WO2023274414A1 - 一种平稳释放氟维司群的微球及制备方法 - Google Patents
一种平稳释放氟维司群的微球及制备方法 Download PDFInfo
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- WO2023274414A1 WO2023274414A1 PCT/CN2022/103462 CN2022103462W WO2023274414A1 WO 2023274414 A1 WO2023274414 A1 WO 2023274414A1 CN 2022103462 W CN2022103462 W CN 2022103462W WO 2023274414 A1 WO2023274414 A1 WO 2023274414A1
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- Prior art keywords
- sustained
- pharmaceutical composition
- fulvestrant
- release
- plga
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- 239000004005 microsphere Substances 0.000 title claims abstract description 143
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 title claims abstract description 97
- 229960002258 fulvestrant Drugs 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims description 26
- 229920000642 polymer Polymers 0.000 claims abstract description 69
- 239000004626 polylactic acid Substances 0.000 claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 32
- 238000013268 sustained release Methods 0.000 claims abstract description 31
- 239000012730 sustained-release form Substances 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 19
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- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 11
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical class C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
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- 239000000661 sodium alginate Substances 0.000 claims description 2
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- 239000000600 sorbitol Substances 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 1
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- 239000000843 powder Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
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- 238000002474 experimental method Methods 0.000 description 3
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- 239000000463 material Substances 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
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- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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Images
Classifications
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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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
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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
- A61K9/0012—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
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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
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
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- 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
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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Definitions
- the invention relates to a sustained-release microsphere composition and a preparation method thereof, in particular to a fulvestrant sustained-release microsphere composition and a preparation method thereof.
- Breast cancer is the cancer with the highest morbidity and mortality among women, and the development of HR-positive breast cancer is closely related to the level of estrogen in the body.
- Antiestrogens are the mainstay of treatment for this type of breast cancer.
- Fulvestrant is an anti-estrogen drug, which is different from conventional aromatase inhibitors. It can down-regulate estrogen receptors without partial agonistic activity. Division group still has clinical curative effect.
- Fulvestrant has poor water solubility and low oral bioavailability.
- the fulvestrant preparation currently on the market is a long-acting intramuscular oily injection
- the formulation was 5% w/v fulvestrant, 10% w/v ethanol, 10% w/v benzyl alcohol, 15% w/v benzyl benzoate, and 60% w/v castor oil. Since the preparation is a highly viscous solution with low drug content, two injections of 5ml are required to be administered slowly intramuscularly. Due to the long injection time and the irritating ingredients contained in the preparation, it causes strong muscle irritation and occasionally causes allergic reactions, which affects the safety and compliance of the drug. Therefore, for the improvement of fulvestrant preparations, improvements are generally made from the aspects of increasing drug loading, reducing viscosity, and selecting less irritating excipients while ensuring long-acting properties.
- Patent WO2003006064 increases the concentration of fulvestrant to 100mg/ml by using solvents such as ethanol and lactic acid ester, which reduces the injection volume;
- patent CN 111388406 A provides a prescription for fulvestrant pharmaceutical preparations with a larger drug load, The better two groups of formulas reported by it are respectively: (1) 20% PLGA, 10% fulvestrant, 50% ethyl lactate, 8% benzyl alcohol, 10% ethanol formula; (2) 25% PLGA, 25% Fulvestrant, 45% NMP and 5% benzyl alcohol formulation.
- the drug loading of the above formulation can be increased to 250mg/ml, but the use of irritating auxiliary agents and the high viscosity of the formulation have not been improved.
- Patent US2019134059 discloses a formulation of fulvestrant microparticle dispersion suspension.
- the formula is an aqueous suspension of drug particles.
- it can avoid the use of irritating additives such as castor oil and ethanol.
- the viscosity of the preparation is low and the drug content can reach about 150mg/ml, so it can improve the compliance
- the control of its drug release rate is not ideal, and there are drug burst release phenomena and drug delayed release phenomena.
- Patents CN101108168, CN102264372 and US2012121711 have reported the method of preparing fulvestrant microspheres by using a single polymer.
- the drug loading of the microsphere preparation is low (drug loading is 5-20%), which requires increasing the injection volume.
- the release cycle ratio of the microsphere formulation to achieve the effective therapeutic concentration of the drug in vivo Short, so the frequency of drug injection needs to be increased, which affects the compliance of medication; the drug release behavior of the microsphere preparation in the animal body, or there is a drug burst release phenomenon, or there is a drug delayed release phenomenon, which is important for clinical dosage control and administration. Difficulties in the way of medication, affecting the safety and compliance of medication.
- the inventors of the present invention proposed a solution to prepare fulvestrant microspheres by compounding two kinds of polymer materials, and simultaneously control the burst release of the drug through the joint action of the two polymers Behavioral and delayed release phenomena to achieve stable and long-term drug release.
- the present invention provides a pharmaceutical microsphere composition capable of stably releasing fulvestrant, which comprises the following components:
- polymer A is polylactic acid-glycolic acid copolymer (PLGA);
- Polymer B is polylactic acid (PLA).
- the present invention further provides a drug microsphere composition formulation capable of stably releasing fulvestrant, wherein the weight average molecular weight of the polymer PLGA is 7000-70000, and the molar ratio of lactide to glycolide is 20:80 -80:20; the weight average molecular weight of the polymer PLA is 2000-20000; the weight ratio of the polymer PLGA to the polymer PLA is 95:5-50:50; the active ingredient fulvestrant in the pharmaceutical composition The weight content is 20%-80%; the pharmaceutical composition exists in the form of microspheres.
- the present invention further provides a pharmaceutical microsphere composition formulation capable of stably releasing fulvestrant, wherein the polymer PLGA is carboxyl-terminated PLGA; the polymer PLA is carboxyl-terminated racemic PLA.
- the weight average molecular weight of PLGA is 20000-60000, and the molar ratio of lactide and glycolide is 25:75-75:25;
- the weight average molecular weight of PLA is 2000-10000;
- the weight ratio of PLGA to polymer PLA is 90:10-50:50; the weight content of fulvestrant in the pharmaceutical composition is 50%-80%.
- the weight-average molecular weight of PLGA is 30000, and the mol ratio of lactide and glycolide is 50:50;
- the weight-average molecular weight of PLA is 5000;
- the weight of polymer PLGA and polymer PLA The ratio is 80:20;
- the weight content of fulvestrant in the pharmaceutical composition is about 50%.
- the pharmaceutical composition can maintain the blood drug concentration of fulvestrant above 5 ng/ml in animals for more than 30 days.
- the weight-average molecular weight of PLGA is 30000, and the mol ratio of lactide and glycolide is 50:50;
- the weight-average molecular weight of PLA is 5000;
- the weight of polymer PLGA and polymer PLA The ratio is 80:20;
- the weight content of fulvestrant in the pharmaceutical composition is about 75%.
- the pharmaceutical composition can maintain the blood drug concentration of fulvestrant above 5 ng/ml in animals for more than 30 days.
- the weight average molecular weight of PLGA is 50000, and the mol ratio of lactide and glycolide is 50:50;
- the weight average molecular weight of PLA is 5000;
- the weight average molecular weight of polymer PLGA and polymer PLA The ratio is 80:20;
- the weight content of fulvestrant in the pharmaceutical composition is about 50%.
- the pharmaceutical composition can maintain the blood drug concentration of fulvestrant above 5 ng/ml in animals for more than 60 days.
- the weight average molecular weight of PLGA is 50000, and the mol ratio of lactide and glycolide is 50:50;
- the weight average molecular weight of PLA is 5000;
- the weight average molecular weight of polymer PLGA and polymer PLA The ratio is 80:20;
- the weight content of fulvestrant in the pharmaceutical composition is about 75%.
- the pharmaceutical composition can maintain the blood drug concentration of fulvestrant above 5 ng/ml in animals for more than 60 days.
- sustained-release pharmaceutical compositions all exist in the form of microspheres.
- microspheres referred to in the present invention refer to small spherical or quasi-spherical particles formed by uniformly dissolving and (or) dispersing drugs in two polymer materials, with a particle size ranging from 1 to 200 ⁇ m, and are usually prepared as a mixture for injection. Suspension.
- the intrinsic viscosity of PLGA and PLA is measured according to the following conditions: PLGA or PLA is configured into a 0.5% (w/v) solution with chloroform, and its intrinsic viscosity is measured by Ubbelohde viscometer at 30°C.
- PLGA refers to polylactic acid-glycolic acid copolymer
- PLA refers to polylactic acid.
- the molar ratio of lactide to glycolide in PLGA is indicated in brackets after PLGA, for example "PLGA (50/50)” means polylactic acid-hydroxyl with a lactide to glycolide molar ratio of 50:50 Acetic acid copolymer; "PLGA30k” means polylactic acid-glycolic acid copolymer with a weight average molecular weight of 30,000 Daltons; “PLA5k” means polylactic acid with a weight average molecular weight of 5,000 Daltons, and the weight average molecular weight of the polymer described For example, “PLGA with a molecular weight of 30,000” refers to polylactic acid-glycolic acid copolymer with a weight average molecular weight of about 30,000 Daltons; "PLA with a molecular weight of 5,000” means a weight average molecular weight of about
- the fulvestrant microspheres of the present invention can be prepared by conventional methods, such as emulsification solvent evaporation method, spray drying method or spray extraction method or hot melt extrusion method or phase separation method.
- the invention provides a method for preparing fulvestrant microspheres, which is characterized in that it is prepared by an emulsification-solvent evaporation method.
- the present invention further provides a preparation method of fulvestrant microspheres, which is characterized in that: fulvestrant, polymer A and polymer B are dissolved in an organic solvent, and the organic solvent is injected into an aqueous solution containing a stabilizer , using mechanical stirring, membrane emulsification, homogenizer or static mixer, etc. to emulsify, then evaporate the solvent, wash and sieve to obtain microspheres.
- the organic solvent can be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, chloroethane, trichloroethane, etc.), ethyl acetate, ethyl formate, methylhydrofuran, benzyl alcohol or combinations thereof.
- the stabilizer is selected from at least one of polyvinyl alcohol (PVA), sodium carboxymethylcellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate and sodium polyacrylate, or two or more combination.
- the invention provides a fulvestrant sustained-release microsphere sterile powder for injection, which is characterized in that the sterile powder contains a fulvestrant microsphere composition and a freeze-drying protective agent.
- the lyoprotectant is mannitol.
- the invention provides a preparation method of fulvestrant sustained-release microsphere sterile powder for injection, which is characterized in that: add mannitol and an appropriate amount of water for injection into the microsphere composition, disperse evenly, pour it into freeze-dried placed in a freeze dryer to freeze-dry, the freeze-dried product was sieved and mixed, aseptically subpackaged, and capped to obtain a sterile freeze-dried powder.
- the invention provides a method for preparing fulvestrant sustained-release microsphere injection suspension, which is characterized in that the aseptic freeze-dried powder is suspended in an acceptable dispersion medium.
- the dispersion medium is at least one selected from suspending agents, pH regulators, isotonic regulators, surfactants and water for injection.
- the suspending agent can be selected from at least one of sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate and glycerin.
- the isotonicity adjusting agent may be selected from at least one of sodium chloride, glucose, mannitol, and sorbitol.
- the surfactant is a nonionic surfactant, such as polysorbate series (such as Tween 80 or Tween 60), or poloxamer series (such as poloxamer 188).
- the present invention further provides a preparation method of fulvestrant sustained-release microsphere injection suspension, which is characterized in that: dispersing 500 mg of fulvestrant microsphere freeze-dried powder in 3 ml 80 and 0.5w/w% sodium carboxymethyl cellulose in water for injection to prepare fulvestrant sustained-release microsphere injection suspension.
- dispersing 500 mg of fulvestrant microsphere freeze-dried powder in 3 ml 80 and 0.5w/w% sodium carboxymethyl cellulose in water for injection to prepare fulvestrant sustained-release microsphere injection suspension.
- the viscosity of the fulvestrant sustained-release microsphere injection suspension prepared by the present invention is significantly lower than Injection has good needle penetration and can be quickly injected with a thinner needle.
- the fulvestrant microsphere composition according to the embodiment of the present invention is usually administered parenterally, such as intramuscular injection, subcutaneous injection, intradermal injection, intraperitoneal injection and the like. After the fulvestrant microsphere composition according to the embodiment of the present invention is administered to rats at a dose of 26.25 mg/kg, the blood concentration of fulvestrant in the body can be maintained above 5 ng/ml for more than 60 days.
- the fulvestrant microsphere composition provided by the invention can be used for treating estrogen receptor positive breast cancer.
- the fulvestrant microsphere composition provided by the invention can be used to treat breast cancer patients resistant to aromatase inhibitors.
- the dual-polymer composite formula microspheres of the present invention avoid the use of irritating excipients (ethanol, phenylethyl alcohol, benzyl benzoate, castor oil), and can avoid allergic reactions and related side effects caused thereby.
- irritating excipients ethanol, phenylethyl alcohol, benzyl benzoate, castor oil
- the double polymer composite formula microsphere preparation of the present invention overcomes The sudden drug release phenomenon in the early stage of administration reduces the toxic and side effects caused by the high drug concentration in the blood caused by the sudden release.
- the drug-loading capacity of the double-polymer composite formula microsphere preparation of the present invention is higher, and the content of fulvestrant in the injection microsphere suspension can reach 125mg/ml, which can reduce the injection volume, reduce the pain of the patient, and improve Medication adherence.
- the viscosity of the double-polymer composite formula microsphere suspension of the present invention is greatly reduced, so that finer injection needles can be used for administration, reducing the pain of patients and improving medication compliance.
- the sustained release time of the double-polymer composite formula microspheres of the present invention can reach more than 60 days, thereby reducing the frequency of administration.
- the double-polymer composite formula microsphere preparation prepared by blending two kinds of polymers of the present invention overcomes the drug burst phenomenon in the early stage of administration of single polymer microspheres and the drug release hysteresis in the mid-term of administration, making the drug The release in vivo is smooth and controlled.
- the drug-loading capacity of the double-polymer composite formula microsphere preparation of the present invention is higher, and the content of fulvestrant in the injection microsphere suspension can reach 125 mg/ml, which can reduce the injection volume, reduce the pain of the patient, and improve Medication adherence.
- the double-polymer composite formula microsphere preparation of the present invention releases drugs stably and long-term in animals, and the sustained release time can reach more than 60 days, thereby reducing the frequency of administration.
- Figure 1 The in vitro release curve of the microsphere formulation in Test Example 1, which shows that the PLA composite formulation with a specific molecular weight and ratio has no lag period in vitro release, and the release rate is more uniform.
- Fig. 2 The in vitro release curve of the microsphere formula in Test Example 2, which shows that the in vitro release of the double-polymer composite formula microsphere microspheres of the present invention has no lag period and the release is more uniform.
- Fig. 3 the blood drug concentration curve of the microsphere formulation in Test Example 3, which shows that the blood drug concentration in the double polymer composite formula microsphere of the present invention is more stable.
- Fig. 4 the blood drug concentration curve of the microsphere formula in Test Example 4, which shows that the blood drug concentration in the double polymer composite formula microsphere of the present invention is more stable, and the drug release period can be made longer by formula adjustment.
- FIG. 5 micrographs of the double-polymer composite formula microspheres in Example 9, which show that the double-polymer composite formula microspheres of the present invention are spherical and round, and no drug crystals are exposed.
- the particle size distribution of the microspheres is 20-100 ⁇ m, the drug loading capacity of the microspheres is 73.1%, and the encapsulation efficiency is 90%.
- the microscope photo of the microspheres is shown in Figure 5, which shows that the microspheres of the double-polymer composite formula of the present invention are spherical and round, and no drug crystals are exposed.
- Test drug microsphere formulations with different molecular weights of PLA and incorporation ratios were prepared from Examples 1-6, respectively.
- Test drug Fulvestrant microspheres were prepared from Examples 2, 3, 7, 8 and Comparative Examples 1, 2, 3.
- Double-polymer composite formula microspheres, single-polymer formula microspheres and fulvestrant original preparation of the present invention Rat in vivo release comparison test
- Test drug Fulvestrant microspheres were prepared according to Examples 3 and 9 and Comparative Examples 1 and 2
- Test animals 30 healthy female rats, weighing about 220g
- the animals were randomly divided into 5 groups, 6 animals in each group, and 26.25mg/kg (calculated as fulvestrant) was intramuscularly injected respectively, and 15min, 0.5h, 2h, 4h, 8h, 1d, 2d, 4d after administration, On 7d, 14d, 21d, 28d, 35d, and 42d, 1.5ml of venous blood was collected from the orbit of the rat, and immediately transferred into a heparin-treated centrifuge tube, centrifuged for 10min (4000rpm), separated from the plasma, and stored in a -80°C refrigerator for testing. The concentration of fulvestrant in plasma was monitored, and the results are shown in FIG. 3 .
- the double-polymer composite formula microspheres of the present invention release drugs stably in the body, without obvious burst release and lag phase, and can maintain the blood drug concentration above 5 ng/ml for more than 30 days (Fig. 3 (b)).
- the double-polymer composite formula microsphere of the present invention is significantly better than the original preparation of fulvestrant and single polymer formulation microspheres.
- Double-polymer composite formula microspheres, single-polymer formula microspheres and fulvestrant original preparation of the present invention Rat in vivo release comparison test
- Test drug Fulvestrant microspheres were prepared according to Examples 10 and 11 and Comparative Example 3.
- Test animals 24 healthy female rats, weighing about 220g
- the animals were randomly divided into 4 groups, 6 animals in each group, and 26.25mg/kg (calculated as fulvestrant) was intramuscularly injected respectively, and 15min, 0.5h, 2h, 4h, 8h, 1d, 2d, 4d after administration, On 7d, 14d, 21d, 28d, 35d, 42d, 56d, 64d, 70d, 84d, take 1.5ml of venous blood from the orbit of the rat, and immediately transfer it into a heparin-treated centrifuge tube, centrifuge for 10min (4000rpm), separate the plasma, and Stored in a refrigerator at 80°C until testing. The concentration of fulvestrant in plasma was monitored, and the results are shown in Figure 4.
- the double-polymer composite formula microspheres of the present invention release drugs stably in the body, without obvious burst release and lag phase, and the blood drug concentration of fulvestrant in the body can be maintained above 5 ng/ml for more than 60 days .
- the double-polymer composite formula microspheres of the present invention are significantly better than the original preparation of fulvestrant and single polymer formulation microspheres.
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Abstract
一种氟维司群缓释药物组合物，包含以下组分：氟维司群或其药学上可接受的盐或其溶剂化物、聚合物A和聚合物B，聚合物A为聚乳酸-羟基乙酸共聚物（PLGA），聚合物B为聚乳酸（PLA）。该缓释药物组合物以微球形式存在，可通过相乳化-溶剂挥发法制备得到。该缓释微球可克服药物释放过程中的突释现象和药物迟滞释放问题，具有高载药量、高包封率和长效释放等优点，可用于治疗乳腺癌。
Description
本申请要求申请日为2021年7月2日的中国专利申请2021107513658的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种缓释微球组合物及其制备方法，尤其是氟维司群缓释微球组合物及其制备方法。
乳腺癌是女性发病率最高、死亡率最高的癌症，其中HR阳性乳腺癌的发生发展与体内雌激素水平密切相关。抗雌激素药物是该类型乳腺癌的主要治疗用药。氟维司群(fulvestrant)为一种抗雌激素药物，不同于常规芳香酶抑制剂，该药能下调雌激素受体而无部分激动活性，因此对他莫昔芬治疗失败的患者，氟维司群仍具有临床疗效。
氟维司群水溶性差，口服生物利用度低，目前上市的氟维司群制剂为长效的肌注油性注射剂
配方为5％w/v氟维司群、10％w/v乙醇、10％w/v苯甲醇、15％w/v苯甲酸苄酯、以及60％w/v蓖麻油。由于该制剂为低药物含量的高粘稠溶液，给药时需缓慢肌注两针，每针5ml。由于注射时长，且制剂中含有刺激性成分，造成强烈的肌肉刺激，偶尔会引发过敏反应，影响了用药安全性和顺应性。因此针对氟维司群制剂的改良，一般在保证长效性的同时，从载药量提高、粘度降低、选用刺激性小的辅料等方面进行改进。
专利WO2003006064通过采用乙醇和乳酸酯等溶剂将氟维斯群的浓度提高至100mg/ml，减少了注射体积；专利CN 111388406 A提供了载药量更大的氟维司群药物制剂组方，其报道的较优两组配方分别为：(1)20％PLGA，10％氟维司群，50％乳酸乙酯，8％苯甲醇，10％乙醇配方；(2)25％PLGA，25％氟维司群，45％NMP和5％苯甲醇配方。上述配方载药量可提高到250mg/ml，但是刺激性助剂的使用以及制剂的高粘度仍未得到改善。
专利US2019134059公开了一种氟维司群微粒分散混悬剂配方。该配方属于药物微粒的水混悬液，一方面能够避免蓖麻油、乙醇等刺激性助剂的使用，一方面制剂粘度较低且药物含量可达150mg/ml左右，因此可以提高给药的顺应性，但其释药速度的控制上 不够理想，存在药物突释现象以及药物迟滞释放现象。
专利CN101108168、CN102264372和US2012121711报道了采用单一聚合物制备氟维司群微球的方法，该微球制剂的载药量偏低(载药量在5-20％)，从而需要加大注射体积，同时该微球制剂在体内达到药物有效治疗浓度的释放周期比
短，从而需要增加药物注射的频率，影响了用药的依从性；该微球制剂在动物体内的药物释放行为，或存在药物突释现象，或存在药物迟滞释放现象，给临床用药剂量控制以及给药方式带来困难，影响了用药安全性和依从性。
发明内容
针对氟维司群制剂存在的问题，本发明的发明人提出了用两种聚合物材料复合制备氟维司群微球的解决方案，通过两种聚合物的联合作用，同时控制药物的突释行为和迟滞释放现象，实现药物释放的平稳和长效。
经过发明人的千百次试验，本发明提供了一种能够平稳释放氟维司群的药物微球组合物，包含以下组分：
1)活性成分氟维司群或其药学上可接受的盐或其溶剂化物；
2)聚合物Α；
3)聚合物Β。
其中，聚合物Α为聚乳酸-羟基乙酸共聚物(PLGA)；聚合物Β为聚乳酸(PLA)。
本发明进一步提供了一种能够平稳释放氟维司群的药物微球组合物配方，其中，聚合物PLGA的重均分子量为7000-70000，丙交酯和乙交酯的摩尔比为20∶80-80∶20；聚合物PLA的重均分子量为2000-20000；聚合物PLGA与聚合物PLA的重量比为95∶5-50∶50；所述活性成分氟维司群在药物组合物中的重量含量为20％-80％；所述药物组合物以微球形式存在。
本发明进一步提供了一种能够平稳释放氟维司群的药物微球组合物配方，其中，聚合物PLGA为端羧基PLGA；聚合物PLA为端羧基消旋PLA。
本发明的一个优选实施例中，PLGA的重均分子量为20000-60000，丙交酯和乙交酯的摩尔比为25∶75-75∶25；PLA的重均分子量为2000-10000；聚合物PLGA与聚合物PLA的重量比为90∶10-50∶50；氟维司群在药物组合物中的重量含量为50％-80％。
本发明的一个更优选实施例中，PLGA的重均分子量为30000，丙交酯和乙交酯的摩 尔比为50∶50；PLA的重均分子量为5000；聚合物PLGA与聚合物PLA的重量比为80∶20；氟维司群在药物组合物中的重量含量为50％左右。该药物组合物在动物体内能够维持氟维司群的血药浓度在5ng/ml以上达30天以上。
本发明的一个更优选实施例中，PLGA的重均分子量为30000，丙交酯和乙交酯的摩尔比为50∶50；PLA的重均分子量为5000；聚合物PLGA与聚合物PLA的重量比为80∶20；氟维司群在药物组合物中的重量含量为75％左右。该药物组合物在动物体内能够维持氟维司群的血药浓度在5ng/ml以上达30天以上。
本发明的一个更优选实施例中，PLGA的重均分子量为50000，丙交酯和乙交酯的摩尔比为50∶50；PLA的重均分子量为5000；聚合物PLGA与聚合物PLA的重量比为80∶20；氟维司群在药物组合物中的重量含量为50％左右。该药物组合物在动物体内能够维持氟维司群的血药浓度在5ng/ml以上达60天以上。
本发明的一个更优选实施例中，PLGA的重均分子量为50000，丙交酯和乙交酯的摩尔比为50∶50；PLA的重均分子量为5000；聚合物PLGA与聚合物PLA的重量比为80∶20；氟维司群在药物组合物中的重量含量为75％左右。该药物组合物在动物体内能够维持氟维司群的血药浓度在5ng/ml以上达60天以上。
上述缓释药物组合物均以微球形式存在。
本发明所指的微球是指药物均匀地溶解和(或)分散于两种高分子材料中所构成的小球形或类球形颗粒，粒径范围为1～200μm，且通常制备成注射用混悬剂。
PLGA和PLA的特性粘度按如下条件进行测定：将PLGA或PLA用氯仿配置成0.5％(w/v)的溶液，于30℃采用乌式粘度计测定其特性粘度。
为方便描述，文中所述的PLGA系指聚乳酸-羟基乙酸共聚物；PLA系指聚乳酸。PLGA中丙交酯相对于乙交酯的摩尔比在PLGA之后的括号中表示，例如“PLGA(50/50)”表示丙交酯与乙交酯的摩尔比为50:50的聚乳酸-羟基乙酸共聚物；“PLGA30k”表示为重均分子量30000道尔顿的聚乳酸-羟基乙酸共聚物；“PLA5k”表示为重均分子量5000道尔顿的聚乳酸，其中所描述的聚合物重均分子量为近似值，比如，“分子量为30000的PLGA”系指重均分子量约为30000道尔顿的聚乳酸-羟基乙酸共聚物；“分子量为5000的PLA”系指重均分子量约为5000道尔顿的聚乳酸。
本发明的氟维司群微球可以采用常规方法制备，例如乳化溶剂挥发法，喷雾干燥法 或者喷雾萃取法或者热熔挤出法或者相分离法。
本发明提供了一种氟维司群微球的制备方法，其特征在于采用乳化-溶剂挥发法制备。
本发明进一步提供了一种氟维司群微球的制备方法，其特征在于：将氟维司群、聚合物A和聚合物B溶于有机溶剂中，将有机溶剂注入含有稳定剂的水溶液中，利用机械搅拌、膜乳化、均质机或者静态混合器等方式乳化，然后挥干溶剂，洗涤筛分得到微球。有机溶剂可选自卤代烃(如二氯甲烷、氯仿、氯乙烷、三氯乙烷等)、乙酸乙酯、甲酸乙酯、甲氢呋喃、苯甲醇或其组合。稳定剂选自聚乙烯醇(PVA)、羧甲基纤维素钠(CMC-Na)、聚乙烯吡咯烷酮(PVP)、聚甲基丙烯酸钠和聚丙烯酸钠中的至少一种，或两种及以上组合。
本发明提供了一种注射用氟维司群缓释微球无菌粉末，其特征在于无菌粉末含有氟维司群微球组合物和冻干保护剂。
本发明的一个优选实施例中，冻干保护剂为甘露醇。
本发明提供了一种注射用氟维司群缓释微球无菌粉末的制备方法，其特征在于：将微球组合物中加入甘露醇和适量注射用水，分散均匀后，将其倒入冻干瓶中，放置在冷冻干燥机中冻干，冻干的产品过筛混合，无菌分装，轧盖，得到无菌冻干粉末。
本发明提供了一种氟维司群缓释微球注射用混悬液的制备方法，其特征在于，将无菌冻干粉末混悬于可接受的分散溶媒中。分散溶媒选自助悬剂、pH调节剂、等渗调节剂、表面活性剂和注射用水中的至少一种。助悬剂可以选自羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、海藻酸钠和甘油中的至少一种。等渗调节剂可以选自氯化钠、葡萄糖、甘露醇、和山梨醇中的至少一种。表面活性剂为非离子型表面活性剂，如聚山梨酯系列(如吐温80或吐温60)、或泊洛沙姆系列(如泊洛沙姆188)。
本发明进一步提供了一种氟维司群缓释微球注射用混悬液的制备方法，其特征在于：将500mg氟维司群微球冻干粉末分散于3ml含有0.1w/w％吐温80和0.5w/w％羧甲基纤维素钠的注射用水中，制成氟维司群缓释微球注射用混悬液。当微球的载药量为50％时，混悬液中氟维司群含量为83mg/ml；当微球的载药量为75％时，混悬液中氟维司群含量为125mg/ml，高于
注射剂(
注射剂中氟维司群含量为50mg/ml)。
本发明制得的氟维司群缓释微球注射用混悬液的粘度显著低于
注射剂，通针性良好，可以用更细的针头快速推注。
根据本发明实施方式的氟维司群微球组合物通常采用肠胃外给药，例如肌肉注射、皮下注射、皮内注射、腹膜内注射等。本发明实施方式的氟维司群微球组合物按照26.25mg/kg剂量对大鼠给药后体内维持氟维司群的血药浓度在5ng/ml以上的时间可以达到60天以上。
本发明提供的氟维司群微球组合物可以用于治疗雌激素受体阳性乳腺癌。
本发明提供的氟维司群微球组合物可以用于治疗对芳香酶抑制剂耐药的乳腺癌患者。
本发明的有益效果是：
与上市药物
相比：
1)本发明的双聚合物复合配方微球避免了刺激性辅料(乙醇、苯乙醇、苯甲酸苄酯、蓖麻油)的使用，可以避免由此造成的过敏反应以及相关的毒副作用。
2)本发明的双聚合物复合配方微球制剂克服
给药前期的药物突释现象，降低由突释造成的血液中药物浓度过高而带来的毒副作用。
3)本发明的双聚合物复合配方微球制剂载药量更高，注射微球混悬液中氟维司群的含量可以达到125mg/ml，可以减少注射体积，减轻患者的痛苦程度，提高用药依从性。
4)本发明的双聚合物复合配方微球混悬液粘度大大降低，从而可以使用更细的注射针头给药，减轻患者的痛苦程度，提高用药依从性。
5)本发明的双聚合物复合配方微球的缓释时间可以达到60天以上，从而可以降低给药的频率。
与专利公开的单一聚合物配方微球技术相比：
1)本发明的通过两种聚合物共混制备的双聚合物复合配方微球制剂，克服了单一聚合物微球给药前期的药物突释现象和给药中期的药物释放迟滞问题，使得药物在体内的释放平稳而且可控。
2)本发明的双聚合物复合配方微球制剂载药量更高，注射微球混悬液中氟维司群的含量可以达到125mg/ml，可以减少注射体积，减轻患者的痛苦程度，提高用药依从性。
3)本发明的双聚合物复合配方微球制剂动物体内药物释放平稳而且长效，缓释时间可以达到60天以上，从而可以降低给药的频率。
图1、试验例1中微球配方体外释放曲线，其表明特定分子量和比例的PLA复合配方体外释放无迟滞期，释放速度更均匀。
图2、试验例2中微球配方体外释放曲线，其表明本发明的双聚合物复合配方微球微球体外释放无迟滞期，释放更均匀。
图3、试验例3中微球配方的血药浓度曲线，其表明本发明的双聚合物复合配方微球体内血药浓度更加平稳。
图4、试验例4中微球配方的血药浓度曲线，其表明本发明的双聚合物复合配方微球体内血药浓度更平稳，而且可以通过配方调整使得药物释放周期更长。
图5、实施例9中的双聚合物复合配方微球的显微镜照片，其表明本发明的双聚合物复合配方微球球形圆整，无药物晶体裸露。
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明，具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。
实施例1
称取95mg分子量为30000的PLGA(50/50)、5mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.1％，包封率89％。
实施例2
称取90mg分子量为30000的PLGA(50/50)、10mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布 20-100μm，载药量为51.3％，包封率89％。
实施例3
称取80mg分子量为30000的PLGA(50/50)、20mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.1％，包封率88％。
实施例4
称取70mg分子量为30000的PLGA(50/50)、30mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为51.1％，包封率90％。
实施例5
称取80mg分子量为30000的PLGA(50/50)、20mg分子量为2000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.7％，包封率88％。
实施例6
称取80mg分子量为30000的PLGA(50/50)、20mg分子量为10000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为52.1％，包封率90％。
实施例7
称取90mg分子量为50000的PLGA(50/50)、10mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.3％，包封率89％。
实施例8
称取70mg分子量为50000的PLGA(50/50)、30mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.3％，包封率89％。
实施例9
称取48mg分子量为30000的PLGA(50/50)、12mg分子量为5000的PLA以及140mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，微球载药量为73.1％，包封率90％。微球的显微镜照片如图5所示，图片表明本发明的双聚合物复合配方微球球形圆整，无药物晶体裸露。
实施例10
称取80mg分子量为50000的PLGA(50/50)、20mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为51.1％，包封率91％。
实施例11
称取48mg分子量为50000的PLGA(50/50)、12mg分子量为5000的PLA以及140mg 的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，微球载药量为75.5％，包封率93％。
实施例12
称取80mg分子量为7000的PLGA(50/50)、20mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.2％，包封率89％。
实施例13
称取80mg分子量为70000的PLGA(50/50)、20mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为52.5％，包封率92％。
实施例14
称取80mg分子量为30000的PLGA(75/25)、20mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.2％，包封率88％。
实施例15
称取80mg分子量为30000的PLGA(25/75)、20mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。 之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为51.3％，包封率90％。
实施例16
称取80mg分子量为30000的PLGA(50/50)、20mg分子量为20000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为51.9％，包封率90％。
实施例17
称取60mg分子量为30000的PLGA(50/50)、40mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.5％，包封率88％。
实施例18
称取50mg分子量为30000的PLGA(50/50)、50mg分子量为5000的PLA以及100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.2％，包封率88％。
实施例19
称取80mg分子量为30000的PLGA(50/50)、20mg分子量为5000的PLA以及25mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为19.7％，包封率88％。
实施例20
称取80mg分子量为30000的PLGA(50/50)、20mg分子量为5000的PLA以及65mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为39.0％，包封率88％。
对比实验1
称取100mg分子量为15000的PLGA(50/50)、100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.2％，包封率89％。
对比实验2
称取100mg分子量为30000的PLGA(50/50)、100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为50.5％，包封率90％。
对比实验3
称取100mg分子量为50000的PLGA(50/50)、100mg的氟维司群，搅拌溶解在1ml二氯甲烷中，将其加入到含有冷至6℃的200ml PVA溶液(0.1％)的烧杯中。开启均质机，均质乳化1min。之后室温搅拌3-5h，使有机溶剂挥发。之后用筛网对产物筛分，用去离子水洗涤，冻干，得到粉末状微球。微球粒径分布20-100μm，载药量为49.9％，包封率88％。
试验例1
PLA分子量和比例对氟维司群微球的体外释放的影响
(1)试验材料
试验药物：不同分子量PLA以及掺入比例的微球配方分别由实施例1-6制备得到。
(2)方法与结果
准确称取微球5mg将其分散在80ml含0.1％CTAB的pH7.4的磷酸缓冲液(PB)溶液中，恒温(37℃)恒速(100rpm)振荡，3h，6h，1d，2d，3d，7d，14d，21d，28d时，取出1ml溶液，测试其中药物浓度，并补加1ml新鲜释放介质。其累积释放结果如表1和图1所示：
表1、PLA分子量和比例对氟维司群微球的体外释放的影响
(3)结论：
1)从表1和图1的(a)可以得出PLA5k的优选比例为10-20％；
2)从表1和图1的(b)可以看出PLA的分子量为2000时复合配方的突释增加；PLA分子量为10000时，复合配方突释小，但存在迟滞期。从而得出双聚合物复合配方中的PLA的合适分子量为5000左右。
试验例2
双聚合物复合配方微球(实施例2、3、7、8)和单一聚合物微球(对比例1、2、3)的体外释放对比试验
(1)试验药物：氟维司群微球由实施例2、3、7、8和对比例1、2、3制备得到。
(2)方法与结果
准确称取微球5mg将其分散在80ml含0.1％CTAB的pH7.4的磷酸缓冲液(PB)溶液中，恒温(37℃)恒速(100rpm)振荡，3h，6h，1d，2d，3d，7d，14d，21d，28d，时，取出1ml溶液，测试其中药物浓度，并补加1ml新鲜释放介质。其累积释放结果如表2和图2所示：
表2、双聚合物复合配方微球和单一聚合物配方微球的体外释放数据
(1)结论：
表2和图2的数据表明，与单一聚合物配方的微球(对比例1、2、3)相比，本发明的双聚合物复合配方微球(实施例2、3、7)的体外释放更平稳，突释小，无迟滞期。
试验例3
本发明双聚合物复合配方微球和单一聚合物配方微球以及氟维司群原研制剂
的大鼠体内释放对比试验
(1)试验材料
试验药物：氟维司群微球按照实施例3和9和对比例1和2制备得到
试验动物：健康雌性大鼠30只，体重约220g
(2)方法与结果
动物随机分为5组，每组6只，分别肌注26.25mg/kg(以氟维司群计)，并在给药后15min，0.5h，2h，4h，8h，1d，2d，4d，7d，14d，21d，28d，35d，42d由大鼠眼眶取静脉血1.5ml，并立即移入肝素处理的离心管中，离心10min(4000rpm)，分离血浆，于-80℃冰箱中保存待测。监测血浆中氟维司群的浓度，结果如图3所示。
(3)结论：
图3结果表明：
1)氟维司群原研制剂
体内药物释放突释大，Cmax在20ng/ml以上，后续血药浓度下降较微球组快(图3的(a))；
2)单一聚合物配方微球(对比例1)的体内药物释放行为与原研
相近，出现显著的药物释放突释现象；单一聚合物配方微球(对比例2)则出现显著的释放迟滞期(图3的(a))；
3)本发明的双聚合物复合配方微球在体内药物释放平稳，无明显的突释和迟滞期出现，并且可将血药浓度维持在5ng/ml以上的时间可达30天以上(图3的(b))。
本发明的双聚合物复合配方微球显著优于氟维司群原研制剂
和单一聚合物配方微球。
试验例4
本发明双聚合物复合配方微球和单一聚合物配方微球以及氟维司群原研制剂
的大鼠体内释放对比试验
(1)试验材料
i.试验药物：氟维司群微球按照实施例10和11和对比例3制备得到。
ii.试验动物：健康雌性大鼠24只，体重约220g
(2)方法与结果
动物随机分为4组，每组6只，分别肌注26.25mg/kg(以氟维司群计)，并在给药后15min，0.5h，2h，4h，8h，1d，2d，4d，7d，14d，21d，28d，35d，42d，56d，64d，70d，84d由大鼠眼眶取静脉血1.5ml，并立即移入肝素处理的离心管中，离心10min(4000rpm)，分离血浆，于-80℃冰箱中保存待测。监测血浆中氟维司群的浓度，结果如图4所示。
(3)结论：
图4结果表明：
1)氟维司群原研制剂
体内药物释放突释大，Cmax在20ng/ml以上，后续血药浓度下降较微球组快；
2)单一聚合物配方微球(对比例3)的体内药物释放行为存在明显的突释现象；
3)本发明的双聚合物复合配方微球在体内药物释放平稳，无明显的突释和迟滞期出现，体内氟维司群的血药浓度维持在5ng/ml以上的时间可达60天以上。
4)本发明的双聚合物复合配方微球显著优于氟维司群原研制剂
和单一聚合物配方微球。
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于本领域普通技术人员是显而易见的且包括在本发明的范围内。
Claims (15)
- 一种缓释药物组合物，其特征在于其包含以下组分：1)活性成分氟维司群或其药学上可接受的盐或其溶剂化物；2)聚合物Α；3)聚合物Β。
- 根据权利要求1所述的缓释药物组合物，其特征在于，所述的聚合物Α为聚乳酸-羟基乙酸共聚物(PLGA)；所述的聚合物Β为聚乳酸(PLA)。
- 根据权利要求1-2所述的缓释药物组合物，其特征在于，所述的PLGA的重均分子量为7000-70000，丙交酯和乙交酯的摩尔比为20∶80-80∶20；PLA的重均分子量为2000-20000；PLGA与PLA的重量比为95∶5-50∶50；所述活性成分氟维司群在药物组合物中的重量含量为20％-80％；所述药物组合物以微球形式存在。
- 根据权利要求1-3所述的缓释药物组合物，其特征在于所述PLGA为端羧基PLGA，其重均分子量为20000-60000；PLGA中丙交酯与乙交酯的摩尔比约为25∶75-75∶25。
- 根据权利要求1-3所述的缓释药物组合物，其特征在于所述PLA为端羧基消旋聚乳酸，其重均分子量为2000-10000。
- 根据权利要求1-5所述的缓释药物组合物，其特征在于所述的PLGA与PLA的重量比为90∶10-50∶50。
- 根据权利要求1-6所述的缓释药物组合物，其特征在于所述活性成分氟维司群在药物组合物中的重量含量为50％-80％。
- 一种氟维司群缓释药物组合物，其特征在于，其特征在于其包含以下组分：活性成分氟维司群或其药学上可接受的盐或其溶剂化物、聚乳酸-羟基乙酸共聚物(PLGA)和聚乳酸(PLA)；其中，PLGA的重均分子量为20000-60000，丙交酯和乙交酯的摩尔比为50∶50；PLA的重均分子量为2000-10000；PLGA与PLA的重量比为80∶20；所述活性成分在药物组合物中的重量含量为50％-80％；所述药物组合物以微球形式存在。
- 权利要求1-8所述的缓释药物组合物在治疗乳腺癌中的用途。
- 一种注射用缓释微球，其特征在于包含权利要求1-8所述的缓释药物组合物。
- 根据权利要求10所述的注射用缓释微球，其特征在于含有权利要求1-8所述的缓释药物组合物和冻干保护剂。
- 根据权利要求11所述的注射用缓释微球，其特征在于所述的冻干保护剂为甘露醇。
- 一种注射用缓释微球混悬液，其特征在于权利要求10-12所述的注射用缓释微球混悬于药学可接受的分散溶媒中；所述分散溶媒选自助悬剂、pH调节剂、等渗调节剂、表面活性剂、水、或生理盐水的一种或多种；所述助悬剂选自羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、海藻酸钠、或甘油；所述等渗调节剂选自氯化钠、葡萄糖、甘露醇、或山梨醇；所述表面活性剂为非离子型表面活性剂，选自聚山梨酯系列或泊洛沙姆系列。
- 一种制备权利要求1-8所述的缓释药物组合物的方法，其特征在于选自：相分离法、乳化-溶剂挥发法、或喷雾干燥法。
- 一种权利要求14所述的缓释药物组合物的制备方法，其特征在于：乳化-溶剂挥发法。
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