CN109010273A - A kind of Eliquis nano suspension and preparation method thereof - Google Patents
A kind of Eliquis nano suspension and preparation method thereof Download PDFInfo
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- 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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Abstract
The invention belongs to pharmaceutical technology field, a kind of Eliquis nano suspension and preparation method thereof is disclosed.Eliquis is a kind of new oral anticoagulant, is clinically used for preventing and treating thrombus.Eliquis poorly water-soluble, permeability is low, limits its oral administration biaavailability.Eliquis nano suspension prepared by the present invention is prepared using a small amount of natrii tauroglycocholas and Polyvinylcaprolactame-polyvinyl acetate-polyethylene glycol graft copolymerization (Soluplus) as combinative stability agent using high pressure homogenization method.The solubility and dissolution rate of drug can be improved in the nano suspension of preparation, improves the permeability of drug, is conducive to enhance oral absorption, improves bioavilability, and formulation and technology is easy, easy to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of Eliquis nano suspension and preparation method thereof.
Background technique
Eliquis (Apixaban) chemical name is (1- (4- methoxyphenyl) [4- (2- oxo-piperidine-of -7- oxo -6
1- yl) phenyl] -4,5,6,7- tetrahydro -1H- pyrazoles [3,4-c] pyridine-3-carboxamides, molecular formula C25H25N5O4, molecular weight is
459.50, structural formula is as follows:
Eliquis is a kind of new oral anticoagulation, highly selective, reversible X a blood coagulation factor inhibitors, from 2011
Year, the medicine listed in Europe, was to be developed jointly to develop by Pfizer and Bristol Myers Squibb；Acquisition China national food in 2013
The import drug permit that Drug Administration issues is selected a time the adult patients of displacement technique, in advance for hip joint or knee joint
Anti- phlebothrombosis event, and in 2013 in China's approval listing, tablet format 2.5mg/ piece, daily oral 2 times, every time one
Piece.Eliquis is non-ionized drugs, and solubility is not influenced by pH, the solubility of Eliquis in water be 0.02~
0.04mg/ml (37 DEG C), the slightly soluble in ethyl alcohol, methanol dissolve in DMSO, and according to States Pharmacopoeia specifications, it belongs to insoluble medicine in water
Object；Meanwhile belonging to BCS Group III drug (high-dissolvability/low according to Biopharmaceutics Classification system (BCS) classification Eliquis
Penetrating pharmaceutical), it is low-permeability drug again, so Eliquis exists because dissolution rate is slow, gastrointestinal tract mucous permeability
The low problem of oral administration biaavailability caused by difference, Eliquis tablet human oral bioavilability only 50%.
Nano suspension is to be proposed first by German M ü ller nineteen ninety-five, it is the sub-micrometer colloidal point of pure drug particle
The system of dissipating is different from general carrier nanoparticle, it is free of framework material, it is a small amount of surface covered by drug by means of surface
The stabilization of activating agent and/or polymer is obtained in an aqueous medium to be less than 1000nm particle size dispersion, and usual partial size is small
In 500nm, drug exists in nano suspension with crystal or unformed state, and medicine preparation is increased at nano suspension
The specific surface area of drug can significantly improve the solubility and dissolution rate of drug, in addition, diameter of aspirin particle reduce, moreover it is possible to improve with
The adhesion of mucous membrane improves the bioavilability of drug to extend the residence time of drug in vivo, and nano suspension can be wide
It is general for taking orally, external application, injection, the administration of ophthalmically acceptable and pulmonary administration approach.The technology of preparing of nano suspension has " arriving from childhood big "
(bottom up) and " from large to small " (top down) two class technology, ordinary precipitation process belongs to " arriving from childhood big " technology, " arrogant
To small " technology includes polishing (such as Nanocrystals), water mesohigh homogeneous method (such as Dissocubes), in non-aqueous media
High pressure homogenization method (such as Nanopure) and the high-pressure homogeneous combined method (such as Nanoedge) of precipitating.
For the low problem of bioavilability existing for Eliquis, the present invention discloses a kind of Eliquis nanometer suspension
Agent, it can improve the solubility and dissolution rate of drug, increase the permeability of drug, be conducive to the oral suction for improving Eliquis
Characteristic is received, the bioavilability of drug is improved.Eliquis suspension formulation and technology of the present invention is simple, and stabilizing agent dosage is few, just
In production.
Summary of the invention
The object of the present invention is to provide a kind of Eliquis nano suspensions and preparation method thereof.
The present invention is directed to prepare Eliquis nano suspension, increase the solubility and dissolution rate of Eliquis, improves
The permeability of Eliquis, so as to improve the oral absorption characteristic and bioavilability of Eliquis.
The Eliquis nano suspension is made of Eliquis, stabilizer and water, in mass ratio Eliquis: being stablized
Agent: water=1: 0.1~0.05: 1.5~2.8.
The Eliquis nano suspension, wherein stabilizer be lauryl sodium sulfate, natrii tauroglycocholas, Tween 80,
Poloxamer F127, PVP K30 (PVPK30), polyvinyl alcohol (PVA), the poly- acetic acid second of Polyvinylcaprolactame-
One of enester-polyethyleneglycol-graft copolymer (Soluplus) is a variety of.
The Eliquis nano suspension, the wherein preferred natrii tauroglycocholas of stabilizer and Soluplus combination.
The Eliquis nano suspension, it is characterised in that: the medicine dispersed in the Eliquis nano suspension
Object particle diameter is 50~280nm.
The Eliquis nano suspension, it is characterised in that: the drug particle drug content of dispersion is greater than 90%.
The Eliquis nano suspension, wherein water is one of deionized water, distilled water, water for injection.
The Eliquis nano suspension, preparation method are high pressure homogenization method, it is specific the preparation method is as follows:
Natrii tauroglycocholas, Soluplus are dissolved in deionized water；Eliquis is added under stiring, is ultrasonically treated 10min,
Keep drug fully dispersed in water；So slightly mixed with high speed disperser with 5000rpm~1000rpm 3~8min of rotating speed cutting
Suspension；High pressure homogenizer recycles 3~15 times to get Eliquis nano suspension under 800bar~1800bar pressure again.It receives
Rate is greater than 90%.
The Eliquis nano suspension, drug solubility are greater than 50mg/100ml, and Medicated Permeation FACTOR P e is big
In 1 × 10-5cm/s。
The Eliquis nano suspension, it is characterised in that: be suitable for oral, external application, the administration of drug administration by injection approach.
Eliquis nano suspension agent of the present invention has the following advantages:
(1) Eliquis nano suspension partial size prepared by the present invention is nanoscale, increase the solubility of drug with it is molten
Rate out, and diameter of aspirin particle reduces, moreover it is possible to it improves and changes with the adhesion of mucous membrane to extend the residence time of drug in vivo
The bioavilability of kind drug；
(2) Eliquis nano suspension prepared by the present invention, can increase the infiltration coefficient of drug, be conducive to improve drug
It absorbs, improves bioavilability；
(3) Eliquis nano suspension prepared by the present invention, stabilizer supplementary product consumption is few, highly-safe；
(4) method of Eliquis nano suspension prepared by the present invention, simple process, cost is relatively low and is suitable for industry
Mass production.
Detailed description of the invention
Fig. 1 be embodiment 7, Eliquis suspension, Eliquis physical mixture cumulative in vitro release profiles.
Specific embodiment
Form is described in further details above content of the invention by the following examples, but should be noted that of the invention
Protection scope should not be by any restrictions of these examples.
Embodiment 1
20mg Eliquis is weighed in 35ml water, 10min is ultrasonically treated, keeps drug fully dispersed in water；With high speed
Disperser shears 5min under the conditions of 10000rpm, obtains thick suspension；Above-mentioned thick suspension progress is high-pressure homogeneous, exist first
800bar homogeneous 2 times, later under 1800bar pressure homogeneous 12 times to get Eliquis nano suspension.Measure nanometer suspension
The partial size of agent is 754nm, and polydispersity coefficient (PDI) is 0.378.
Embodiment 2
5mg PVPK30 is weighed in 50ml water, 20mg Eliquis is added under stiring, 10min is ultrasonically treated, makes medicine
Object is fully dispersed in water；5min is sheared under the conditions of 10000rpm with high speed disperser, obtains thick suspension；It will be above-mentioned thick mixed
Suspension carry out it is high-pressure homogeneous, first at 800bar homogeneous 2 times, later under 1800bar pressure homogeneous 12 times to get Eliquis
Nano suspension.The partial size for measuring nano suspension is 386.7nm, and polydispersity coefficient (PDI) is 0.167.
Embodiment 3
1mg natrii tauroglycocholas is weighed in 35ml water, 20mg Eliquis is added under stiring, 10min is ultrasonically treated, makes medicine
Object is fully dispersed in water；5min is sheared under the conditions of 10000rpm with high speed disperser, obtains thick suspension；It will be above-mentioned thick mixed
Suspension carry out it is high-pressure homogeneous, first at 800bar homogeneous 2 times, later under 1800bar pressure homogeneous 12 times to get Eliquis
Nano suspension.The partial size for measuring nano suspension is 401.6nm, and polydispersity coefficient (PDI) is 0.11.
Embodiment 4
5mg natrii tauroglycocholas is weighed, 20mg Eliquis, ultrasonic treatment is added in 50ml water in 20mg PVA under stiring
10min keeps drug fully dispersed in water；5min is sheared under the conditions of 10000rpm with high speed disperser, obtains thick suspension；
Above-mentioned thick suspension progress is high-pressure homogeneous, first at 800bar homogeneous 2 times, homogeneous 12 times under 1800bar pressure later, i.e.,
Obtain Eliquis nano suspension.The partial size for measuring nano suspension is 237.7nm, and polydispersity coefficient (PDI) is 0.069.
Embodiment 5
1.5mg Soluplus is weighed in 35ml water, 20mg Eliquis is added under stiring, is ultrasonically treated 10min,
Keep drug fully dispersed in water；5min is sheared under the conditions of 10000rpm with high speed disperser, obtains thick suspension；It will be above-mentioned
Thick suspension carry out it is high-pressure homogeneous, first at 800bar homogeneous 2 times, later under 1800bar pressure homogeneous 12 times to get Ah piperazine
Husky class's nano suspension.The partial size for measuring nano suspension is 201nm, and polydispersity coefficient (PDI) is 0.037.
Embodiment 6
0.5mg natrii tauroglycocholas is weighed, 24mg Eliquis is added in 40ml water in 1.5mg Soluplus under stiring,
It is ultrasonically treated 10min, keeps drug fully dispersed in water；5min is sheared under the conditions of 10000rpm with high speed disperser, is obtained
Thick suspension；Above-mentioned thick suspension progress is high-pressure homogeneous, first at 800bar homogeneous 2 times, later under 1800bar pressure
Matter 9 times to get Eliquis nano suspension.The partial size for measuring nano suspension is 154nm, and polydispersity coefficient (PDI) is
0.008。
Embodiment 7
0.51mg natrii tauroglycocholas is weighed, it is husky that 24mg Ah piperazine is added in 40ml water in 1.04mg Soluplus under stiring
Class is ultrasonically treated 10min, keeps drug fully dispersed in water；5min is sheared under the conditions of 10000rpm with high speed disperser, is obtained
To thick suspension；Above-mentioned thick suspension progress is high-pressure homogeneous, first at 800bar homogeneous 2 times, later under 1800bar pressure
Homogeneous 9 times to get Eliquis nano suspension, yield 90%~94.32%.The partial size for measuring nano suspension is
114.6nm, polydispersity coefficient (PDI) are 0.005.In Eliquis nano suspension after nanoparticle freeze-drying, with HPLC method
Measuring solid nano grain medicament contg is 90.9%.
Embodiment 8
The accumulative dissolution rate in vitro research of embodiment 7, Eliquis physical mixture, Eliquis suspension
Eliquis physical mixture weighs natrii tauroglycocholas, Soluplus stirring and dissolving in 40ml by 7 recipe quantity of embodiment
In water, 24mg Eliquis (5~50 μm of partial size) is added under stiring, ultrasonic treatment 10min is made.Eliquis suspension is logical
It crosses and weighs Eliquis bulk pharmaceutical chemicals 24mg, water 40ml, ultrasonic treatment 10min is added to be made.Ah piperazine is measured using bag filter method for releasing
The extracorporeal releasing characteristic of husky class's nano suspension.7 Eliquis nano suspension of 2ml embodiment (parallel three parts) are measured to be placed in
Analyse bag in, by bag filter be placed in 100ml pH be 6.8 PBS solution in, separately take be equivalent to isoconcentration Eliquis suspension with
Eliquis physical mixture (parallel three parts) 2ml is placed in bag filter, is placed in the PBS solution that 100ml pH is 6.8.It will burn
Cup is put into constant temperature oscillator, and imposing a condition is 37 DEG C of temperature, shakes rate 100rpm, respectively at 0.5,1,2,3,4,6,8,
10, dissolution medium 1ml 12, is taken for 24 hours, while supplementing the fresh dissolution medium of 1ml isothermal, the dissolution medium HPLC of taking-up immediately
It is analyzed, is calculated cumulative release rate (the result is shown in Figure 1) at 279nm.
The result shows that the rate of release of 7 Eliquis nano suspension of embodiment is husky better than Eliquis suspension and Ah piperazine
Class's physical mixture, and the release of Eliquis nano suspension is complete.
Embodiment 9
Embodiment 7, Eliquis physical mixture, the solubility of Eliquis suspension and osmotic coefficient investigating
Solubility test: the Eliquis nano suspension of Example 7 and physical mixture and Eliquis respectively
Bulk pharmaceutical chemicals suspension is appropriate, is placed in 50ml volumetric flask, and pure water constant volume is added, after sealing, volumetric flask is placed in isothermal vibration device
(37 DEG C, 100rpm) concussions are for 24 hours.It stands, crosses 0.45 μm of miillpore filter, discard primary filtrate, subsequent filtrate is received, using efficient liquid phase
Chromatograph measurement, drug solubility the results are shown in Table 1.
Permeability measurement: it uses Parallel artificial membrane's permeability experiment (PAMPA), using artificial phospholipid as biological film medicine
Object cross-film barrier measures Medicated Permeation coefficient.PAMPA is by 96 hole filter plates by receiver board (lower plywood) and donor plate (96 holes
Plate, top plate) it separates.Specific implementation method are as follows: using the lecithin of 1% (w/v)/dodecane solution as manual application's liquid, to
5 1% lecithin of μ L/dodecane solution is added in donor plate, after coating, 125 μ L is added into supply plate immediately and contain drug solns,
The PBS buffer solution that 200 μ L pH are 6.8 is added in receiver board, places 96 hole filter plates on receiver sheet, immobilized artificial membrane is enable to touch
Supply liquid.This device is put in constant temperature oscillator, temperature is 37 DEG C, under the conditions of 75rpm, it is taken out after placing 16h,
It is centrifuged 30min under the conditions of 10000rpm, is analyzed at 279nm with HPLC, the results are shown in Table 1.
1. solubility of table (S, mg/100ml) and infiltration coefficient (Pe, cm/s) and measurement result
Seen from table 1, the Eliquis nano suspension prepared using natrii tauroglycocholas and Soluplus as combinative stability agent,
Drug solubility can be significantly improved, the permeability of drug is increased, is conducive to the oral absorption characteristic for improving Eliquis, improves mouth
Take bioavilability.
Claims (8)
1. a kind of Eliquis nano suspension, drug solubility is greater than 50mg/100ml, Medicated Permeation FACTOR P e is greater than 1 ×
10-5Cm/s, the Eliquis nano suspension are made of Eliquis, stabilizer and water, in mass ratio Eliquis: being stablized
Agent: water=1: 0.1~0.05: 1.5~2.8.
2. according to Eliquis nano suspension described in right 1, wherein stabilizer be lauryl sodium sulfate, natrii tauroglycocholas,
Tween 80, poloxamer F127, PVP K30 (PVPK30), polyvinyl alcohol (PVA), Polyvinylcaprolactame-are poly-
One of vinyl acetate-polyethyleneglycol-graft copolymer (Soluplus) is a variety of.
3. according to Eliquis nano suspension described in right 1, the wherein preferred natrii tauroglycocholas of stabilizer and Soluplus combination.
4. according to Eliquis nano suspension described in right 1, it is characterised in that: the Eliquis nano suspension Chinese medicine
Object particle diameter is 50~280nm.
5. according to Eliquis nano suspension described in right 1, it is characterised in that: drug particle drug content is greater than
90%.
6. wherein water is deionized water, in distilled water, water for injection according to Eliquis nano suspension described in right 1
It is a kind of.
7. preparation method is high pressure homogenization method, and specific preparation method is such as according to Eliquis nano suspension described in right 1
Under:
Natrii tauroglycocholas, Soluplus are dissolved in deionized water；Eliquis is added under stiring, is ultrasonically treated 10min, makes medicine
Object is fully dispersed in water；So slightly it is suspended with high speed disperser with 5000rpm~10000rpm 3~8min of rotating speed cutting
Agent；High pressure homogenizer recycles 3~15 times to get Eliquis nano suspension under 800bar~1800bar pressure again.
8. according to Eliquis nano suspension described in right 1, it is characterised in that: be suitable for oral, external application, drug administration by injection way
Diameter administration.
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Cited By (6)
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| CN110193084A (en) * | 2019-07-02 | 2019-09-03 | 付纪军 | It is a kind of containing Polyvinylcaprolactame-polyvinyl acetate-polyethyleneglycol-graft copolymer pharmaceutical preparation and preparation method thereof |
| WO2020034989A1 (en) * | 2018-08-14 | 2020-02-20 | 江苏恒瑞医药股份有限公司 | Injectable pharmaceutical composition and preparation method therefor |
| CN111000820A (en) * | 2020-01-09 | 2020-04-14 | 新发药业有限公司 | Apixaban tablet |
| WO2021160144A1 (en) * | 2020-02-13 | 2021-08-19 | 江苏恒瑞医药股份有限公司 | Method for preventing or treating thromboembolisms by means of apixaban injection |
| WO2023072967A1 (en) | 2021-10-27 | 2023-05-04 | Pharma-Data S.A. | Apixaban suspension and preparation method |
| CN116098872A (en) * | 2022-12-06 | 2023-05-12 | 苏州大学 | Apixaban long-acting microsphere for injection and preparation method thereof |
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| NL2029536B1 (en) * | 2021-10-27 | 2023-05-26 | Pharma Data S A | Apixaban suspension and preparation method |
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| CN116098872A (en) * | 2022-12-06 | 2023-05-12 | 苏州大学 | Apixaban long-acting microsphere for injection and preparation method thereof |
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