymer can be easily by the open loop approach preparation of melt polymerization with lactide and glycolide monomer.In addition, racemic DL-lactide, L-lactide and D-lactide polymer are commercially available.The L-polymer is higher and absorb slow than the crystallinity of DL-polymer again.Except the copolymer that contains Acetic acid, hydroxy-, bimol. cyclic ester and DL-lactide or L-lactide, the copolymer of L-lactide and DL-lactide is commercially available.The homopolymer of lactide or Acetic acid, hydroxy-, bimol. cyclic ester also is commercially available.
When biodegradable and/or biocompatible polymer were PLGA, PLA or poly-(Acetic acid, hydroxy-, bimol. cyclic ester), the amount of lactide and Acetic acid, hydroxy-, bimol. cyclic ester can change in this polymer.In other side, biodegradable polymer contains 0 to 100 % by mole, 40 to 100 % by mole, 50 to 100 % by mole, 60 to 100 % by mole, 70 to 100 % by mole or 80 to 100 % by mole of lactides and 0 to 100 % by mole, 0 to 60 % by mole, 10 to 40 % by mole, 20 to 40 % by mole or 30 to 40 % by mole of Acetic acid, hydroxy-, bimol. cyclic esters, and wherein the amount of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 100 % by mole.In other side, biodegradable polymer can be PLA, 95:5 PLGA 85:15 PLGA, the 75:25 PLGA, the 65:35 PLGA, or the 50:50 PLGA, wherein ratio is mol ratio.
Biodegradable and/or biocompatible polymer also can be poly-(caprolactone) or lactide caprolactone copolymer.Polymer can be poly-(lactide-caprolactone), in many-side, it can be the 95:5 lactide caprolactone copolymer, the 85:15 lactide caprolactone copolymer, the 75:25 lactide caprolactone copolymer, 65:35 lactide caprolactone copolymer, or 50:50 lactide caprolactone copolymer, wherein ratio is mol ratio.
Various bioactivators or other excipient can be present in the microgranule.Bioactivator disclosed herein can be water miscible or at least part of solvable in the disclosed nonpolar alkane in this article.
Example comprises micromolecule without limitation, peptide, oligopeptide (for example, octreotide), protein such as hormone, enzyme, antibody, receptor binding protein, antibody fragment, antibody conjugates, nucleotide such as aptamer, iRNA, siRNA, microRNA, DNA, RNA, antisensenucleic acids or this type of material, the similar thing of antisensenucleic acids or this type of material, VEGF inhibitor, macrolide, dopamine agonist, dopamine antagonist, low molecular weight compound, high-molecular weight compounds, or the bioactivator of puting together.
Other bioactivator can comprise anabolica, antacid, anti-asthmatic, Anticholesterolemic and lipotropism agent, anticoagulant, anticonvulsant, diarrhea, the anti-emetic, anti-infective comprises antibacterium and antimicrobial, anti-inflammatory agent, anti-manic dose, metabolic antagonist, antiemetic, antitumor agent, anoretic, psychosis, antipyretic and analgesics, Anticonvulsants, antithrombotic agents, antitussive, anti-uric acid agent, the antianginal agent, hydryllin, appetite suppressant, biological product, cerebral vasodilator (cerebral dilators), coronary artery dilator (coronary dilators), bronchodilator, cytotoxic agent, decongestant, diuretic, diagnostic agent, erythrocyte generates agent, expectorant, gastro-intestinal sedative, blood glucose increasing agent (hyperglycemic agents), hypnotic, blood sugar lowering, immunomodulator, ion exchange resin, aperient, mineral supplements, mucolytic agent, the neuromuscular medicine, peripheral vasodilators, psychotropic drugs, tranquilizer, beta stimulant, thyroid and antithyroid drug, tissue growth agent, uterorelaxant, vitamin, or antigenic substance.
Also have other bioactivator to comprise inhibitor for androgen, polysaccharide, somatomedin, hormone, anti-angiogenesis, dextromethorphan, dextromethorphan hydrobromide, narcotine, pentoxyverine citrate, Coldrin (Nippon Shinyaku), chlorphenamine maleate, phenindamine tartrate, mepyramine maleate, doxylamine succinate, phenyltoloxamine citrate, phenylephrine hydrochloride, phenylpropanolamine HC1, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine sulfate morphine, mineral supplements, colestyramine, N-acecainide, acetaminophen, aspirin, ibuprofen, phenylpropanolamine HC1, caffeine, guaifenesin, aluminium hydroxide, magnesium hydroxide, peptide, polypeptide, protein, aminoacid, hormone, interferon, cytokine, and vaccine.
The representative drugs that can be used as bioactivator includes but not limited to peptide medicament, protein drug, therapeutic antibodies, anticalins, desensitization material, antigen, anti-infective such as antibiotic, antimicrobial, antiviral, antibiotic, parasiticide, antifungal material and their combination, anti-allergic drug, androgen steroidal, decongestant, hypnotic, steroidal anti-inflammatory medicine, anticholinergic, sympathomimetic, tranquilizer, miotic, psychostimulant (psychic energizers), tranquilizer, vaccine, estrogen, progestational agents, humoral agent (humoral agents), prostaglandins, analgesic, anti-spasmodics, antimalarial, antihistaminic, the key role medicine, antibiotic medicine, NSAID (non-steroidal anti-inflammatory drug), antiparkinsonian drug, antihypertensive, β-adrenergic blocking agent, nutrient, anti-TNF agent and benzene phenanthridine alkaloid class.Reagent can also be can play analeptic, tranquilizer, sleep peacefully, the material of analgesia, anticonvulsant action, and analog.
Other bioactivator includes but not limited to analgesic such as acetaminophen, aspirin and analog; Anesthetis such as lignocaine, eagle (xylocaine) and analog are revealed in match; Anorexigenic such as dexadrine, phendimetrazine tartrate and analog; Anti-arthritic such as methylprednisolone, ibuprofen and analog; Anti-asthmatic such as terbutaline sulphate, theophylline, ephedrine and analog; Antibiotic such as sulfanilamide are different
Azoles, benzylpenicillin, ampicillin, cephalosporins, amikacin, gentamycin, Tetracyclines, chloromycetin, erythromycin, clindamycin, isoniazid, rifampicin and analog; Antifungal agent such as amphotericin B, nystatin, ketoconazole and analog; Antiviral agents such as acyclovir, amantadine and analog; Anticarcinogen such as cyclophosphamide, methotrexate, etretinate and analog; Anticoagulant such as heparin, warfarin and analog; Anticonvulsant such as phenytoin Sodium, diazepam and analog; Antidepressants such as isocarboxazid, amoxapine and analog; Antihistamine example hydrochloric acid diphenhydramine, chlorphenamine maleate and analog; Psychosis such as clozapine, haloperidol, carbamazepine, gabapentin, topiramate, amfebutamone, Sertraline, alprazolam, buspirone, risperidone, Aripiprazole, olanzapine, Quetiapine, Ziprasidone, iloperidone and analog; Hormone such as insulin, progestogen, estrogen, adrenocortical hormone, glucocorticoid, androgen and analog; Tranquilizer such as chlorpromazine (thorazine), diazepam, chlorpromazine hydrochloride, reserpine, hydrochloric acid chlorine nitrogen
And analog; Anti-spasmodics such as belladonna alkaloids, bentrl hydrothloride and analog; Vitamin and mineral such as basic aminoacid, calcium, ferrum, potassium, zinc, vitamin B12 and analog; Cardiovascular drugs example hydrochloric acid prazosin, nitroglycerin, propranolol hydrochloride, hydralazine hydrochloride, pancreatic lipase, succinate dehydrogenase and analog; Peptides and proteins such as LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptide, somatotropin releasing factor (growth releasing factor), angiotensin, FSH, EGF, BMP (BMP), erythropoietin (EPO), interferon, interleukin, collagen protein, Fibrinogen, insulin, factor Ⅷ, factor Ⅸ
Alpha-Glucosidase,
Vassopressin, ACTH, human serum albumin, gamma Globulin, structural protein, blood products albumen, compound protein, enzyme, antibody, monoclonal antibody and analog; Prostaglandin; Nucleotide; Carbohydrate; Lipid; Anesthetis such as morphine, codeine and analog, psychotherapy's medicine (psychotherapeutics); Antimalarial drug, levodopa, diuretic such as furosemide, spironolactone and analog; Antiulcerative example hydrochloric acid ranitidine (rantidine HCl), cimetidine hydrochloride and analog.
Bioactivator can be immunomodulator also, comprises, for example, cytokine, interleukin class, interferon, colony stimulating factor, tumor necrosis factor and analog; Allergen such as cat Dander, birch pollen, dermatophagoides pteronyssinus, cyanines showy flowers of herbaceous plants powder and analog; Bacterium living beings antigen such as streptococcus pneumoniae (Streptococcus pneumoniae), Haemophilus influenzae (Haemophilus influenzae), staphylococcus aureus (Staphylococcus aureus), streptococcus radiatus (Streptococcus pyrogenes), rod bacillus (Corynebacterium diphteriae), listerisa monocytogenes in mjme (Listeria monocytogenes), anthrax bacillus (Bacillus anthracis), clostridium tetani (Clostridium tetani), bacillus botulinus (Clostridium botulinum), bacillus perfringens (Clostridium perfringens), Neisseria meningitidis (Neisseria meningitides), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Streptococcus mutans (Streptococcus mutans), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Salmonella typhi (Salmonella typhi), haemophilus parainfluenzae (Haemophilus parainfluenzae), the special bacterium (Bordetella pertussis) of pertussis Boulder, francisella tularensis (Francisella tularensis), Yersinia pestis (Yersinia pestis), vibrio cholera (Vibrio cholerae), legionella pneumophilia (Legionella pneumophila), mycobacterium tuberculosis (Mycobacterium tuberculosis), Mycobacterium leprae (Mycobacterium leprae), Treponoma palladium (Treponema pallidum), leptospria interrogans (Leptspirosis interrogans), Bo Shi borrelia vincentii (Borrelia burgddorferi), campylobacter jejuni (Campylobacter jejuni) and analog; Such as antigen such as the variola of virus, influenza A and B, respiratory syncytial, parainfluenza, measles, HIV, SARS, varicella zoster, herpes simplex 1 and 2, cytomegalovirus (cytomeglavirus), Ai Baisitan-epstein-Barr virus (Epstein-Barr), rotavirus, rhinovirus, adenovirus, human papillomavirus, poliovirus, parotitis, rabies, rubella, Coxsackie virus (coxsackieviruses), equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocytic choriomeningitis, hepatitis B and analog; Such as fungus, the antigen of protozoacide and parasite biology such as Cryptococcus histolyticus (Cryptococcuc neoformans), Histoplasma capsulatum (Histoplasma capsulatum), Candida albicans (Candida albicans), Oidium tropicale (Candida tropicalis), Nocardia asteroides (Nocardia asteroids), rickettsia rickettsii (Rickettsia ricketsii), rickettsia exanthematotyphi (Rickettsia typhi), mycoplasma pneumoniae (Mycoplasma pneumoniae), chlamydia felis (Chlamyda psittaci), chlamydia trachomatis (Chlamydia trachomatis), plasmodium falciparum (Plasmodium falciparum), trypanosoma (Trypanasoma brucei), Entamoeba histolytica (Entamoeba histolytica), Mus toxoplasma (Toxoplasma gondii), trichomonas vaginitis (Trichomonas vaginalis), Schistosoma mansoni (Schistosoma mansoni) and analog.This type of antigen can be the whole biological form of deactivation, peptide, albumen, glycoprotein, carbohydrate form or their combination.
Bioactivator can also comprise antibiotic.Antibiotic can be, for example, and one or more in the following antibiotic: amikacin, gentamycin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, ansamycins, geldanamycin, herbimycin, carbacephem, Loracarbef, Carbapenems, ertapenem, doripenem, imipenum/cilastatin, meropenem, cephalosporins (first generation), cefadroxil, cefazolin sodium, cefalotin, cefalexin, cephalosporins (second filial generation), cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cephalosporins (third generation), cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cephalosporins (the 4th generation), cefepime, cephalosporins (the 5th generation), cephalo is than general, glycopeptide class, teicoplanin, vancomycin, macrolide, azithromycin, clarithromycin, dirithromycin, erythromycin, Roxithromycin, triacetyloleandomycin, Ketek, spectinomycin, monobactams, aztreonam, penicillins, amoxicillin, ampicillin, the azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, the methicillin, nafcillin, oxazacillin, penicillin, piperacillin, ticarcillin, polypeptide, bacitracin, polymyxin E, polymyxin B, quinolones, ciprofloxacin, enoxacin, Gatifloxacin, levofloxacin, lomefloxacin, Moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, sulfonamides, mafenide, prontosil (early discovery), sulfacetamide, sulfamethizole, amine benzene sulfanilamide (Sulfanilimide) (early discovery), sulfasalazine, sulfanilamide is different
Azoles, trimethoprim, trimethoprim-sulfalene
Azoles (bactrim) (TMP-SMX), Tetracyclines comprises demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline etc.; Arsphenamine, chloromycetin, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, isoniazid, Linezolid, metronidazole, mupirocin, nitrofurantoin, Platensimycin, pyrazinamide, quinupristin/dalfopristin, rifampicin (U.S. claims Rifampin), tinidazole, Ropinerole, ivermectin, moxidectin, A Fanuo peptide, cilengitide, or their compositions.On the other hand, bioactivator can be the combination of rifampicin (U.S. claims Rifampin) and minocycline.
Embodiment
Providing the following example is the complete open and explanation that how to prepare and estimate the claimed chemical compound of the present invention, compositions, product, device and/or method in order to provide to those of ordinary skills; purely be intended to the present invention is illustrated, rather than be intended to limit the scope that the inventor considers its invention.Ceasing to transmit make great efforts to guarantee at the accuracy aspect the number (such as amount, temperature etc.), but also should illustrate and can have some mistakes and deviation.Unless refer else, umber is parts by weight, and temperature is take ℃ as unit or at room temperature, and pressure is under atmospheric pressure or near atmospheric pressure.
Embodiment 1
Adopt emulsion process preparation precipitation microgranule.Microgranule is dry, process to remove residual dichloromethane (DCM) with heptane subsequently.The result is as shown in table 1.The microgranule that the 1h heptane is processed refers to the persistent period that microgranule washs in heptane.
Table 1
Embodiment 2
Adopt emulsion process preparation precipitation microgranule.Drying does not process to remove residual dichloromethane with wet microgranule with heptane.The result is as shown in table 2.0.5h the microgranule that heptane is processed refers to the persistent period that microgranule washs in heptane.
Table 2
Embodiment 3
Adopt emulsion process preparation precipitation microgranule.Microgranule is dry, process to remove residual dichloromethane with heptane subsequently.The result is as shown in table 3.The microgranule that 2h and 4h heptane are processed refers to the persistent period that microgranule washs in heptane.
Table 3
Embodiment 4
Adopt emulsion process preparation precipitation microgranule.Microgranule is dry, process to remove residual dichloromethane with heptane subsequently.The result is as shown in table 1.The microgranule that the 2h heptane is processed refers to the persistent period that microgranule washs in heptane.
Table 4
Embodiment 5
Adopt emulsion process preparation precipitation microgranule.Microgranule is dry, process to remove residual dichloromethane with heptane subsequently.The result is as shown in table 2.The microgranule that the 2h heptane is processed refers to the persistent period that microgranule washs in heptane.
Table 5
Embodiment 6
Adopt emulsion process preparation precipitation microgranule.Microgranule is dry, process to remove residual dichloromethane with heptane subsequently.The result is as shown in table 3.The microgranule that the 2h heptane is processed refers to the persistent period that microgranule washs in heptane.
Table 6
Can carry out various modifications and variations to chemical compound, complex (composites), test kit (kits), article (articles), device, compositions and the method described herein.In the description of considering chemical compound disclosed herein, complex, test kit, article, device, compositions and method with after implementing, the other side of chemical compound, complex, test kit, article, device, compositions and the method for describing herein will be apparent.Description and embodiment are considered to exemplary.
Claims (16)
1. method that reduces residual organic solvent in the microgranule comprises:
(a) in nonpolar alkane, microgranule is combined with surfactant solution and obtains dispersion liquid;
(b) mix this dispersion liquid;
(c) collect microgranule;
(d) this microgranule of rinsing; With
(e) microgranule is dry
Wherein in step (a) before, microgranule comprises at least 2% residual organic solvent, and described residual organic solvent comprises halogenated solvent, ethyl acetate or their mixture.
2. the process of claim 1 wherein that residual organic solvent comprises the C1-C4 halogenated alkane.
3. the method for arbitrary aforementioned claim, wherein residual organic solvent comprises the C1-C4 chloralkane.
4. the method for arbitrary aforementioned claim, wherein residual organic solvent comprises dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride, vinyl chloride, 2,2,2-trichloroethane, or their mixture.
5. the method for arbitrary aforementioned claim, wherein residual organic solvent comprises ethyl acetate.
6. the method for arbitrary aforementioned claim, wherein surfactant comprises sorbitol monostearate, dehydrated sorbitol mono-fatty acid ester, Polysorbate 80 or their combination.
7. the method for arbitrary aforementioned claim, wherein nonpolar alkane, water or their the compositions rinsing of microgranule usefulness surfactant-free.
8. the method for arbitrary aforementioned claim, wherein heptane, water or their the compositions rinsing of microgranule usefulness surfactant-free.
9. the method for arbitrary aforementioned claim, wherein the logical sieving separating of microgranule is collected.
10. the method for arbitrary aforementioned claim, wherein microgranule comprises PLA, poly-(Acetic acid, hydroxy-, bimol. cyclic ester), PLGA, or their copolymer, blend or mixture.
11. the method for arbitrary aforementioned claim, wherein microgranule comprises capsule in bioactivator wherein.
12. the method for arbitrary aforementioned claim, wherein bioactivator is water miscible.
13. the method for arbitrary aforementioned claim, wherein bioactivator comprises oligopeptide.
14. the method for arbitrary aforementioned claim, wherein bioactivator comprises octreotide.
15. the method for arbitrary aforementioned claim, wherein bioactivator is at least part of dissolving in the nonpolar alkane.
16. the method for arbitrary aforementioned claim, wherein bioactivator has at least dissolubility of 0.1mg/mL in nonpolar alkane.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38805010P | 2010-09-30 | 2010-09-30 | |
| US61/388,050 | 2010-09-30 | ||
| PCT/US2011/053655 WO2012044671A2 (en) | 2010-09-30 | 2011-09-28 | Method for removing residual organic solvent from microparticles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103370057A true CN103370057A (en) | 2013-10-23 |
Family
ID=45094869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800471235A Pending CN103370057A (en) | 2010-09-30 | 2011-09-28 | Method for removing residual organic solvent from microparticles |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP2621473A2 (en) |
| JP (1) | JP5808413B2 (en) |
| CN (1) | CN103370057A (en) |
| AU (1) | AU2011308893B2 (en) |
| CA (1) | CA2813301A1 (en) |
| IL (1) | IL225254A0 (en) |
| RU (1) | RU2013119811A (en) |
| WO (1) | WO2012044671A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104382848A (en) * | 2014-10-20 | 2015-03-04 | 齐鲁制药有限公司 | Tacrolimus suspending eye drop liquid and preparation method thereof |
| CN109718209A (en) * | 2017-10-30 | 2019-05-07 | 浙江圣兆药物科技股份有限公司 | A kind of microballoon lyophilized method of remaining Risperidone of low ethanol |
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| US5876761A (en) * | 1989-07-07 | 1999-03-02 | Novartis Ag | Sustained release formulations of water soluble peptides |
| US20050181059A1 (en) * | 2003-09-30 | 2005-08-18 | Spherics, Inc. | Nanoparticulate therapeutic biologically active agents |
| US20080051561A1 (en) * | 2001-08-31 | 2008-02-28 | Alkermes, Inc. | Residual solvent extraction method and microparticles produced thereby |
| WO2008157540A1 (en) * | 2007-06-20 | 2008-12-24 | Alkermes, Inc. | Quench liquids and washing systems for production of microparticles |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4637905A (en) * | 1982-03-04 | 1987-01-20 | Batelle Development Corporation | Process of preparing microcapsules of lactides or lactide copolymers with glycolides and/or ε-caprolactones |
| AU5741590A (en) | 1989-05-04 | 1990-11-29 | Southern Research Institute | Improved encapsulation process and products therefrom |
| HU221294B1 (en) * | 1989-07-07 | 2002-09-28 | Novartis Ag | Process for producing retarde compositions containing the active ingredient in a polymeric carrier |
| US5739265A (en) * | 1995-09-20 | 1998-04-14 | Clariant Finance (Bvi) Ltd. | Fractionation of phenol formaldehyde condensate and photoresist compositions produced therefrom |
-
2011
- 2011-09-28 RU RU2013119811/05A patent/RU2013119811A/en not_active Application Discontinuation
- 2011-09-28 JP JP2013531765A patent/JP5808413B2/en not_active Expired - Fee Related
- 2011-09-28 WO PCT/US2011/053655 patent/WO2012044671A2/en active Application Filing
- 2011-09-28 EP EP11771308.1A patent/EP2621473A2/en not_active Withdrawn
- 2011-09-28 CN CN2011800471235A patent/CN103370057A/en active Pending
- 2011-09-28 CA CA2813301A patent/CA2813301A1/en not_active Abandoned
- 2011-09-28 AU AU2011308893A patent/AU2011308893B2/en not_active Ceased
-
2013
- 2013-03-17 IL IL225254A patent/IL225254A0/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5876761A (en) * | 1989-07-07 | 1999-03-02 | Novartis Ag | Sustained release formulations of water soluble peptides |
| US20080051561A1 (en) * | 2001-08-31 | 2008-02-28 | Alkermes, Inc. | Residual solvent extraction method and microparticles produced thereby |
| US20050181059A1 (en) * | 2003-09-30 | 2005-08-18 | Spherics, Inc. | Nanoparticulate therapeutic biologically active agents |
| WO2008157540A1 (en) * | 2007-06-20 | 2008-12-24 | Alkermes, Inc. | Quench liquids and washing systems for production of microparticles |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104382848A (en) * | 2014-10-20 | 2015-03-04 | 齐鲁制药有限公司 | Tacrolimus suspending eye drop liquid and preparation method thereof |
| CN104382848B (en) * | 2014-10-20 | 2017-04-26 | 齐鲁制药有限公司 | Tacrolimus suspending eye drop liquid and preparation method thereof |
| CN109718209A (en) * | 2017-10-30 | 2019-05-07 | 浙江圣兆药物科技股份有限公司 | A kind of microballoon lyophilized method of remaining Risperidone of low ethanol |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2813301A1 (en) | 2012-04-05 |
| RU2013119811A (en) | 2014-11-10 |
| AU2011308893A1 (en) | 2013-05-09 |
| WO2012044671A2 (en) | 2012-04-05 |
| IL225254A0 (en) | 2013-06-27 |
| AU2011308893B2 (en) | 2015-04-23 |
| JP5808413B2 (en) | 2015-11-10 |
| EP2621473A2 (en) | 2013-08-07 |
| JP2013538854A (en) | 2013-10-17 |
| WO2012044671A3 (en) | 2013-03-14 |
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