CN106913528A - Eliquis micropill and preparation method thereof - Google Patents
Eliquis micropill and preparation method thereof Download PDFInfo
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- CN106913528A CN106913528A CN201511003627.3A CN201511003627A CN106913528A CN 106913528 A CN106913528 A CN 106913528A CN 201511003627 A CN201511003627 A CN 201511003627A CN 106913528 A CN106913528 A CN 106913528A
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- eliquis
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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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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Abstract
The present invention relates to Eliquis micropill and preparation method thereof, blank capsule core, medicated layer and coatings are followed successively by from inside to outside, wherein, the medicated layer is made up of micronizing Eliquis, adhesive and disintegrant, and the Eliquis micropill is included：The blank capsule core of 60-84 weight portions, the micronizing Eliquis of 2-7 weight portions；The binder of 3-10 weight portions；5-20 part by weight of disintegrant；And the coatings of 2-8 weight portions.Thus, the Eliquis micropill outward appearance rounding for obtaining, uniform particle diameter, compared to marketed tablet, with more preferable stability, faster, bioavilability is higher for dissolution rate.
Description
Technical field
The invention belongs to field of medicine preparations, specifically, the present invention relates to a kind of Eliquis micropill and preparation method thereof.
Background technology
Chemical entitled 4,5,6,7- tetrahydrochysenes -1- (4- the methoxyphenyls) -7- oxos -6- [4- (2- of Eliquis (compound shown in formula 1)
Oxo -1- piperidyls) phenyl] -1H- pyrazolos [3,4-C] pyridine-3-carboxamide is a kind of oral Selective activation X factors suppression
Preparation, directly acts on factor Xa, is developed jointly by Pfizer and Bristol Myers Squibb, is ratified by FDA in 2012
Listing, can pre- preventing thrombosis.
However, because Eliquis are water insoluble, have that dissolution velocity is slow, dissolution in vitro is low, bioavilability is low lacks
Point, the absorption to medicine has a significant impact.
Active material is the crystal formation of N-1 or H2-2 in the pharmaceutical composition that patent CN102770126A is provided, and it is included has
D90 is equal to or less than the crystalline Eliquis particle and medicinal diluent or load of about 89 μm of (being measured through laser scattering method)
Body, most preferably D90 are less than 25 μm.Specify that its granularity is that determination is measured by laser scattering technology in the specification, and
Composition is prepared using dry granulation process.This invention increases dissolution by reducing raw material granularity, and it uses dry granulation process
Prepare, there is the problems such as time-consuming, energy consumption consumption is big, low production efficiency, and product yield is relatively low in industrialized production.
Patent CN102908324A in order to solve the above technical problems, Eliquis are prepared into solid dispersions, then with place
The microcrystalline cellulose of side's amount；PVPP；Superfine silica gel powder is well mixed direct tablet compressing.The process for preparing solid dispersions is：
Macrogol 6000 is heated to 60 DEG C of meltings, it is 10000-20000r/min to add Eliquis to be stirred vigorously；After stirring
Fused mass 0 DEG C of solidification 2h of rapid cooling under conditions of -20 DEG C；Solidfied material is crushed and crosses 80 mesh sieves and 20 DEG C of drying under reduced pressure 4h,
Obtain Eliquis solid dispersions.Although the patent solves the problems, such as the dissolution of Eliquis in theory, its water solubility is carried
Body has used 10-20 parts of surfactant polyethylene 6000, and need to heat in preparation technology, be stirred vigorously, low temperature cold
But solidification, normal temperature drying under reduced pressure, complex steps, and be difficult to operate, are not easy to realize a large amount of productions；Main is in patient
Also substantial amounts of Macrogol 6000 has been taken while medication, bigger side effect and adverse reaction has been brought to patient.
Therefore, current Eliquis preparation still has much room for improvement.
The content of the invention
It is contemplated that solving one of technical problem in correlation technique to a certain extent.Therefore, one object of the present invention exists
In a kind of Eliquis micropill is proposed, it takes in industrialized production, and short, energy ezpenditure is small, and production efficiency easy to operate is high,
Product yield is high, and product quality stabilization, and compared to marketed tablet, with more preferable stability, dissolution rate is faster, raw
Thing availability is higher.
According to the first aspect of the invention, the present invention proposes a kind of Eliquis micropill, and the Eliquis micropill is by introversion
Blank capsule core, medicated layer and coatings are followed successively by outward, wherein, the medicated layer is by micronizing Eliquis, binder and collapses
Solution agent is constituted, and the Eliquis micropill is included：The blank capsule core of 60-84 weight portions, the micronizing Ah piperazine of 2-7 weight portions is husky
The coatings of class, the binder of 3-10 weight portions, 5-20 part by weight of disintegrant and 2-8 weight portions.
Some embodiments of the invention, the Eliquis micropill is included：The blank capsule core of 60-80 weight portions, 2-6 weights
The coating of the micronizing Eliquis of amount part, the binder of 3-8 weight portions, the disintegrant of 8-16 weight portions and 2~5 weight portions
Layer.
Some embodiments of the invention, the applicant has been surprisingly found that medicated layer binder is in control Eliquis micropill
Suspension, its concentration is 2.0 mass %-5.0 mass %, can produce unexpected technique effect to the quality assurance of product,
Medicine-feeding rate is low when can solve the problems, such as that blank capsule core is added medicine to, while can solve the problems, such as that Eliquis are difficult dissolution.In addition
Due to Eliquis, hygroscopicity is very strong in itself, product absorbed water in prolonged storage caused by dissolution is slack-off, bad stability
Phenomenon, it is also possible to be well solved by controlling this concentration.By research, when bonding agent concentration is less than 2.0 mass %,
Whether solid phase lamination or liquid phase lamination are taken, medicine-feeding rate is all relatively low, causes the waste of raw material, and product yield is low.Simultaneously
Bonding agent concentration is too low, and the compactness of micropill is poor, and due to Eliquis, hygroscopicity is strong in itself, in prolonged storage easily
Water suction causes that dissolution is slack-off, stability is bad.Bonding agent concentration is higher than 5.0 mass %, and micropill not easy disintegrating, dissolution is slow,
And glutinous ball phenomenon is easily produced in technical process, it is impossible to ensure product quality.And work as Eliquis micropill in preparation technology
Bonding agent concentration in 2.0 mass %-5.0 mass %, ensure that product quality, improve product bioavilability and
Stability.
Some embodiments of the invention, the Eliquis can be micronized, the system of the Eliquis containing micronizing
Agent can further improve the bioavilability of product, be taken with the waste for reducing drug, and can avoid heavy dose of administration
The adverse reaction of appearance.According to a particular embodiment of the invention, it is described micronizing Eliquis particle diameter D90 for 100 μm with
Under, preferably less than 10 μm.
Some embodiments of the invention, micronizing includes ball mill grinding, vibrating membrane crushing or pharmacy micro mist etc. air-flow crushing
Change technology.The particle diameter of particulate can be determined using Laser Scattering Particle instrument (Mastersizer 20000).
Some embodiments of the invention, the blank capsule core refers to without drug ingedient, for being risen necessary to prepare micropill
Mould master batch, can be selected from microcrystalline cellulose capsule core, sucrose capsule core, sucrose-starch capsule core and lactose capsule core, preferably lactose capsule core.
Embodiments in accordance with the present invention, the binder is selected from starch slurry, PVP, methylcellulose (MC), hydroxypropyl
Base cellulose (HPC), Hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC-Na), polyvinylpyrrolidine
At least one in ketone (PVP), polyethylene glycol (PEG), preferably PVP, hydroxypropyl cellulose and hypromellose
At least one in element, preferably PVP.
Embodiments in accordance with the present invention, the disintegrant is selected from Ac-Di-Sol (CCNa), low-substituted hydroxypropyl
At least one in base cellulose (L-HPC), microcrystalline cellulose, PVPP and sodium carboxymethyl starch (CMS-Na),
It is preferred that at least one in Ac-Di-Sol and microcrystalline cellulose.
According to the second aspect of the invention, the present invention also proposes a kind of Eliquis micro pill capsule, the Eliquis micropill glue
It is intracapsular to be filled with above-mentioned Eliquis micropill.When Eliquis are made into tablet, even if by moisture control in drying process of pelletizing
Be obtained it is very low, but still can bring moisture into compressing tablet, but Eliquis are made encapsulated after micropill, can make whole
Preparation technology is carried out in constantly drying, until being coated link, can effectively control the moisture in micropill.
As embodiments of the invention part is proved, as the content of micro pill capsule, prepare according to embodiments of the present invention
The Eliquis micropill for obtaining, micropill surface smoothness is high, outward appearance rounding, uniform particle diameter, hardness are moderate, storage stability
Height, and described Eliquis micropill, compared to marketed tablet, with dissolution rate higher, bioavilability is also obtained
Greatly improve.
According to the third aspect of the invention we, the present invention proposes a kind of method for preparing above-mentioned Eliquis micropill, including：There is provided
The blank capsule core of 60-84 weight portions；By the micronizing Eliquis of 2-7 weight portions, the binder and 5-20 of 3-10 weight portions
The disintegrant dissolving of weight portion, medicine-feeding treatment is carried out using liquid phase lamination method or solid-phase layer area method to the blank capsule core, with
Just medicated layer is formed on the surface of the blank capsule core；Treatment is dried to the blank capsule core that the surface forms medicated layer；
The blank capsule core that the medicated layer is formed by the surface of the dried process is coated treatment, so as in the medicated layer
Surface formed coatings, to obtain Eliquis micropill.
Some embodiments of the invention, the medicine-feeding treatment is carried out using multifunctional fluidized bed or centrifugal granulator.Root
According to one embodiment of the present of invention, the medicine-feeding treatment is using multifunctional fluidized bed.
Some embodiments of the invention, the liquid phase lamination method includes：The micronizing Ah piperazine of the 2-7 weight portions is husky
Class, the binder of 3-10 weight portions, the disintegrant of 5-20 weight portions is dissolved in 1000~1100 milliliters of water, stirs simultaneously
Sieving is processed, to obtain carrying medicine suspension；The load medicine suspension is carried out into medicine-feeding treatment to the blank capsule core.
Some embodiments of the invention, the solid-phase layer area method includes：The binder of the 3-10 weight portions is dissolved in
In 1000~1100 milliliters of water, stir and sieve treatment, to obtain upper drug solns；By the micro mist of the 2-7 weight portions
The disintegrant for changing Eliquis and 5-20 weight portions is well mixed, and obtains medicine mixed-powder；By upper drug solns and described
Medicine mixed-powder to the blank capsule core to carrying out medicine-feeding treatment.
Some embodiments of the invention, the medicine-feeding treatment is carried out using multifunctional fluidized bed, controls the medicine-feeding treatment
Condition be：Air quantity is 100-105m3/h, and liquid supply speed is 6-10g/min, and atomizing pressure is 1.7bar, and EAT is
50-55 DEG C, temperature of charge is 40-45 DEG C, and spacer ring is highly 10cm；Dry 30min；
Some embodiments of the invention, the Cotton seeds are carried out using multifunctional fluidized bed, control the Cotton seeds
Condition be：Air quantity is 110-115m3/h, and liquid supply speed is 10-12g/min, and atomizing pressure is 2.0bar, and EAT is
50-55 DEG C, 40-45 DEG C of temperature of charge, spacer ring height 15cm；Dry 30min.
In the fourth aspect of the present invention, the present invention proposes a kind of method for preparing above-mentioned Eliquis micropill, and methods described is used
Liquid phase lamination method, specifically：
(1) preparation of medicine suspension is carried：To in deionized water add recipe quantity through micronization technology process binder, Ah
Piperazine sand class, disintegrant, lasting stirring, sieving obtain the drug suspension containing Eliquis；
(2) drug suspension containing Eliquis is loaded onto in blank capsule core；
(3) coatings are loaded onto on drug-loaded layer；
(4) dry.
Specific example of the invention, the moisture after drying in micropill accounts for the 0.1-0.5% of micropill gross mass.
According to the fifth aspect of the invention, the present invention proposes a kind of method for preparing above-mentioned Eliquis micropill, and methods described is adopted
Solid-phase layer area method is used, specifically：
(1) preparation of binder：PVP is dissolved in deionized water；
(2) Eliquis, disintegrant are well mixed；
(3) binder and mixed-powder are loaded onto in blank capsule core；
(4) coatings are loaded onto on drug-loaded layer；
(5) dry.
Specific example of the invention, the moisture after drying in micropill accounts for the 0.1-0.5% of micropill gross mass.
Above-mentioned liquid phase lamination method and solid-phase layer area method can be used multifunctional fluidized bed preparation, or be prepared using centrifugal granulator.
It is preferred that using multifunctional fluidized bed preparation.Some embodiments of the invention, inventor it has been investigated that, use fluid bed
Liquid phase lamination method, can produce unexpected technique effect to the quality of product, can both solve product in long term storage
The slack-off phenomenon of dissolution caused by being absorbed water in journey, can reduce the generation about material again, increase the stability of preparation.Liquid phase
Lamination method bottom is sprayed, solid-phase layer area method side spray.Using solid-phase layer area method it sometimes appear that the limited problem of dissolution, and yield
There is no liquid phase lamination high, prepared with centrifugal granulating during micropill, it will experience powder as fluid bed side spray and play female screening,
The capsule core lamination megastage long, so the whole production process production time is comparatively slow.Other centrifugal granulating is to operator
The skill requirement of member is very high, and the technique of female screening is essential, and this step easily makes yield relatively low, plays female process
Middle to continue to be used in the middle of next group after drying and crushing sieving than larger particle, an a little bit smaller ball can move to next pot
Use.The equipment is not complete simultaneously is properly used for coating operations, because being coated except that must use high concentration using centrifugal granulating
Organic solvent, while speed can not be too fast when being coated, and will at any time add superfine talcum powder, otherwise easy adhesion.And it is many
Function fluid bed can overcome the shortcoming of centrifugal granulating, and preparation process is simple to operation, and be easily achieved a large amount of productions so that
Whole preparation technology is carried out in constantly drying until Eliquis are made micro pill capsule by final coating.Therefore most preferably fluidize
Bed liquid phase lamination method.
Drying steps in the liquid phase lamination method and solid-phase layer area method, can use drying, vacuum drying, fluidized drying,
Fluidized bed drying is convenient and time-saving, therefore it is preferred that fluidized drying.
In the sixth aspect of the present invention, the present invention proposes purposes of the Eliquis micro pill capsule in medicine is prepared, the medicine
Thing be used to treat include DVT (deep venous thrombosis, DVT) and pulmonary embolism (pulmonary embolism,
PE) in interior phlebothrombosis disease.
The present invention compared with prior art, with following advantage：
(1) embodiments in accordance with the present invention, the present invention carries out process optimization using fluid bed liquid phase lamination method, obtains Ah piperazine husky
Class's micropill and micro pill capsule preparation technology, method are simply easy to operate and control, and product quality stabilization, it is easy to accomplish industry
Change large-scale production, reduce production cost and energy ezpenditure, there is important breakthrough to micro pill capsule technical market；
(2) present invention prepares Eliquis micropill and micro pill capsule using micronization technology first, and it is not go public both at home and abroad
Product forms；
(3) the Eliquis micropill that the present invention is provided, with outward appearance rounding is bright and clean, uniform particle diameter, hardness it is moderate.And pass through
Experimental studies have found that, Eliquis micro pill capsule of the invention compared to tablet, with fast dissolution rate in vitro, even if plus
Dissolution also will not be slack-off after speed is tested 6 months；With vivo biodistribution availability higher；And accelerated test stability is more preferable；
(4) Eliquis micropill of the invention is coated, increased the stability of main ingredient, and effectively mask Eliquis
Taste simultaneously reduces gastrointestinal irritation, increases the compliance of patient's medication；It is easy to carry and use.
Brief description of the drawings
Fig. 1 shows Eliquis assay linear relationship.
Specific embodiment
Embodiments of the invention are described below in detail.The embodiments described below is exemplary, is only used for explaining the present invention,
And be not considered as limiting the invention.Unreceipted particular technique or condition in embodiment, according to document in the art
Described technology or condition are carried out according to product description.Agents useful for same or the unreceipted production firm person of instrument, are
Can by city available from conventional products.
Conventional method
(1) in Eliquis micro pill capsule micropill moisture assay method
Determination of moisture room dehumidifies, and relative humidity starts following operation when being less than 30%：
(1) Eliquis micropill is taken appropriate, in careful finely ground in mortar；
(2) about 1g fine powders are weighed a, is poured slowly into moisture teller (plum Teller-support benefit V20 Ka Erfeixiushi moisture
Analyzer) in, it is pre-mixed 60 seconds, start determination of moisture；
(3) it is repeated three times, averages as Eliquis micropill moisture.
(2) HPLC methods determine the medicament contg of Eliquis micro pill capsule
(1) HPLC conditions
Chromatographic column：C18, 150mm × 4.6mm, 3.5 μm,；Column temperature：25℃；
Mobile phase：10mmol ammonium acetate solutions-acetonitrile (65:35)；Flow velocity：1.0ml/min；Detector：UV；Detection wavelength：
280nm；Sampling volume：15μl.
(2) prepared by need testing solution
Take Eliquis micro pill capsule appropriate, by content micropill in careful finely ground in mortar, precision is weighed in right amount, use
Acetonitrile-water (50：50) dissolve and dilute constant volume, obtain the Eliquis concentration about solution of 25ug/ml, take continuous filter
Liquid is need testing solution.
(3) prepared by reference substance solution
Precision weighs Eliquis reference substance in right amount, with acetonitrile-water (50：50) dissolve and dilute constant volume, obtain Ah piperazine
Husky class's concentration is about the solution of 25 μ g/ml, as reference substance stock solution, then with acetonitrile-water (50：50) dilute successively.
It is 1 μ g/ml, 5 μ g/ml, 10 μ g/ml, 15 μ g/ml, 20 μ g/ml, the Eliquis reference substance of 25 μ g/ml to obtain concentration
Solution.
(4) computational methods
By the Eliquis control that concentration is 1 μ g/ml, 5 μ g/ml, 10 μ g/ml, 15 μ g/ml, 20 μ g/ml, 25ug/ml
Product solution enters HPLC successively, obtains peak area, and the concentration-peak area standard curve for drawing Eliquis is
Y=120.12X-2.3758 (r=1.0000), as shown in Figure 1；Need testing solution is entered into HPLC, need testing solution is obtained
Peak area, substitute into standard curve, calculate Eliquis in need testing solution concentration be C μ g/ml.
(3) Mass Spectrometry Conditions
(1) Mass Spectrometry Conditions
Liquid phase systems：Varian Pro Star；Automatic sampler：The automatic samplers of Varian 410；Mass spectrograph：Varian
310 LC-MS/MS triple quadrupole mass spectrometers (ESI ion guns)；Chromatographic column：Varian Inertsil 3 ODS-3
(150mm × 2mm, 3 μm).
Chromatographic condition：Mobile phase (water of 80% methyl alcohol+20%)；Flow velocity (0.3ml/min)；Sweep time (10min)；From
Component pattern：Electron spray ionisation (ESI), positive ion mode；
The condition of scanning：Detector：1000V；Needle：5000V；Shield：600V；Spray Chamber
Temperature：55℃；Nebulizing Gas Pressure：55psi；Drying Gas Pressure：18psi, Drying
Gas Temperature(℃)：250 DEG C, Capilary Voltage 30 (V), Coll.Energy 30 (v)；
Mass analyzer：Triple quadrupole bar；Sampling volume：10μl.
(2) blood sample treatments method
Take in 3.0ml blood plasma in test tube, add 5.0ml acetonitriles (including 200ng internal standards)；Shake up, mechanical shaking extraction 1
Min, 4 DEG C of centrifugations 15min (10000r/min), takes upper organic layer 5ml, air stream drying at 70 DEG C, and residue is with 100 μ l
Flowing phased soln, the μ l of sample introduction 10.
(4) capillary tube method determines the clotting time
Auricular vein is broken with acupuncture at interval of 10min after administration, and uses capillary draw blood, autoblood flows into capillary
Start timing in glass tube, after blood fills glass tube, take out glass tube and lie against on desktop, every 15-30
Second, breaking glass pipe about 5mm length, and slowly pull open to the left and right, whether the observation place of fractureing has blood clotting silk.From taking blood
To as clotting time time for occurring blood clotting silk first.
Embodiment
The fluid bed liquid phase lamination method of embodiment 1 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material is crushed to its D90=6 μm with GTM-50 airslide disintegrating mills；Carry medicine
Layer suspension is prepared：2250ml water is measured, PVP is dissolved in wherein, now binded agent concentration and be about 2.0 mass %,
The Eliquis raw material after recipe quantity is crushed, microcrystalline cellulose and Ac-Di-Sol are added, stirring extremely divides
Dissipate uniform, cross 60 mesh sieves and obtain drug-loaded layer suspension；Load medicine, technological parameter are carried out with WBF-2G is multifunctional fluidized bed
It is as follows：Air quantity 100m3/ h, liquid supply speed 6g/min, atomizing pressure 1.7bar, 50 DEG C of EAT, temperature of charge
40 DEG C, spacer ring height 10cm；Medicine-feeding terminates rear fluidized bed drying 30min, and parameter is as follows：Air quantity 90m3/ h, feed flow
Speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, 30 DEG C of temperature of charge, spacer ring height 10cm；It is coated
Liquid is prepared：Recipe quantity Opadry 03F is weighed, is dissolved in 760ml water, stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；
It is coated with WBF-2G is multifunctional fluidized bed, parameter is as follows：Air quantity 110m3/ h, liquid supply speed 10g/min, mist
Change pressure 2.0bar, 50 DEG C of EAT, 40 DEG C of temperature of charge, spacer ring height 15cm；Coating terminates rear fluid bed and does
Dry, parameter is as follows：Air quantity 100m3/ h, liquid supply speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, thing
30 DEG C of material temperature degree, spacer ring height 15cm；Dry 30min and terminate drying program, yield 96.2% determines moisture 0.34%；
With capsule board filler capsule 2.5mg specifications, finished product 9550.
The fluid bed liquid phase lamination method of embodiment 2 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material is crushed to its D90=6 μm with GTM-50 airslide disintegrating mills；Carry medicine
Layer suspension is prepared：4500ml water is measured, PVP is dissolved in wherein, now binded agent concentration and be about 1.0 mass %,
The Eliquis raw material after recipe quantity is crushed, microcrystalline cellulose and Ac-Di-Sol are added, stirring extremely divides
Dissipate uniform, cross 60 mesh sieves and obtain drug-loaded layer suspension；Load medicine, technological parameter are carried out with WBF-2G is multifunctional fluidized bed
It is as follows：Air quantity 100m3/ h, liquid supply speed 6g/min, atomizing pressure 1.7bar, 50 DEG C of EAT, temperature of charge
40 DEG C, spacer ring height 10cm；Medicine-feeding terminates rear fluidized bed drying 30min, and parameter is as follows：Air quantity 90m3/ h, feed flow
Speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, 30 DEG C of temperature of charge, spacer ring height 10cm；It is coated
Liquid is prepared：Recipe quantity Opadry 03F is weighed, is dissolved in 760ml water, stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；
It is coated with WBF-2G is multifunctional fluidized bed, parameter is as follows：Air quantity 110m3/ h, liquid supply speed 10g/min, mist
Change pressure 2.0bar, 50 DEG C of EAT, 40 DEG C of temperature of charge, spacer ring height 15cm；Coating terminates rear fluid bed and does
Dry, parameter is as follows：Air quantity 100m3/ h, liquid supply speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, thing
30 DEG C of material temperature degree, spacer ring height 15cm；Dry 30min and terminate drying program, yield 75.2% determines moisture 0.21%；
With capsule board filler capsule 2.5mg specifications, finished product 7422.
The fluid bed liquid phase lamination method of embodiment 3 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material is crushed to its D90=6 μm with GTM-50 airslide disintegrating mills；Carry medicine
Layer suspension is prepared：900ml water is measured, PVP is dissolved in wherein, now binded agent concentration and be about 5.0 mass %,
The Eliquis raw material after recipe quantity is crushed, microcrystalline cellulose and Ac-Di-Sol are added, stirring extremely divides
Dissipate uniform, cross 60 mesh sieves and obtain drug-loaded layer suspension；Load medicine, technological parameter are carried out with WBF-2G is multifunctional fluidized bed
It is as follows：Air quantity 100m3/ h, liquid supply speed 6g/min, atomizing pressure 1.7bar, 50 DEG C of EAT, temperature of charge
40 DEG C, spacer ring height 10cm；Medicine-feeding terminates rear fluidized bed drying 30min, and parameter is as follows：Air quantity 90m3/ h, feed flow
Speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, 30 DEG C of temperature of charge, spacer ring height 10cm；It is coated
Liquid is prepared：Recipe quantity Opadry 03F is weighed, is dissolved in 760ml water, stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；
It is coated with WBF-2G is multifunctional fluidized bed, parameter is as follows：Air quantity 110m3/ h, liquid supply speed 10g/min, mist
Change pressure 2.0bar, 50 DEG C of EAT, 40 DEG C of temperature of charge, spacer ring height 15cm；Coating terminates rear fluid bed and does
Dry, parameter is as follows：Air quantity 100m3/ h, liquid supply speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, thing
30 DEG C of material temperature degree, spacer ring height 15cm；Dry 30min and terminate drying program, yield 94.3% determines moisture 0.20%；
With capsule board filler capsule 2.5mg specifications, finished product 9401.
The fluid bed liquid phase lamination method of embodiment 4 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material is crushed to its D90=6 μm with GTM-50 airslide disintegrating mills；Drug-loaded layer is mixed
Suspension is prepared：650ml water is measured, PVP is dissolved in wherein, now binded agent concentration and be about 7.0 mass %, then add
Enter the Eliquis raw material after recipe quantity is crushed, microcrystalline cellulose and Ac-Di-Sol, stirring is equal to disperseing
It is even, cross 60 mesh sieves and obtain drug-loaded layer suspension；Load medicine is carried out with WBF-2G is multifunctional fluidized bed, technological parameter is as follows：
Air quantity 100m3/ h, liquid supply speed 6g/min, atomizing pressure 1.7bar, 50 DEG C of EAT, 40 DEG C of temperature of charge,
Spacer ring height 10cm；Medicine-feeding terminates rear fluidized bed drying 30min, and parameter is as follows：Air quantity 90m3/ h, liquid supply speed
0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, 30 DEG C of temperature of charge, spacer ring height 10cm；Coating solution is matched somebody with somebody
System：Recipe quantity Opadry 03F is weighed, is dissolved in 760ml water, stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；With
WBF-2G is multifunctional fluidized bed to be coated, and parameter is as follows：Air quantity 110m3/ h, liquid supply speed 10g/min, atomization
Pressure 2.0bar, 50 DEG C of EAT, 40 DEG C of temperature of charge, spacer ring height 15cm；Coating terminates rear fluidized bed drying,
Parameter is as follows：Air quantity 100m3/ h, liquid supply speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, material temperature
30 DEG C of degree, spacer ring height 15cm；Dry 30min and terminate drying program, yield 93.7% determines moisture 0.25%；
With capsule board filler capsule 2.5mg specifications, this time ball is sticked excessively in technical process, finished product is 7301.
Embodiment 1-4 self-control Eliquis micro pill capsules yield, output, dissolution rate compare.
The embodiment 1-4 of table 1 self-control Eliquis micro pill capsules yield, output, dissolution rate
When bonding agent concentration is relatively low as can be seen from the table, although dissolution is rapid, yield is low, causes the waste of raw material,
When bonding agent concentration is higher, glutinous ball is very more, and output is low, and micro pill capsule disintegration dissolution is slow.Binder is dense
When degree is for about 2.0 mass %, 5.0 mass % respectively, high income of adding medicine to, micropill outward appearance rounding is bright and clean, uniform particle diameter, hard
Degree is moderate, with fast dissolution rate in vitro.
The self-control Eliquis micro pill capsule of embodiment 1-4 is respectively at 60 degree of high temperature, high humidity RH92.5%, high light decentralization
Put 10 days, detection sample size, dissolution rate, relevant material.
The embodiment 1-4 of table 2 self-control Eliquis micro pill capsule influence factor experiments
As can be seen from the table, when bonding agent concentration is too low, the micropill compactness for obtaining is poor, causes that product is hygroscopic to be caused
Less stable, during binder excessive concentration, although influence factor tests relevant material does not have significant changes, but molten
Out-degree is very low always, and dissolution is slow, when bonding agent concentration is respectively about 2.0 mass %, 5.0 mass %, is influenceed
Factorial experiments, dissolution rate, content, relevant material change without conspicuousness, have good stability.
The centrifugal granulating liquid phase lamination method of embodiment 5 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material is crushed to its D90=6 μm with GTM-50 airslide disintegrating mills；Carry medicine
Layer suspension is prepared：1500ml water is measured, PVP is dissolved in wherein, now binded agent concentration and be about 3.0 mass %,
The Eliquis raw material after recipe quantity is crushed, microcrystalline cellulose and Ac-Di-Sol are added, stirring extremely divides
Dissipate uniform, cross 60 mesh sieves and obtain drug-loaded layer suspension；Added medicine to LZW-300 centrifugal granulating seed-coating machines, parameter
It is as follows：Air quantity 60m3/ h, liquid supply speed 10g/min, atomizing pressure 1.8bar, 55 DEG C of EAT, temperature of charge
40 DEG C, rotary speed 20r/min；Medicine-feeding terminates 60 DEG C of rear baking oven and dries 2h；Coating solution is prepared：Weigh recipe quantity Europe
Bar is dissolved in 760ml water for II, and stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；With LZW-300 centrifugal granulating bags
Clothing machine is coated, and parameter is as follows：Air quantity 60m3/ h, liquid supply speed 8g/min, atomizing pressure 1.8bar, enter wind-warm syndrome
55 DEG C of degree, 40 DEG C of temperature of charge, rotary speed 25r/min；Coating terminates 60 DEG C of rear baking oven and dries 6h；Yield 92.3%,
Determine moisture 0.32%；With 9222, capsule board filler capsule.
The centrifugal granulating solid-phase layer area method of embodiment 6 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material airslide disintegrating mill is crushed to its D90=6 μm；Binder is prepared：
1500ml water is measured, PVP K30 is dissolved in wherein, now binded agent concentration and be about 3.0 mass %, stirring extremely divides
Dissipate uniform, cross 60 mesh sieves and obtain final product；Mixing：Eliquis raw material, microcrystalline cellulose and crosslinking after recipe quantity is crushed
Sodium carboxymethylcellulose is well mixed；Added medicine to LZW-300 centrifugal granulating seed-coating machines, parameter is as follows：Air quantity
50m3/ h, liquid supply speed 10g/min, atomizing pressure 1.6bar, 55 DEG C of EAT, 40 DEG C of temperature of charge, rotating disk turn
Fast 20r/min, feed hopper rotating speed 6r/min；Medicine-feeding terminates rear fluidized bed drying 20min；Coating solution is prepared：Weigh place
Side amount Opadry 03F, is dissolved in 760ml water, and stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；Use multi-functional fluidisation
Bed is coated, and parameter is as follows：Air quantity 110m3/ h, liquid supply speed 14g/min, atomizing pressure 2.0bar, enter wind-warm syndrome
55 DEG C of degree, 50 DEG C of temperature of charge, spacer ring height 20cm；Coating terminates rear fluidized bed drying 1 hour, yield 90.6%,
Moisture 0.12% is determined, with 9060, capsule board filler capsule.
The fluid bed solid-phase layer area method of embodiment 7 prepares Eliquis micropill and micro pill capsule
The crushing of bulk drug：Eliquis raw material airslide disintegrating mill is crushed to its D90=6 μm；Binder is prepared：
1500ml water is measured, PVP K30 is dissolved in wherein, now binded agent concentration and be about 3.0 mass %, stirring extremely divides
Dissipate uniform, cross 60 mesh sieves and obtain final product；Mixing：Eliquis raw material, microcrystalline cellulose and crosslinking after recipe quantity is crushed
Sodium carboxymethylcellulose is well mixed；Added medicine to fluid bed, technological parameter is as follows：Air quantity 100m3/ h, feed flow speed
Degree 6g/min, atomizing pressure 1.7bar, 50 DEG C of EAT, 40 DEG C of temperature of charge, spacer ring height 10cm；Medicine-feeding knot
Fluidized bed drying 30min after beam, parameter is as follows：Air quantity 90m3/ h, liquid supply speed 0g/min, atomizing pressure 1.3bar,
40 DEG C of EAT, 30 DEG C of temperature of charge, spacer ring height 10cm；Coating solution is prepared：Recipe quantity Opadry 03F is weighed,
It is dissolved in 760ml water, stirring is crossed 60 mesh sieves and obtained final product to being uniformly dispersed；Wrapped with WBF-2G is multifunctional fluidized bed
Clothing, parameter is as follows：Air quantity 110m3/ h, liquid supply speed 10g/min, atomizing pressure 2.0bar, 50 DEG C of EAT,
40 DEG C of temperature of charge, spacer ring height 15cm；Coating terminates rear fluidized bed drying, and parameter is as follows：Air quantity 100m3/ h,
Liquid supply speed 0g/min, atomizing pressure 1.3bar, 40 DEG C of EAT, 30 DEG C of temperature of charge, spacer ring height 15cm；
Dry 15min and take out a small amount of micropill measure moisture 2.23%, dry 30min and terminate drying program, yield 96.2% is surveyed
Determine moisture 0.34%；With capsule board filler capsule 2.5mg specifications, finished product 9550.
Embodiment 8 prepares Apixaban tablet
The crushing of bulk drug：Eliquis raw material airslide disintegrating mill is crushed to its D90=6 μm；Recipe quantity is crushed
Rear Eliquis raw material, lactose monohydrate, Ac-Di-Sol, PVP K30 and microcrystalline cellulose
It is well mixed, plus appropriate water softwood, the granulation of 20 mesh sieves is crossed, half an hour to moisture is dried in 60 degree of baking ovens is
1.12%, 20 mesh sieve whole grains are crossed, No. 6 stampings, yield 97.6% determines moisture 0.68%, totally 9700.
The experiment of the influence factor of embodiment 9 is investigated
Apixaban tablet prepared by Eliquis micro pill capsule and embodiment 8 prepared by Example 1, carry out influence because
Element experiment, with reference to the C medicine stability test guidelines of two annex of China's coastal port XX.Investigate respectively
Stability under the conditions of illumination 4500XL, 60 DEG C of high temperature and high humidity 92.5%, detailed results are shown in Table 3.
The influence factor Experimental Comparison result of the Eliquis micro pill capsule of table 3 and Apixaban tablet
It can be seen that the stability of Eliquis micro pill capsule of the invention is better than Eliquis tablet.
The Acceleration study of embodiment 10 is investigated
The Apixaban tablet that Eliquis micro pill capsule prepared by Example 1 is prepared with embodiment 8, is placed in temperature
40 DEG C ± 2 DEG C, in the environment of relative humidity 75% ± 5%, relevant index is determined in the 1st, 2,3, June.
The Eliquis micro pill capsule of table 4 and Eliquis tablet accelerated test result
It can be seen that the stability of Eliquis micro pill capsule of the invention is better than Eliquis tablet.
The bioavailability study of embodiment 11
By Eliquis micro pill capsule with listed Eliquis tablet (lot number 3C83767, specification 2.5mg, producer：U.S.A applies when hundred
Your treasured) bioavailability study is carried out in healthy male rabbit.
By test preparation：The micro pill capsule of embodiment 1 is used as by test preparation；
Reference preparation：The trade name Ai Le appropriate Apixaban tablet for having listed；
Experimental program：Healthy male rabbit 3 (body weight 14-15kg), is divided into 3 groups, every group 1, is tested using dual crossing
Design, rabbit orally gives reference preparation and by test preparation respectively by 2.5mg/ rabbit single.Fasting 1 day before administration,
Gastric infusion simultaneously gives 50ml running water, and administration can give feed after 4 hours.In (i.e. 0 hour) before oral administration, give
0.5,1,2,3,4,5,6,8,10,24 hours after medicine, blood 3mL is taken through rabbit foreleg vein clump, put room in centrifuge tube
Temperature stands 30 minutes, 10000r/min, is centrifuged under the conditions of 4 DEG C 15 minutes and separates serum, and liquid is used after being processed through organic solvent
The concentration of Eliquis in phase chromatographic tandem mass spectrometric determination rabbit anteserum, pharmacokinetic parameter uses WinNonlinTM
(5.3 editions) calculate according to non-compartment model, the results are shown in Table 5.
The male rabbit of table 5 orally gives reference preparation or the pharmacokinetic parameters by Eliquis after test preparation
F (relative bioavailability)=AUC (receives test preparation)0-24h/ AUC (reference preparation)0-24h× 100%
Pharmacokinetic experiments result shows, is 129.89% by the relative bioavailability of test preparation, i.e., by test preparation compared with reference system
Agent has oral administration biaavailability higher.
The clinical trial of embodiment 12
By Eliquis micro pill capsule with listed Apixaban tablet (lot number 3C83767, specification 2.5mg, producer：U.S.A applies expensive when hundred
It is precious) anticoagulation clinical trial is carried out in healthy male rabbit.
Experimental program：1st, rabbit 1 is taken, its normal blood clotting time is determined.
2nd, after above-mentioned experiment is finished, from Rabbit Heart blood sampling 10mL, this blood 1mL is respectively put into following 3 test tubes.
There is solution made by the commercially available Apixaban tablet of 0.1mL 4% in first test tube.
There is solution made by Eliquis micro pill capsule in the embodiment 1 of 0.1mL 4% in second test tube.
There is 0.1mL physiological saline in third test tube.
Blood is put into test tube, in shake a moment, is subsequently placed on rack for test tube, and 10min or so observes each test tube blood whether there is solidification now
As and note down result.
3rd, surveyed once per 10min later, done altogether 3 times, the effect of relatively more various medicines.
Experimental result is shown in Table 6.
The male rabbit of table 6 orally gives reference preparation or by blood coagulation clinical trial result after test preparation
Anticoagulation clinical trial result shows there is more preferable curative effect compared with reference preparation by test preparation.
Found by specific embodiment experimental study, when preparing Eliquis micropill, by bonding agent concentration control in 2.0 matter
In the range of amount %-5.0 mass %, raw material medicine-feeding yield can be significantly improved, promote the dissolution of product, and slow down high humidity
The influence of the condition on production dissolution such as moisture absorption and illumination high temperature, effectively reduces the increase about material, increases product steady
It is qualitative, can effectively control the product quality of micro pill capsule being made of the Eliquis micropill.
In the description of the invention, it is to be understood that term " first ", " second " are only used for describing purpose, without being understood that
To indicate or implying relative importance or the implicit quantity for indicating indicated technical characteristic.Thus, " first ", " are defined
Two " one or more this feature can be expressed or be implicitly included to feature.In the description of the invention, " multiple "
Two or more are meant that, unless otherwise expressly limited specifically.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specific example ",
Or the description of " some examples " etc. means to combine specific features, structure, material or feature bag that the embodiment or example are described
It is contained at least one embodiment of the invention or example.In this manual, to the schematic representation of above-mentioned term necessarily
It is directed to identical embodiment or example.And, the specific features of description, structure, material or feature can be any
Combined in an appropriate manner in individual or multiple embodiments or example.Additionally, in the case of not conflicting, the skill of this area
Can be combined for the feature of the different embodiments or example described in this specification and different embodiments or example by art personnel
And combination.
Although embodiments of the invention have been shown and described above, it is to be understood that above-described embodiment be it is exemplary,
It is not considered as limiting the invention, one of ordinary skill in the art within the scope of the invention can be to above-described embodiment
It is changed, changes, replacing and modification.
Claims (10)
1. a kind of Eliquis micropill, it is characterised in that the Eliquis micropill is followed successively by blank capsule core, contains from inside to outside
Medicine layer and coatings, wherein, the medicated layer is made up of micronizing Eliquis, binder and disintegrant,
The Eliquis micropill is included：
The blank capsule core of 60-84 weight portions；
The micronizing Eliquis of 2-7 weight portions；
The binder of 3-10 weight portions；
The disintegrant of 5-20 weight portions；And
The coatings of 2-8 weight portions.
2. Eliquis micropill according to claim 1, it is characterised in that the Eliquis micropill is included：
The blank capsule core of 60-80 weight portions；
The micronizing Eliquis of 2-6 weight portions；
The binder of 3-8 weight portions；
The disintegrant of 8-16 weight portions；And
The coatings of 2-5 weight portions.
3. Eliquis micropill according to claim 1, it is characterised in that the binder in the Eliquis micropill
Solution is configured to, its concentration is 2.0 mass %-5.0 mass %.
4. Eliquis micropill according to claim 1, it is characterised in that the particle diameter of the micronizing Eliquis
D90 is less than 100 μm, preferably less than 10 μm.
5. Eliquis micropill according to claim 1, it is characterised in that the blank capsule core is selected from microcrystalline cellulose
Capsule core, sucrose capsule core, sucrose-starch capsule core and lactose capsule core are at least one, preferably lactose capsule core.
6. Eliquis micropill according to claim 1, it is characterised in that the binder is selected from starch slurry, poly-
Dimension ketone, methylcellulose, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and
At least one at least one in polyethylene glycol, preferably PVP, hydroxypropyl cellulose and Hydroxypropyl methylcellulose, it is excellent
Elect PVP as.
7. Eliquis micropill according to claim 1, it is characterised in that the disintegrant is selected from cross-linked carboxymethyl
At least one in sodium cellulosate, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, PVPP and sodium carboxymethyl starch,
It is preferred that at least one in Ac-Di-Sol and microcrystalline cellulose.
8. a kind of Eliquis micro pill capsule, it is characterised in that be filled with claim 1-7 in the Eliquis micro pill capsule
Eliquis micropill described in any one.
9. a kind of method for preparing the Eliquis micropill described in claim any one of 1-7, including：
The blank capsule core of 60-84 weight portions is provided；
By the disintegrant dissolving of the micronizing Eliquis, the binder of 3-10 weight portions and 5-20 weight portions of 2-7 weight portions,
Medicine-feeding treatment is carried out to the blank capsule core using liquid phase lamination method or solid-phase layer area method, so as in the table of the blank capsule core
Face forms medicated layer；
Treatment is dried to the blank capsule core that the surface forms medicated layer；
The blank capsule core that the medicated layer is formed by the surface of the dried process is coated treatment, to contain described
The surface of medicine layer forms coatings, to obtain Eliquis micropill；
Optionally, the medicine-feeding treatment is carried out using multifunctional fluidized bed or centrifugal granulator, it is preferable that using multi-functional
Fluid bed；
Optionally, the liquid phase lamination method includes：
The disintegrant of the micronizing Eliquis, the binder of 3-10 weight portions and 5-20 weight portions of 2-7 weight portions is dissolved in
In 1000~1100 milliliters of water, stir and sieve treatment, to obtain carrying medicine suspension；
The load medicine suspension is carried out into medicine-feeding treatment to the blank capsule core；
Optionally, the solid-phase layer area method includes：
The binder of 3-10 weight portions is dissolved in 1000~1100 milliliters of water, stir and sieve treatment, on obtaining
Drug solns；
The disintegrant of the micronizing Eliquis of the 2-7 weight portions and 5-20 weight portions is well mixed, medicine mixing is obtained
Powder；
By the upper drug solns and the medicine mixed-powder to carrying out medicine-feeding treatment to the blank capsule core.
10. method according to claim 9, it is characterised in that the medicine-feeding treatment is carried out using multifunctional fluidized bed,
Control it is described medicine-feeding treatment condition be：Air quantity is 100-105m3/ h, liquid supply speed is 6-10g/min, and atomizing pressure is
1.7bar, EAT is 50-55 DEG C, and temperature of charge is 40-45 DEG C, and spacer ring is highly 10cm；Dry 30min；
Optionally, the Cotton seeds are carried out using multifunctional fluidized bed, and the condition for controlling the Cotton seeds is：Air quantity is
110-115m3/h, liquid supply speed is 10-12g/min, and atomizing pressure is 2.0bar, and EAT is 50-55 DEG C, temperature of charge
40-45 DEG C, spacer ring height 15cm；Dry 30min.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107661306A (en) * | 2017-10-30 | 2018-02-06 | 武汉中钰钰民医药科技有限公司 | Omeprazole enteric-coated preparation and preparation method thereof |
| WO2019204193A1 (en) * | 2018-04-16 | 2019-10-24 | Bristol-Myers Squibb Company | Apixaban formulations |
| CN111521707A (en) * | 2020-05-11 | 2020-08-11 | 苏州必宜生物科技有限公司 | Method for determining apixaban concentration in blood plasma by LC-MS/MS |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011106478A2 (en) * | 2010-02-25 | 2011-09-01 | Bristol-Myers Squibb Company | Apixaban formulations |
| CN102908324A (en) * | 2012-10-31 | 2013-02-06 | 南京正科制药有限公司 | Apixaban tablet |
-
2015
- 2015-12-25 CN CN201511003627.3A patent/CN106913528A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011106478A2 (en) * | 2010-02-25 | 2011-09-01 | Bristol-Myers Squibb Company | Apixaban formulations |
| CN102908324A (en) * | 2012-10-31 | 2013-02-06 | 南京正科制药有限公司 | Apixaban tablet |
Non-Patent Citations (4)
| Title |
|---|
| 张兆旺: "《中药药剂学》", 31 March 2007, 中国中医药出版社 * |
| 李津明等: "《现代制药技术》", 30 April 2005, 中国医药科技出版社 * |
| 李维凤等: "《药学专业知识(二)（第八版）》", 31 March 2014, 中国医药科技出版社 * |
| 林宁等: "《药剂学》", 31 January 2008, 湖北科学技术出版社 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107661306A (en) * | 2017-10-30 | 2018-02-06 | 武汉中钰钰民医药科技有限公司 | Omeprazole enteric-coated preparation and preparation method thereof |
| WO2019204193A1 (en) * | 2018-04-16 | 2019-10-24 | Bristol-Myers Squibb Company | Apixaban formulations |
| US20210145817A1 (en) * | 2018-04-16 | 2021-05-20 | Bristol-Myers Squibb Company | Apixaban formulations |
| JP2021521242A (en) * | 2018-04-16 | 2021-08-26 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Apixaban preparation |
| JP7382957B2 (en) | 2018-04-16 | 2023-11-17 | ブリストル－マイヤーズ スクイブ カンパニー | Apixaban formulation |
| US11896586B2 (en) * | 2018-04-16 | 2024-02-13 | Bristol-Myers Squibb Company | Apixaban formulations |
| AU2019255599B2 (en) * | 2018-04-16 | 2024-02-29 | Bristol-Myers Squibb Holdings Ireland Unlimited Company | Apixaban formulations |
| EP4353312A3 (en) * | 2018-04-16 | 2024-07-17 | Bristol-Myers Squibb Company | Apixaban formulations |
| CN111521707A (en) * | 2020-05-11 | 2020-08-11 | 苏州必宜生物科技有限公司 | Method for determining apixaban concentration in blood plasma by LC-MS/MS |
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