WO2015100843A1 - 基于蛋白质的药理活性物质组合物及其制备方法和应用 - Google Patents
基于蛋白质的药理活性物质组合物及其制备方法和应用 Download PDFInfo
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- WO2015100843A1 WO2015100843A1 PCT/CN2014/072009 CN2014072009W WO2015100843A1 WO 2015100843 A1 WO2015100843 A1 WO 2015100843A1 CN 2014072009 W CN2014072009 W CN 2014072009W WO 2015100843 A1 WO2015100843 A1 WO 2015100843A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This invention relates to drug delivery systems, and more particularly to a pharmacologically active substance delivery system, and more particularly to protein-based pharmacologically active substance compositions, and methods of making and using same.
- Intravenous drug delivery quickly and directly balances blood flow to the rest of the body.
- the drug is carried in a stable carrier, and the drug can be gradually released in the blood vessel after the intravenous dose of the impact dose.
- Nanotechnology has outstanding value in improving the efficacy of drugs.
- nanotechnology can improve the pharmacokinetics of the pharmacologically active ingredients carried in vivo by improving the pharmacokinetic process of the nanoparticles themselves in the organism.
- Nanotechnology can effectively improve the solubility and dissolution rate of hydrophobic pharmacologically active substances and improve the bioavailability of pharmacologically active substances.
- nanotechnology can effectively prolong the blood circulation time of pharmacologically active ingredients and increase the enrichment of pharmacologically active ingredients in disease tissues and targets.
- nanotechnology to improve the clinical application value of pharmacologically active substances must consider the following issues:
- the materials used must be clinically safe, and the components of the prepared nanocomposites are also clinically safe; the prepared pharmacologically active substance compositions
- the nanostructures should remain stable, at least one kind No serious agglomeration or dissociation occurs in the bed-acceptable injection.
- compositions of the pharmacologically active substance materials which have been clinically approved should be selected as raw materials, such as albumin, protamine, antibody, immunoglobulin and the like. These clinically approved materials are used as raw materials, and nano-assembled with pharmacologically active substances can obtain a composition-safe pharmacologically active substance composition, which can ensure the high clinical safety of the prepared pharmacologically active substance composition as much as possible.
- the nanostructure of the prepared pharmacologically active composition should be diluted with a clinically acceptable injection to maintain a relatively stable nanostructure, especially the maximum particle size distribution (TEM or dynamic light scattering analysis (Number% statistics, Malvern)) It should still be in the range of 10-200 nm.
- the pharmacologically active substance composition is severely agglomerated after being dissolved and diluted by the injection solution, and the maximum particle size distribution is increased above 10-15 micrometers, capillary blockage or infarction may occur, resulting in local bleeding, ischemia or Hypoxia and possible tissue death.
- the capillaries at the diseased tissue have enhanced permeability and retention (EPR effect), and the nanoparticles can be effectively enriched in tumor tissue by passive targeting. This requires that the particle size of the nanoparticles is smaller than a certain size.
- nanoparticles smaller than 400 nm can be enriched in the tumor by the EPR effect (Cancer Research, 1995, 55 (17): 3752-3756.) Studies have shown that nanoparticles smaller than 200 nm can be more efficiently enriched in tumor sites (Nature nanotechnology, 2007, 2 (12): 751-760.). Moreover, studies have shown that nanomedicines with a diameter of about 100 ⁇ are most efficiently enriched in tumor tissues (Int. J.
- nanostructure size of the pharmacologically active substance composition is relatively stable in the range of 10-200 nm, which not only ensures the in vivo safety of the nano material, but also achieves effective enrichment of disease tissues such as tumors, and can pass 200nm or 220nm filter membrane filtration sterilization.
- paclitaxel An example of a pharmacologically active substance is paclitaxel. It is a natural product, first isolated from the Pacific yew tree (Taxus brevifolia) (J. Am. Chem. Soc. 93: 2325 (1971)). In anti-mitotic drugs, paclitaxel containing a diterpene carbon skeleton exhibits a unique mode of action for microtubule proteins that cause mitotic spindle formation. Unlike other anti-mitotic drugs such as vinblastine or colchicine that block tubulin assembly, paclitaxel is a plant product known to inhibit the process of tubulin depolymerization and thus prevent cell replication.
- Paclitaxel a naturally occurring biguanide, shows significant anti-tumor and anti-cancer effects on a variety of tumors.
- Paclitaxel has excellent antitumor activity against a wide range of tumor models such as B16 melanoma, L1210 leukemia, MX-1 breast tumor and CS-1 colon tumor xenograft, and has been widely used in clinical tumor treatment.
- the low water solubility of paclitaxel makes administration to humans a problem. Indeed, delivery of drugs that are inherently insoluble or poorly soluble in aqueous media can be severely compromised if delivered orally. To this end, the paclitaxel formulation currently used requires cremphor to solubilize the drug.
- paclitaxel itself does not exhibit excessive toxic effects, but the emulsifier/cosolvent used to solubilize the drug causes a severe allergic reaction.
- Current dosing regimens include administration of antihistamines and steroids to alleviate the allergic side effects of cremphor prior to injecting the drug.
- Protein microspheres have been reported in the literature as carriers for pharmacologically active substances or diagnostic products. Using heat Albumin microspheres were prepared by sexual or chemical crosslinking. Heat-denatured microspheres are from an emulsified mixture
- the process of preparing chemically crosslinked microspheres involves treating the emulsion with glutaraldehyde to gel the protein, then washing and storing it for later use. This preparation method is described by Lee et al. (Science 213: 233-235 (1981)) and U.S. Patent No. 4,671,954.
- the size of the protein microspheres prepared by the above method is larger than 10 ⁇ m, and the clinical safety risk of intravenous administration is large, which limits the possibility of further clinical application.
- a conventional method for preparing drug-containing nanoparticles is to dissolve polylactic acid or other biocompatible water-insoluble polymer in a water-immiscible solvent (such as methylene chloride or other chlorinated, fat or aromatic solvents). Inside, the pharmacologically active substance is dissolved in the polymer solution, a surfactant is added to the oil phase or the aqueous phase, an oil-in-water emulsion is formed by an appropriate method, and the emulsion is slowly evaporated under vacuum. If the oil droplets are small enough and stable upon evaporation, an aqueous suspension of the polymer is obtained.
- a water-immiscible solvent such as methylene chloride or other chlorinated, fat or aromatic solvents.
- the clinically marketed drug Abraxane is an albumin paclitaxel nano drug with a particle size of about 130 nm prepared by emulsion method combined with high pressure homogenization.
- the preparation process must use an organic solvent that is immiscible with water.
- the active substance is mixed with the aqueous albumin solution to form a two-phase organic phase and an aqueous phase, and then homogenized by high pressure to form particles having a size of less than 200 nm (refer to US005916596A; CN1515244A).
- the present invention provides a protein-based pharmacologically active substance composition which does not require the addition of an emulsifier and a solubilizing agent, thereby avoiding an allergic reaction and not rapidly diluting due to dissolution of the injection solution.
- the dissociation is below the lOnm size, thereby improving the enrichment effect at the tumor site and improving the biodistribution.
- the invention also provides methods of making the compositions and uses thereof.
- the present invention provides a pharmacologically active substance delivery system comprising a solid or liquid pharmacologically active substance and a protein coated particle, wherein the protein coating has a free protein associated therewith, the pharmacological activity A portion of the substance is contained in the protein coating, another portion of the pharmacologically active substance is associated with the free protein; the particles have an average diameter of 10 to 200 nm, and the maximum dynamic hydrated particle size when dispersed in the aqueous solution Above lOnm.
- the part of the pharmacologically active substance associated with the free protein can be rapidly released, but the part of the pharmacologically active substance contained in the protein coating does not It is released quickly in a short time, but is slowly and stably released over a long period of time, thus improving blood circulation time.
- the most significant difference between the pharmacologically active substance delivery system of the present invention and such previously reported compositions is that the particles of the pharmacologically active substance delivery system of the present invention have an average diameter of 10 to 200 nm and maximum kinetics when dispersed in an aqueous solution.
- the combined particle size is above lOnm, which avoids the weakening of the passive targeting effect caused by the capillary filtration of the glomerulus; when the previously reported composition is dispersed in an aqueous solution, the maximum dynamic hydrated particle size is rapidly reduced to lOnm.
- the passive targeting effect is impaired due to capillary drainage of the glomerulus.
- the "aqueous solution” means a biologically acceptable aqueous solution such as water, physiological saline, a buffer solution, a glucose solution, a vitamin solution, an amino acid solution or a mixture thereof.
- physiological saline is used as an aqueous solution for diluting the pharmacologically active substance delivery system, and in the physiological saline of 0.1 mg/mL, the maximum dynamic hydrated particle diameter of the particles is about 100 nm.
- the maximum kinetic hydrated particle diameter of the particles when dispersed in 0.1 mg/mL of physiological saline is above 10 nm, preferably at least 20 nm, more preferably from 50 to 180 nm, for example, 60 nm, 70 nm, 80 nm. 100 nm, 120 nm, 150 nm, 160 nm, 170 nm, 175 nm, 60-150 nm, 70-100 nm, 80-120 nm, 120-150 nm or 130-170 nm.
- the pharmacologically active substance delivery system of the present invention may be in the form of a dry powder of granules, or the particles of the pharmaceutically active substance delivery system may be suspended in a biocompatible aqueous solution.
- the biocompatible aqueous solution may be an acceptable injection, more preferably physiological saline, glucose injection or buffer.
- the present invention provides a method of preparing the pharmacologically active substance delivery system of the first aspect, comprising:
- the pharmacologically active substance may be a water-insoluble (hydrophobic) pharmacologically active substance, a water-soluble (hydrophilic) pharmacologically active substance or an amphiphilic pharmacologically active substance.
- a mixed solution can be prepared by the following steps:
- a mixed solution can be prepared by the following steps:
- amphiphilic pharmacologically active substance For the amphiphilic pharmacologically active substance, one of the above may be selected.
- the protein is selected from the group consisting of albumin, protamine, antibody, immunoglobulin, casein, insulin, lysozyme, fibrinogen, lipase, collagen, fibronectin, glass lignin, go One or more of ferritin, ferritin, hemoglobin, preferably human serum albumin, recombinant human serum albumin, protamine, antibody, ferritin or desferrin, most preferably human serum albumin.
- the pharmacologically active substance is selected from the group consisting of an antineoplastic agent, an analgesic/antipyretic agent, an anesthetic agent, an antiasthmatic drug, an antibiotic, an antidepressant, an antidiabetic agent, an antifungal agent, an antihypertensive drug, Anti-inflammatory Medicine, tumor complications, adjuvant therapy, biotech drugs, anti-anxiety drugs, immunosuppressants, anti-migraine drugs, sedatives/hypnotics, anti-angina drugs, antipsychotics, anti-manic drugs, antiarrhythmic drugs, anti-arthritis drugs , gout, anticoagulant, thrombolytic, antifibrinolytic, hemorheological, antiplatelet, anticonvulsant, anti-Parkinson, antihistamine/analgesic, calcium modulator, antibacterial Agents, antivirals, antimicrobials, anti-infectives, bronchodilators, hormones, hypog
- the biocompatible aqueous solution is an acceptable injection, more preferably physiological saline, glucose injection or buffer.
- the water-miscible organic solvent is selected from the group consisting of ethanol, hydrazine, hydrazine-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, methanol, propanol, glycerol, octanol a mixed solvent of one or more of dioxane and methylpyrrolidone.
- the method for removing the water-miscible organic solvent in the step (2) comprises: spray drying, vacuum evaporation, freeze drying, using a falling film evaporator, dialysis or ultrafiltration.
- the method of the present invention the operating pressure of the high pressure homogenizer in the 3000-30000 lbs / inch 2, and more preferably in the 6000-25000 lbs / inch 2, and most preferably in the 9000-18000 pounds / inch 2.
- the drying method comprises freeze drying, spray drying, vacuum distillation or a combination thereof.
- the present invention provides the use of the pharmacologically active substance delivery system of the first aspect in the preparation of a pharmaceutical preparation for delivering a pharmacologically active substance to a subject.
- the invention also provides the use of the pharmacologically active substance delivery system of the first aspect for the preparation of a pharmaceutical formulation for reducing the side effects of a medicament.
- the beneficial effects of the present invention are: Compared with the prior art, the present invention does not use organic which is immiscible with water. Solvent, but using a water-miscible organic solvent to dissolve the pharmacologically active substance, to prepare a pharmacologically active substance delivery system, the maximum dynamic hydrated particle size of the aqueous solution is above lOnm, avoiding capillary filtration of the glomerulus As a result, the passive targeting effect is impaired, so that the enrichment effect and biodistribution of the pharmacologically active substance of the present invention at the tumor site are improved.
- MCF-7 human breast cancer cells Treatment of MCF-7 human breast cancer cells with the pharmacologically active substance delivery system of the present invention showed that it has a strong anti-proliferative effect on MCF-7 human breast cancer cells, and the efficacy test for treating tumor animal models shows that it can Significant inhibition of tumor growth.
- FIG. 1 is a particle size distribution diagram of albumin-paclitaxel nanoparticles reconstituted with physiological saline (1 mg/mL) in the first embodiment of the present invention (curve 1) and a commercially available Abraxane reconstituted with physiological saline (1 mg/mL).
- Path profile (curve 2).
- FIG. 2 is a particle size distribution diagram of the albumin-paclitaxel nanoparticles reconstituted with physiological saline (0.1 mg/mL) in the first embodiment of the present invention (curve 1) and a commercially available Abraxane reconstituted with physiological saline (O.lmg/ Particle size distribution of mL) (curve 2).
- Figure 3 is a graph showing the results of in vitro treatment of MCF-7 breast cancer cells by albumin-paclitaxel nanoparticles in Example 1 of the present invention.
- Example 4 is an experimental result of the albumin-paclitaxel nanoparticles used in the treatment of MCF-7 breast cancer-bearing mice in Example 1 in which the curve 1 is the result of the treatment group and the curve 2 is the result of the control group.
- Fig. 5 is a view showing the distribution of albumin-paclitaxel nanoparticles in different organs after intravenous injection of MCF-7 breast cancer-bearing mice in Example 1 of the present invention.
- the invention adopts an anti-solvent method combined with high-pressure homogenization to form pharmacologically active substance nanoparticles.
- Antisolvent method The combination with high-pressure homogenization is extremely important.
- the anti-solvent method can combine proteins with pharmacologically active substances and form agglomerates larger than lOnm.
- High-pressure homogenization can reduce the particle size of nanoparticles to below 200nm, which is convenient to use 200nm or 220nm. The membrane of the pore size is filtered and sterilized.
- the pharmacologically active substance nanoparticles of the present invention are nano-preparations prepared according to high shear conditions (for example, sonication or high-pressure homogenization, etc.), without using any conventional surfactant, and without using any polymer core material to form Nanoparticle matrix.
- the present invention uses a protein (e.g., human serum albumin or recombinant human serum albumin, etc.) as a stabilizer.
- the particle size of the nanoparticles of the present invention can be controlled by adjusting the pressure of the high pressure homogenization and the number of high pressure homogenizations for sterile filtration through a 0.22 or 0.2 micron pore size filter. It is extremely important and meaningful that the resulting nanoparticles can be filtered through a 0.22 micron pore size filter because the protein will be thermally coagulated and cannot be sterilized by conventional methods such as autoclaving.
- the pharmacologically active substance nanoparticles provided by the invention are not easily dissociated to less than lOnm under the dilution of the acceptable injection solution, which is extremely important for the passive targeting of the nanoparticles to the tumor site by the EPR effect, which is due to the size of lOnm.
- the nanoparticles are easily excreted rapidly by glomerular filtration, impairing the passive targeting of nanoparticles (Nature Reviews Drug Discovery, 2008, 7 (9): 771-782.).
- the pharmacologically active substance delivery system comprises a solid or liquid pharmacologically active substance and a particle composed of a protein coating, wherein the protein coating has a free protein associated therewith, and a part of the pharmacologically active substance is contained in the In the protein coating; another portion of the pharmacologically active substance is associated with the free protein and is immediately bioavailable when administered to a mammal.
- a large number of common pharmacologically active substances circulating in the blood bind to carrier proteins by hydrophobic or ionic interactions, the most common example being serum albumin.
- the method of the present invention and the composition thus produced are pharmacologically active substances which have been "pre-bounded by hydrophobic or hydrogen bonding or polar interaction or ionic interaction or physical entrapment or electrostatic interaction" prior to administration.
- the ability to bind paclitaxel and other drugs using human serum albumin can increase the ability of paclitaxel to incorporate into the surface of the particles. Since albumin appears on colloidal drug particles (formed upon removal of an organic solvent), the formation of a colloidal dispersion which is stable for a long period of time is promoted due to the combined action of electrical repulsion and steric stabilization.
- the invention also provides submicron particles in powder form that can be reconstituted in water or physiological saline. This powder is obtained by freeze-drying after removing moisture.
- Human serum albumin serves as a structural component of the nanoparticles of the present invention, and also acts as a cryoprotectant and a reconstitution adjuvant.
- the granules prepared by the method of the present invention which can be filtered through a 0.22 micron or 0.2 micron pore size filter are dried or lyophilized to produce a sterile solid formulation for intravenous injection.
- the preparation method of the pharmacologically active substance preparation for in vivo delivery comprises:
- the pharmacologically active substance is mixed with an aqueous medium and an organic solvent to give a water-miscible protein mixture (free of surfactant in the mixture) and placed in a pressure range of / in a high pressure homogenizer at 3000 to 30,000 lbs 2 .
- the organic solvent can be selectively removed from the mixture after being subjected to high shear conditions; it can also be selectively removed from the mixture and then subjected to high shear conditions.
- the above process of forming the mixture may be adding the organic solution to the aqueous solution, or adding the aqueous solution to the organic solvent, and the mixing may be performed by ultrasonic, magnetic stirring, mechanical stirring, homogenization or high shear agitator. It can also be other methods that can promote the mixing of the two.
- the water-insoluble pharmacologically active substance may be dissolved in an organic solvent, and the water-soluble and amphiphilic pharmacologically active substance may be previously dissolved in an aqueous solution of albumin.
- an organic solvent and an aqueous protein solution is further processed (in a typical operating pressure of 3000-30000 lbs / inch 2 by a high pressure homogenizer, in 6000-25000 lbs / inch 2 more, most preferably 9000-18000 pounds / inch 2), in order to make the majority (90% Number statistical hydrodynamic diameter) particles is less than 200nm, 200nm or facilitate product through 220nm Aperture filter membrane filtration sterilization.
- the method of removing the organic solvent in the mixture includes spray drying, vacuum distillation, freeze drying, falling film evaporator, dialysis or ultrafiltration.
- the drying method includes a rotary evaporator, a falling film evaporator, a spray dryer, a freeze dryer or Similar equipment.
- the powder obtained by the drying treatment contains the pharmacologically active substance and the protein, and can be redispersed in a suitable aqueous medium at any suitable time to obtain a suspension which can be administered to a mammal.
- composition prepared by the above method of the present invention is not easily dissociated to a size of 10 nm or less in the case where the acceptable injection solution is dissolved and diluted.
- compositions prepared by the above methods are not only less toxic, but also have no myelosuppressive effects.
- in vivo delivery means the delivery of a pharmacologically active substance via oral, intravenous, subcutaneous, intraperitoneal, intrathecal, intramuscular, inhalation, topical, transdermal, rectal, vaginal or the like.
- aqueous solution means an aqueous liquid, including water, physiological saline, a buffer solution, A glucose solution, a vitamin solution, an amino acid solution, or other biologically acceptable aqueous solution or mixture thereof.
- biocompatible means that the substance does not significantly alter or affect the biological system into which it is introduced in any detrimental manner.
- the preparation of the existing Abraxane (albumin-bound paclitaxel) clearly indicates that an organic solvent (such as chloroform) which is immiscible with water must be used, otherwise it cannot be achieved.
- the Abraxane drug powder is very easily dissociated to below 10 nm during the dissolution and dilution with physiological saline.
- the maximum kinetic hydration particle size distribution of the physiological saline solution of Abraxane at 1 mg/mL is about 100 nm, and diluted with physiological saline.
- the maximum hydration particle size distribution of the physiological saline solution of Abraxane to 0.1 mg/mL is less than 10 nm.
- water-miscible organic solvent such as ethanol, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile or methanol is used in the preparation of the albumin-paclitaxel conjugate.
- water-miscible organic solvent such as ethanol, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile or methanol is used in the preparation of the albumin-paclitaxel conjugate.
- albumin-paclitaxel conjugate prepared by the present invention is not easily dissociated to less than lOnm during the dissolution and dilution with physiological saline, for example, prepared by the present invention.
- the albumin-paclitaxel conjugate retains a maximum kinetic hydration particle size distribution of about 100 nm diameter when it is diluted with physiological saline to 0.1 mg/mL.
- the pharmacologically active substances which can be used in the practice of the present invention include: pharmacologically active drugs, diagnostic agents, nutritive substances and the like.
- pharmacologically active drugs are as follows: analgesics/antipyretics (eg, aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, propane sulfoxide Phenol, pethidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride, codeine phosphate, dihydrocodeine tartrate, analgesic acid hydrochloride, hydrocodone bitartrate, levomorphine tartrate Conne, diflunisal, triethanolamine salicylate, nalbuphine hydrochloride, mefenamic acid, cyclobutanol tartrate, choline salicylate, bupropidazole, benz
- doxorubicin hydrochloride doxorubicin
- epirubicin daunorubicin
- doxorubicin doxorubicin
- zorubicin chlorambucil
- phenylacetate United States
- ifosfamide ifosfamide
- trofosfamide actinomycin, bleomycin, gentamicin, tretamine, triethylenephosphoramide (TPA), thiotepa, M3 ⁇ 4 ⁇ ( solaziquone ) , triaziquone , carboquone , mitomycin , mitoxantrone , bisantrene , etoposide , etoposide phosphate , teniposide , 5- Fluorouracil, tegafur, tegadifor, deoxyfluorouridine
- N-palmitoyl-ara-C ancitabine, azacitidine, gemdtabine, 6-oxime mercaptan monohydrate, 6-thiohypoxanthine, Sulfoxone sodium, thioguanine, azathioprine, pentostatin, aminopterin, methotrexate, metal platinum derivatives (carboplatin, cis Platinum, oxaliplatin, nedaplatin, sulplatin, etc.), homoharringtonine and its derivatives, busulfan, carmustine (BCNU), lomustine ( Lomustine, CCNU), semustine (Me-CCNU), nimustine (ACNU), Nimustine hydrochloride, ranimustine, streptozotocin (streptozotocin), chlorozotocin (DCNU), raltitrexed, pemetrexed
- camptothecin irinotecan, irinotecan hydrochloride, 10-hydroxycamp Alkali, topotecan, 7-ethyl-10 hydroxycamptothecin, topotecan hydrochloride, 10-hydroxycamptothecin, etc.
- benzene mustard sterol vinblastine and its derivatives (vinblastine, vincristine) , vindesine, vinorelbine
- ком ⁇ онент (ado-trastuzumab emtansine), natural LHRH polypeptide (Buserelin, Buserelin) and its derivatives, Nafarelin, Leuprolide, Goserelin, Triptor (Triptorelin), asparaginase, PEGylated asparaginase, recombinant interleukin 2, recombinant tumor necrosis factor, interferon a2a, interferon ot2b, endostatin, etc.; biologics for adjuvant treatment of tumor complications Drugs (eg, recombinant keratinocyte growth factor Palifermin, recombinant urate oxidase Rasburicase, etc.); anti-anxiety drugs (eg, hydroxyhydroxydetidine, buspirone hydrochloride, cyproterone Nitrozine, chlordiazepoxide, noroxydamine, diammine carboxylic acid potassium salt, diaze
- anti-migraine drugs eg, ergotamine tartrate, naphthoyl hydrochloride, montestin galactosamine, dichloroaldehyde Antipyrine, etc.
- sedatives/hypnotics eg, barbiturates (eg pentobarbital, sodium pentobarbital, sodium barbital), benzodiazepines (eg flurazepam) Hydrochloride, triazolam, tomazeparm, midazolam hydrochloride, etc.
- anti-angina drugs eg, beta-adrenergic antagonists, calcium channel blockers
- nifedipine, diltiazem hydrochloride, etc. nitrates (eg nitroglycerin, isosorbide dinitrate, pentaerythritol nitrate, butyl tetranitrate, etc.); antipsychotics ( For example, haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, methotrexate hydrochloride, tibothioxate, fluphenazine hydrochloride, fluphenazine phthalate, flufen Natidine heptanoate, trifluoperazine hydrochloride, chlorpromazine hydrochloride, perphenazine, lithium citrate, prochlorperazine, etc.; anti-manic drugs (eg, lithium carbonate, etc.); antiarrhythmic drugs (eg, bromobenzylammonium tosylate, esmolol hydrochloride
- anticoagulants eg, heparin, heparin sodium, warfarin, etc.
- thrombolytic agents eg, urokinase, streptokinase, recombinant plasminogen activation
- Agents etc.
- anti-fibrous solvents eg, aminocaproic acid, etc.
- hemorheological drugs eg, pentoxifylline, etc.
- antiplatelet drugs eg, aspirin, anpirin, ascriptin , etc.
- Anticonvulsant eg, valproic acid, sodium divalproate, phenytoin, phenytoin, clonazepam, phenylephrine, phenobarbital, phenobarbital Sodium, carbamazepine, sodium barbital, methyl succinyl, methyl barbital, phenobarbital, mefentestin, phenylsuccinamide, p-methyldione, ethylphenytoin, phenylacetyl Urea, sodium barbital, chlordiazepine, trimethyldione, etc.; anti-Parkinson drugs (eg, ethosuxamine, etc.); antihistamines/antipruritics (eg, hydroxyzine hydrochloride, Diphenhydramine hydrochloride, chlorpheniramine, brompheniramine maleate, cyproheptadine hydrochloride, terfenadine, chlorphenir
- erythromycin ethylsuccinate erythromycin, odorless erythromycin, erythromycin lactobionate, erythromycin stearate, erythromycin ethylsuccinate, etc.
- tetracyclines eg tetracycline hydrochloride, Doxycycline hydrochloride, hydrochloric acid Methamidolide, etc.
- anti-infectives eg, GM-CSF, etc.
- bronchodilators eg, sympathomimetic (eg, epinephrine hydrochloride, isoproterenol sulfate, terbuta sulfate) Lin, ethyl isoproterenol, ethyl isoproterenol mesylate, ethyl isoproterenol hydrochloride, salbutamol sulfate, salbutamol, dimethyltoluene me
- Proteins that can be used as stabilizers in the present invention include albumin (containing 35 cysteines), protamine, immunoglobulin, casein, insulin (containing 6 cysteines), hemoglobin (each ⁇ 2 ⁇ 2 unit has 6 cysteine residues), lysozyme (containing 8 cysteine residues), immunoglobulin, ⁇ -2-macroglobulin, fibronectin, vitronectin fibrinogen, Lipase and the like.
- proteins, peptides, enzymes, antibodies, and mixtures thereof are stabilizers conventionally used in the present invention.
- Preferred proteins are albumin, protamine and antibodies.
- Proteins such as ⁇ -2-macroglobulin can be used to enhance the uptake of granules of pharmacologically active substances encased by macrophages in the outer shell, or to promote the incorporation of such hulls into the liver and spleen.
- Specific antibodies can also be used to direct these nanoparticles to specific sites.
- the organic solvent which can be used in the present invention is particularly preferably an organic solvent which is miscible with water or a mixture thereof Things. Since the protein is insoluble in the organic solvent, the protein in the mixed solution is agglomerated by mixing with the water-miscible organic solvent and water, and the pharmacologically active substance is encapsulated in the protein agglomerate during the protein agglomeration to form a complex.
- the organic medium in the polymeric shell can vary, a variety of different pharmacologically active materials can be used in the formation of the polymeric shell wall, and a variety of proteins as well as other natural or synthetic polymers can be used. These uses are also quite extensive, and in addition to biomedical applications (eg, drug delivery, diagnostic reagents (for contrast), artificial blood, and parenteral nutrition), the polymeric shell structure of the present invention can also be incorporated into cosmetic applications, such as Used in skin care creams or hair care products, perfume fragrances, medium pressure sensitive inks.
- the purpose of this example was to demonstrate the preparation of nanoparticles using high pressure homogenization.
- 30 mg of paclitaxel was dissolved in 3.0 ml of ethanol.
- An aqueous solution of 27.0 ml of human serum albumin (1% w/v) was added to the solution.
- the resulting mixture was placed in a rotary evaporator and evaporated at 20 ° C under reduced pressure of OO mmHG for 40-30 minutes to remove ethanol. It was then homogenized for 5 minutes at low RPM to form a crude emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the resulting dispersion is translucent and the paclitaxel particles are typically less than 200 nm in diameter (quantitative, Malvern Zetasizer).
- the dispersion was freeze-dried to form a dry powder without any antifreeze.
- the dry powder can be reconstituted with sterile water or physiological saline, and the particle diameter of the solution obtained by reconstitution is still kept below 200 nm.
- the purpose of this example was to demonstrate the preparation of paclitaxel nanoparticles using cavitation and high shear stress in ultrasonic treatment.
- 20 mg of paclitaxel was dissolved in 2.0 ml of ethanol.
- 4.0 ml of human serum albumin solution (5 % w/v) was added to the solution.
- the mixture was homogenized at low RPM for 5 minutes to form a crude emulsion which was then transferred to a 40 kHz sonication cell.
- ultrasonic treatment at level 0 for 1 minute.
- the mixture was then transferred to a rotary evaporator and evaporated at 40 ° C under reduced pressure of GOmmHg) for 20-30 minutes to remove the organic solvent.
- Paclitaxel particles are obtained, typically having a diameter of less than 200 nm (quantitative statistics, Malvern Zetasizer).
- the dispersion was freeze-dried to form a dry powder without any antifreeze.
- the dry powder can be reconstituted with sterile water or physiological saline, and the particle size of the solution obtained by reconstitution remains at 200 nm or less.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 30 mg of paclitaxel was dissolved in 3 ml of ethanol.
- the solution was then added to an aqueous solution of 29.4 ml of human serum albumin (1% w/v) and the mixture was homogenized at low RPM for 5 minutes to form a crude emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the obtained system was placed in a rotary evaporator, and the organic solvent was quickly removed by evaporation at 40 ° C under reduced pressure of GOmmHg) for 15-30 minutes.
- the resulting dispersion is translucent and the resulting paclitaxel particles are typically less than 200 nm in diameter (quantitative statistics, Malvern Zetasizer).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or physiological saline, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 30 mg of paclitaxel was dissolved in 3 ml of ethanol.
- the solution was then added to an aqueous solution of 29.4 ml of human serum albumin (1% w/v).
- the resulting mixture was spray dried to remove the organic solvent to obtain a dried mixture.
- the dried mixture was reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a crude emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the resulting dispersion is translucent and the resulting paclitaxel particles are typically less than 200 nm in diameter (quantitative statistics, Malvern Zetasizer).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or physiological saline, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 30 mg of paclitaxel was dissolved in 3 ml of ethanol. The solution was then added to an aqueous solution of 29.4 ml of human serum albumin (1% w/v) and the mixture was homogenized at low RPM for 5 minutes to form a crude emulsion which was then transferred to a high pressure homogenizer (Avestin). The emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles. The resulting system was spray dried to remove the organic solvent. The resulting dispersion is translucent and the resulting paclitaxel particles are typically less than 200 nm in diameter (quantitative statistics, Malvern Zetasizer).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or physiological saline, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 30 mg of paclitaxel was dissolved in 3 ml of ethanol.
- the solution was then added to an aqueous solution of 29.4 ml of human serum albumin (1% w/v), and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the resulting dispersion is translucent and the resulting paclitaxel particles are typically less than 200 nm in diameter (quantitative statistics, Malvern Zetasizer).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or physiological saline, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 65 mg of paclitaxel was dissolved in 6 ml of ethanol.
- the solution was then added to an aqueous solution of 29.4 ml of human serum albumin (3 % w/v), and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the resulting dispersion is translucent and the resulting paclitaxel particles are typically less than 200 nm in diameter (quantitative statistics, Malvern Zetasizer).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or physiological saline, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 65 mg of 10-hydroxycamptothecin was dissolved in 6 ml of hydrazine, hydrazine-dimethylformamide.
- the solution was then added to an aqueous solution of 29.4 ml of human serum albumin (3 % w/v), and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- Avestin high pressure homogenizer
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- 10-hydroxycamptothecin The diameter of the particles is generally less than 200 nm (transmission electron microscopy).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or physiological saline, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 65 mg of vinorelbine was dissolved in 6 ml of methanol.
- the solution was then added to an aqueous solution of 29.4 ml of human serum albumin (3 % w/v), and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the resulting vinorelbine particles are typically less than 200 nm in diameter (transmission electron microscopy).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or water for injection, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 100 mg of vinorelbine was dissolved in 10 ml of methanol.
- the solution was then added to an aqueous solution of 90 ml of human serum albumin (1% w/v), and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the resulting vinorelbine particles are typically less than 200 nm in diameter (transmission electron microscopy).
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile paclitaxel dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or water for injection, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 100 mg of indocyanine green and 900 mg of human serum albumin were dissolved in 90 ml of water. Then, 20 ml of ethanol was added to the solution, and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the diameter of the resulting phthalocyanine green particles is generally less than 200 nm.
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile phthalocyanine green dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or water for injection, and the particle size is kept below 200 nm.
- the purpose of this example is to describe the preparation of sterile filtered drug particles.
- 100 mg of doxorubicin hydrochloride and 900 mg of human serum albumin were dissolved in 90 ml of water.
- 20 ml of ethanol was added to the solution, and the resulting mixture was subjected to high pressure homogenization and spray drying to remove the organic solvent to obtain a dried mixture.
- the dried mixture was then reconstituted with an aqueous solution and homogenized for 5 minutes at low RPM to form a coarse emulsion which was then transferred to a high pressure homogenizer (Avestin).
- the emulsification is performed at 9000-18000 pound / inch 2, at least 6 cycles.
- the resulting doxorubicin particles are typically less than 200 nm in diameter.
- the dispersion was passed through a 0.22 micron micropore filter, thereby obtaining a sterile doxorubicin dispersion.
- the dispersion was freeze dried without any antifreeze.
- the obtained cake is reconstituted by adding sterile water or water for injection, and the particle size is kept below 200 nm.
- the albumin-paclitaxel nanoparticles prepared in Example 1 of the present invention and the commercially available Abraxane were respectively reconstituted and diluted with physiological saline, and the results are shown in Fig. 1 and Fig. 2, and the white prepared in Example 1 of the present invention.
- the reconstituted concentration of protein-paclitaxel nanoparticles was Img/mL
- the maximum kinetic hydration particle size was about 100 nm; when diluted to 0.1 mg/mL, the maximum kinetic hydration particle size remained at about 100 nm.
- the maximum kinetic hydration particle size is about 100 nm; but when diluted to 0.1 mg/mL, the maximum kinetic hydration particle size falls below 10 nm. It was confirmed that the albumin-paclitaxel nanoparticles prepared in Example 1 of the present invention were not easily dissociated rapidly to below lOnm upon reconstitution dilution.
- MCF-7 human breast cancer cells were treated in vitro with the albumin-paclitaxel nanoparticles prepared in Example 1. After MCF-7 cells in logarithmic growth phase were trypsinized, the complete medium was resuspended into a cell suspension and then inoculated into a 96-well plate per well ⁇ placed at 37 ° C, 5% CO 2 incubator After incubation, different concentrations of the taxol nanoparticles prepared according to the method of Example 1 were added after 24 hours. MTT assay was performed after 24h.
- MTT was added to ⁇ 5 mg/mL 4 h before the termination of culture, and the culture solution was aspirated, then ⁇ DMSO was added to terminate the reaction, and the OD value was measured by a microplate reader at 570 nm. The experiment was repeated three times. The experimental results are shown in Fig. 3. The results show that the prepared paclitaxel nanoparticles have anti-proliferative effect on MCF-7 cells, and the higher the concentration of nanoparticles, the stronger the anti-proliferative effect.
- paclitaxel nanoparticles Treatment of tumor animal models with paclitaxel nanoparticles.
- the taxol nanoparticles prepared according to the method of Example 1 were used.
- the drug preparation was tested on a mouse xenografted MCF-7 human breast tumor model.
- MCF-7 breast tumors were implanted subcutaneously in mice and treatment started when the tumor grew to a size of approximately 150-300 mg.
- the above indicators were achieved due to tumor growth for 12 days, so treatment was started on the 13th day after transplantation.
- the paclitaxel nanoparticles were treated as a suspension in physiological saline at a dose of 10 mg/kg to treat tumor-bearing mice, and intravenous injection was given on the 13th day. There were 7 animals in the treatment group.
- the control tumor-bearing group of 7 animals was treated in the same manner, but only physiological saline was received. The size of the tumor was monitored over time. The result is shown in Figure 4.
- the tumor weight of the control group showed a great increase, and the animals in this group were sacrificed between the 28th and 39th days.
- the treatment group showed a significant effect, and on the 33rd day, the tumor volume of all the treatment groups was significantly smaller than the control group.
- albumin-paclitaxel nanoparticles During the preparation of albumin-paclitaxel nanoparticles, the albumin was subjected to Cy5 labeling of fluorescent dyes to prepare fluorescently labeled albumin-paclitaxel nanoparticles. After administration of a dose of 10 mg/kg to tumor-bearing mice, the fluorescence intensity of different organs of tumor-bearing mice treated with albumin-paclitaxel nanoparticles was quantified by a small animal fluorescence imaging system, and the results are shown in FIG. The results showed that the concentration of albumin-paclitaxel nanoparticles in the tumor was significantly higher than that in other tissues, indicating that the albumin-paclitaxel nanoparticles of the present invention were significantly enriched in the tumor.
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Abstract
一种基于蛋白质的药理活性物质组合物及其制备方法和应用。所述药理活性物质输送***,包括固体或液体的药理活性物质及蛋白质包衣构成的颗粒,其中所述蛋白质包衣具有与其缔合的游离蛋白质,所述药理活性物质的一部分包含在所述蛋白质包衣中,所述药理活性物质的另一部分与游离蛋白质缔合;所述颗粒的平均直径为10—200nm,其分散于水性溶液时的最大动力学水合粒径在10nm以上。该药理活性物质输送***不会因注射液的溶解稀释迅速解离至10nm尺寸以下,因此提高在肿瘤部位的富集效果,改善生物分布。
Description
基于蛋白质的药理活性物质组合物及其制备方法和应用 技术领域
本发明涉及药物输送***, 尤其涉及药理活性物质输送***, 特别涉及基 于蛋白质的药理活性物质组合物及其制备方法和应用。
背景技术
静脉内药物输送可迅速、 直接地与携带药物到身体其余部位的血流达到平 衡。 为了避免注射后短时间血管内出现药物峰值浓度, 将药物携带于稳定载体 内, 可在冲击剂量静脉注射后使药物在血管内逐渐释放。
但是, 一方面, 许多常见的临床药物疏水性较大, 难以分散在水性液体环 境中, 造成给药方式和药物吸收的困难。 通过静脉给药时, 需要使用 Cremphor 等助溶剂, 而这些助溶剂的使用有可能引起严重的临床副作用。 而且, 通过使 用助溶剂的给药方式所造成的药理活性成份在疾病组织和靶点的富集效果有 限。 另一方面, 许多水溶性好的临床药物分子的体内清除速度快, 血药浓度下 降速度快, 其治疗疗效有待进一步提高。
纳米技术对提高药物疗效有突出价值。 一方面, 纳米技术可以通过改善纳 米颗粒本身在生物体内的药代药动过程而改善所携带药理活性成分在生物体内 的药代药动过程。 纳米技术能够有效提高疏水药理活性物质的溶解度和溶解速 率, 提高药理活性物质的生物可利用度。 而且, 纳米技术能够有效地延长药理 活性成分的血液循环时间, 提高药理活性成分在疾病组织和靶点的富集程度。
使用纳米技术改善药理活性物质的临床应用价值必须考虑以下问题: 所使 用的材料必须是临床安全的, 所制备得到的纳米组合物的成份也都是临床安全 的; 制备得到的药理活性物质组合物的纳米结构应该保持稳定, 在至少一种临
床可接受的注射液中不发生严重的团聚或者解离。
在药理活性物质的组合物制备过程中, 应尽量选择已经临床批准的材料作 为原料, 例如白蛋白、 鱼精蛋白、 抗体、 免疫球蛋白等。 以这些临床批准的材 料为原料, 经过与药理活性物质进行纳米组装可以得到成份安全的药理活性物 质组合物, 能够尽可能的保证所制备的药理活性物质组合物具有较高的临床安 全性。 制备得到的药理活性物质组合物的纳米结构经过临床可接受的注射液的 稀释应该保持相对稳定的纳米结构, 特别是最大粒径分布 (透射电镜或者动态 光散射分析 (Number%统计, Malvern) ) 应该仍保持在 10-200nm范围内。 一 方面, 如果药理活性物质组合物被注射液溶解稀释后发生严重的团聚, 最大粒 径分布增长到 10-15 微米级以上时, 可能会引起毛细血管堵塞或梗塞, 导致局 部出血、 缺血或缺氧和可能的组织死亡。 另一方面, 对于一些疾病的治疗, 如 肿瘤的治疗, 疾病组织处的毛细血管具有增强的通透性和滞留性(EPR效应), 纳米粒子能够通过被动靶向方式有效地富集于肿瘤组织, 这要求纳米粒子的粒 径小于一定尺寸, 有文献研究表明, 尺寸小于 400nm的纳米颗粒能够通过 EPR 效应富集于肿瘤部位 (Cancer research, 1995, 55 ( 17) : 3752-3756. ) , 还有研究 表明, 尺寸小于 200nm 的纳米颗粒能够更有效地富集于肿瘤部位 (Nature nanotechnology, 2007, 2 ( 12) : 751-760. ) 。 而且, 有研究表明, 直径 100匪左 右的纳米药物能够最有效地富集于肿瘤组织 (Int. J. Pharm., 121 ( 1995 ) , 195-203; Nature nanotechnology, 2011, 6 ( 12) : 815-823 ) , 而血液中粒径小于 lOnm的纳米粒子容易通过肾小球的毛细血管过滤排出, 被动靶向效果受到削弱 (Nature Reviews Drug Discovery, 2008, 7 (9 ) : 771-782. ) 。 因此, 药理活性物 质组合物的纳米结构尺寸在 10-200nm范围内保持相对稳定极为重要, 不但能够 保证纳米材料的体内安全性, 实现肿瘤等疾病组织的有效富集, 而且能够通过
200nm或者 220nm滤膜过滤除菌。
一个药理活性物质的例子是紫杉醇。 它是一种天然产物, 首先是从太平洋 紫杉树 (Taxus brevifolia) 分离出来 (J.Am.Chem.Soc.93 : 2325 ( 1971 ) ) 。 在 抗有丝***药中, 含一个二萜碳骨架的紫杉醇对引起有丝***纺锤体形成的微 管蛋白质呈现独特的作用模式。 与其它抗有丝***药如长春碱或秋水仙碱阻止 微管蛋白装配大不相同的是, 紫杉醇是一种已知能抑制微管蛋白解聚过程、 因 而阻止细胞复制过程的植物产品。
紫杉醇这种天然存在的双萜类化合物对多种肿瘤显示有明显的抗肿瘤和抗 癌作用。 紫杉醇对范围广泛的肿瘤模型如 B16黑素瘤、 L1210白血病、 MX-1乳 房肿瘤和 CS-1结肠肿瘤异种移植物有优异的抗肿瘤活性, 并已广泛应用于临床 肿瘤治疗。 然而, 紫杉醇的水溶解度低使对人给药成为问题。 确实, 输送在水 性介质中固有地不溶或难溶的药物, 如果口服输送无效可能会受到严重的损 害。 为此, 目前所用的紫杉醇配方需要 cremphor来使药物增溶。
在临床使用中, 紫杉醇本身不显示过度的毒性作用, 但用于增溶药物的乳 化剂 /助溶剂引起了严重的过敏反应。 目前的给药制度包含在注射药物之前, 给 予病人抗组胺药和类固醇以减弱 cremphor的过敏副作用。
为改进紫杉醇的水溶解度, 几个研究人员用能赋予较高水溶解度的官能团 修饰了它的化学结构。 其中, 磺化衍生物 (Kingston 等, 美国专利 5,059,699 ( 1991 ) ) 和氨基酸酯 (Mathew等, J.Med.Chem.35 : 145-151 ( 1992 ) ) 显示 有明显的生物活性。 经修饰产生的水溶性衍生物有利于静脉内输送溶解在无害 载体如生理盐水中的紫杉醇。 然而, 这种修饰使药物制剂的成本增加, 可能诱 发不需要的副反应和 /或过敏反应, 可能降低药物的疗效。
文献曾报道过用蛋白质微球作为药理活性物质或诊断产品的载体。 用热变
性或化学交联的方法制备了白蛋白微球。 热变性微球是从一种乳化的混合物
(例如, 将要掺入的物质白蛋白和一种合适的油)在温度 100°C至 150°C之间制 备的。 然后, 用一种适宜的溶剂将微球洗涤并储存备用。 Leucuta 等 (International Journal of Pharmaceutics 41: 213-217 ( 1988 ) ) 介绍了热变性微 球的制备方法。
制备化学交联微球的过程包括用戊二醛处理乳剂以将蛋白质胶联, 然后洗 涤和储存备用。 Lee等(Science 213 : 233-235 ( 1981 ) )和美国专利 No.4,671,954 介绍了这种制备方法。
上述方法制备的蛋白质微球尺寸大于 10微米, 静脉方式给药的临床安全风 险较大, 限制了其进一步临床应用的可能性。
制备含药纳米颗粒的一种常规方法是将聚乳酸或其它生物亲容性的水不溶 性聚合物溶于与水不溶混的溶剂(如二氯甲垸或其它氯化的、 脂肪或芳香溶剂) 内, 将药理活性物质溶解于此聚合物溶液中, 在油相或水相中加入表面活性 剂, 通过适当的方法形成水包油乳剂, 于真空下将乳剂缓慢蒸发。 如油滴足够 小并在蒸发时稳定, 就得到一种聚合物的水混悬液。 因为药物在开始时就存在 于聚合物溶液中, 所以用这种方法可能得到一种组合物, 其中药物分子在其内 被由一种聚合基质形成的颗粒所捕捉。 有研究人员报告了用溶剂蒸发制备含各 种药物的微球和纳米颗粒的方法, 例如参见 Tice和 Gilley, Journal of controlled Release 2: 343-352 ( 1985 ) ; Bodmeier和 McGinity, Int. J. Pharmaceutics 43: 179 ( 1988 ) ; Cavalier等, J. Pharm. Pharmacol.38: 249 ( 1985 ) ; 和 d'Souza 等, WO 94/10980。
临床上市药物 Abraxane是通过乳液法结合高压均质制备出粒径约为 130nm 的白蛋白紫杉醇纳米药物。 其制备过程必须使用与水不互溶的有机溶剂溶解药
理活性物质, 与白蛋白水溶液混匀形成两相的有机相和水相, 再经过高压均质 形成尺寸小于 200nm 的颗粒 (参考 US005916596A; CN1515244A ) 。 但是 Abraxane粉末在临床使用中迅速解离形成尺寸小于 lOnm的单个白蛋白尺寸大 小的颗粒, 并没有改善紫杉醇分子的生物分布和血液循环时间 (Chem. Soc. Rev., 2012, 41, 2971-3010) 。 因此, 通过改变工艺制备纳米结构稳定的白蛋白 / 药理活性物质组合物, 通过肿瘤部位的 EPR效应提高药理活性物质在肿瘤部位 的富集效果, 改善生物分布, 这些都是本领域亟需解决的问题。
发明内容
针对现有技术的不足, 本发明提供一种基于蛋白质的药理活性物质组合 物, 所述组合物不需要加入乳化剂和增溶剂, 因此避免引起过敏反应, 并且不 会因注射液的溶解稀释迅速解离至 lOnm尺寸以下, 因此提高在肿瘤部位的富 集效果, 改善生物分布。 本发明还提供所述组合物的制备方法及其应用。
在第一方面, 本发明提供一种药理活性物质输送***, 包括固体或液体的 药理活性物质及蛋白质包衣构成的颗粒, 其中所述蛋白质包衣具有与其缔合的 游离蛋白质, 所述药理活性物质的一部分包含在所述蛋白质包衣中, 所述药理 活性物质的另一部分与游离蛋白质缔合; 所述颗粒的平均直径为 10至 200nm, 其分散于水性溶液时的最大动力学水合粒径在 lOnm以上。
具有上述特征的药理活性物质输送***通过静脉注射进入人体血液中后, 与游离蛋白质缔合的那部分药理活性物质能够快速释放, 但是包含在所述蛋白 质包衣中的那部分药理活性物质不会在短时间内快速释放, 而是在一个较长的 时间内缓慢稳定地释放, 因此改善了血液循环时间。 本发明的药理活性物质输 送***与此前报道的此类组合物的最显著的区别在于本发明的药理活性物质输 送***的颗粒的平均直径为 10至 200nm, 其分散于水性溶液时的最大动力学水
合粒径在 lOnm 以上, 避免了肾小球的毛细血管过滤排出而导致的被动靶向效 果削弱; 此前报道的此类组合物分散于水性溶液时, 其最大动力学水合粒径迅 速降低到 lOnm 以下, 由于肾小球的毛细血管过滤排出而导致被动靶向效果削 弱。
本发明中, 所谓"水性溶液"是指水、 生理盐水、 缓冲溶液、 葡萄糖溶液、 维生素溶液、 氨基酸溶液或它们的混合物等生物可接受的水性溶液。 本发明特 别研究了生理盐水作为水性溶液用于稀释所述药理活性物质输送***的情况, 在 O. lmg/mL的生理盐水中, 所述颗粒的最大动力学水合粒径在 lOOnm左右。 因此, 作为本发明的优选, 所述颗粒分散于 O. lmg/mL 的生理盐水时的最大动 力学水合粒径在 lOnm 以上、 优选在 20nm 以上、 更优选 50-180nm, 例如 60nm、 70nm、 80nm、 100nm、 120nm、 150nm、 160nm、 170nm、 175nm、 60-150nm、 70-100nm, 80-120nm、 120-150nm或 130-170nm。
本发明所述药理活性物质输送***可以是以颗粒干粉的形式存在, 也可以 将所述药理活性物质输送***的颗粒悬浮于生物相容性水溶液中。 其中, 所述 生物相容性水溶液可以为可接受的注射液, 更优选为生理盐水、 葡萄糖注射液 或缓冲液。
在第二方面, 本发明提供一种制备第一方面所述的药理活性物质输送*** 的方法, 包括:
( 1 )将蛋白质、 药理活性物质、 生物相容性水溶液和与水互溶的有机溶剂 混合制成混合溶液;
(2 ) 除去与水互溶的有机溶剂再进行高压均质, 或者进行高压均质再除去 与水互溶的有机溶剂, 得到纳米悬浮液, 然后通过干燥得到干粉状的药理活性 物质输送***。
本发明的方法与现有技术最显著的区别在于采用与水互溶的有机溶剂代替 现有技术中的与水不互溶的有机溶剂。 发明人出乎意料地发现本发明的方法制 得的药理活性物质输送***不会因注射液的溶解稀释迅速解离至 lOnm尺寸以 下。
本发明的方法中, 药理活性物质可以是水不溶性(疏水性)药理活性物质、 水溶性 (亲水性) 药理活性物质或双亲性药理活性物质。
针对水不溶性药理活性物质, 可以通过以下步骤制备混合溶液:
( la) 将蛋白质溶于生物相容性水溶液中, 形成蛋白质溶液; 将水不溶性 药理活性物质溶于与水互溶的有机溶剂中, 形成药理活性物质溶液;
( lb ) 将所述药理活性物质溶液与所述蛋白质溶液混合。
针对水溶性药理活性物质, 可以通过以下步骤制备混合溶液:
( la) 将蛋白质和水溶性药理活性物质共同溶于生物相容性水溶液中, 形 成蛋白质 /水溶性药理活性物质混合溶液;
( lb) 将与水互溶的有机溶剂与所述蛋白质 /水溶性药理活性物质混合溶液 混合。
针对双亲性药理活性物质, 可以选择上述二者之一。
本发明的方法中, 所述蛋白质选自白蛋白、 鱼精蛋白、 抗体、 免疫球蛋 白、 酪蛋白、 胰岛素、 溶菌酶、 纤维蛋白原、 脂肪酶、 胶原蛋白、 纤维连接 素、 玻璃连接素、 去铁蛋白、 铁蛋白、 血红蛋白中的一种或多种, 优选人血清 白蛋白、 重组人血清白蛋白、 鱼精蛋白、 抗体、 铁蛋白或去铁蛋白, 最优选人 血清白蛋白。
本发明的方法中, 所述药理活性物质选自抗肿瘤药、 镇痛剂 /退热剂、 麻醉 剂、 平喘药、 抗生素、 抗抑郁药、 抗糖尿病药、 抗真菌剂、 抗高血压药、 消炎
药、 肿瘤并发症辅助治疗生物技术药物、 抗焦虑药、 免疫抑制剂、 抗偏头痛 药、 镇静剂 /***、 抗心绞痛药、 抗精神病药、 抗躁狂药、 抗心律失常药、 抗 关节炎药、 痛风剂、 抗凝剂、 溶栓剂、 抗纤溶药、 血液流变学剂、 抗血小板 药、 抗惊厥药、 抗帕金森药物、 抗组胺药 /止痒药、 钙调节剂、 抗菌剂、 抗病毒 药、 抗微生物药、 抗感染药、 支气管扩张药、 激素、 降血糖药、 降血脂药、 蛋 白质、 核酸、 红血球生成刺激剂、 抗溃疡 /抗反流剂、 止恶心药 /止吐剂、 维生 素或成像剂。
本发明的方法中, 所述生物相容性水溶液为可接受的注射液, 更优选为生 理盐水、 葡萄糖注射液或缓冲液。
本发明的方法中, 所述与水互溶的有机溶剂选自乙醇、 Ν,Ν-二甲基甲酰 胺、 四氢呋喃、 二甲亚砜、 丙酮、 乙腈、 甲醇、 丙醇、 丙三醇、 辛醇、 二氧六 环和甲基吡咯垸酮中的一种或多种的混合溶剂。
本发明的方法中, 所述步骤 (2) 中除去与水互溶的有机溶剂的方法包括: 喷雾干燥、 减压蒸发、 冷冻干燥、 采用降膜蒸发器、 透析或超滤。
本发明的方法中, 所述高压均质的操作压力在 3000-30000磅 /英寸 2内, 更 优选在 6000-25000磅 /英寸 2内, 最优选在 9000-18000镑 /英寸 2内。
本发明的方法中, 所述干燥的方法包括冷冻干燥、 喷雾干燥、 减压蒸馏或 它们的组合。
在第三方面, 本发明提供第一方面所述的药理活性物质输送***在制备将 药理活性物质输送到受试者的药物制剂中的应用。
本发明还提供第一方面所述的药理活性物质输送***在制备减少药剂副作 用的药物制剂中的应用。
本发明的有益效果为: 相对于现有技术, 本发明不使用与水不互溶的有机
溶剂, 而是使用与水互溶的有机溶剂溶解药理活性物质, 制备药理活性物质输 送***, 其分散于水性溶液时的最大动力学水合粒径在 lOnm 以上, 避免了肾 小球的毛细血管过滤排出而导致的被动靶向效果削弱, 因此本发明的药理活性 物质在肿瘤部位的富集效果及生物分布得到改善。 采用本发明的药理活性物质 输送***对 MCF-7人乳腺癌细胞进行处理显示其对 MCF-7人乳腺癌细胞具有很 强的抗增殖作用, 对肿瘤动物模型进行治疗的药效试验显示其能显著抑制肿瘤 的生长。
附图说明
图 1为本发明实施例 1中白蛋白 -紫杉醇纳米粒子用生理盐水复溶(lmg/mL) 的粒径分布图 (曲线 1 ) 和市售 Abraxane用生理盐水复溶(lmg/mL) 的粒径分 布图 (曲线 2) 。
图 2 为本发明实施例 1 中白蛋白 -紫杉醇纳米粒子用生理盐水复溶 ( O.lmg/mL ) 的粒径分布图 (曲线 1 ) 和市售 Abraxane 用生理盐水复溶 (O.lmg/mL) 的粒径分布图 (曲线 2) 。
图 3为本发明实施例 1中白蛋白-紫杉醇纳米粒子用于体外治疗 MCF-7乳腺 癌细胞的实验结果。
图 4为本发明实施例 1中白蛋白 -紫杉醇纳米粒子用于治疗 MCF-7乳腺癌荷 瘤小鼠的实验结果, 其中曲线 1为治疗组结果, 曲线 2为对照组结果。
图 5为本发明实施例 1中白蛋白-紫杉醇纳米粒子通过静脉注射 MCF-7乳腺 癌荷瘤小鼠后, 在不同器官的分布情况。
具体实 i ¾r式
下面将对本发明进行详细阐述。
本发明采用反溶剂法结合高压均质生成药理活性物质纳米颗粒。 反溶剂法
和高压均质的结合极为重要, 反溶剂法能够将蛋白质与药理活性物质结合在一 起并形成大于 lOnm 的团聚物质, 高压均质能够减小纳米粒子的颗粒尺寸至 200nm以下, 便于使用 200nm或 220nm孔径的滤膜过滤除菌。 本发明的药理活 性物质纳米颗粒是按照高剪切力条件 (例如超声处理或高压均质等) 制备的纳 米制剂, 不需使用任何常规表面活性剂, 并且不需使用任何聚合物核心物质以 形成纳米颗粒基质。 本发明用蛋白质 (例如人血清白蛋白或重组人血清白蛋白 等) 作为稳定剂。
通过调节高压均质的压力和高压均质的次数能够控制本发明纳米颗粒的粒 径, 以便通过 0.22或 0.2微米孔径的过滤器无菌过滤。 生成的纳米颗粒能通过 0.22 微米孔径的过滤器过滤是极为重要和有意义的, 这是由于蛋白质会热凝 固, 不能用常规方法如压热法灭菌。 本发明提供的药理活性物质纳米颗粒在可 接受的注射液的稀释下不易解离至 lOnm以下, 这对于纳米粒子通过 EPR效应 被动靶向累积于肿瘤部位是极为重要的, 这是由于 lOnm尺寸以下的纳米粒子 容易通过肾小球过滤迅速排出体外, 削弱纳米粒子的被动靶向能力 (Nature Reviews Drug Discovery, 2008, 7 (9) : 771-782. ) 。
本发明提供的药理活性物质输送***, 包括固体或液体的药理活性物质及 蛋白质包衣构成的颗粒, 其中所述蛋白质包衣具有与其缔合的游离蛋白质, 所 述药理活性物质的一部分包含在所述蛋白质包衣中; 所述药理活性物质的另一 部分与游离蛋白质缔合, 在给予哺乳动物时可立即生物有效。
大量在血液中循环的常见药理活性物质通过疏水或离子相互作用与载体蛋 白质结合, 其中最普通的例子是血清白蛋白。 本发明的方法和由此而产生的组 合物是在给药前已"预先通过疏水或氢键或极性作用或离子相互作用或物理包 埋或静电作用结合"蛋白质的药理活性物质。
利用人血清白蛋白结合紫杉醇以及其它药物的能力可以提高紫杉醇并入颗 粒表面的能力。 因为白蛋白出现在胶体药物颗粒(在除去有机溶剂时形成)上, 由于电排斥和空间稳定的合并作用, 促进了能长时间稳定的胶体分散体的形 成。
本发明也提供能在水或生理盐水中重组的粉末形式亚微米颗粒。 这种粉末 是在除去水分后经冷冻干燥得到的。 人血清白蛋白作为本发明纳米颗粒的结构 组分, 也作为冷冻保护剂和重组辅助剂。 本发明方法制备的能通过 0.22微米或 者 0.2 微米孔径的过滤器过滤的颗粒, 经干燥或冷冻干燥后产生可供静脉内注 射用的无菌固体配方。
本发明提供的供体内输送的药理活性物质制剂的制备方法包括:
将药理活性物质、 与水互溶的有机溶剂和蛋白质的水性介质进行混合得到 混合物 (在该混合物内不含表面活性剂) 并置于压力范围在 3000至 30000磅 / 英寸 2的高压均质器内。 有机溶剂可以在经受高剪切条件处理后, 有选择性地 从混合物中除去; 也可以先从混合物中有选择的除去, 再接受高剪切条件处 理。
上述形成混合物的过程可以是将有机溶液加入至水性溶液, 也可以是将水 性溶液加入至有机溶剂, 混合过程中的条件可以是超声、 磁搅拌、 机械搅拌、 匀浆或高剪切搅拌器, 也可以是其他可以促进两者混合的方法。 混合之前, 水 不溶性药理活性物质可以溶解在有机溶剂中, 水溶性和双亲性药理活性物质可 以预先溶解在白蛋白的水性溶液中。
在研究过程中, 本发明人充分认识到, 虽然在适当的条件下将药理活性物 质、 有机溶剂和蛋白质的水性溶液混合在一起也能得到最大粒径分布小于 200nm 的组合物, 但是可控性较差, 不同批次之间的差异较大, 不利于放大生
产, 尽管多次努力提高药理活性物质的载药量都难以同时接近 Abraxane的载药 量(10%)和最大动力学水合直径(约 100-130nm) , 在实际生产中, 会给产品 质量控制、 放大生产带来巨大困难, 难以通过 200nm或者 220nm孔径滤膜过滤 除菌, 安全性和有效性难以得到保障, 从而限制其临床实际应用。 因而, 本发 明人经过艰苦的实验和工艺研究发现需要将药理活性物质、 有机溶剂和蛋白质 水性溶液的混合物进一步通过高压均质器进行加工处理 (典型的操作压力在 3000-30000磅 /英寸 2, 在 6000-25000磅 /英寸 2更好, 最优选在 9000-18000镑 / 英寸 2 ), 才能使大部分( 90%,Number统计)粒子的水合动力学直径小于 200nm, 有利于产品通过 200nm或者 220nm孔径滤膜过滤除菌。
除去混合物中的有机溶剂的方法包括喷雾干燥、 减压蒸馏、 冷冻干燥、 降 膜蒸发器、 透析或超滤等方法。
为了得到可复溶的药理活性物质 -蛋白质的复合物, 需要将药理活性物质的 蛋白质复合物的溶液干燥处理, 干燥的方法包括旋转蒸发器、 降膜蒸发器、 喷 雾干燥器、 冷冻干燥器或类似设备。 干燥处理得到的粉末含药理活性物质和蛋 白质, 可于任何合适的时间, 在适宜的水性介质中再分散以得到能对哺乳动物 给药的混悬液。
本发明用上述方法制备的组合物在可接受的注射液溶解稀释情况下, 不易 解离成 10nm尺寸以下。
本发明用上述方法制备的组合物, 例如紫杉醇和白蛋白形成的纳米颗粒, 不但毒性低, 而且没有骨髓抑制作用。
本发明中, "体内输送"是指经由口服、 静脉内、 皮下、 腹腔、 鞘内、 肌 内、 吸入、 外用、 经皮、 直肠、 ***或类似途径输送药理活性物质。
本发明中, "水性溶液"是指含水的液体, 包括水、 生理盐水、 缓冲溶液、
葡萄糖溶液、 维生素溶液、 氨基酸溶液或者其它生物可接受的水性溶液或者其 混合物。
本发明中, "生物相容性"是指物质不会明显地以任何有害的方式改变或影 响它被引入的生物***。
本发明中, "(药理活性物质)输送***"、 "(药理活性物质)组合物"、 "(药 理活性物质) 制剂"、 " (药理活性物质) 纳米颗粒"和" (药理活性物质-蛋白) 复合物 "及其它类似概念在一定程度上含义是相同的。 在具体的语境中在不产 生矛盾的前提下, 这些概念是可以替换的。
与本发明不同的是, 现有 Abraxane (白蛋白结合型紫杉醇) 的制备过程中 明确表示必须使用与水不互溶的有机溶剂 (如氯仿) , 否则无法实现。 而且, Abraxane 药物粉末在用生理盐水溶解稀释过程中, 非常容易解离至 10nm 以 下, 例如, lmg/mL的 Abraxane的生理盐水溶液的最大动力学水合粒径分布约 为 100nm, 而经生理盐水稀释至 O.lmg/mL的 Abraxane的生理盐水溶液的最大 动力学水合粒径分布小于 10nm。 本发明的方法, 制备白蛋白-紫杉醇结合物的 过程中仅仅使用与水互溶的有机溶剂, 如乙醇、 N, N-二甲基甲酰胺、 四氢呋 喃、 二甲亚砜、 丙酮、 乙腈、 甲醇、 丙醇、 丙三醇、 辛醇、 二氧六环、 甲基吡 咯垸酮或它们的混合溶剂。 本发明制备的白蛋白-紫杉醇结合物与 Abraxane在 性质上的差异在于本发明制备的白蛋白 -紫杉醇结合物在用生理盐水溶解稀释过 程中, 不容易解离至 lOnm以下, 例如本发明制备的白蛋白 -紫杉醇结合物在用 生理盐水溶解稀释至 O. lmg/mL时, 仍保持大约 lOOnm直径的最大动力学水合 粒径分布。 这一特点对于白蛋白 -紫杉醇结合物发挥体内抗肿瘤能力极为重要, 因为已经有多篇文献证明大约 lOOnm动力学水合直径的纳米粒子在肿瘤部位具 有最好的富集效果(Cancer research, 1995, 55 ( 17): 3752-3756; Int. J. Pharm., 121
( 1995 ) , 195-203; Nature nanotechnology, 2011, 6 ( 12 ) : 815-823 ) , 能够有效 提高肿瘤部位的药物浓度。 而容易解离至 10nm以下的 Abraxane的生物分布和 血液循环时间并没有得到明显改善 (Chem. Soc. Rev., 2012, 41, 2971-3010) 。
能够用于本发明实施的药理活性物质包括: 药理活性药物、 诊断试剂和营 养用物质等。 药理活性药物举例如下: 镇痛剂 /退热剂 (如, 阿斯匹林, 对乙酰 氨基酚, 布洛芬, 萘普生钠, 盐酸叔丁啡, 盐酸丙氧酚, 萘磺酸丙氧酚, 盐酸 哌替啶, 盐酸二氢***酮, 硫酸***, 盐酸羟考酮, 磷酸可待因, 酒石酸二氢 可待因, 盐酸镇痛新, 重酒石酸二氢可待因酮, 酒石酸左啡诺, 二氟尼酸, 水 杨酸三乙醇胺, 盐酸纳布啡, 甲芬那酸, 环丁吗喃醇酒石酸盐, 水杨酸胆碱, 布他比妥, 柠檬酸苄苯醇胺, 柠檬酸苯海拉明, 甲氧异丁嗪, 盐酸桂麻黄碱, 眠尔通, 等) ; 麻醉剂 (如, 环丙垸, 恩氟垸, 氟垸, 异氟垸, 甲氧氟垸, 一 氧化氮, 普鲁泊福 (丙酚) , ***, 戊巴比妥钠, 等) ; 平喘药 (如, 氮卓司 汀, 酮替芬, Traxanox, 等); 抗生素(如, 新霉素, 链霉素, 氯霉素, 头孢菌 素, 氨比西林, 青霉素, 四环素, 等) ; 抗抑郁药 (如, 甲苯噁唑辛, 奥昔哌 汀, 盐酸多虑平, 阿莫沙平, ***唑酮, 盐酸阿米替林, 麦普替林盐酸盐, 硫酸苯乙肼, 盐酸去甲丙咪嗪, 盐酸去甲替林, 硫酸反苯环丙胺, 盐酸氟西 汀, 盐酸多虑平, 盐酸米帕明, 双羟水杨酸米帕明, 去甲替林, 盐酸阿米替 林, 异唑肼, 盐酸去甲丙咪嗪, 马来酸三甲丙咪嗪, 盐酸普罗替林, 等) ; 抗 糖尿病药 (如, 胰岛素, 双胍类, 激素, 硫酰脲衍生物类, 等) ; 抗真菌药 (如, 灰黄霉素, 酮康唑, 两性霉素 B, 制霉菌素, 杀念菌素, 等); 抗高血压 药 (如, ***, 普罗帕酮, 烯丙氧心安, 硝苯吡啶, 利血平, 樟脑磺酸咪 噻芬, 盐酸酚苄明, 帕吉林盐酸盐, 脱甲氧利血平, 二氮嗪, 硫酸胍乙啶, 长 压定, 萝芙木碱, 硝普钠, 缓脉灵, 蛇根混合碱, 甲磺酸酚妥拉明, 利血平,
等) ; 消炎药 (如, 〔非甾体类〕 消炎痛, 萘普生, 布洛芬, ramifenazone, 炎 痛喜康, 〔类固醇类〕皮质酮, ***, 氟噁米松, 氢化可的松, 强的松龙, 强的松, 等) ; 抗肿瘤药 (如, 紫杉醇 (Taxol ) 及其衍生物, 多西紫杉醇
(taxotere) 及其衍生物, 盐酸阿霉素, 阿霉素, 表阿霉素, 柔红霉素, 多柔比 星, 佐柔比星, 苯丁酸氮芥 (chlorambucil ) , 苯乙酸氮芥, 美法伦
(melphalan) , 乌拉莫司汀 (uramustine) , 磷酸雌莫司汀 (estramustine ) , 泼 尼莫司汀 ( prednimustine ), 氮甲 ( formylmerphalan ), 异芳芥 ( betamerphalan ), 邻脂芳芥 (ocaphane ) , 环磷酰胺 (cyclophosphamide ) , 异环磷酰胺
(ifosfamide) , 曲磷胺 (trofosfamide ) , 放线菌素, 博来霉素, 正定霉素, 曲 他胺( tretamine ), 替哌( triethylenephosphoramide, TEPA ), 塞替派 ( thiotepa ), M¾酉昆 ( solaziquone ) , 酉昆 ( triaziquone ) , 皮酉昆 (carboquone ) , 裂霉素, 米托蒽醌, 比生群 (bisantrene ) , 依托泊苷, 依托泊苷磷酸酯, 替尼 泊苷, 5-氟尿嘧啶, 替加氟 (tegafur) , 双喃氟啶 (tegadifor) , 去氧氟尿苷
(doxifluridine) , 卡莫氟(carmofur) , 卡培他滨(capecitabine) , 盐酸阿糖胞 苷 (cytarabine hydrochloride) , 阿糖胞苷 (cytarabine ) , 单磷酸阿糖胞苷, 二 磷酸阿糖胞苷, 三磷酸阿糖胞苷, 依诺他宾 (enocitabine ) , 棕榈酰阿糖胞苷
(N-palmitoyl-ara-C) , 安西他滨 (ancitabine) , 阿扎胞苷 (azacitidine) , 吉西 他滨(gemdtabine) , 6-嘌呤硫醇一水合物, 6-硫代次黄嘌呤核苷酸, 磺巯嘌呤 钠(sulfomercaprine sodium), 硫鸟嘌呤, 硫唑嘌呤, 喷司他丁(pentostatin), 氨基蝶呤(aminopterin) , 甲氨蝶呤(methotrexate) , 金属铂类衍生物(卡铂, 顺铂, 奥沙利铂, 奈达铂, 舒铂, 等) , 高三尖杉酯碱(homoharringtonine)及 其衍生物, 白消安 (busulfan) , 卡莫司汀 (BCNU) , 洛莫司汀 (lomustine, CCNU) , 司莫司汀(semustine, Me-CCNU), 尼莫司汀(nimustine, ACNU),
尼莫司汀盐酸盐, 雷莫司汀(ranimustine) , 链佐星(链脲霉素, streptozotocin) , 氯脲霉素 ( chlorozotocin, DCNU ) , 雷替曲塞 ( raltitrexed ) , 培美曲塞
(pemetrexed) , 秋水仙碱(colchicine) , 秋水仙胺, 鬼臼乙叉甙, 干扰素, 喜 树碱及其衍生物 (喜树碱, 伊立替康, 盐酸伊立替康, 10-羟基喜树碱, 拓扑替 康, 7-乙基 -10 羟基喜树碱, 盐酸拓扑替康, 10-羟基喜树碱, 等) , 苯芥胆甾 醇, 长春碱及其衍生物(长春碱, 长春新碱, 长春地辛(vindesine) , 长春瑞滨
( vinorelbine ) , 酒石酸长春瑞滨, 盐酸长春瑞滨, 等) , 甲磺酸伊马替尼
(imatinib mesylate) , 达沙替尼 (dasatinib ) , 吉非替尼 (gefitinib ) , 厄洛替 尼 (erlotinib) , 索拉菲尼 (sorafenib) , 苹果酸舒尼替尼 ( simitinib malate ) , 硼替佐米(bortezomib) , 三苯氧胺, 鬼臼乙叉甙, 哌酰硫垸, 卟吩姆钠, 二氢 口卜吩 e6 (Chlorin e6, Ce6) , 5-氨基酮戊酸 ( 5-aminolaevulinic acid , ALA) , 维替泊芬 (Verteporfin) , 替莫泊芬 (temoporfm) , 酞菁硅, 二氯酞菁硅, 酞 菁锌, 靶向 CD52 重组人源化单抗 (Campath, MabCampath) , 重组靶向人上 皮生长因子受体 IgG2K单抗 (Vectibix) , mIn-标记和 9QY-标记靶向 CD20鼠单 抗(Zevalin), 靶向 CD20131I-标记和非标记鼠单克隆抗体(BEXXAR), 碘 [1311] 肿瘤细胞核人鼠嵌合单克隆抗体(唯美生, Vivatuxin), 靶向 CD33结合化疗药 单抗(Mylotarg), 靶向白介素 2: 白喉毒素融合蛋白(Ontak, Onzar) , Kadcyla
( ado-trastuzumab emtansine ) , 天然 LHRH多肽 (布舍瑞林, Buserelin) 及其 衍生物, 那法瑞林(Nafarelin) , 亮丙瑞林(Leuprolide ), 戈舍瑞林(Goserelin), 曲普瑞林(Triptorelin) , 天冬酰胺酶, 聚乙二醇化天冬酰胺酶, 重组白介素 2, 重组肿瘤坏死因子, 干扰素 a2a, 干扰素 ot2b, 内皮抑制素, 等) ; 肿瘤并发症 辅助治疗生物技术药物 (如, 重组角化细胞生长因子 Palifermin, 重组尿酸氧化 酶 Rasburicase, 等) ; 抗焦虑药 (如, 氯羟去甲安定, 盐酸丁螺环酮, 环丙二
氮卓, 盐酸利眠宁, 去甲羟安定, 安定羧酸钾盐, 安定, 双羟萘酸羟嗪, 盐酸 羟嗪, 阿普***, 氟哌利多, 哈拉西泮, 芬那露, 丹曲林, 等) ; 免疫抑制剂
(如, 环孢菌素, 硫唑嘌呤, 咪唑立宾, FK506 (tacrolimus ) , 等) ; 抗偏头 痛药 (如, 酒石酸麦角胺, 盐酸萘心安, 半乳糖二酸异美汀, 二氯醛安替比 林, 等) ; 镇静剂 /催眠药 (如, 巴比妥类 〔如戊巴比妥, 戊巴比妥钠, 司可巴 比妥钠〕 , 苯二氮卓类〔如氟西泮盐酸盐, ***仑, 托马西泮(tomazeparm) , 咪达***盐酸盐, 等〕) ; 抗心绞痛药 (如, β-肾上腺能拮抗剂, 钙通道阻滞剂
〔如: 硝苯吡啶, 盐酸硫氮卓酮, 等〕 , 硝酸盐类 〔如: ***, 硝酸异山 梨醇酯, 硝酸戊四醇酯, 丁四硝酯, 等〕) ; 抗精神病药 (如, 氟哌啶醇, 琥珀 酸洛沙平, 盐酸洛沙平, 硫利哒嗪, 盐酸甲硫哒嗪, 替沃噻吨, 盐酸氟奋乃 静, 氟奋乃静癸酸酯, 氟奋乃静庚酸酯, 盐酸三氟拉嗪, 盐酸氯丙嗪, 奋乃 静, 柠檬酸锂, 丙氯拉嗪, 等) ; 抗躁狂药 (如, 碳酸锂, 等) ; 抗心律失常 药 (如, 溴苄铵甲苯磺酸盐, 艾司洛尔盐酸盐, 盐酸维拉帕米, 乙胺碘呋酮, 恩卡胺盐酸盐, 地高辛, 洋地黄毒甙, 盐酸美西律, 吡二丙胺磷酸盐, 盐酸普 鲁卡因胺, 硫酸奎尼丁, 葡萄糖酸奎尼丁, 奎尼丁聚半乳糖醛酸盐, 醋酸氟卡 胺, 盐酸妥卡胺, 盐酸利多卡因, 等) ; 抗关节炎药 (如, 保泰松, 舒林酸, 青霉胺, 水杨酰水杨酸, 炎痛喜康, 硫唑嘌呤, 消炎痛, 甲氯灭酸钠, 硫代苹 果酸金钠, 苯酮苯丙酸, 金诺芬, 硫代葡萄糖金, 痛灭定, 等) ; 抗痛风药
(如, 秋水仙碱, 别嘌醇, 等) ; 抗凝剂 (如, 肝素, 肝素钠, 华法令钠, 等) ; 血栓溶解剂 (如, 尿激酶, 链激酶, 重组纤溶酶原激活剂, 等) ; 抗纤 溶剂 (如, 氨基己酸, 等) ; 血液流变学药物 (如, 己酮可可碱, 等) ; 抗血 小板药物 (如, 阿斯匹林, 安匹林, ascriptin, 等) ·' 抗惊厥药 (如, 丙戊酸, 二丙戊酸钠, 苯妥英, 苯妥英钠, 氯硝安定, 去氧苯比妥, ***, 苯巴比
妥钠, 卡马西平, 异戊巴比妥钠, 甲琥胺, 甲基巴比妥, 甲基***, 美芬 妥英, 苯琥胺, 对甲双酮, 乙苯妥英, 苯乙酰脲, 司可巴比妥钠, 氯氮卓二 钾, 三甲双酮, 等); 抗帕金森药物(如, 乙琥胺, 等); 抗组胺药 /止痒剂(如, 盐酸羟嗪, 盐酸苯海拉明, 扑尔敏, 马来酸溴苯吡胺, 盐酸赛庚啶, 特非那 丁, 富马酸氯苯苄咯, 盐酸吡咯胺, 马来酸卡比沙明, 盐酸二苯拉林, 酒石酸 苯茚胺, 马来酸哌吡庚啶, 苄吡二胺, 马来酸右旋氯苯吡胺, 盐酸甲地嗪, 酒 石酸异丁嗪, 等) ; 用于钙调节的药物 (如, 降血钙素, 甲状旁腺素, 等) ; 抗菌剂 (如, 硫酸丁胺卡那霉素, 氨曲南, 氯霉素, 棕榈酸氯霉素, 琥珀酸氯 霉素钠, 盐酸环丙沙星, 盐酸克林霉素, 棕榈酸克林霉素, 磷酸克林霉素, 甲 硝唑, 盐酸甲硝唑, 硫酸庆大霉素, 盐酸林可霉素, 硫酸妥布拉霉素, 盐酸万 古霉素, 硫酸多粘菌素 B, 多粘菌素 E 甲磺酸钠, 硫酸多粘菌素 E, 银纳米粒 子, 等); 抗病毒药(如, γ干扰素, 叠氮胸苷, 盐酸金刚垸胺, 利巴韦林, 无 环鸟苷, 等) ; 抗微生物药 (如, 头孢菌素 (如: 头孢唑啉钠, 头孢拉定, 头 孢克罗, 头孢匹林钠, 头孢唑肟钠, 头孢哌酮钠, 头孢替坦二钠, 头孢呋肟 酯, 头孢噻肟钠, 一水合头孢羟氨苄, 头孢他啶, 头孢氨苄, 头孢噻吩钠, 盐 酸一水合头孢氨苄, 头孢孟多钠, 头孢西丁钠, 头孢尼西钠, 头孢雷特, 头孢 三嗪钠, 头孢他啶, 头孢羟氨苄, 头孢拉定, 头孢呋新钠, 等) , 青霉素类
(如: 氨苄西林, 阿莫西林, 苄星青霉素 G, 邻氯青霉素, 氨苄青霉素钠, 青 霉素 G钾, 青霉素 V钾, 氧哌嗪青霉素钠, 苯唑青霉素钠, 盐酸氨苄青霉素碳 酯, 邻氯青霉素钠, 替卡西林钠, 阿洛西林钠, 羧茚青霉素钠卡茚西林, 青霉 素 G钾, 普鲁卡因青霉素 G, 甲氧西林钠, 新青霉素 III钠, 等) , 红霉素类
(如: 琥乙红霉素, 红霉素, 无味红霉素, 乳糖醛酸红霉素, 红霉素硬脂酸 酯, 琥乙红霉素, 等) , 四环素类 (如: 盐酸四环素, 盐酸强力霉素, 盐酸二
甲胺四环素, 等), 等); 抗感染药(如, GM-CSF, 等); 支气管扩张药(如, 拟交感神经类 (如: 盐酸肾上腺素, 硫酸异丙喘宁, 硫酸特布他林, 乙基异丙 肾上腺素, 甲磺酸乙基异丙肾上腺素, 盐酸乙基异丙肾上腺素, 硫酸舒喘灵, 舒喘灵, 甲磺酸双甲苯苄醇, 盐酸异丙肾上腺素, 硫酸特布他林, 酒石酸肾上 腺素, 硫酸异丙喘宁, 肾上腺素, 酒石酸肾上腺素) , 抗胆碱能药 (如: 溴化 异丙托品) , 黄嘌呤类 (如: 氨茶碱, 喘定, 硫酸异丙喘宁, 氨茶碱) , 肥大 细胞稳定剂 (如: 色甘酸钠) , 吸入皮质激素类 (如: 氟尼缩松倍氯米松, 一 水合二丙酸倍氯米松) , 舒喘灵, 二丙酸倍氯米松 (BDP ) , 溴化异丙托品, 喘乐宁, 酮替芬, 沙米特罗, xinafoate, 硫酸特布他林, 去炎松, 氨茶碱, 萘 多罗米钠, 硫酸异丙喘宁, 舒喘灵, 氟尼缩松, 等) , 等) ; 激素 (如, 雄性 激素类 (如: 达那唑, 环戊丙酸睾酮, 氟***, 乙基睾酮, 庚酸睾酮, 甲基 睾酮, 氟***, 环戊丙酸睾酮) , ***类 (如: ***, 雌酮, 结合雌激 素), 孕酮类(如: 醋酸甲氧孕酮, 醋炔诺酮), 皮质类固醇类(如: 去炎松, 倍他米松, 磷酸倍他米松钠, ***, 磷酸***钠, 醋酸***, 强 的松, 甲基强的松龙悬液, 去炎松缩酮, 甲基强的松龙, 磷酸强的松龙钠, 琥 珀酸甲基强的松龙钠, 琥珀酸氢化考的松钠, 琥珀酸甲基强的松龙钠, 六氯化 曲安缩松, 氢化可的松, 环戊丙酸氢化可的松, 强的松龙, 醋酸氟化可的松, 醋酸帕拉米松, 强的松龙叔丁乙酯, 强的松龙醋酸酯, 强的松龙磷酸钠, 琥珀 酸氢化可的松钠, 等) , 甲状腺激素类 (如: 左旋甲状腺素钠, 等) , 等) ; 降血糖药 (如, 人胰岛素, 纯化牛胰岛素, 纯化猪胰岛素, 优降糖, 氯磺丙 脲, 格列吡嗪, 甲磺丁脲, 甲磺氮卓脲, 等) ; 降血脂药 (如, 安妥明, 右旋 甲状腺素钠, 丙丁酚, 美降脂, 烟酸, 等) ; 蛋白质 (如, 脱氧核糖核酸酶, 藻酸酶, 超氧化歧化酶, 脂肪酶, 等) ; 核酸 (如, 编码任何治疗用蛋白质的
正义或反义核酸, 包括这里提到的任何蛋白质, CPG寡核苷酸, 等) ; 红血球 生成刺激剂 (如, 红细胞生成素, 等) ; 抗溃疡 /抗反流药物 (如, 法莫替丁, 甲氰咪胍, 盐酸雷尼替丁, 等) ; 止恶心药 /止吐剂 (如, 盐酸美克洛嗪, *** 隆, 丙氯拉嗪, 承暈宁, 盐酸异丙嗪, 硫乙哌丙嗪, 东莨菪碱, 等) ; 维生素 (如, 维生素 A, B, C, D, E, K, 等); 其他药物(如, 米托坦, visadine, 亚硝脲盐, 蒽环类抗生素、 甲基羟基玫瑰树碱, 等) ; 成像剂 (如, 四氧化三 铁纳米粒子(AG-USPIO, 等) , 含礼纳米粒子(氧化礼纳米粒子, 等) , 金属 礼的配合物(Gd-DTPA, Gd-EOB-DTPA, Gd-BOPTA (Multihance, 莫迪司) , Mn-DPDP (Telsascan, 泰乐影), Gd-D03A-butro Gd-DTPA-BMA (欧乃影), Gd-HP-D03A, 等), 含碘化合物(碘普罗胺 (优维显)、 碘克沙醇、 碘佛醇、 碘海醇 (欧乃派克) 、 泛影葡胺、 泛影酸钠、 泛影酸、 碘化油, 等) , 金纳米 粒子, 硫化铋纳米粒子, 吲哚菁绿及其衍生物, 荧光素, 荧光素钠, 亚甲基 蓝, 等) 。
作为稳定剂能够用于本发明的蛋白类包括白蛋白 (含有 35个半胱氨酸) 、 鱼精蛋白、 免疫球蛋白、 酪蛋白、 胰岛素(含有 6个半胱氨酸)、 血红蛋白(每 一个 α2β2单位有 6个半胱氨酸残基) 、 溶菌酶 (含有 8个半胱氨酸残基) 、 免 疫球蛋白、 α-2-巨球蛋白、 纤维连接素、 玻璃连接素纤维蛋白原、 脂肪酶等。 其中蛋白质、 肽、 酶、 抗体及其它们的混合物是本发明常规用的稳定剂。 优选 的蛋白质是白蛋白、 鱼精蛋白和抗体。 象 α-2-巨球蛋白这样的蛋白质, 可以用 于增强巨噬样细胞对外壳包裹的药理活性物质颗粒的摄取, 或可以促进这种外 壳包裹颗粒进入到肝脏和脾脏。 特异抗体也可以用来将这些纳米颗粒导向到特 定部位。
能够用于本发明的有机溶剂特别优选易与水互溶的有机溶剂或者其混合
物。 由于蛋白质不溶于有机溶剂, 随着与水互溶的有机溶剂和水的混合, 混合 溶液中的蛋白质发生团聚, 在蛋白质团聚过程中会将药理活性物质包裹在蛋白 质团聚物中, 从而形成复合物。
本领域的技术人员知晓, 在本发明范围和精神范围内, 可以进行多种变 化。 聚合壳内的有机介质可以变化, 在聚合壳壁的形成中可以使用多种不同的 药理活性物质, 并且可以使用多种蛋白质以及其它天然或者合成的聚合物。 这 些用途也是相当广泛的, 除生物医学 (例如药物的输送、 诊断试剂 (用于造 影) 、 人造血和肠外营养剂) 外, 本发明的该聚合壳结构还可以加入到化妆品 用途中, 例如皮肤护理霜或护发产品、 香水香料中使用, 压力敏感性墨水中 等。
下面将结合实施例对本发明的实施方案进行详细描述。 本领域技术人员将 会理解, 以下实施例仅为本发明的优选实施例, 以便于更好地理解本发明, 因 而不应视为限定本发明的范围。
制备例 1
本实施例的目的是证明利用高压均质制备纳米颗粒。 将 30mg 紫杉醇 (Paclitaxel) 溶于 3.0ml乙醇。 溶液中加入 27.0ml人血清白蛋白 (l %w/v) 的 水性溶液。 将得到的混合物放到旋转 (Rotary ) 蒸发器内, 在 40 °C减压下 OOmmHG) 蒸发 20-30分钟除去乙醇。 然后在低 RPM下匀浆 5分钟以形成粗 制乳化液, 再将其转移到高压匀浆器内 (Avestin) 。 接着在 9000-18000磅 /英寸 2 (psi) 下进行至少再高压均质循环 5次。 得到的分散液为半透明, 紫杉醇颗粒 的直径一般为小于 200nm (数量统计, Malvern Zetasizer) 。 不加任何防冻剂, 将分散液冷冻干燥形成干粉。 该干粉可以使用无菌水或者生理盐水复溶, 复溶 得到的溶液中的粒子粒径仍然保持在 200nm以下。
制备例 2
本实施例的目的是证明利用超声波处理中的空化作用和高剪切应力制备紫 杉醇纳米颗粒。 将 20mg紫杉醇溶于 2.0ml乙醇中。 溶液中加入 4.0ml人血清白 蛋白溶液(5 %w/v) 。 将混合物在低 RPM下匀浆 5分钟, 形成粗制乳剂, 然后 将其转移到 40kHz的超声处理池内。 在 60-90 %的功率, 0级下超声处理 1分 钟。 然后将混合物转移到旋转蒸发器内, 在 40°C减压下 GOmmHg)蒸发 20-30 分钟, 除去有机溶剂。 得到紫杉醇微粒, 其直径一般为小于 200nm (数量统计, Malvern Zetasizer) 。 不加任何防冻剂, 将分散液冷冻干燥形成干粉。 该干粉可 以使用无菌水或者生理盐水复溶, 复溶得到的溶液中的粒子粒径仍然保持在 200nm以下。
制备例 3
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 30mg 紫杉 醇溶于 3ml的乙醇中。 然后将溶液加入 29.4ml人血清白蛋白 (l %w/v) 的水性 溶液中, 混合物在低 RPM下匀浆 5分钟形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸 2下进行, 至少进行 6个循环。 将得到 的***放入回转蒸发器内, 在 40°C减压 GOmmHg)蒸发 15-30分钟使有机溶剂 迅速除去。 最终得到的分散液呈半透明状态, 所得紫杉醇颗粒的直径一般小于 200nm (数量统计, Malvern Zetasizer) 。 将分散液通过 0.22微米微孔过滤器, 由此得到无菌的紫杉醇分散液。 将分散液冷冻干燥, 不加任何防冻剂。 所得饼 块加入无菌水或生理盐水后复溶, 再构成颗粒大小保持 200nm以下。
制备例 4
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 30mg 紫杉 醇溶于 3ml的乙醇中。 然后将溶液加入 29.4ml人血清白蛋白 (l %w/v) 的水性
溶液中, 将得到的混合物进行喷雾干燥以除去有机溶剂得到干燥的混合物。 用 水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5分钟形成粗乳剂, 然后转移 到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸 2下进行, 至少进行 6 个循环。 最终得到的分散液呈半透明状态, 所得紫杉醇颗粒的直径一般小于 200nm (数量统计, Malvern Zetasizer) 。 将分散液通过 0.22微米微孔过滤器, 由此得到无菌的紫杉醇分散液。 将分散液冷冻干燥, 不加任何防冻剂。 所得饼 块加入无菌水或生理盐水后复溶, 再构成颗粒大小保持 200nm以下。
制备例 5
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 30mg 紫杉 醇溶于 3ml的乙醇中。 然后将溶液加入 29.4ml人血清白蛋白 (l %w/v) 的水性 溶液中, 混合物在低 RPM下匀浆 5分钟形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸 2下进行, 至少进行 6个循环。 将得到 的***进行喷雾干燥以除去有机溶剂。 最终得到的分散液呈半透明状态, 所得 紫杉醇颗粒的直径一般小于 200nm (数量统计, Malvern Zetasizer) 。 将分散液 通过 0.22 微米微孔过滤器, 由此得到无菌的紫杉醇分散液。 将分散液冷冻干 燥, 不加任何防冻剂。 所得饼块加入无菌水或生理盐水后复溶, 再构成颗粒大 小保持 200nm以下。
制备例 6
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 30mg 紫杉 醇溶于 3ml的乙醇中。 然后将溶液加入 29.4ml人血清白蛋白 (l %w/v) 的水性 溶液中, 将得到的混合物进行进行高压均质再喷雾干燥以除去有机溶剂得到干 燥的混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5分钟 形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸
2下进行, 至少进行 6个循环。 最终得到的分散液呈半透明状态, 所得紫杉醇颗 粒的直径一般小于 200nm (数量统计, Malvern Zetasizer) 。 将分散液通过 0.22 微米微孔过滤器, 由此得到无菌的紫杉醇分散液。 将分散液冷冻干燥, 不加任 何防冻剂。 所得饼块加入无菌水或生理盐水后复溶, 再构成颗粒大小保持 200nm以下。
制备例 7
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 65mg 紫杉 醇溶于 6ml的乙醇中。 然后将溶液加入 29.4ml人血清白蛋白 (3 %w/v) 的水性 溶液中, 将得到的混合物进行进行高压均质再喷雾干燥以除去有机溶剂得到干 燥的混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5分钟 形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸 2下进行, 至少进行 6个循环。 最终得到的分散液呈半透明状态, 所得紫杉醇颗 粒的直径一般小于 200nm (数量统计, Malvern Zetasizer) 。 将分散液通过 0.22 微米微孔过滤器, 由此得到无菌的紫杉醇分散液。 将分散液冷冻干燥, 不加任 何防冻剂。 所得饼块加入无菌水或生理盐水后复溶, 再构成颗粒大小保持 200nm以下。
制备例 8
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 65mg的 10- 羟基喜树碱溶于 6ml的 Ν,Ν-二甲基甲酰胺中。 然后将溶液加入 29.4ml人血清白 蛋白 (3 %w/v) 的水性溶液中, 将得到的混合物进行进行高压均质再喷雾干燥 以除去有机溶剂得到干燥的混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5分钟形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳 化在 9000-18000镑 /英寸 2下进行, 至少进行 6个循环。 所得 10-羟基喜树碱颗
粒的直径一般小于 200nm (透射电镜) 。 将分散液通过 0.22微米微孔过滤器, 由此得到无菌的紫杉醇分散液。 将分散液冷冻干燥, 不加任何防冻剂。 所得饼 块加入无菌水或生理盐水后复溶, 再构成颗粒大小保持 200nm以下。
制备例 9
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 65mg 的长 春瑞滨溶于 6ml的甲醇中。 然后将溶液加入 29.4ml人血清白蛋白 (3 %w/v) 的 水性溶液中, 将得到的混合物进行进行高压均质再喷雾干燥以除去有机溶剂得 到干燥的混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5 分钟形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 / 英寸 2下进行, 至少进行 6个循环。 所得长春瑞滨颗粒的直径一般小于 200nm (透射电镜) 。 将分散液通过 0.22微米微孔过滤器, 由此得到无菌的紫杉醇分 散液。 将分散液冷冻干燥, 不加任何防冻剂。 所得饼块加入无菌水或注射用水 后复溶, 再构成颗粒大小保持 200nm以下。
制备例 10
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 lOOmg的长 春瑞滨溶于 10ml的甲醇中。 然后将溶液加入 90ml人血清白蛋白 (l %w/v) 的 水性溶液中, 将得到的混合物进行进行高压均质再喷雾干燥以除去有机溶剂得 到干燥的混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5 分钟形成粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 / 英寸 2下进行, 至少进行 6个循环。 所得长春瑞滨颗粒的直径一般小于 200nm (透射电镜) 。 将分散液通过 0.22微米微孔过滤器, 由此得到无菌的紫杉醇分 散液。 将分散液冷冻干燥, 不加任何防冻剂。 所得饼块加入无菌水或注射用水 后复溶, 再构成颗粒大小保持 200nm以下。
制备例 11
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 lOOmg的吲 哚菁绿和 900mg的人血清白蛋白溶于 90ml的水中。 然后向溶液加入 20ml 乙 醇, 将得到的混合物进行进行高压均质再喷雾干燥以除去有机溶剂得到干燥的 混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5分钟形成 粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸 2下 进行, 至少进行 6个循环。 所得吲哚菁绿颗粒的直径一般小于 200nm。 将分散 液通过 0.22微米微孔过滤器, 由此得到无菌的吲哚菁绿分散液。 将分散液冷冻 干燥, 不加任何防冻剂。 所得饼块加入无菌水或注射用水后复溶, 再构成颗粒 大小保持 200nm以下。
制备例 12
本实施例的目的是介绍可无菌滤过的药物颗粒的制备过程。 将 lOOmg的盐 酸阿霉素和 900mg的人血清白蛋白溶于 90ml的水中。 然后向溶液加入 20ml乙 醇, 将得到的混合物进行进行高压均质再喷雾干燥以除去有机溶剂得到干燥的 混合物。 然后, 用水性溶液将干燥的混合物复溶, 在低 RPM下匀浆 5分钟形成 粗乳剂, 然后转移到高压匀浆器内 (Avestin) 。 乳化在 9000-18000镑 /英寸 2下 进行, 至少进行 6个循环。 所得阿霉素颗粒的直径一般小于 200nm。 将分散液 通过 0.22 微米微孔过滤器, 由此得到无菌的阿霉素分散液。 将分散液冷冻干 燥, 不加任何防冻剂。 所得饼块加入无菌水或注射用水后复溶, 再构成颗粒大 小保持 200nm以下。
试验例 1
将本发明实施例 1中制备的白蛋白-紫杉醇纳米粒子和市售 Abraxane分别用 生理盐水复溶、 稀释, 其结果如图 1和图 2所示, 本发明实施例 1中制备的白
蛋白-紫杉醇纳米粒子复溶浓度为 Img/mL时, 最大动力学水合粒径为 lOOnm左 右; 稀释至 O.lmg/mL时, 最大动力学水合粒径依然保持在 lOOnm左右。 而市 售 Abraxane复溶浓度为 Img/mL时, 最大动力学水合粒径为 lOOnm左右; 但稀 释至 O.lmg/mL时, 最大动力学水合粒径降至 10nm以下。 证明本发明实施例 1 中制备的白蛋白 -紫杉醇纳米粒子在复溶稀释时不易迅速解离至 lOnm以下。
试验例 2
用实施例 1中制备的白蛋白 -紫杉醇纳米粒子对 MCF-7人乳腺癌细胞进行体 外治疗。 将处于对数生长期的 MCF-7细胞用胰酶消化后, 完全培养基重悬成细 胞悬液 随之将其接种于 96孔板 每孔 ΙΟΟμ 置于 37°C、 5%C02培养箱培养, 24h后加入不同浓度的按照实施例 1方法制备的紫杉醇 (taxol) 纳米颗粒。 24h 后进行 MTT检测。 培养终止前 4h加入 ΙΟμΙ^ 5mg/mL的 MTT, 吸弃培养液后加 ΙΟΟμΙ^ DMSO终止反应, 酶标仪 570nm检测 OD值。 实验重复三次。 实验结果 如图 3, 结果显示所制备的紫杉醇纳米颗粒对 MCF-7细胞有抗增殖作用, 且纳 米粒子的浓度越高, 其抗增殖作用越强。
试验例 3
用紫杉醇纳米颗粒对肿瘤动物模型的治疗。 采用按照实施例 1 方法制备的 紫杉醇 (taxol) 纳米颗粒。 将此药物的制剂对小鼠异种移植的 MCF-7人乳腺肿 瘤模型进行实验。 在小鼠皮下种植 MCF-7 乳腺肿瘤, 当肿瘤长到大约 150-300mg尺寸时开始治疗。 因肿瘤生长 12天可达到上述指标, 故在移植后第 13天开始治疗。
紫杉醇纳米颗粒作为生理盐水中的混悬液以 10mg/kg 的剂量治疗荷瘤小 鼠, 在第 13天给予静脉内注射。 治疗组有 7只动物。 7只动物的对照荷瘤组用 按同样方法, 但仅接受生理盐水。 随时间监视肿瘤的大小。 结果如图 4所示,
对照组的肿瘤重量显示极大的增加, 这一组的动物均在第 28天至 39天之间将 其处死。 而治疗组显示有显著的效果, 在第 33天所有治疗组动物的肿瘤体积明 显比对照组小得多。
试验例 4
在白蛋白 -紫杉醇纳米颗粒制备过程中, 对白蛋白进行荧光染料 Cy5标记, 从而制备出具有荧光标记的白蛋白 -紫杉醇纳米颗粒。 对荷瘤小鼠给予 10mg/kg 剂量的给药后, 对接受白蛋白-紫杉醇纳米颗粒治疗的荷瘤小鼠不同器官的荧光 强度通过小动物荧光成像***进行定量, 其结果如图 5所示, 结果显示: 肿瘤 中白蛋白-紫杉醇纳米颗粒的浓度明显高于其它组织, 说明本发明白蛋白 -紫杉 醇纳米颗粒在肿瘤中有明显的富集。
申请人声明, 本发明通过上述实施例来说明本发明的详细特征以及详细方 法, 但本发明并不局限于上述详细特征以及详细方法, 即不意味着本发明必须 依赖上述详细特征以及详细方法才能实施。 所属技术领域的技术人员应该明 了, 对本发明的任何改进, 对本发明选用组分的等效替换及辅助成分的添加、 具体方式的选择等, 均落在本发明的保护范围和公开范围之内。
Claims
1、 一种药理活性物质输送***, 包括固体或液体的药理活性物质及蛋白 质包衣构成的颗粒, 其中所述蛋白质包衣具有与其缔合的游离蛋白质, 所述药 理活性物质的一部分包含在所述蛋白质包衣中, 所述药理活性物质的另一部分 与游离蛋白质缔合; 所述颗粒的平均直径为 10至 200nm, 其分散于水性溶液时 的最大动力学水合粒径在 lOnm以上。
2、 根据权利要求 1 所述的药理活性物质输送***, 其特征在于, 所述颗 粒分散于 O.lmg/mL的生理盐水时的最大动力学水合粒径在 lOnm以上、 优选在 20nm以上、 更优选 50-180nm。
3、 根据权利要求 1或 2所述的药理活性物质输送***, 其特征在于, 所述 颗粒悬浮于生物相容性水溶液中;
优选地, 所述生物相容性水溶液为可接受的注射液, 更优选为生理盐水、 葡萄糖注射液或缓冲液。
4、 一种制备权利要求 1-3任一项所述的药理活性物质输送***的方法, 包 括:
( 1 )将蛋白质、 药理活性物质、 生物相容性水溶液和与水互溶的有机溶剂 混合制成混合溶液;
(2 )除去与水互溶的有机溶剂再进行高压均质, 或者进行高压均质再除去 与水互溶的有机溶剂, 得到纳米悬浮液, 然后通过干燥得到干粉状的药理活性 物质输送***。
5、 根据权利要求 4所述的方法, 其特征在于, 所述步骤 (1 ) 具体包括: ( la) 将蛋白质溶于生物相容性水溶液中, 形成蛋白质溶液; 将水不溶性 药理活性物质溶于与水互溶的有机溶剂中, 形成药理活性物质溶液;
( lb ) 将所述药理活性物质溶液与所述蛋白质溶液混合。
6、 根据权利要求 4所述的方法, 其特征在于, 所述步骤 (1 ) 具体包括: ( la) 将蛋白质和水溶性药理活性物质共同溶于生物相容性水溶液中, 形 成蛋白质 /水溶性药理活性物质混合溶液;
( lb)将与水互溶的有机溶剂与所述蛋白质 /水溶性药理活性物质混合溶液 混合。
7、 根据权利要求 4-6任一项所述的方法, 其特征在于, 所述蛋白质选自白 蛋白、 鱼精蛋白、 抗体、 免疫球蛋白、 酪蛋白、 胰岛素、 溶菌酶、 纤维蛋白 原、 脂肪酶、 胶原蛋白、 纤维连接素、 玻璃连接素、 去铁蛋白、 铁蛋白、 血红 蛋白中的一种或多种, 优选人血清白蛋白、 重组人血清白蛋白、 鱼精蛋白、 抗 体、 铁蛋白或去铁蛋白, 最优选人血清白蛋白;
优选地, 所述药理活性物质选自抗肿瘤药、 镇痛剂 /退热剂、 麻醉剂、 平 喘药、 抗生素、 抗抑郁药、 抗糖尿病药、 抗真菌剂、 抗高血压药、 消炎药、 肿 瘤并发症辅助治疗生物技术药物、 抗焦虑药、 免疫抑制剂、 抗偏头痛药、 镇静 剂 /***、 抗心绞痛药、 抗精神病药、 抗躁狂药、 抗心律失常药、 抗关节炎 药、 痛风剂、 抗凝剂、 溶栓剂、 抗纤溶药、 血液流变学剂、 抗血小板药、 抗惊 厥药、 抗帕金森药物、 抗组胺药 /止痒药、 钙调节剂、 抗菌剂、 抗病毒药、 抗 微生物药、 抗感染药、 支气管扩张药、 激素、 降血糖药、 降血脂药、 蛋白质、 核酸、 红血球生成刺激剂、 抗溃疡 /抗反流剂、 止恶心药 /止吐剂、 维生素或成 像剂;
优选地, 所述生物相容性水溶液为可接受的注射液, 更优选为生理盐水、 葡萄糖注射液或缓冲液;
优选地, 所述与水互溶的有机溶剂选自乙醇、 Ν,Ν-二甲基甲酰胺、 四氢呋 喃、 二甲亚砜、 丙酮、 乙腈、 甲醇、 丙醇、 丙三醇、 辛醇、 二氧六环和甲基吡
咯垸酮中的一种或多种的混合溶剂。
8、 根据权利要求 4-7任一项所述的方法, 其特征在于, 所述步骤 (2) 中 除去与水互溶的有机溶剂的方法包括: 喷雾干燥、 减压蒸发、 冷冻干燥、 采用 降膜蒸发器、 透析或超滤;
优选地, 所述高压均质的操作压力在 3000-30000磅 /英寸 2内, 更优选在 6000-25000磅 /英寸 2内, 最优选在 9000-18000镑 /英寸 2内;
优选地, 所述干燥的方法包括冷冻干燥、 喷雾干燥、 减压蒸馏或它们的组 合。
9、 根据权利要求 1-3任一项所述的药理活性物质输送***在制备将药理活 性物质输送到受试者的药物制剂中的应用。
10、 根据权利要求 1-3 任一项所述的药理活性物质输送***在制备减少药 剂副作用的药物制剂中的应用。
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