CN116098872B - Apixaban long-acting microsphere for injection and preparation method thereof - Google Patents
Apixaban long-acting microsphere for injection and preparation method thereof Download PDFInfo
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- CN116098872B CN116098872B CN202211559153.0A CN202211559153A CN116098872B CN 116098872 B CN116098872 B CN 116098872B CN 202211559153 A CN202211559153 A CN 202211559153A CN 116098872 B CN116098872 B CN 116098872B
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- 239000004005 microsphere Substances 0.000 title claims abstract description 127
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 229960003886 apixaban Drugs 0.000 title claims abstract description 104
- 238000002347 injection Methods 0.000 title claims abstract description 23
- 239000007924 injection Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 120
- 239000000725 suspension Substances 0.000 claims abstract description 49
- 239000000243 solution Substances 0.000 claims abstract description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 37
- 229940079593 drug Drugs 0.000 claims abstract description 29
- 229920000642 polymer Polymers 0.000 claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 14
- 239000002245 particle Substances 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 9
- 239000008346 aqueous phase Substances 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 6
- 238000004108 freeze drying Methods 0.000 claims abstract description 4
- 229920001577 copolymer Polymers 0.000 claims description 35
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 34
- 239000000843 powder Substances 0.000 claims description 21
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 17
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- 206010003658 Atrial Fibrillation Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 239000003146 anticoagulant agent Substances 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 206010050902 Postoperative thrombosis Diseases 0.000 claims 1
- 238000007395 thrombosis prophylaxis Methods 0.000 claims 1
- 238000011068 loading method Methods 0.000 abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 9
- 239000012071 phase Substances 0.000 abstract description 9
- 208000032843 Hemorrhage Diseases 0.000 abstract description 6
- 208000007536 Thrombosis Diseases 0.000 abstract description 6
- 208000034158 bleeding Diseases 0.000 abstract description 6
- 230000000740 bleeding effect Effects 0.000 abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract 2
- 229920006237 degradable polymer Polymers 0.000 abstract 1
- 238000005538 encapsulation Methods 0.000 description 19
- 238000003760 magnetic stirring Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 206010067484 Adverse reaction Diseases 0.000 description 5
- 229920001213 Polysorbate 20 Polymers 0.000 description 5
- 230000006838 adverse reaction Effects 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 230000001186 cumulative effect Effects 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 230000008014 freezing Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 229940088679 drug related substance Drugs 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 2
- 108010074860 Factor Xa Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960004203 carnitine Drugs 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 238000004364 calculation method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000005977 kidney dysfunction Effects 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000009861 stroke prevention Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
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
- A61K9/14—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
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
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- Hematology (AREA)
- Urology & Nephrology (AREA)
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Abstract
The invention discloses apixaban long-acting microsphere for injection and a preparation method thereof, wherein degradable polymer is dissolved in organic solvent to obtain polymer solution; uniformly dispersing apixaban micropowder in a polymer solution to form solid-in-oil (S/O) suspension; and (3) dropwise adding the S/O suspension into an aqueous phase under the stirring condition, removing the organic solvent in the suspension, solidifying, washing, collecting the microspheres, and freeze-drying to obtain the microsphere finished product. Wherein the organic solvent is selected from ethyl acetate, dichloromethane, methanol, dimethyl sulfoxide and the like; the water phase contains an additive, and the concentration of the additive is 0.001-0.05 g/mL. The apixaban microsphere disclosed by the invention is simple in preparation process, suitable in particle size, high in drug loading, small in burst release, obvious in slow release effect, and capable of being used for preventing thrombus and reducing bleeding risk.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of apixaban long-acting microspheres for injection.
Background
Apixaban is a new generation of potent, reversible, direct and highly selective active site inhibitors of Xa, the structure of which is shown in the following figure. For the treatment of osteoarthritis-related disorders, including the prevention of venous thromboembolism in patients following hip or knee replacement surgery; stroke prevention in patients with atrial fibrillation; can be used for treating acute coronary syndrome. It acts primarily on factor Xa, binds to factor Xa active sites in a highly complementary manner, inhibits free FXa and binds to blood clots, and thus inhibits thrombin activity. By inhibiting FXa, thrombin generation can be inhibited and thrombosis can be prevented.
The current oral preparation of apixaban on the market at home and abroad mainly comprises the recommended administration of apixaban for 35 days, the recommended continuous administration of apixaban for 36 months and the recommended continuous administration of apixaban for 3 months, wherein the oral preparation of apixaban is required to be taken on time every day, and the compliance of patients is poor; the tablet also contains more auxiliary material components, and some patients allergic to the auxiliary material components are forbidden. Meanwhile, the main adverse reaction of apixaban is bleeding, the common oral immediate-release preparation easily reaches higher required concentration, and the fluctuation of blood concentration is larger, so that serious adverse reaction is caused. Therefore, in order to improve the compliance of patients, reduce the bleeding risk, expand the application range of the patients, and develop the apixaban long-acting microsphere has important significance. The prior art reports on apixaban long-acting microspheres rarely, only one technical proposal is that a halogen organic solvent is used as a solvent, fatty acid or triglyceride is added into a disperse phase, an emulsifying solvent volatilization method and a microfluidic method are used for preparing the microspheres, auxiliary materials fatty acid (C12-C18) or triglyceride are used for inhibiting drug crystallization and forming polymer apixaban precipitate in the prescription, wherein carnitine is needed to be used as a carrier when long-chain fatty acid enters mitochondria for oxidation energy supply, and the carnitine is generated in the liver and kidney of a human body, so that side effects are large, and the use limit is particularly limited for patients with liver and kidney dysfunction. In addition, the traditional O/W emulsification method is difficult to ensure high encapsulation efficiency and drug loading rate of the microspheres, has a large burst release phenomenon, and causes adverse reaction and bleeding.
Disclosure of Invention
In order to solve the technical problems, the apixaban microsphere for injection is prepared by adopting a water-in-oil-in-solid (S/O/W) technology without using unconventional fatty acid or lipid materials, has a simple preparation method, remarkably improves the encapsulation rate and the drug loading rate, can reduce burst release, and further reduces adverse reaction and bleeding phenomenon.
The invention is realized by the following technical scheme:
the preparation method of the apixaban long-acting microsphere for injection comprises the following steps: dispersing apixaban micropowder in a polymer solution to form a suspension; and then dripping the suspension into an aqueous phase solution, removing the organic solvent, and washing to obtain the apixaban long-acting microsphere for injection. Preferably, the suspension is added dropwise into an aqueous phase solution, then the organic solvent is removed by volatilization, and the suspension is solidified in water, then washed and finally freeze-dried, thus obtaining the apixaban long-acting microsphere for injection.
Specifically, the preparation method of the apixaban long-acting microsphere for injection comprises the following steps:
(1) Firstly, dissolving a polymer in an organic solvent to obtain a polymer solution;
(2) Uniformly dispersing apixaban micropowder in a polymer solution to form an S/O suspension;
(3) Dissolving the additive in water to obtain an aqueous phase solution;
(4) Dropwise adding the suspension in the step (2) into the aqueous phase solution in the step (3) under the condition of stirring, removing the organic solvent, washing and collecting the microspheres, and freeze-drying to obtain the apixaban long-acting microspheres for injection.
In the invention, the polymer is selected from one or more of polylactic acid-glycolic acid copolymer, polylactic acid-polyethylene glycol and polycaprolactone, preferably polylactic acid-glycolic acid copolymer. Preferably, the polylactic acid-glycolic acid copolymer has a number average molecular weight of 5 kDa to 150 kDa; the molar ratio of the glycolide to the glycolide is 85:15-50:50; preferably, the molecular weight of the polylactic acid-glycolic acid copolymer is 12 kDa-150 kDa; preferably, the molar ratio of glycolide to glycolide is 50:50.
In the invention, the weight ratio of the apixaban micropowder to the polymer is 1:2-50, preferably 1:3-10.
In the invention, the additive is one or more selected from polyvinyl alcohol, polysorbate 20, polysorbate 80, polyethylene glycol and sodium dodecyl sulfate; preferably polyvinyl alcohol; the concentration of the additive is 0.001 g/mL-0.05 g/mL; preferably 0.01 g/mL to 0.02 g/mL.
In the present invention, the volume ratio of the suspension to the aqueous phase solution is 1:5 to 50, preferably 1:10 to 20, such as 1:15.
In the invention, apixaban bulk drug is prepared into apixaban micropowder; the D50 particle size of the apixaban micropowder is 1-10 mu m; preferably, the apixaban bulk drug is ground to prepare apixaban micro powder; or the apixaban bulk drug is separated out by a solvent to prepare apixaban micro powder.
The invention discloses an apixaban long-acting microsphere for injection prepared by the preparation method of the apixaban long-acting microsphere for injection, and application of the apixaban long-acting microsphere for injection in preparation of a slow-release drug; furthermore, the apixaban long-acting microsphere for injection is applied to the preparation of medicaments for treating diseases related to thrombus prevention after osteoarthritis operation, medicaments for preventing apoplexy of patients suffering from atrial fibrillation, medicaments related to thrombus prevention such as acute coronary syndrome and the like.
The beneficial effects of the invention are as follows: the invention adopts a novel S/O/W preparation method, obviously improves the encapsulation efficiency and the drug loading rate, can reduce burst release, and further reduces adverse reaction and bleeding phenomenon; in particular, the invention uses polymer, organic solvent, additive, water and apixaban micropowder as raw materials, and does not need other substances such as small molecule reagent, fatty acid, glyceride and the like, and the obtained apixaban long-acting microsphere has high encapsulation rate and drug-loading capacity and excellent release performance.
The foregoing description is only an overview of the technical solution of the present invention, and in order to make the technical means of the present invention more clearly understood, it can be implemented according to the content of the specification, and the following detailed description of the preferred embodiments of the present invention will be given with reference to the accompanying drawings.
Drawings
FIG. 1 is a scanning electron microscope image of apixaban microsphere prepared in invention example 2;
FIG. 2 is a scanning electron microscope image of apixaban microsphere prepared in invention example 6;
FIG. 3 is a scanning electron microscope image of apixaban microsphere prepared in invention example 7;
FIG. 4 is a graph showing the in vitro release profile of apixaban microspheres prepared in example 1 and example 2 at 37 ℃;
FIG. 5 is a graph showing the in vitro release profile of apixaban microspheres prepared in example 6 and example 7 at 37 ℃.
Detailed Description
The invention is further described below with reference to examples and figures. The raw materials adopted by the invention are existing products, and the specific preparation operation and performance test are conventional technologies. The apixaban drug substance was ground in a mortar to obtain apixaban fine powder having a D50 of 5 μm, which was used for examples other than comparative example 1 and comparative example 2. In the embodiment, the dropping of the S/O suspension is continuous dropping below the liquid level; removing the organic solvent in a fume hood by adopting a conventional stirring volatilization method; microspheres were collected using stainless steel sieves (pore sizes 38.5 μm and 150 μm, respectively, between them); freeze dryer model: FDU-2110.
Example 1
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 3 mL of ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL being 0.01g/mL under the magnetic stirring at the rpm, the stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, 10 min is solidified, the microspheres are collected and washed 3 times by water, and after the microspheres are pre-frozen in a refrigerator with the temperature of minus 80 ℃ for 10 h, the microspheres are freeze-dried for 48 h, and the microsphere powder apixaban microspheres are obtained.
Example 2
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=60 kDa) in 3 mL of ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL being 0.01 g/mL under the magnetic stirring at the rpm, the stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water to be solidified for 10 min, the microspheres are collected and washed 3 times by water, the suspension is placed into a refrigerator with the temperature of minus 80 ℃ to be pre-frozen for 10 h, and then the suspension is frozen and dried for 48 h, so as to obtain the microsphere powder apixaban microspheres.
Example 3
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=12 kDa) in 3 mL of ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into 45 mL g/mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at the rpm, 17 min (volatilized ethyl acetate) is continuously stirred, then 225 mL water is added, 10 min is solidified, the microspheres are collected and washed 3 times with water, the suspension is placed into a refrigerator with the temperature of minus 80 ℃ for pre-freezing for 10 h, and then 48 h is frozen and dried, thus obtaining the microsphere powder apixaban microspheres.
Example 4
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 5mL of ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL being 0.01g/mL under the magnetic stirring at the rpm, the stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, 10 min is solidified, the microspheres are collected and washed 3 times by water, and after the microspheres are pre-frozen in a refrigerator with the temperature of minus 80 ℃ for 10 h, the microspheres are freeze-dried for 48 h, and the microsphere powder apixaban microspheres are obtained.
Example 5
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 3mL of ethyl acetate, and then uniformly dispersing 50mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL being 0.01 g/mL under the magnetic stirring at the rpm, the stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, 2 h is solidified, the microspheres are collected and washed 3 times by water, and the microspheres are placed into a refrigerator with the temperature of minus 80 ℃ to be pre-frozen for 10h, and then the microspheres are frozen and dried for 48 h, so as to obtain the microsphere powder apixaban microspheres.
Example 6
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 3mL of ethyl acetate, and then uniformly dispersing 50mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 Under the magnetic stirring of rpm, the S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL of 0.01 g/mL, the stirring is continued for 17 min, ethyl acetate is volatilized, the microspheres are collected and washed 3 times by water, the suspension is placed into a refrigerator with the temperature of minus 80 ℃ to be prefreezed for 10 h, and then the suspension is frozen and dried for 48 h, so that the microsphere powder apixaban microspheres are obtained.
Example 7
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=75:25, mw=90 kDa) in 3mL of ethyl acetate, and then uniformly dispersing 50mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 Under the magnetic stirring of rpm, the S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL of 0.01 g/mL, the stirring is continued for 17 min, ethyl acetate is volatilized, the microspheres are collected and washed 3 times by water, the suspension is placed into a refrigerator with the temperature of minus 80 ℃ to be prefreezed for 10 h, and then the suspension is frozen and dried for 48 h, so that the microsphere powder apixaban microspheres are obtained.
Example 8
Firstly, dissolving a polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 200 mg into ethyl acetate of 3.5 mL, and uniformly dispersing 50 mg apixaban micropowder into an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form an S/O suspension; 500 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 0.01 g/mL of 50 mL under the magnetic stirring at the rpm, the stirring is continued for 20 min (volatilized ethyl acetate), then the mixture is added into 200 mL water, 10min is solidified, the microspheres are collected and washed 3 times by water, and after the microspheres are pre-frozen in a refrigerator with the temperature of minus 80 ℃ for 10 h, the microspheres are freeze-dried for 48 h, and the microsphere powder apixaban microspheres are obtained.
Example 9
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 2.5 of mL ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 0.01 g/mL of 40 mL under the magnetic stirring at the rpm, stirring is continued for 15 min (volatilized ethyl acetate), then 250mL of water is added, 10min is solidified, the microspheres are collected and washed 3 times with water, and after the microspheres are pre-frozen in a refrigerator with the temperature of minus 80 ℃ for 10 h, the microspheres are frozen and dried for 48 h, so as to obtain the microsphere powder apixaban microspheres.
Example 10
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 3 mL of ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 700 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL being 0.02 g/mL under the magnetic stirring at the rpm, stirring is continued for 15 min (volatilized ethyl acetate), then the mixture is added into 200mL water, 15 min is solidified, the microspheres are collected and washed 3 times by water, and the microspheres are placed into a refrigerator with the temperature of minus 80 ℃ to be pre-frozen for 10 h, and then are frozen and dried for 48 h, so as to obtain the microsphere powder apixaban microspheres.
Comparative example 1
Dissolving apixaban crude drug in dichloromethane to form an oil phase, dripping the oil phase into Tween 80 solution with the concentration of 0.01g/mL, homogenizing 8: 8 min under 5000 rpm, volatilizing an organic solvent under magnetic stirring (800: 800 rpm) until the drug is separated out, centrifuging, and discarding the supernatant; washing with water, collecting precipitate, pre-freezing at-80deg.C for 10 h, and lyophilizing for 48: 48 h to obtain apixaban micropowder with D50 of 5 μm.
Firstly, dissolving a polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88: 88 kDa) of 150 mg into ethyl acetate of 3mL, and uniformly dispersing 50 mg apixaban micropowder obtained by the solvent precipitation method into an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into 45 mL of 0.01 g/mL polyvinyl alcohol water solution under the magnetic stirring at rpm, 17 min (volatilized ethyl acetate) is continuously stirred, then 225 mL of water is added, 10 min is solidified, the microspheres are collected and washed 3 times with water, the suspension is placed into a refrigerator at the temperature of minus 80 ℃ for pre-freezing for 10h, and then 48 h is frozen and dried, so as to obtain the microsphere powder apixaban microspheres.
Comparative example 2
The apixaban crude drug is ground in a mortar to obtain apixaban micro powder with the D50 of 30 mu m.
Firstly, dissolving 150mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88: 88 kDa) in 3 mL ethyl acetate, and then uniformly dispersing 50mg apixaban micropowder (D50:30 μm) in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 The S/O suspension is dripped into a polyvinyl alcohol water solution with the concentration of 45 mL being 0.01 g/mL under the magnetic stirring at the rpm, the stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, 10 min is solidified, the microspheres are collected and washed 3 times by water, and after the microspheres are pre-frozen in a refrigerator with the temperature of minus 80 ℃ for 10 h, the microspheres are freeze-dried for 48 h, and the microsphere powder apixaban microspheres are obtained.
Comparative example 3
Firstly, dissolving 150 mg of polylactic acid-glycolic acid copolymer (the molar ratio of glycolide to glycolide=50:50, mw=88 kDa) in 3 mL of ethyl acetate, and then uniformly dispersing 50 mg of apixaban micropowder in an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form S/O suspension; 600 Under magnetic stirring at rpm, the S/O suspension 3S is rapidly added into 45 mL aqueous solution of polyvinyl alcohol with the concentration of 0.01g/mL, 1500 rpm is magnetically stirred for 10 minutes, then the formed emulsion 10S is rapidly added into 225 mL water, 500 rpm is magnetically stirred for 5 hours, microspheres are collected and washed 3 times by water, and after being pre-frozen in a refrigerator at-80 ℃ for 10 h, the microspheres are freeze-dried for 48 h, so as to obtain microsphere powder apixaban microspheres.
Comparative example 4
Weighing 50 mg apixaban micropowder and 150 mg polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) and dissolving in 3mL methylene dichloride together to form an oil phase, continuously dropwise adding the oil phase into 45 mL polyvinyl alcohol aqueous solution with mass concentration of 0.01g/mL for emulsification under the condition of 350 rpm, continuously stirring for 10 minutes, and volatilizing methylene dichloride; adding the preliminarily formed microspheres into 225 mL water, solidifying 10min, collecting the microspheres, washing with water for 3 times, pre-freezing in a refrigerator at-80 ℃ for 10 h, and freeze-drying for 48 h to obtain microsphere powder apixaban microspheres.
Test example 1 microsphere particle size
Microspheres prepared in examples 1 to 10 and comparative examples 1 to 4 were respectively dispersed in water, and the particle size of the microspheres was measured by using a BT-2001 laser particle size distribution analyzer. The results are shown in Table 1, and the particle size (particularly median diameter) of the microspheres of the examples is below 90 mm, and the microspheres are suitable for injection.
As can be seen from Table 1, the microspheres of comparative example 1 have a larger particle size than those of example 1, and the drug substance reduced by the milling method has a good dispersibility and a preferable particle size than the drug substance reduced by the solvent precipitation method. The microspheres prepared in comparative example 4 had a larger particle size than the examples, and the main microspheres were inferior in formability and dispersibility.
Test example 2 microsphere morphology
The microspheres prepared in examples 2, 6 and 7 were observed by a scanning electron microscope, and the results are shown in fig. 1,2 and 3, respectively, and it can be seen that the apixaban microspheres are spherical or spheroid and have smooth surfaces.
Test example 3 microsphere drug loading and encapsulation efficiency
Octadecylsilane chemically bonded silica is used as a filler; using 10 mmol/L ammonium acetate and acetonitrile (65:35) as mobile phases, regulating the flow rate to ensure that the main peak outlet time is about 9 minutes, and the detection wavelength is 280: 280 nm; weighing apixaban reference substance 10 mg, placing in a 50mL volumetric flask, adding mobile phase, dissolving, diluting to scale, and shaking; weighing 1mL, placing in a 10mL volumetric flask, diluting to scale with mobile phase, and shaking to obtain control solution; microspheres 10 mg prepared in examples 1-10 were respectively taken, precisely weighed, placed in a 10mL centrifuge tube, added with 1mL of acetonitrile for complete dissolution, added with 7 mL methanol for precipitation of polylactic acid-glycolic acid copolymer, centrifuged (10000 r/min,10 min), and the supernatant was taken in a 50mL volumetric flask, and added with methanol for volume metering to scale. Precisely measuring 20mL, injecting into a liquid chromatograph, and recording a chromatogram; and taking apixaban reference substance, measuring by the same method, and calculating by peak area according to an external standard method to obtain the total medicine quantity. Further converted into the drug-loading rate and encapsulation efficiency of the microsphere. The results are shown in Table 2. The calculation formula of drug loading and encapsulation efficiency is as follows:
The microspheres prepared in the examples have higher encapsulation efficiency than those prepared in the comparative examples. It can be seen that varying the molecular weight and concentration of PLGA50/50 has little effect on microsphere encapsulation efficiency and drug loading. Although the PLGA type has no obvious effect on the encapsulation rate of the microsphere, the PLGA type has larger effect on the later release of the microsphere, and the PLGA50/50 has better release degree than the PLGA 75/25. The increase of curing in the process can improve the encapsulation efficiency of the microspheres to a certain extent, but the decrease of the encapsulation efficiency of the microspheres is caused after the curing time is increased from 10min to 120 min. The apixaban crude drug D50 is greatly improved in encapsulation efficiency, and the apixaban crude drug D50 can be reduced to 5 mu m by adopting a solvent precipitation method, but compared with a grinding method, the apixaban crude drug D50 has the advantages that the microsphere particle size formed by the crude drug with reduced particle size is larger, the drug encapsulation effect is poor, and the encapsulation efficiency is about 84%.
The result of comparative example 3 shows that the result of the encapsulation efficiency of the apixaban microsphere prepared by the existing preparation method of the drug-loaded microsphere is relatively poor, and the expected ideal effect cannot be achieved, which indicates that the existing preparation method of the drug-loaded microsphere is not applicable to the preparation of the apixaban microsphere. The result of comparative example 4 shows that the Apixaban microsphere is prepared by adopting the O/W method, and the phenomenon of 'quicksand' appears in the preparation process (drug precipitation), so that the microsphere is difficult to encapsulate, and the microsphere encapsulation rate is low, which is only about 37%. The apixaban microsphere is prepared by adopting an S/O/W method, so that the phenomenon of 'quicksand' of the drug can be avoided, the encapsulation efficiency is above 85%, and in particular, the apixaban microsphere does not use fatty acid and other auxiliary materials, has relatively simpler components, and has higher drug loading rate and safer property.
Test example 4 in vitro Release of microspheres
2G sodium hydroxide was weighed and dissolved in 500: 500 mL water, 105: 105 mL was discarded, 6.8: 6.8 g potassium dihydrogen phosphate and 605: 605 mL water were added to dissolve together, and 0.02% (w/v) Tween 20 was added to obtain a PBS solution containing 0.02% Tween 20 with a release medium of pH 7.4.
20 Mg balls of the Aripid Sha Banwei prepared in examples 1-2 and examples 6-7 were weighed separately into 50mL conical flasks with stoppers, 50mL of PBS solution containing 0.02% Tween 20 was added, the mixture was placed into a 37℃water bath constant temperature shaking pot, 1mL was taken at different time points of 4h, 1 d, 2d, 3 d and 7 d … …, centrifuged (10000 rpm,10 min), the supernatant was taken out to 0.7 mL, and 0.7 mL of PBS solution containing 0.02% Tween 20 was supplemented, the solution was changed every other day, and then HPLC analysis was performed to calculate the cumulative release percentage, and a cumulative release percentage-time release profile was drawn. The results are shown in FIGS. 4 to 5. From the release profile of fig. 4, the microsphere of example 1 has a small burst release, the burst release in 4h is only 2.26%, the cumulative release in 24. 24h is 8.27%, the overall release is slow, the sustained release can be achieved for 84 days, the cumulative release reaches 90%, and the obvious slow release effect is achieved. From the release profile of FIG. 5, the in vitro release of example 6 was slower than that of example 7, indicating that the use of the polylactic acid-glycolic acid copolymer in a ratio of 50/50 had a superior in vitro release, which was sustained for 42 days or more. The composition is applicable to the treatment of antithrombotic related diseases such as the prevention of thrombus after osteoarthritis operation, the prevention of apoplexy of patients suffering from atrial fibrillation and the like.
In conclusion, the S/W/O method and the grinding method are combined to control the particle size of the bulk drug, so that better encapsulation efficiency and drug loading rate can be obtained, and particularly, the release performance of the apixaban microsphere is very good.
Claims (6)
1. The preparation method of the apixaban long-acting microsphere for injection is characterized by comprising the following steps: dissolving a polymer in an organic solvent to obtain a polymer solution; dispersing apixaban micropowder in a polymer solution to form a suspension; then dropwise adding the suspension into the aqueous phase solution under the stirring condition, volatilizing the organic solvent and solidifying, washing, collecting, and freeze-drying to obtain the apixaban long-acting microsphere for injection; in the polymer solution, the polymer is selected from polylactic acid-glycolic acid copolymer, and the organic solvent is selected from ethyl acetate; in the suspension, the weight ratio of apixaban micro powder to polymer is 1:2-50; the volume ratio of the suspension to the aqueous phase solution is 1:5-50; the aqueous phase solution comprises an additive and water, wherein the additive is selected from polyvinyl alcohol, and the concentration of the additive is 0.001-0.05 g/mL; the number average molecular weight of the polylactic acid-glycolic acid copolymer is 5 kDa-150 kDa, and the molar ratio of the glycolide to the glycolide is 85:15-50:50.
2. The preparation method of the apixaban long-acting microsphere for injection according to claim 1, wherein apixaban bulk drug is prepared into apixaban micro powder; the D50 particle size of the apixaban micropowder is 1-10 mu m.
3. The method for preparing the apixaban long-acting microsphere for injection according to claim 2, wherein apixaban bulk drug is ground to prepare apixaban micro powder.
4. The apixaban long-acting microsphere for injection prepared by the preparation method of the apixaban long-acting microsphere for injection according to claim 1.
5. The use of apixaban long-acting microsphere for injection according to claim 4 for preparing a sustained release medicament.
6. The use of the apixaban long-acting microsphere for injection according to claim 4 for preparing a medicament for treating osteoarthritis postoperative thrombosis prevention diseases, a medicament for preventing apoplexy in patients with atrial fibrillation, and an antithrombotic medicament for acute coronary syndrome.
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