CN116098872A - 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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- 229960003886 apixaban Drugs 0.000 title claims abstract description 107
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- 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
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- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
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- 238000003801 milling Methods 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K9/0012—Galenical forms characterised by the site of application
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- 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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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P9/00—Drugs for disorders of the cardiovascular system
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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 0.01g 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 a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, 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; 600 The S/O suspension is dripped into 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at rpm, stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, solidification is carried out for 10 min, 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 frozen and dried for 48 h, thus obtaining microsphere powder apixaban microspheres.
Example 2
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=60 kDa) of 150 mg into 3 mL ethyl acetate, 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; 600 The S/O suspension is dripped into a 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at the rpm, stirring is continued for 17 min (ethyl acetate volatilization), then 225 mL water is added for solidification 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 ℃ for pre-freezing for 10 h, and then the suspension is frozen and dried for 48 h, thus obtaining the microsphere powder apixaban microspheres.
Example 3
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=12 kDa) of 150 mg into 3 mL ethyl acetate, and uniformly dispersing 50 mg apixaban micro powder into an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form an S/O suspension; 600 The S/O suspension is dripped into 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at the rpm, stirring is continued for 17 min (ethyl acetate volatilization), then the mixture is added into 225 mL water, solidification is carried out for 10 min, the microspheres are collected and washed 3 times by water, the suspension is put into a refrigerator with the temperature of minus 80 ℃ for pre-freezing for 10 h, and then the suspension is frozen and dried for 48 h, thus obtaining the microsphere powder apixaban microspheres.
Example 4
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 5 mL ethyl acetate, 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; 600 The S/O suspension is dripped into 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at rpm, stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, solidification is carried out for 10 min, 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 frozen and dried for 48 h, thus obtaining microsphere powder apixaban microspheres.
Example 5
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, 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; 600 The S/O suspension is dripped into a 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at the rpm, stirring is continued for 17 min (ethyl acetate volatilization), then the mixture is added into 225 mL water, 2 h 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 6
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, 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; 600 Under the magnetic stirring at rpm, the S/O suspension is dripped into 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring is continued for 17 min, ethyl acetate is volatilized, 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 the suspension is frozen and dried for 48 h, so as to obtain the microsphere powder apixaban microspheres.
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 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 the magnetic stirring at rpm, the S/O suspension is dripped into 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL, stirring is continued for 17 min, ethyl acetate is volatilized, 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 the suspension is frozen and dried for 48 h, so as to obtain the microsphere powder apixaban microspheres.
Example 8
Firstly, dissolving a polylactic acid-glycolic acid copolymer (the molar ratio of the glycolide to the glycolide=50:50, and the Mw=88 kDa) of 200 mg into 3.5 mL ethyl acetate, and then 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 50mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at rpm, stirring is continued for 20 min (ethyl acetate volatilization), then 200 mL water is added, solidification is carried out for 10 min, 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 frozen and dried for 48 h, thus obtaining microsphere powder apixaban microspheres.
Example 9
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into ethyl acetate of 2.5 mL, and uniformly dispersing the apixaban micropowder of 50 mg into an ethyl acetate solution containing the polylactic acid-glycolic acid copolymer to form an S/O suspension; 600 The S/O suspension is dripped into a 40 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at the rpm, stirring is continued for 15 min (ethyl acetate volatilization), then the mixture is added into 250mL of water, solidification is carried out for 10 min, 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, thus obtaining the microsphere powder apixaban microspheres.
Example 10
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, 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; 700 The S/O suspension is dripped into a 45 mL polyvinyl alcohol water solution with the concentration of 0.02 g/mL under the magnetic stirring at the rpm, stirring is continued for 15 min (ethyl acetate volatilization), then the mixture is added into 200 mL water, solidification is carried out for 15 min, 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 frozen and dried for 48 h, thus obtaining 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 for 8 min under 5000 rpm, volatilizing an organic solvent under magnetic stirring (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 h to obtain apixaban micropowder with D50 of 5 μm.
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, 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 an S/O suspension; 600 The S/O suspension is dripped into 45 mL polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at rpm, stirring is continued for 17 min (ethyl acetate volatilization), then the mixture is added into 225 mL water, solidification is carried out for 10 min, microspheres are collected and washed 3 times by water, the suspension is put into a refrigerator with the temperature of minus 80 ℃ for pre-freezing for 10 h, and then the suspension is frozen and dried for 48 h, thus obtaining the microsphere powder apixaban microsphere.
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 a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, and then uniformly dispersing 50 mg apixaban micropowder (D50:30 μm) 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 polyvinyl alcohol water solution with the concentration of 0.01g/mL under the magnetic stirring at rpm, stirring is continued for 17 min (volatilized ethyl acetate), then the mixture is added into 225 mL water, solidification is carried out for 10 min, 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 frozen and dried for 48 h, thus obtaining microsphere powder apixaban microspheres.
Comparative example 3
Firstly, dissolving a polylactic acid-glycolic acid copolymer (molar ratio of glycolide to glycolide=50:50, mw=88 kDa) of 150 mg into 3 mL ethyl acetate, 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; 600 Under the magnetic stirring of rpm, the S/O suspension 3S is quickly added into a polyvinyl alcohol aqueous solution with the concentration of 45 mL of 0.01g/mL, the magnetic stirring is carried out for 10 minutes at 1500 rpm, then the formed emulsion 10S is quickly added into 225 mL water, the magnetic stirring is carried out for 5 hours at 500 rpm, the microspheres are collected and washed 3 times by water, the microspheres are placed in a refrigerator with the temperature of minus 80 ℃ for pre-freezing for 10 h, and the microspheres are obtained by freeze-drying 48 h.
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 3 mL 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 for 10 min, collecting the microspheres, washing with water for 3 times, pre-freezing for 10 h in a refrigerator at-80 ℃, 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 within the range of 90 mm and is 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; the flow rate is adjusted to lead the main peak to be out of the peak time to be about 9 minutes by taking 10 mmol/L ammonium acetate and acetonitrile (65:35) as mobile phases, and the detection wavelength is 280 nm; weighing apixaban reference substance 10 mg, placing in a50 mL volumetric flask, adding mobile phase to dissolve and dilute to scale, and shaking; weighing 1mL, placing in a 10 mL 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 10 mL centrifuge tube, added with 1mL of acetonitrile for complete dissolution, added with 7 mL of methanol for precipitation of polylactic acid-glycolic acid copolymer, centrifuged (10000 r/min,10 min), and the supernatant was taken in a50 mL volumetric flask, and added with methanol for volume metering to scale. Precisely measuring 20 mL, 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 10 min 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
2, g sodium hydroxide was weighed and dissolved in 500, mL water, 105, mL was discarded, 6.8, g potassium dihydrogen phosphate and 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.
Separately, 20 mg balls of apices Sha Banwei prepared in examples 1-2 and examples 6-7 were weighed into 50mL conical flasks with stoppers, 50mL 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 4 h, 1 d, 2 d, 3 d and 7 d … …, centrifuged (10000 rpm,10 min), the supernatant was taken out to 0.7 mL, and 0.7 mL 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 in example 1 has a small burst release, the burst release in 4 h is only 2.26%, the cumulative release in 24 h 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 (10)
1. The preparation method of the apixaban long-acting microsphere for injection is characterized by comprising the following steps: dispersing apixaban micropowder in a polymer solution to form a suspension; and then 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.
2. The method for preparing apixaban long-acting microsphere for injection according to claim 1, wherein the polymer in the polymer solution is one or more selected from polylactic acid-glycolic acid copolymer, polylactic acid-polyethylene glycol and polycaprolactone, and the solvent comprises ethyl acetate.
3. 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; in the suspension, the weight ratio of the apixaban micropowder to the degradable polymer is 1:2-50.
4. The method for preparing apixaban long-acting microspheres for injection according to claim 3, wherein apixaban bulk drug is ground to prepare apixaban micro powder.
5. The method for preparing apixaban long-acting microsphere for injection according to claim 1, wherein the volume ratio of the suspension to the aqueous solution is 1:5-50.
6. The method for preparing apixaban long-acting microspheres for injection according to claim 1, wherein the suspension is added dropwise to the aqueous phase solution.
7. The method for preparing apixaban long-acting microspheres for injection according to claim 1, wherein the aqueous solution comprises an additive and water, the additive being one or more selected from the group consisting of polyvinyl alcohol, polysorbate, polyethylene glycol and sodium dodecyl sulfate; the concentration of the additive is 0.001-0.05 g/mL.
8. The apixaban long-acting microsphere for injection prepared by the preparation method of the apixaban long-acting microsphere for injection according to claim 1.
9. The use of apixaban long-acting microsphere for injection according to claim 1 for preparing a sustained release medicament.
10. The use of the apixaban long-acting microsphere for injection according to claim 1 for preparing medicines for treating diseases related to thrombus prevention after osteoarthritis operation, medicines for preventing apoplexy of patients suffering from atrial fibrillation, medicines related to antithrombotic property such as acute coronary syndrome and the like.
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| CN109010273A (en) * | 2018-10-08 | 2018-12-18 | 中国药科大学 | A kind of Eliquis nano suspension and preparation method thereof |
| KR102045721B1 (en) * | 2019-03-27 | 2019-11-18 | 주식회사 씨트리 | Compositions of dispersion phase for preparation of apixaban loaded microsphere and biocompatible polymer based apixaban loaded microsphere prepared therefrom |
| WO2020165379A1 (en) * | 2019-02-15 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Plga-based microspheres, preparation methods and uses thereof |
| CN113786393A (en) * | 2021-09-07 | 2021-12-14 | 浙江工业大学 | Rivaroxaban microsphere and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109010273A (en) * | 2018-10-08 | 2018-12-18 | 中国药科大学 | A kind of Eliquis nano suspension and preparation method thereof |
| WO2020165379A1 (en) * | 2019-02-15 | 2020-08-20 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Plga-based microspheres, preparation methods and uses thereof |
| KR102045721B1 (en) * | 2019-03-27 | 2019-11-18 | 주식회사 씨트리 | Compositions of dispersion phase for preparation of apixaban loaded microsphere and biocompatible polymer based apixaban loaded microsphere prepared therefrom |
| CN113786393A (en) * | 2021-09-07 | 2021-12-14 | 浙江工业大学 | Rivaroxaban microsphere and preparation method and application thereof |
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