WO2017084522A1 - 一种新型抗癌药物纳米制剂及其制备方法 - Google Patents

一种新型抗癌药物纳米制剂及其制备方法 Download PDF

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WO2017084522A1
WO2017084522A1 PCT/CN2016/105142 CN2016105142W WO2017084522A1 WO 2017084522 A1 WO2017084522 A1 WO 2017084522A1 CN 2016105142 W CN2016105142 W CN 2016105142W WO 2017084522 A1 WO2017084522 A1 WO 2017084522A1
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composition
polyethylene glycol
polybutylene glycol
nanoparticles
drug
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PCT/CN2016/105142
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English (en)
French (fr)
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余波
余嘎尔
张晓敏
张英新
姚举
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杭州普施康生物科技有限公司
先进聚合物材料公司
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Priority to JP2018544389A priority Critical patent/JP6772282B2/ja
Priority to US15/776,406 priority patent/US20180369389A1/en
Priority to EP16865699.9A priority patent/EP3378493B1/en
Publication of WO2017084522A1 publication Critical patent/WO2017084522A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/14—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
    • 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
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and in particular to a novel polymer pharmaceutical composition preparation comprising an active substance and a polyethylene glycol-polybutylene glycol copolymer.
  • Polymeric carriers are emerging drug delivery technologies with advances in pharmacological research, biomaterial science, and clinical medicine.
  • Low-molecular drugs have the advantages of high efficacy and ease of use, but they also have great side effects.
  • low molecular drugs enter the human body by oral or injection, with rapid metabolism, short half-life and lack of selectivity.
  • a polymer carrier refers to a polymer which has no pharmacological action itself and does not react with a drug, and serves as a carrier for a drug, which is formed by weak hydrogen bonding with a drug, or a low molecular drug is attached to a polymer by a polycondensation reaction. On the main chain.
  • polymer materials are used as a delivery system for low molecular drugs.
  • polymer materials as a carrier for small molecule drugs can increase the duration of action of the drug, increase the selectivity of the drug, and reduce the toxicity of small molecule drugs.
  • micron and nanoscale polymer carriers such as nanomicelles, vesicles and nanoparticles, such polymer carriers can effectively disperse drug molecules into them, using various responses of the carrier, Achieve drug delivery and controlled release.
  • Nanoparticles-based drug delivery systems are produced by applying nanotechnology and nanomaterials to the pharmaceutical field. They use nanoparticles (NP) as a drug delivery system. Nanoparticle (NP) is a kind of solid colloidal particles composed of high molecular substances with a particle size ranging from 10 to 1000 nm. It can be dispersed in water to form an approximate colloidal solution. Due to the uniqueness and superiority of nanoparticle as a drug carrier, it has become an important research direction of medicine at home and abroad.
  • the excipients used to prepare the nanoparticle preparations are mostly polymer degradable polymers. Polyester is the most widely studied and widely used biodegradable polymer material. Polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-polyglycolic acid copolymer (PLGA) and poly- are commonly used. Caprolactone (PCL) and the like.
  • the present application relates to a composition
  • a composition comprising an active substance and a polyethylene glycol-poly Butylene glycol copolymer.
  • the polyethylene glycol-polybutylene glycol copolymer has a structure as shown in formula I, II or III
  • n, n1 and n2 are each independently from 1 to 3000, m is from 1 to 1500, and R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H and C 1 -C 3 alkyl.
  • the polyethylene glycol-polybutylene glycol copolymer has a molecular weight of from 0.1 K to 300 K.
  • the composition is a nanoparticle.
  • the nanoparticles have a particle size between 10 and 500 nm. In certain embodiments, the nanoparticles have a particle size between 10 and 100 nm.
  • the active material is a hydrophobic material.
  • the active substance is selected from the group consisting of an anti-tumor drug, an antibiotic drug, a cardiovascular drug, an anti-diabetic drug, and a non-steroidal anti-inflammatory drug.
  • the active substance is paclitaxel and a derivative thereof.
  • the active substance is paclitaxel, docetaxel or cabazitaxel.
  • the mass ratio of the active material to the polyethylene glycol-polybutylene glycol copolymer is from 0.01 to 1. In a certain In some embodiments, the mass ratio of the active material to the polyethylene glycol-polybutylene glycol copolymer is from 0.1 to 0.3.
  • the composition further includes other polymers.
  • the present application relates to a method of preparing a composition as described herein, comprising the steps of: (a) dissolving a polyethylene glycol-polybutylene glycol copolymer and an active material with an organic solvent; b) adding the organic phase to the aqueous phase solution to form an oil-water mixture; (c) removing the organic solvent in the oil-water mixture under reduced pressure.
  • the step (b) further comprises treating the oil-water mixture using a low shear force.
  • the low shear force is agitation
  • the method still further comprises the step (d) of drying the product of step (c).
  • the drying in step (d) is accomplished by freeze drying.
  • the organic solvent comprises tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetone, N,N-dimethylformamide, or a mixture thereof.
  • the ratio of the organic phase to the aqueous phase is from 1:10 to 20:1. In certain embodiments, the ratio of the organic phase to the aqueous phase is from 0.5:1 to 2:1.
  • the present application relates to the use of a composition of the present application in the manufacture of a medicament for the alleviation, treatment or prevention of a disease.
  • the application relates to the use of a composition of the present application for the relief, treatment or prevention of a disease.
  • the present application is directed to a method of alleviating, treating or preventing a disease comprising the use of an effective amount of a composition of the present application to a subject in need thereof.
  • the disease is cancer.
  • the present application relates to the use of a polyethylene glycol-polybutylene glycol copolymer for the manufacture of a medicament for the treatment of a disease.
  • the present application relates to a method of preparing a medicament, characterized in that it comprises mixing an active substance and a polyethylene glycol-polybutylene glycol copolymer.
  • Figure 1 is a particle size distribution diagram and a transmission electron microscope (TEM) image of nanoparticles.
  • Figure 2 is a graph showing the in vitro release of paclitaxel-loaded (PTX) EB nanoparticles compared to Taxol.
  • Figure 3 is a pharmacokinetic profile of paclitaxel-loaded (PTX) EB nanoparticles compared to Taxol.
  • Figure 4 is a graph of cellular uptake of FITC-loaded EB nanoparticles.
  • Figure 5 is a graph showing in vivo imaging and tissue imaging of tumor-bearing nude mice bearing DIR-loaded EB nanoparticles.
  • Figure 6 is a graph showing tumor and body weight of tumor-bearing nude mice as a function of injection time in an in vivo pharmacodynamic experiment. It included a negative control PBS, a positive control Taxol, and paclitaxel-loaded EB nanoparticles prepared in Example 1 of the present application.
  • One aspect of the present invention provides a composition comprising an active material and a polyethylene glycol-polybutylene glycol copolymer.
  • the polyethylene glycol-polybutylene glycol copolymer is a polyethylene glycol-poly 1,2-butanediol copolymer, polyethylene glycol-poly1,3-butanediol copolymer , polyethylene glycol-polytetramethylene glycol copolymer or a mixture thereof.
  • the polyethylene glycol-polybutylene glycol copolymer is a random copolymer, an alternating copolymer, a block copolymer, or a graft copolymer.
  • the polyethylene glycol-polybutylene glycol copolymer is a block copolymer.
  • the polyethylene glycol-polybutylene glycol copolymer is a diblock copolymer or a triblock copolymer. In some embodiments, the polyethylene glycol in the polyethylene glycol-polybutylene glycol copolymer is a tail modified polyethylene glycol. In some embodiments, the polyethylene glycol in the polyethylene glycol-polybutylene glycol copolymer is polyethylene glycol monomethyl ether (mPEG).
  • mPEG polyethylene glycol monomethyl ether
  • the polyethylene glycol-polybutylene glycol copolymer has a structure as shown in Formula I, Formula II or Formula III
  • n, n1, n2 are each independently selected from the group consisting of 1-3000, m is selected from 1-1500, and R 1 , R 2 , R 3 and R 4 are each independently selected from H and C 1 -C 3 alkyl.
  • n, n1, and n2 are each independently 1-2500, 1-2000, 1-1500, 1-1200, 1-1000, 1-800, 1-600, 1-500, 1-400.
  • m is 1-1200, 1-1000, 1-800, 1-600, 1-500, 1-400, 1-300, 1-200, 1-180, 1-170, 1- 160, 1-150, 1-140, 1-130, 1-120, 1-118, 1-110, 1-100, 1-90, 1-80, 1-70, 1-60, 1-50 , 3-1500, 5-1200, 8-1000, 10-800, 11-600, 12-500, 13-300, 15-200, 15-180, 15-150, 15-140, 15-120, 15 -110, 15-100, 18-100, 18-90, 20-80, 25-75 or 25-70.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from H and CH 3 .
  • the polyethylene glycol-polybutylene glycol copolymer has a molecular weight of from 0.1 K to 300 K. In some embodiments, the polyethylene glycol-polybutylene glycol copolymer has a molecular weight of 0.1K-280K, 0.1K-250K, 0.1K-200K, 0.1K-180K, 0.1K-150K, 0.1K- 120K, 0.1K-100K, 0.1K-80K, 0.1K-60K, 0.1K-50K, 0.1K-40K, 0.1K-30K, 0.1K-25K, 0.1K-22K, 0.1K-20K, 0.1K- 18K, 0.1K-16K, 0.1K-15K, 0.1K-14K, 0.1K-13K, 0.1K-12K, 0.1K-10K, 0.1K-8K, 0.1K-7K, 0.1K-6K, 0.1K- 5K, 0.1K-4K, 0.3K-300K, 0.5K-300K, 0.1K-4K
  • the molecular weight described in the present application may be a weight average molecular weight or a number average molecular weight.
  • the molecular weight can be detected using methods commonly used in the art, for example, by light scattering, ultracentrifugation sedimentation rate or gel chromatography.
  • the polyethylene glycol-polybutylene glycol copolymer has a molar ratio of ethylene glycol to butanediol repeating units of from 1:5 to 6:1.
  • the molar ratio of ethylene glycol to butanediol repeating units in the polyethylene glycol-polybutylene glycol copolymer is 1:4-6:1, 1:3-6:1, 1: 2-6:1, 1:1-6:1, 2:1-6:1, 3:1-6:1, 4:1-6:1, 5:1-6:1, 1:5- 5:1, 1:5-4:1, 1:5-3:1, 1:5-2:1, 1:5:1, 1:5-1:2, 1:5-1: 3, 1:4-4:1, 1:3-3:1, 1:2-3:1 or 1:1.3-2.5:1.
  • alkyl refers to a saturated hydrocarbyl group which may be straight or branched.
  • Cn-m alkyl refers to an alkyl group having from n to m carbon atoms. In certain embodiments, the alkyl group contains from 1 to 12, from 1 to 8, from 1 to 6, from 1 to 4, from 1 to 3, or from 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.
  • the synthesis method of the polyether copolymer can be carried out by an anionic polymerization method.
  • An exemplary method of preparing the polyethylene glycol-polybutylene glycol copolymer of the present application is as follows:
  • the compositions of the present application are solid formulations.
  • the composition is a nanoparticle.
  • the composition is a dried nanoparticle.
  • the composition is a lyophilized nanoparticle.
  • the nanoparticles have a particle size between 10 and 500 nm. In some embodiments, the nanoparticles have a particle size of 10 to 400 nm, 10 to 300 nm, 10 to 250 nm, 10 to 200 nm, 10 to 150 nm, 10 to 120 nm, 10 to 100 nm, 10 to 90 nm, 20 to 90 nm, 30-90 nm or 40-90 nm. In some embodiments, the nanoparticles have a particle size between 10 and 100 nm. The particle size can be measured using methods commonly used in the art, such as scanning electron microscopy and light scattering. In some embodiments, the particle size is detected using a light scattering method. In some embodiments, the particle size is detected using a laser dynamic scatterometer.
  • the nanoparticles of the present application have an acceptable dispersion coefficient. In some embodiments, the nanoparticles of the present application have a dispersion coefficient of no greater than 0.3, 0.2, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, or 0.11. In some embodiments, the nanoparticles of the present application have a dispersion coefficient of from 0.1 to 0.2.
  • compositions of the present application can be further modified.
  • the compositions of the present application may be further coated, for example, with a sustained release or controlled release coating.
  • targeting groups eg, antibodies, ligands, specific substrates, etc.
  • macromolecules can be modified on the surface of the compositions of the present application to further improve the targeting or other motivation of the claimed compositions. The parameters are used or used to trace the compositions of the present application.
  • the composition also includes other ingredients that are pharmaceutically acceptable.
  • the additional ingredients include a surfactant.
  • the surfactant may be a cationic surfactant, an anionic surfactant or a nonionic surfactant.
  • the additional ingredients include lyoprotectants including, but not limited to, lactose, mannose, dextran, sucrose, and glycine.
  • the additional ingredients include solutions including, but not limited to, sodium chloride solution, dextrose solution, PBS buffer, ethanol solution, and the like.
  • pharmaceutically acceptable refers to such compounds, materials, compositions and or dosage forms which, within the scope of sound medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, Allergies or other problems and complications commensurate with a reasonable benefit/risk ratio and are effective for the intended use.
  • compositions of the present application are suitable for administration by any suitable route, for example by oral administration (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous , intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion).
  • oral administration including buccal or sublingual
  • rectal including nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous , intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion).
  • parenteral administration including parenteral administration.
  • compositions of the present application are for intravenous infusion administration.
  • the active substance is a hydrophobic substance.
  • hydrophobic substance refers to a material having a soluble mass of less than 1 g, 0.1 g, 0.01 g, 1 mg or 0.5 mg in 100 g of water at 25 °C.
  • the active substance is selected from the group consisting of an anti-tumor drug, an antibiotic drug, a cardiovascular drug, an anti-diabetic drug, and a non-steroidal anti-inflammatory drug.
  • An illustrative example of the active substance of the present application may be: an anti-tumor drug such as yew Alcohol, docetaxel, cabazitaxel, 5-fluorouracil, etoposide, phenylalanine mustard, chlorambucil, hexamethyl melamine, methotrexate, nitrosourea, norvinine , teniposide, homoharringtonine, hydroxycamptothecin, etc.; antibiotic drugs, such as chloramphenicol, erythromycin, erythromycin, erythromycin ethylsuccinate, medimycin, josamycin, Clarithromycin, rostamycin, sulfadiazine, trimethoprim, nitrofurantoin, rivimipin
  • Cardiovascular drugs such as nifedipine, nicardipine, nitrendipine, nilvadipine, cinnarizine, aceclopine, morpholine, digitalis, digoxigenin, edamaric, go Acetyl scutellaria, propafenone, amiodarone, nitroglycerin, pentylenetetral ester, cyclomandelic acid, tocopheryl nicotinate, etc.; antidiabetic drugs such as toluene yellow butyl urea, glibenclamide, glipizide, etc.
  • Non-steroidal anti-inflammatory drugs such as clomazepine, cyproheptadine, phenothiazine, ketotifen, trinisone, and the like.
  • the structure of each of the above specific drugs can be found in the drug specifications approved by the drug regulatory authorities of various countries or regions, such as the China Food and Drug Administration, the US Food and Drug Administration, the Japan Pharmaceutical and Medical Device Administration, or the European Medicines Agency. Those ones.
  • the active substance is paclitaxel and a derivative thereof. In some embodiments, the active substance is paclitaxel, docetaxel or cabazitaxel (7 ⁇ , 10 ⁇ -dimethoxy docetaxel) and derivatives thereof.
  • the compounds referred to in the present application include salts, esters, meso-forms, racemates and isomers thereof of the compounds.
  • Isomers as described herein include cis and trans isomers and optical isomers.
  • derivative refers to a compound formed by the substitution of an atom or group of atoms in a parent compound molecule with another atom or group of atoms.
  • Derivatives of paclitaxel include, but are not limited to, succinic acid and glutaric acid derivatives of paclitaxel, sulfonate derivatives, amino acid derivatives, phosphate derivatives, organic acid esters and carbonate derivatives, N-methylpyridinium salts , polyethylene glycol derivatives, polymethacrylic acid derivatives, polyglutamic acid or polyaspartic acid derivatives.
  • the mass ratio of the active material to the polyethylene glycol-polybutylene glycol copolymer in the composition is from 0.01 to 1. In some embodiments, the mass ratio of the active material to the polyethylene glycol-polybutylene glycol copolymer in the composition is 0.02 to 1, 0.03 to 1, 0.04 to 1, 0.05 to 1, 0.06 to 1, 0.08.
  • the polyethylene glycol-polybutylene glycol copolymer of the present application encapsulates the active material therein as a matrix and forms spherical particles and other shaped particles.
  • the use of a polyethylene glycol-polybutylene glycol copolymer as a matrix component has one or more of the following advantages compared to a non-nanoparticulate dosage form of the active material or a nanoparticulate dosage form made of other polymeric materials: 1. Prevention of activity Material precipitation; 2, obtaining particles with smaller particle size; 3, better monodispersity; 4, more convenient preparation method; 5, higher encapsulation efficiency; 6, more excellent targeting; 7, longer Cycle time; 8, higher efficacy; 9, higher active substance loading.
  • Another aspect of the invention provides a method of preparing a composition of the invention.
  • the method of preparing the composition of the present invention comprises the steps of: (a) dissolving the polyethylene glycol-polybutylene glycol copolymer and the active material with an organic solvent; (b) adding the organic phase to the aqueous phase The solution is formed to form an oil-water mixture; (c) the organic solvent in the oil-water mixture is removed under reduced pressure.
  • the method further comprises the step (d) of drying the product of step (c).
  • step (d) of drying the product of step (c).
  • One skilled in the art can select a suitable drying method depending on the specific conditions, such as freeze drying, spray drying, and the like.
  • the drying in step (d) is accomplished by freeze drying.
  • the organic solvent comprises tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, acetone, N,N-dimethylformamide, or a mixture thereof. In some embodiments, the organic solvent is acetone.
  • the step (b) further comprises treating the oil-water mixture using a low shear force.
  • the low shear forces described herein may be provided by agitation, shearing or homogenization, provided that the shear forces are not greater than the shear forces provided by mechanical agitation of 1000 rpm, 800 rpm, 700 rpm, 600 rpm, 500 rpm or 400 rpm.
  • the low shear force is agitation.
  • the low shear force is mechanical agitation.
  • the agitation speed is 100-1000 rpm, 100-800 rpm, 100-700 rpm, 100-600 rpm, 100-500 rpm, or 100-400 rpm.
  • the ratio of the organic phase to the aqueous phase is 1:10 to 20:1, 1:10 to 18:1, 1:10 to 15:1. 1:10 ⁇ 12:1, 1:10 ⁇ 10:1, 1:10 ⁇ 8:1, 1:10 ⁇ 5:1, 1:10 ⁇ 3:1, 1:10 ⁇ 2:1, 1: 10 to 1:1, 1:8 to 1:1, 1:6 to 1:1, 1:4 to 1:1, 1:3 to 1:1, 1:2.5 to 1:1, 1:2 to 1:1, 1:8 ⁇ 20:1, 1:6 ⁇ 20:1, 1:4 ⁇ 20:1, 1:2 ⁇ 20:1, 1:1 ⁇ 20:1, 2:1 ⁇ 20: 1, 4:1 to 20:1, 5:1 to 20:1, 8:1 to 20:1, 10:1 to 20:1, 15:1 to 20:1, 1:18 to 20:1 1:8 to 15:1, 1:6 to 12:1, 1:5 to 10:1, 1:4 to 8:1, 1:3 to 5:1, 1:3 to 2:1, 1: 3 to 1:1, 1:2.5 to 1:1.5, 1:2.3 to 1:1.8 or 1:2.1 to 1:1
  • the reduced pressure described herein can be carried out by any suitable means in the art, such as rotary evaporation, reduced pressure drying, and the like.
  • the organic solvent is removed by rotary evaporation under reduced pressure.
  • the vacuum under reduced pressure rotary evaporation is less than 0.6 atmospheres, 0.5 atmospheres, 0.4 atmospheres, 0.3 atmospheres, 0.2 atmospheres, 0.1 atmospheres.
  • the vacuum under reduced pressure rotary evaporation is 0.1-0.6 atmospheres, 0.1-0.5 atmospheres, 0.1-0.4 atmospheres, 0.1-0.3 atmospheres, or 0.1-0.2 atmospheres.
  • the encapsulation efficiency can be measured using methods commonly used in the art, such as dextran gelation, ultracentrifugation or dialysis. In some embodiments, the encapsulation efficiency is measured using a dialysis method.
  • the composition prepared by the method of the present application has an encapsulation efficiency of not less than 80%, 83%, 85%, 87%, 89%, 90%, 92%, 93%, 94%, or 95%. .
  • One aspect of the present application relates to the use of a composition of the present application in the manufacture of a medicament for the alleviation, treatment or prevention of a disease.
  • a further aspect of the present application relates to the use of a composition of the present application for the relief, treatment or prophylaxis of a disease.
  • Another aspect of the present application relates to a method of alleviating, treating or preventing a disease comprising administering an effective amount of a composition of the present application to a subject in need thereof.
  • the disease is cancer.
  • Remission,” “treatment,” or “prevention” of a disease or condition includes preventing or mitigating a condition, reducing the rate at which a condition arises or develops, reducing the risk of developing a condition, preventing or delaying with certain A condition-related symptom develops, reduces or terminates a condition associated with a condition, produces a complete or partial reversal of a condition, cures a condition, or a combination of the above.
  • an effective amount means an amount of a drug which can achieve a disease or symptom of a guest or which can prevent or prevent the occurrence of a disease or symptom.
  • An effective amount may be an amount that relieves one or more diseases or symptoms of the guest to a certain extent; one or more physiological or biochemical parameters associated with the cause of the disease or symptom may be partially or fully restored to normal.
  • compositions provided herein will depend on a variety of factors well known in the art, such as body weight, age, past medical history, current treatment being received, the health of the subject and the strength of the drug interaction, allergies, hypersensitivity and side effects. , as well as the route of administration and the extent of disease progression. A person skilled in the art (e.g., a physician or veterinarian) may reduce or increase the dosage accordingly in accordance with these or other conditions or requirements.
  • the compositions provided herein can be administered at a therapeutically effective dose of between about 0.01 mg/kg to about 100 g/kg (eg, about 0.01 mg/kg, about 0.5 mg/kg, about 1 mg/kg). Kg, about 2 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/ Kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/ Kg, about 100 mg/kg, about 200 mg/kg, about 500 mg/kg, about 1 g/kg, about 5 g/kg, about 10 g/kg, about 20 g/kg, about 50 g/kg, about 70 g/kg, about 90 g/ Kg or about 100
  • a particular dose can be divided into multiple doses, such as once a day, twice a day or more, twice or more per month, once a week, once every two weeks, once every three weeks, once a month, or Every two months or more.
  • the dosage administered can vary with the course of the treatment.
  • the initial dose administered can be higher than the subsequent dose.
  • the administered dose is adjusted during the course of treatment depending on the response of the subject to be administered.
  • the dosage regimen can be adjusted to achieve an optimal response (eg, therapeutic response). For example, a single dose may be administered or multiple divided doses administered over a period of time.
  • Yet another aspect of the invention provides the use of a polyethylene glycol-polybutylene glycol copolymer for the manufacture of a medicament for the treatment of a disease.
  • the medicament further comprises an active substance.
  • Another aspect of the invention provides a method of preparing a medicament comprising mixing an active substance and a polyethylene glycol-polybutylene glycol copolymer.
  • polyethylene glycol-polybutylene glycol copolymer used in this example is obtained from advanced polymerization in Canada.
  • the particle size was measured using a laser dynamic scatterometer (Beckman Coulter LS 13320) with an average particle size of 22.4 ⁇ 1.6 nm and a dispersion coefficient of 0.118.
  • the particle size distribution results and the transmission electron micrograph are shown in Fig. 1.
  • the encapsulation efficiency of the nanoparticles was 86.4 ⁇ 3%, and the specific detection method of the encapsulation efficiency is shown in Example 7.
  • the particle diameter was measured using a laser dynamic scattering instrument, and the average particle diameter was 40.44 ⁇ 2.5 nm, and the dispersion coefficient was 0.158.
  • the encapsulation efficiency of the nanoparticles was 90.4 ⁇ 3%, and the specific detection method of the encapsulation efficiency is shown in Example 7.
  • the particle diameter was measured using a laser dynamic scattering instrument, and the average particle diameter was 60.02 ⁇ 3.1 nm, and the dispersion coefficient was 0.128.
  • the encapsulation efficiency of the nanoparticles is 91.3 ⁇ 2%, and the specific detection method of the encapsulation efficiency is shown in Example 7.
  • the particle diameter was measured using a laser dynamic scattering instrument, and the average particle diameter was 80.13 ⁇ 2.7 nm, and the dispersion coefficient was 0.154.
  • the encapsulation efficiency of the nanoparticles was 90.1 ⁇ 3.1%, and the specific detection method of the encapsulation efficiency is shown in Example 7.
  • the sample can be stabilized for more than 48 hours at 25 ° C and more than 36 hours at 4 ° C. It can be seen that the paclitaxel polyethylene glycol-polybutylene glycol nanoparticles of the present application have very good stability.
  • the content of paclitaxel was measured by liquid chromatography.
  • the paclitaxel standard solution was taken at a concentration of 0.25-50 ⁇ g/ml, and tested according to the above chromatographic conditions. The peak area was fitted to the paclitaxel concentration curve to establish a regression equation.
  • the nanoparticle suspension of the present application is firstly centrifuged at 1000 rpm for 10 minutes to remove the drug crystals which are not encapsulated, and then centrifuged at 10,000 rpm for 30 minutes, the supernatant is aspirated, and then reconstituted with high-purity water and then dissolved in an equivalent volume of acetonitrile to dissolve.
  • the obtained solution was assayed for the content of paclitaxel according to the above chromatographic conditions.
  • the nanoparticle suspension without any treatment was dissolved in the same volume of acetonitrile, and the content of paclitaxel was measured according to the same HPLC conditions.
  • the encapsulation rate is calculated using the following formula.
  • Encapsulation efficiency (%) amount of nanoparticle encapsulated drug / total amount of drug input ⁇ 100%
  • the average encapsulation efficiency of the nanoparticles of the present application is 83 to 95%.
  • Example 8 In vitro release of paclitaxel polyethylene glycol-polytetramethylene glycol nanoparticles
  • the in vitro release test uses a dialysis bag diffusion method.
  • the dialysis bag was immersed in distilled water for several minutes, one end was screwed and knotted, and the dialysis bag was washed by adding distilled water from the other end, and washed three times.
  • the nanoparticles prepared in Example 1 were diluted to 10 mL with distilled water, 1 mL was taken as a zero point, and the remaining 9 mL was placed in a dialysis bag, and the dialysis bag was tied.
  • the dialysis bag was placed in 50 mL of PBS buffer (pH 7.4, containing 0.2% Tween 80), and dialyzed by shaking at 37 ° C in a 100 rpm shaker.
  • 1.0 mL of the PBS solution outside the dialysis bag was taken and 1.0 mL of the blank release medium was simultaneously replenished.
  • Each sample of the sample was added to 1.0 mL of acetonitrile, mixed uniformly, and analyzed by HPLC, and the conditions were the same as in Example 5.
  • the paclitaxel content in each sampling point was measured, and the cumulative release percentage was calculated to prepare a release curve.
  • the BEL-7402 cells in the logarithmic growth phase were plated with confocal plates (repeated three times), 2 mL of cell suspension per well, cell concentration of 6 ⁇ 10 5 /well, and cultured overnight to adhere.
  • the cells were lightly washed twice with PBS, and then fixed in 300 ⁇ L of 4% paraformaldehyde (v/v) for 20 min per well.
  • DIR-NPs DIR-loaded polyethylene glycol-polybutylene glycol.
  • A549 tumor-bearing nude mice were injected with 200 ⁇ L DIR-NPs solution in the tail vein, and the nude mice were anesthetized at 2 hours, 8 hours and 24 hours after administration, and the tumor-bearing mice were photographed by fluorescence of a living animal imager.
  • the nude mice were sacrificed, and the organs, liver, spleen, lungs, kidneys and tumors were taken immediately for fluorescence imaging of the living imager.
  • the fluorescence photographing excitation wavelength was 730 nm
  • the emission wavelength was 790 nm
  • the exposure time was 1 min
  • X-ray photographing was performed with an exposure time of 30 s.
  • the image is processed by the software Kodak MI In Vivo Fx Pro, and the fluorescent image is superimposed with the X-ray image to increase the pseudo-color, and the fluorescence distribution of the internal organs is determined according to the position of the X-ray picture.
  • the obtained nude images of the nude mice and tissues are shown in Fig. 5.
  • Example 12 In vivo drug efficacy test of paclitaxel polyethylene glycol-polytetramethylene glycol nanoparticles
  • the paclitaxel polyethylene glycol-polybutanediol nanoparticles prepared in Example 1 were compared with the currently used paclitaxel injection in the mouse lung cancer cell A549 cell line subcutaneous tumor model to compare their respective effects on inhibiting tumor growth.
  • the experimental results show that paclitaxel polyethylene glycol-polybutylene glycol nanoparticles have a good inhibitory effect on tumor growth in the subcutaneous tumor model of A549 cell line.
  • the paclitaxel polyethylene glycol-polybutylene glycol nanoparticle dosage form (paclitaxel dosage 10 mg/kg) is less toxic and has a long-lasting effect compared to the paclitaxel injection dosage (10 mg/kg paclitaxel). It takes a long time to be administered frequently. Tumor inhibition results and body weight changes in nude mice are shown in Figure 6.

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Abstract

本发明涉及一种新型聚合物材料组合物纳米制剂，其特征在于，所述组合物包括活性物质和聚乙二醇-聚丁二醇共聚物。本发明还涉及制备该组合物的方法，以及其在制备药物中的用途。

Description

一种新型抗癌药物纳米制剂及其制备方法 技术领域
本发明涉及药物制剂领域，特别涉及一种新型聚合物药物组合物制剂，所述组合物包括活性物质和聚乙二醇-聚丁二醇共聚物。
背景技术
高分子载体是随着药物学研究、生物材料科学和临床医学的发展而新兴的给药技术。低分子药物具有疗效高、使用方便等优点，但同时也存在很大副作用。通常，低分子药物通过口服或注射进入人体内，代谢速度快，半衰期短，缺乏选择性。高分子载体是指本身没有药理作用、也不与药物发生反应的高分子，其作为药物的载体，依靠与药物之间微弱的氢键结合形成，或者通过缩聚反应将低分子药物连接到聚合物主链上。其中高分子材料作为低分子药物的传递系统。
用高分子材料作为小分子药物的载体可以增加药物的作用时间，提高药物的选择性并降低小分子药物的毒性。近期迅速发展的是微米和纳米尺度的高分子载体，如：纳米胶束、囊泡和纳米粒等，这类高分子载体可有效的将药物分子分散到其中，利用载体的各种响应方式，实现药物的输送和控制释放。
其中，纳米粒给药系统(Nanoparticles-based drug delivery systems)是将纳米技术和纳米材料应用于药学领域产生的，它以纳米粒(Nanoparticles，NP)作为药物载体的一种药物输送体系。纳米粒(Nanoparticle，NP)是一类由高分子物质组成的固态胶体粒子，粒径大小介于10～1000nm，可分散在水中形成近似胶体溶液。由于纳米粒作为药物载体性质上的独特性和优越性，其已成为国内外医药学的重要研究方向。
用于制备纳米粒制剂的辅料多为高分子可降解聚合物。聚酯类是迄今为止研究最多，应用最广的生物可降解高分子材料，常用的有聚乳酸(PLA)、聚羟基乙酸(PGA)、聚乳酸-聚羟基乙酸共聚物(PLGA)和聚-己内酯(PCL)等。
虽然现有技术中已有一些高分子材料可供制备纳米粒，但是现有技术中的材料尚存在诸多缺陷，因此本领域对新的可用于制备纳米粒的高分子材料还有迫切需要。
发明概述
一方面，本申请涉及一种组合物，其特征在于，所述组合物包括活性物质和聚乙二醇-聚 丁二醇共聚物。
在某些实施方式中，所述聚乙二醇-聚丁二醇共聚物具有如式I、Ⅱ或Ⅲ式所示的结构
Figure PCTCN2016105142-appb-000001
，其中n、n1和n2各自独立的为1-3000，m为1-1500，R1、R2、R3和R4各自独立的选自H和C1-C3烷基。
在某些实施方式中，所述聚乙二醇-聚丁二醇共聚物的分子量为0.1K-300K。
在某些实施方式中，所述组合物为纳米颗粒。在某些实施方式中，所述纳米颗粒的粒径在10-500nm。在某些实施方式中，所述纳米颗粒的粒径在10-100nm。
在某些实施方式中，所述活性物质为疏水性物质。在某些实施方式中，所述活性物质选自抗肿瘤药物、抗生素药物、心血管药物、抗糖尿病药物和非甾体抗炎药物。在某些实施方式中，所述活性物质是紫杉醇及其衍生物。在某些实施方式中，所述活性物质是紫杉醇、多西他赛或卡巴他赛。
在某些实施方式中，所述活性物质与聚乙二醇-聚丁二醇共聚物的质量比是0.01～1。在某 些实施方式中，所述活性物质与聚乙二醇-聚丁二醇共聚物的质量比是0.1-0.3。
在某些实施方式中，所述组合物还包括其它的聚合物。
另一方面，本申请涉及制备本申请所述的组合物的方法，其特征在于，包括如下步骤：(a)将聚乙二醇-聚丁二醇共聚物和活性物质用有机溶剂溶解；(b)将有机相加到水相溶液中以形成油水混合物；(c)减压除去所述油水混合物中的所述有机溶剂。
在某些实施方式中，所述步骤(b)还包括使用低剪切力处理所述油水混合物。
在某些实施方式中，所述低剪切力是搅拌。
在某些实施方式中，所述方法还进一步包括步骤(d)干燥步骤(c)的产物。在某些实施方式中，所述步骤(d)中的所述干燥是通过冷冻干燥完成的。
在某些实施方式中，所述有机溶剂包括四氢呋喃、1,4-二氧六环、二甲基亚砜、丙酮、N,N-二甲基甲酰胺或其混合物。
在某些实施方式中，所述有机相和水相的比例为1:10～20:1。在某些实施方式中，所述有机相和水相的比例为0.5:1～2:1。
再一方面，本申请涉及本申请的所述的组合物在制备用于缓解、治疗或预防疾病的药物中的用途。
一方面，本申请涉及本申请的组合物用于缓解、治疗或预防治病的用途。
另一方面，本申请涉及一种缓解、治疗或预防疾病的方法，包括向需要其的客体使用有效量的本申请的组合物。
在某些实施方式中，所述疾病是癌症。
又一方面，本申请涉及聚乙二醇-聚丁二醇共聚物在制备用于治疗疾病的药物中的用途。
还一方面，本申请涉及一种制备药物的方法，其特征在于，所述方法包括混合活性物质和聚乙二醇-聚丁二醇共聚物。
附图说明
图1是纳米粒的粒径分布图和透射电镜(TEM)图。
图2是与泰素相比的载紫杉醇(PTX)EB纳米粒的体外释放图。
图3是与泰素相比的载紫杉醇(PTX)EB纳米粒的药动学曲线。
图4是载FITC的EB纳米粒的细胞摄取图。
图5是载DIR的EB纳米粒的荷瘤裸鼠活体成像和组织成像图。
图6是体内药效实验中荷瘤裸鼠肿瘤和体重体积随注射时间的变化图。其包括阴性对照PBS、阳性对照泰素和本申请实施例1制备的载紫杉醇的EB纳米粒。
发明详述
本发明的一个方面提供了一种组合物，所述组合物包括活性物质和聚乙二醇-聚丁二醇共聚物。
聚乙二醇-聚丁二醇共聚物
本领域技术人员可以根据实际需要选择所述聚乙二醇-聚丁二醇共聚物的种类以及所具有的性质。
在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物是聚乙二醇-聚1,2-丁二醇共聚物、聚乙二醇-聚1,3-丁二醇共聚物、聚乙二醇-聚1,4-丁二醇共聚物或其混合物。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物是无规共聚物、交替共聚物、嵌段共聚物或接枝共聚物。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物是嵌段共聚物。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物是两嵌段共聚物或三嵌段共聚物。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物中的聚乙二醇是尾部修饰的聚乙二醇。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物中的聚乙二醇是聚乙二醇单甲醚(mPEG)。
在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物具有如式I、式II或式III所示的结构
Figure PCTCN2016105142-appb-000002
Figure PCTCN2016105142-appb-000003
，其中n、n1、n2各自独立的选自1-3000，m选自1-1500，R1、R2、R3和R4各自独立的选自H和C1-C3烷基。在一些实施方式中，n、n1、n2各自独立的为1-2500、1-2000、1-1500、1-1200、1-1000、1-800、1-600、1-500、1-400、1-300、1-200、1-180、1-170、1-160、1-150、1-140、1-130、1-120、1-118、1-110、1-100、1-90、1-80、1-70、1-60、1-50、3-2500、5-2000、8-1500、10-1200、11-800、12-500、13-300、15-200、16-180、16-150、16-140、16-120、20-100、25-80、30-70、35-70或35-60。在一些实施方式中，m为1-1200、1-1000、1-800、1-600、1-500、1-400、1-300、1-200、1-180、1-170、1-160、1-150、1-140、1-130、1-120、、1-118、1-110、1-100、1-90、1-80、1-70、1-60、1-50、3-1500、5-1200、8-1000、10-800、11-600、12-500、13-300、15-200、15-180、15-150、15-140、15-120、15-110、15-100、18-100、18-90、20-80、25-75或25-70。在一些实施方式中，R1、R2、R3和R4各自独立的选自H和CH3。
在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物的分子量为0.1K-300K。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物的分子量为0.1K-280K、0.1K-250K、0.1K-200K、0.1K-180K、0.1K-150K、0.1K-120K、0.1K-100K、0.1K-80K、0.1K-60K、0.1K-50K、0.1K-40K、0.1K-30K、0.1K-25K、0.1K-22K、0.1K-20K、0.1K-18K、0.1K-16K、0.1K-15K、0.1K-14K、0.1K-13K、0.1K-12K、0.1K-10K、0.1K-8K、0.1K-7K、0.1K-6K、0.1K-5K、0.1K-4K、0.3K-300K、0.5K-300K、0.8K-300K、1K-300K、1.2K-300K、1.2K-250K、1.2K-200K、1.2K-150K、1.2K-100K、1.2K-80K、1.2K-60K、1.2K-50K、1.2K-30K、1.2K-20K、1.2K-18K、1.2K-16K、1.2K-15K、1.2K-14K、1.2K-12K、1.2K-11K、1.2K-10K、1.2K-8K、1.2K-6K、1.2K-5K、1.2K-4K、0.5K-150K、0.6K-100K、0.8K-80K、1K-50K、1.5K-40K、1.6K-30K、1.7K-20K、2K-16K、2.5K-14K、3K-13K、3.5K-12K、4K-10K或5K-9K。
本申请中所述的分子量可以是重均分子量或数均分子量。可以使用本领域常用的方法来检测分子量，例如通过光散射法、超速离心沉降速度法或凝胶色谱法进行检测。
在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物中乙二醇和丁二醇重复单元的摩尔比例为1:5-6:1。在一些实施方式中，所述聚乙二醇-聚丁二醇共聚物中乙二醇和丁二醇重复单元的摩尔比例为1:4-6:1、1:3-6:1、1:2-6:1、1:1-6:1、2:1-6:1、3:1-6:1、4:1-6:1、5:1-6:1、1:5-5:1、1:5-4:1、1:5-3:1、1:5-2:1、1:5-1:1、1:5-1:2、1:5-1:3、1:4-4:1、1:3-3:1、1:2-3:1或1:1.3-2.5:1。
本申请中使用的术语“烷基”，无论是作为其他术语的一部分还是单独使用，指饱和的烃基基团，其可以是直链的或支链的。术语“Cn-m烷基”指具有n至m个碳原子的烷基。在某些实施方式中，烷基基团含有1至12、1至8、1至6、1至4、1至3或1至2个碳原子。烷基基团的示例包括但不限于化学基团如甲基、乙基、n-丙基、异丙基、n-丁基、叔丁基、异丁基、仲丁基；高级同系物如2-甲基-1-丁基、n-戊基、3-戊基、n-己基、1,2,2-三甲基丙基等。
聚醚共聚物的合成方法可以用阴离子聚合方法。示例性制备本申请聚乙二醇-聚丁二醇共聚物的方法如下：
Figure PCTCN2016105142-appb-000004
组合物
在一些实施方式中，本申请的组合物为固体制剂。在一些实施方式中，所述组合物为纳米颗粒。在一些实施方式中，所述组合物是干燥的纳米颗粒。在一些实施方式中，所述组合物是冻干的纳米颗粒。
在一些实施方式中，所述纳米颗粒的粒径在10-500nm。在一些实施方式中，所述纳米颗粒的粒径在10-400nm、10-300nm、10-250nm、10-200nm、10-150nm、10-120nm、10-100nm、10-90nm、20-90nm、30-90nm或40-90nm。在一些实施方式中，所述纳米颗粒的粒径在10-100nm。可以使用本领域常用的方法测量粒径，例如扫描电镜法、光散射法。在一些实施方式中，使用光散射法检测粒径。在一些实施方式中，使用激光动态散射仪检测粒径。
本申请纳米粒具有可接受的分散系数。在一些实施方式中，本申请纳米粒的分散系数不大于0.3、0.2、0.19、0.18、0.17、0.16、0.15、0.14、0.13、0.12或0.11。在一些实施方式中，本申请纳米粒的分散系数为0.1-0.2。
本领域技术人员知晓，可以对本申请组合物进行进一步的修饰。在一些实施方式中，可以对本申请的组合物进行进一步的包衣，例如，进行缓释或控释包衣。在一些实施方式中，可以在本申请组合物的表面修饰靶向基团(例如，抗体、配体、特定底物等)或者其他的高分子以进一步改善申请组合物的靶向性或其他动力学参数，或者用于对本申请组合物进行示踪。
本领域技术人员知晓，除了活性物质与聚乙二醇-聚丁二醇共聚物之外，所述组合物还包括药学上可接受的其他成分。在一些实施方式中，所述其他成分包括表面活性剂。所述表面活性剂可以是阳离子表面活性剂、阴离子表面活性剂或非离子表面活性剂。在一些实施方式中，所述其他成分包括冻干保护剂，包括但不限于乳糖、甘露糖、右旋糖酐、蔗糖和甘氨酸。在一些实施方式中，所述其他成分包括溶液，包括但不限于氯化钠溶液，葡萄糖溶液、PBS缓冲液、乙醇溶液等。
本申请所使用的术语“药学上可接受的”是指这样的化合物、原料、组合物和或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。
本申请的组合物适于通过任何合适的途径给药，例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或胃肠外(包括皮下、皮内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内、静脉内或者真皮下注射或输注)途径。在一些实施方式中，本申请的组合物用于胃肠外给药。在一些实施方式中，本申请的组合物用于静脉输注给药。
活性物质
本领域技术人员可以根据实际需要选择适合的活性物质。在一些实施方式中，所述活性物质是疏水性物质。
本申请所使用的术语“疏水性物质”指的是在25℃在100g水中该物质的可溶解质量小于1g、0.1g、0.01g、1mg或0.5mg。
在一些实施方式中，所述活性物质选自抗肿瘤药物、抗生素药物、心血管药物、抗糖尿病药物和非甾体抗炎药物。本申请的活性物质的示例性例子可以是：抗肿瘤药物，例如紫杉 醇、多烯紫杉醇、卡巴他赛、5-氟尿嘧啶、依托泊苷、苯丙氨酸氮芥、苯丁酸氮芥、六甲三聚氰胺、甲氨碟呤、甲环亚硝脲、去甲长春花碱、替尼泊苷、高三尖杉酯碱、羟喜树碱等；抗生素药物，例如氯霉素、红霉素、依托红霉素、琥乙红霉素、麦迪霉素、交沙霉素、克拉霉素、罗他霉素、磺胺嘧啶、甲氧苄氨嘧啶、呋喃妥因、利副平、利福昔明、异丁呱利福霉素、氨苯砜、醋氨苯砜、眯康唑等；心血管药物，如硝苯地平、尼卡地平、尼群地平、尼伐地平、桂利嗪、呱克昔林、吗多明、洋地黄毒甙、地高辛、毛花甙丙、去乙酰毛花甙、普罗帕酮、胺碘酮、硝酸甘油、戊四硝酯、环扁桃酯、烟酸生育酚酯等；抗糖尿病药物，例如甲苯黄丁脲、格列本脲、格列吡嗪等；非甾体抗炎药物，例如氯马撕汀、赛庚啶、苯噻啶、酮替芬、曲尼司等。上述各具体药物的结构可以参见各国家或地区的药品管理部门批准的药品说明书，例如中国食品药品监督管理局、美国食品药品监督管理局、日本药品与医疗器械管理局或者欧洲药品管理局批准的那些。
在一些实施方式中，所述活性物质是紫杉醇及其衍生物。在一些实施方式中，所述活性物质是紫杉醇、多西他赛或卡巴他赛(7Β，10Β-二甲氧基多西紫杉醇)及其衍生物。
本申请所涉及的化合物包括该化合物的盐、酯、内消旋体、外消旋体及其异构体。本申请所述的异构体包括顺反异构体和旋光异构体。
本申请所使用的术语“衍生物”是指母体化合物分子中的原子或原子团被其他原子或原子团取代所形成的化合物。紫杉醇的衍生物包括但不限于紫杉醇的丁二酸和戊二酸衍生物、磺酸盐衍生物、氨基酸衍生物、磷酸盐衍生物、有机酸酯和碳酸酯衍生物、N-甲基吡啶盐、聚乙二醇衍生物、聚甲基丙烯酸衍生物、聚谷氨酸或聚天门冬氨酸衍生物。
组分比例
本领域技术人员可以根据实际需要选择活性物质同聚合物的比例。在一些实施方式中，组合物中所述活性物质与聚乙二醇-聚丁二醇共聚物的质量比是0.01～1。在一些实施方式中，组合物中所述活性物质与聚乙二醇-聚丁二醇共聚物的质量比是0.02～1、0.03～1、0.04～1、0.05～1、0.06～1、0.08～1、0.09～1、0.1～1、0.2～1、0.3～1、0.4～1、0.5～1、0.6～1、0.7～1、0.8～1、0.9～1、0.01～0.9、0.01～0.8、0.01～0.7、0.01～0.6、0.01～0.5、0.01～0.4、0.01～0.3、0.01～0.2、0.01～0.1、0.01～0.09、0.01～0.08、0.01～0.07、0.01～0.06、0.01～0.05、0.01～0.04、0.01～0.03、0.01～0.02、0.03～0.9、0.04～0.6、0.04～0.5、0.04～0.2、0.04～0.1、0.04～0.09、0.04～0.08、0.04～0.07、0.04～0.06或0.04～0.05。
有益效果
不希望受理论的束缚，本申请的聚乙二醇-聚丁二醇共聚物作为基质将活性物质包裹于其中，并且形成球状颗粒及其他形状颗粒。与活性物质的非纳米粒剂型或用其它高分子材料制成的纳米粒剂型相比，使用聚乙二醇-聚丁二醇共聚物作为基质成分具有如下一个或多个优势：1、防止活性物质析出；2、获得粒径更小的颗粒；3、单分散性更好；4、制备方法更加简便；5、包封率更高；6、有更优异的靶向作用；7、更长的循环时间；8、更高的药效；9、更高的活性物质负载量。
本发明的另一个方面提供了一种制备本发明组合物的方法。
制备方法的步骤
在一些实施方式中，制备本发明组合物的方法包括如下步骤：(a)将聚乙二醇-聚丁二醇共聚物和活性物质用有机溶剂溶解；(b)将有机相加到水相溶液中以形成油水混合物；(c)减压除去所述油水混合物中的所述有机溶剂。
在一些实施方式中，所述方法还进一步包括步骤(d)干燥步骤(c)的产物。本领域技术人员可以根据具体情况选择适合的干燥方式，例如冷冻干燥，喷雾干燥等。在一些实施方式中，所述步骤(d)中的所述干燥是通过冷冻干燥完成的。
(a)将聚乙二醇-聚丁二醇共聚物和活性物质用有机溶剂溶解
本领域技术人员可以根据活性物质的溶解性和制备工艺的需要来选择适合的有机溶剂。在一些实施方式中，所述有机溶剂包括四氢呋喃、1,4-二氧六环、二甲基亚砜、丙酮、N,N-二甲基甲酰胺或其混合物。在一些实施方式中，所述有机溶剂是丙酮。
(b)将有机相加到水相溶液中以形成油水混合物
在一些实施方式中，所述步骤(b)还包括使用低剪切力处理所述油水混合物。
本申请所述的低剪切力可以是通过搅拌、剪切或均质提供的，条件是剪切力不高于1000rmp、800rmp、700rmp、600rmp、500rmp或400rmp机械搅拌提供的剪切力。在一些实施方式中，所述低剪切力是搅拌。在一些实施方式中，所述低剪切力是机械搅拌。在一些实施方式中，搅拌的速度为100-1000rmp、100-800rmp、100-700rmp、100-600rmp、100-500rmp或100-400rmp。
在一些实施方式中，所述有机相和水相的比例为1:10～20:1、1:10～18:1、1:10～15:1、 1:10～12:1、1:10～10:1、1:10～8:1、1:10～5:1、1:10～3:1、1:10～2:1、1:10～1:1、1:8～1:1、1:6～1:1、1:4～1:1、1:3～1:1、1:2.5～1:1、1:2～1:1、1:8～20:1、1:6～20:1、1:4～20:1、1:2～20:1、1:1～20:1、2:1～20:1、4:1～20:1、5:1～20:1、8:1～20:1、10:1～20:1、15:1～20:1、1:18～20:1、1:8～15:1、1:6～12:1、1:5～10:1、1:4～8:1、1:3～5:1、1:3～2:1、1:3～1:1、1:2.5～1:1.5、1:2.3～1:1.8或1:2.1～1:1.9。
(c)减压除去所述油水混合物中的所述有机溶剂
本申请所述的减压可以通过本领域的任何适合的方式进行，例如，旋转蒸发、减压干燥等。在一些实施方式中，通过减压旋转蒸发除去有机溶剂。在一些实施方式中，减压旋转蒸发的真空度低于0.6个大气压、0.5个大气压、0.4个大气压、0.3个大气压、0.2个大气压、0.1个大气压。在一些实施方式中，减压旋转蒸发的真空度为0.1-0.6个大气压、0.1-0.5个大气压、0.1-0.4个大气压、0.1-0.3个大气压或0.1-0.2个大气压。
包封率
可以使用本领域常用的方法测量包封率，例如葡聚糖凝胶、超速离心法或透析法。在一些实施方式中，使用透析法测量包封率。
在一些实施方式中，本申请方法制得的组合物的包封率不低于80％、83％、85％、87％、89％、90％、92％、93％、94％或95％。
制药用途、疾病治疗方法和治疗用途
本申请一方面涉及本申请的所述的组合物在制备用于缓解、治疗或预防疾病的药物中的用途。
本申请再一方面涉及本申请的组合物用于缓解、治疗或预防治病的用途。
本申请另一方面涉及一种缓解、治疗或预防疾病的方法，包括向需要其的客体使用有效量的本申请的组合物。
在某些实施方式中，所述疾病是癌症。
对某种疾病或症状的“缓解”、“治疗”或“预防”包括预防或减轻某种状况，降低某种状况兴起或发展的速度，减少发展出某种状况的风险，预防或延迟与某种状况相关的症状发展，减少或终止与某种状况相关的症状，产生某种状况的完全或部分的逆转，治愈某种状况，或以上的组合。
本申请中使用的术语“有效量”是指，可以实现客体的疾病或症状，或者可以预防性地抑制或防止疾病或症状发生的药物的量。有效量可以是将客体的一种或多种疾病或症状缓解到一定程度的药物的量；可以将那些跟疾病或症状成因相关的一种或多种生理或生物化学参数部分或完全恢复到正常的药物的量；和/或可以降低疾病或症状发生的可能性的药物的量。
本申请中提供的组合物的有效剂量依赖于本领域公知的多种因素，例如体重、年龄、过往病史、目前正在接受的治疗、对象的健康状况和药物相互作用的强度、过敏、超敏和副作用，以及给药途径和疾病发展的程度。本领域熟练人员(例如医生或兽医)可根据这些或其它条件或要求相应降低或升高剂量。
在某些实施方式中，本申请提供的组合物可在治疗有效剂量约0.01mg/kg到约100g/kg之间给药(例如，约0.01mg/kg、约0.5mg/kg、约1mg/kg、约2mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约55mg/kg、约60mg/kg、约65mg/kg、约70mg/kg、约75mg/kg、约80mg/kg、约85mg/kg、约90mg/kg、约95mg/kg、约100mg/kg、约200mg/kg、约500mg/kg、约1g/kg、约5g/kg、约10g/kg、约20g/kg、约50g/kg、约70g/kg、约90g/kg或约100g/kg)。某一特定剂量可分为多次间隔给药，例如每天一次、每天两次或更多、每月两次或更多、每周一次、每两周一次、每三周一次、每月一次或每两月或更多月一次。在某些实施方式中，给药剂量可随治疗进程变化。例如，在某些实施方式中，初始给药剂量可比后续给药剂量高。在某些实施方式中，给药剂量在治疗进程中根据给药对象的反应进行调整。
给药方案可通过调整达到最优反应(例如，治疗响应)。例如，可进行单剂量给药或在一段时间分多个分隔的剂量给药。
本发明的又一个方面提供了聚乙二醇-聚丁二醇共聚物在制备用于治疗疾病的药物中的用途。在一些实施方式中，所述药物进一步包括活性物质。
本发明的另一个方面提供了一种制备药物的方法，所述方法包括混合活性物质和聚乙二醇-聚丁二醇共聚物。
具体实施方式
以下对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
除另有明确表示，本实施例使用的聚乙二醇-聚丁二醇共聚物是获得自加拿大先进聚合 物材料公司的如式I所示的聚乙二醇-聚丁二醇共聚物。
实施例1 紫杉醇聚乙二醇-聚丁二醇纳米粒的制备
将40mg聚乙二醇-聚丁二醇共聚物(n＝45,m＝20)和8mg紫杉醇共同溶于10ml丙酮溶剂中作为有机相；将10ml水作为水相；将有机相以5ml/min的速度滴入水相中，在300rmp机械搅拌下形成浅蓝色的纳米粒，搅拌10min后转移到旋转蒸发仪中，真空-0.1MPa下旋转蒸发30min以去除丙酮，得到稳定的纳米粒。
使用激光动态散射仪(贝克曼库尔特LS 13320)检测粒径，平均粒径为22.4±1.6nm，分散系数为0.118，粒径分布结果和透射电镜图如图1所示。纳米粒的包封率为86.4±3％，包封率的具体检测方法参见实施例7。
实施例2 卡巴他赛聚乙二醇-聚丁二醇纳米粒的制备
40mg聚乙二醇-聚丁二醇(n＝45,m＝20)共聚物和4mg卡巴他赛共同溶于10ml丙酮溶剂中作为有机相；将10ml水作为水相；将有机相以5ml/min的速度滴入水相中，在300rmp机械搅拌下形成浅蓝色的纳米粒，搅拌10min后转移到旋转蒸发仪中，真空-0.1MPa下旋转蒸发30min以去除丙酮，得到稳定的长循环纳米粒。
使用激光动态散射仪检测粒径，平均粒径为40.44±2.5nm，分散系数为0.158。纳米粒的包封率为90.4±3％，包封率的具体检测方法参见实施例7。
实施例3 其他聚乙二醇-聚丁二醇纳米粒的制备
使用与实施例1和实施例2的类似方法，使用紫杉醇、多烯紫杉醇或卡巴他赛作为活性物质，使用不同的式I所示的乙二醇-聚丁二醇共聚物(包括(n＝17,m＝16)，(n＝17,m＝20)，(n＝17,m＝22)，(n＝45,m＝10)，(n＝45,m＝15)，(n＝45,m＝20)，(n＝45,m＝23)，(n＝45,m＝25)，(n＝45,m＝28)，(n＝50,m＝70)，(n＝68,m＝22)，(n＝68,m＝27)，(n＝113,m＝90))或式II所示的乙二醇-聚丁二醇共聚物(n1＝45,m＝46,n2＝20)，并且调整不同的乙二醇-聚丁二醇共聚物同活性物质的比例(包括5:1、10:1和20:1)，来制备纳米粒。在上述条件下均应能够制备出粒径小于100nm、粒径分布均匀并且包封率大于70％的纳米粒，具体数据省略。
实施例4 反向滴加制备紫杉醇聚乙二醇-聚丁二醇纳米粒的制备
40mg聚乙二醇-聚丁二醇(n＝113,m＝90)共聚物和4mg紫杉醇共同溶于10ml丙酮溶剂中作为有机相；将10ml水作为水相；将水机相以5ml/min的速度滴入有机相中，在300rmp机 械搅拌下形成纳米粒，搅拌10min后转移到旋转蒸发仪中，真空-0.1MPa下旋转蒸发30min以去除丙酮，得到稳定的长循环纳米粒。
使用激光动态散射仪检测粒径，平均粒径为60.02±3.1nm，分散系数为0.128。纳米粒的包封率为91.3±2％，包封率的具体检测方法参见实施例7。
实施例5 转膜法制备反向滴加制备紫杉醇聚乙二醇-聚丁二醇纳米粒的制备
40mg聚乙二醇-聚丁二醇(n＝50,m＝70)共聚物和4mg紫杉醇共同溶于10ml丙酮溶剂中，于60℃旋转温度下减压旋转成膜，成膜后在真空条件下继续旋转蒸发1h，然后转移到真空干燥箱继续干燥12h，真空干燥结束后在旋转蒸发仪常压下于60℃加水水合30min得到纳米粒。
使用激光动态散射仪检测粒径，平均粒径为80.13±2.7nm，分散系数为0.154。纳米粒的包封率为90.1±3.1％，包封率的具体检测方法参见实施例7。
实施例6 紫杉醇聚乙二醇-聚丁二醇纳米粒的稳定性研究
将实施例1制备的紫杉醇聚乙二醇-聚丁二醇(n＝45,m＝20)纳米粒加0.9％氯化钠注射稀释至紫杉醇含量为l mg/ml，并混匀。将样品置于25℃和4℃恒温箱中，观察样品析出的情况。
经观察发现：样品在25℃条件下可稳定48小时以上，4℃条件下可稳定36小时以上。可见，本申请的紫杉醇聚乙二醇-聚丁二醇纳米粒的稳定性非常好。
实施例7 紫杉醇聚乙二醇-聚丁二醇纳米粒包封率的测定
使用液相高效色谱测紫杉醇的含量。色谱柱：安捷伦C18柱；流动相：乙腈：水(50:50v：v)；检测波长227nm；流速1.0ml/min；进样量20μl。分别取浓度为0.25～50μg/ml的紫杉醇标准品溶液，按照上述色谱条件进行测试，以峰面积对紫杉醇浓度进行曲线拟合，建立回归方程。
将本申请的纳米粒混悬液先1000rmp低速离心10min去掉没有包进去的药物结晶，再10000rmp高速离心30min，将上清液吸掉，然后用高纯水复溶再加入同等体积的乙腈溶解，将溶解得到的溶液按照上述色谱条件测定紫杉醇的含量。同时取未经任何处理的纳米粒混悬液加同样体积的乙腈溶解，按照同样的HPLC条件测紫杉醇的含量。
包封率使用如下公式进行计算。
包封率(％)＝纳米粒包封的药物的量/投入药物总的量×100％
本申请纳米颗粒的平均包封率为83～95％。
实施例8 紫杉醇聚乙二醇-聚丁二醇纳米粒的体外释放实验
体外释放试验采用透析袋扩散法。
将透析袋浸泡在蒸馏水中数分钟，一端旋拧后打结，从另一端加入蒸馏水洗涤透析袋，洗涤3次。将实施例1制备的纳米粒用蒸馏水稀释至10mL，取1mL作为零点，剩余9mL置于透析袋中，扎紧透析袋。将透析袋放入50mL PBS缓冲液(pH7.4，含0.2％吐温80)中，在37℃，100rmp的摇床中振荡透析。在预先设定的时间点取透析袋外PBS液1.0mL并同时补充空白释放介质1.0mL。将各取样点样品加入1.0mL乙腈，混合均匀后，HPLC进样分析，条件同实施例5。测定各取样点中的紫杉醇含量，计算累积释放百分率，制作释放曲线。
体外释放结果如图2所示。由图2可知，本申请的纳米粒能够以一定缓释速率平稳释放活性物质。
实施例9 紫杉醇聚乙二醇-聚丁二醇纳米粒的药动学实验
取SD大鼠8只，体重250±20g，随机分为两组，分别注射泰素和实施例1制备的紫杉醇聚乙二醇-聚丁二醇纳米粒的水溶液(1mg/ml)。每只大鼠尾静脉注射2ml后，于5min、15min、30min、1小时、2小时、4小时、7小时和24小时眼眶取血0.5ml置于肝素管中。4000rmp离心10min后取血浆200μL置于离心管中，加入内标50μL，涡旋混匀。加入350μL乙腈，涡旋混匀2min，13000rmp离心10min，取上清转移过膜装入进样瓶。使用HPLC分析，条件同实施例5。药动曲线如图3所示。
实施例10 载FITC聚乙二醇-聚丁二醇纳米粒的细胞摄取实验
取对数生长期的BEL-7402细胞用共聚焦专用孔板铺板(重复三次)，每孔2mL细胞悬浮液，细胞浓度6×105个/孔，培养过夜使之贴壁。加入包载FITC的聚乙二醇-聚丁二醇(n＝45,m＝20)纳米粒(FITC浓度为100μg/mL)200μL，在培养箱中分别孵育2小时和4小时。细胞用PBS轻洗2次，然后每孔加入300μL 4％多聚甲醛(v/v)固定20min。去除多聚甲醛，每孔加入300μL DAPI染色液(5μg/mL)，染色5min。PBS洗2次后，加入300μL PBS覆盖住细胞，用共聚焦显微镜采集图像。载FITC的EB纳米粒的细胞摄取结果如图4所示。
实施例11 载DIR聚乙二醇-聚丁二醇纳米粒的活体成像实验
在制备纳米粒的过程中，加入DIR染料(代替原药)制备成载DIR的聚乙二醇-聚丁二醇 (n＝45,m＝20)纳米粒(DIR-NPs)，DIR终浓度为100μg/mL。取A549荷瘤裸鼠，分别尾静脉注射200μL DIR-NPs溶液，分别在给药后2小时，8小时和24小时麻醉裸鼠，对荷瘤鼠进行活体动物成像仪荧光拍照。最后处死裸鼠，即时摘取心，肝，脾，肺，肾和瘤等脏器组织，进行活体成像仪荧光拍照。荧光拍照的激发波长为730nm，发射波长790nm，曝光时间为1min，并且进行X光拍照，曝光时间为30s。使用软件Kodak MI In Vivo Fx Pro处理图像，将荧光图像与X光图像进行叠加，增加伪彩，根据X光图片位置确定体内脏器的荧光分布情况。得到的裸鼠和组织活体成像图如图5所示。
实施例12 紫杉醇聚乙二醇-聚丁二醇纳米粒的动物体内药效实验
将实施例1制备的紫杉醇聚乙二醇-聚丁二醇纳米粒同目前临床上使用的紫杉醇注射液在小鼠肺癌细胞A549细胞系皮下瘤模型中比较各自对抑制肿瘤生长的有效性。
实验结果显示：紫杉醇聚乙二醇-聚丁二醇纳米粒对A549细胞系皮下瘤模型中有较好的抑制肿瘤生长的作用。紫杉醇聚乙二醇-聚丁二醇纳米粒剂型(紫杉醇给药剂量为10mg/kg)与紫杉醇注射液剂型(紫杉醇给药剂量为10mg/kg)相比，毒性较小，且疗效持久，不需要长时间频繁给药。肿瘤抑制结果和裸鼠体重变化如图6所示。

Claims (25)

  1. 一种组合物，其特征在于，所述组合物包括活性物质和聚乙二醇-聚丁二醇共聚物。
  2. 根据权利要求1所述的组合物，其特征在于，其中所述聚乙二醇-聚丁二醇共聚物具有如式I、Ⅱ或Ⅲ式所示的结构
    Figure PCTCN2016105142-appb-100001
    ，其中n、n1和n2各自独立的为1-3000，m为1-1500，R1、R2、R3和R4各自独立的选自H和C1-C3烷基。
  3. 根据权利要求1所述的组合物，其特征在于，其中所述聚乙二醇-聚丁二醇共聚物的分子量为0.1K-300K。
  4. 根据权利要求1所述的组合物，其特征在于，其中所述组合物为纳米颗粒。
  5. 根据权利要求4所述的组合物，其特征在于，其中所述纳米颗粒的粒径在10-500nm。
  6. 根据权利要求5所述的组合物，其特征在于，其中所述纳米颗粒的粒径在10-100nm。
  7. 权利要求1的组合物，其特征在于，所述活性物质为疏水性物质。
  8. 权利要求1的组合物，其特征在于，所述活性物质选自抗肿瘤药物、抗生素药物、心血管药物、抗糖尿病药物和非甾体抗炎药物。
  9. 权利要求1的组合物，其特征在于，所述活性物质是紫杉醇及其衍生物。
  10. 权利要求1的组合物，其特征在于，所述活性物质是紫杉醇、多西他赛或卡巴他赛。
  11. 权利要求1的组合物，其特征在于，其中所述活性物质与聚乙二醇-聚丁二醇共聚物的质量比是0.01～1。
  12. 权利要求1的组合物，其特征在于，其中所述活性物质与聚乙二醇-聚丁二醇共聚物的质量比是0.1-0.3。
  13. 权利要求1的组合物，其特征在于，其中所述组合物还包括其它的聚合物。
  14. 一种制备权利要求1-13任一项所述的组合物的方法，其特征在于，包括如下步骤：
    (a)将聚乙二醇-聚丁二醇共聚物和活性物质用有机溶剂溶解；
    (b)将有机相加到水相溶液中以形成油水混合物；
    (c)减压除去所述油水混合物中的所述有机溶剂。
  15. 根据权利要求14所述的方法，其特征在于，所述步骤(b)还包括使用低剪切力处理所述油水混合物。
  16. 根据权利要求15所述的方法，其特征在于，所述低剪切力是搅拌。
  17. 根据权利要求14所述的方法，其特征在于，所述方法还进一步包括步骤(d)干燥步骤(c)的产物。
  18. 根据权利要求17所述的方法，其特征在于，所述步骤(d)中的所述干燥是通过冷冻干燥完成的。
  19. 根据权利要求14所述的方法，其特征在于，所述有机溶剂包括四氢呋喃、1,4-二氧六环、二甲基亚砜、丙酮、N,N-二甲基甲酰胺或其混合物。
  20. 根据权利要求14所述的方法，其特征在于，所述有机相和水相的比例为1:10～20:1。
  21. 根据权利要求20所述的方法，其特征在于，所述有机相和水相的比例为0.5:1～2:1。
  22. 权利要求1-13中任一项所述的组合物在制备用于缓解、治疗或预防疾病的药物中的用途。
  23. 根据权利要求22所述的用途，其特征在于，所述疾病是癌症。
  24. 聚乙二醇-聚丁二醇共聚物在制备用于治疗疾病的药物中的用途。
  25. 一种制备药物的方法，其特征在于，所述方法包括混合活性物质和聚乙二醇-聚丁二醇共聚物。
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