CN109700784A - Ticagrelor sustained-release micro-spheres and its preparation and application - Google Patents
Ticagrelor sustained-release micro-spheres and its preparation and application Download PDFInfo
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- CN109700784A CN109700784A CN201910180321.7A CN201910180321A CN109700784A CN 109700784 A CN109700784 A CN 109700784A CN 201910180321 A CN201910180321 A CN 201910180321A CN 109700784 A CN109700784 A CN 109700784A
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- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 title claims abstract description 82
- 229960002528 ticagrelor Drugs 0.000 title claims abstract description 82
- 238000013268 sustained release Methods 0.000 title claims abstract description 52
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 51
- 239000004005 microsphere Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003405 delayed action preparation Substances 0.000 claims abstract description 37
- 238000013265 extended release Methods 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000002077 nanosphere Substances 0.000 claims abstract description 12
- 229920000294 Resistant starch Polymers 0.000 claims abstract description 9
- 108010073771 Soybean Proteins Proteins 0.000 claims abstract description 9
- 235000021254 resistant starch Nutrition 0.000 claims abstract description 9
- 235000019710 soybean protein Nutrition 0.000 claims abstract description 9
- 241000206672 Gelidium Species 0.000 claims abstract description 7
- 108010059642 isinglass Proteins 0.000 claims abstract description 7
- 229910052627 muscovite Inorganic materials 0.000 claims abstract description 7
- 238000011068 loading method Methods 0.000 claims abstract description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 229920001661 Chitosan Polymers 0.000 claims description 9
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 8
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 8
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 8
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 241000206575 Chondrus crispus Species 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 230000005684 electric field Effects 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 238000013176 antiplatelet therapy Methods 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 2
- -1 5-15% Chemical compound 0.000 claims 1
- 241001474374 Blennius Species 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 14
- 238000001727 in vivo Methods 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 230000000694 effects Effects 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 235000021251 pulses Nutrition 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 7
- 235000010413 sodium alginate Nutrition 0.000 description 7
- 239000000661 sodium alginate Substances 0.000 description 7
- 229940005550 sodium alginate Drugs 0.000 description 7
- 230000009471 action Effects 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000007596 consolidation process Methods 0.000 description 5
- 239000008055 phosphate buffer solution Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000251468 Actinopterygii Species 0.000 description 3
- 210000001772 blood platelet Anatomy 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- 229960003009 clopidogrel Drugs 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000011806 microball Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 239000011805 ball Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to ticagrelor technical fields, more particularly to a kind of ticagrelor sustained-release micro-spheres and its preparation and application, ticagrelor sustained-release micro-spheres of the present invention include the extended-release core and slow release layer for loading ticagrelor, the extended-release core includes nanosphere, the nanosphere is selected from resistant starch microballoon or soybean protein isolate and isinglass mixes microballoon processed, partial size is 400-800nm, porosity is 20-40%, aperture is 30-80nm, ticagrelor sustained release preparation is prepared for based on the ticagrelor sustained-release micro-spheres, the sustained-release micro-spheres surface has positive charge, porosity is high, aperture is small, more ticagrelors can be loaded, and in vivo, the nanosphere is selected from resistant starch microballoon or soybean protein isolate and isinglass mixes microballoon processed and can finally be degraded in vivo, so that being loaded Drug all discharge, drug is utilized completely, and therapeutic effect is stablized.
Description
Technical field
The invention belongs to ticagrelor technical fields, and in particular to a kind of ticagrelor sustained-release micro-spheres and its preparation and answer
With.
Background technique
With aging of population progress faster, cardiovascular disease incidence rate is improved rapidly, and platelet aggregation-against is the treatment heart
The important link of cranial vascular disease.Ticagrelor is a kind of platelet aggregation inhibitor, and clinical efficacy and safety have obtained
Blood platelet inhibits verifying and support with the research of patient's consequence final result (PLATO research) and its multinomial subgroup research.PLATO research
The curative effect for also showing ticagrelor is substantially better than clopidogrel, recommends so being listed in a line by domestic and international multiple guides, and Europe
Guide is even more before the recommendation rank of ticagrelor is listed in clopidogrel by nearly 2 years.Ticagrelor is invertibity knot when acting on
It closes, blood platelet can restore after drug withdrawal, and cardiovascular disease is usually a kind of chronic disease, long-term quantitative medication be needed, to compliance
The bad patient of property has an impact.On the other hand, ticagrelor half-life short, it is rapid-action, when needing long-acting Antiplatelet therapy
It is not ideal enough.
The pharmacokinetics of ticagrelor and the data of pharmacodynamics show, keep certain ticagrelor plasma concentration can be with
Better blood platelet inhibiting rate is provided, however in order to reduce the blood concentration of wave crest, commercially available dosage can only maintain 12 hours medicines
Effect, needs two times a day to be administered to guarantee curative effect of medication
Existing Chinese patent literature CN101904818B discloses a kind of self-assembled composite membrane controlled sustained-release preparation and its system
Preparation Method utilizes the polymer with different charges such as chitosan, sodium alginate, carragheen, carboxymethyl fine by traditional handicraft
Tie up plain sodium etc. and prepare matrixtablets or granule, changed during release based on Human Physiology pH, make two kinds or two kinds with
The upper polymer with different charges occurs interaction and forms insoluble complexes membrane in tablet surface, and skeleton system is automatic
It is changed into self-assembled composite membrane controlled sustained-release tablet or granule, the drug with good slow release effect is made, however, the invention
Say that the technical solution method provided is complicated, vivo biodistribution environment is complicated, and it is difficult to predict unstable for effect.
Summary of the invention
In order to solve the above technical problems, making up the deficiencies in the prior art, the present invention provides a kind of ticagrelor sustained releases to make
Agent and its preparation and application.
The present invention is achieved through the following technical solutions:
The invention discloses a kind of ticagrelor sustained-release micro-spheres, extended-release core and sustained release including being embedded with ticagrelor
Layer, the extended-release core includes nanosphere, and the nanosphere is selected from resistant starch microballoon or soybean protein isolate and fish is bright
Glue mixes microballoon processed, partial size 400-800nm, porosity 20-40%, aperture 30-80nm.
Preferably, the slow release layer is carragheen, sodium alginate or sodium carboxymethylcellulose, is coated on affiliated extended-release core
Outer surface.
The invention also discloses the preparation methods of the ticagrelor sustained-release micro-spheres, comprising the following steps:
Step 1: ticagrelor is crushed, and embeds into the nanosphere and extended-release core is made；
Step 2: the extended-release core surface is coated into slow release layer.
Preferably, the embedding of ticagrelor is mediated by ultrasonic guidance vacuum technique in the extended-release core, the sustained release core
The slow release layer cladding on heart surface is promoted by high-pressure pulse electric.
The invention also discloses a kind of ticagrelor sustained release preparations, including the ticagrelor sustained-release micro-spheres or described for lattice
The ticagrelor sustained-release micro-spheres of auspicious Lip river sustained-release micro-spheres preparation method preparation.
Preferably, further include mass fraction be 0.01%-0.02% Butylated Hydroxyanisole.
Preferably, the ticagrelor sustained release preparation per unit preparation contains ticagrelor 180-240mg.
It preferably, based on mass fraction, further include the calcium carbonate of 5-15%, the microcrystalline cellulose of 1-3%, 0.01-
0.03% magnesium stearate, remaining is chitosan.
The invention also discloses a kind of preparation methods of ticagrelor sustained release preparation, including ticagrelor are sustained micro-
Ball is mixed with remaining raw material, pelletizes and is coated.
The invention also discloses the ticagrelor sustained-release micro-spheres or the ticagrelor sustained-release micro-spheres preparation method to prepare
Ticagrelor sustained-release micro-spheres or the ticagrelor sustained release preparation or the ticagrelor sustained release preparation preparation method system
Application of the standby ticagrelor sustained release preparation in Antiplatelet therapy drug.
The above technical solution of the present invention has the following advantages over the prior art:
1. ticagrelor sustained-release micro-spheres of the present invention include the extended-release core and slow release layer for loading ticagrelor, described slow
Releasing core includes nanosphere, and the nanosphere is selected from resistant starch microballoon or soybean protein isolate and isinglass mixing system is micro-
Ball, partial size 400-800nm, porosity 40-60%, aperture 30-80nm, the sustained-release micro-spheres surface have positive charge,
Porosity is high, and aperture is small, can load more ticagrelors, and in vivo, and it is micro- that the nanosphere is selected from resistant starch
Ball or soybean protein isolate and isinglass mix microballoon processed and can finally be degraded in vivo, so that the drug loaded is all released
It puts, drug is utilized completely, and therapeutic effect is stablized.
2. ticagrelor sustained-release micro-spheres of the present invention, the slow release layer is carragheen, sodium alginate or carboxymethyl cellulose
Plain sodium is coated on affiliated extended-release core outer surface, and the carragheen, sodium alginate or sodium carboxymethylcellulose have negative electricity
Lotus mixes tight in conjunction with microsphere sustained-release core processed with the soybean starch microballoon or soybean protein isolate and isinglass for having positive charge
It is close, extend slow-release time, improves slow release effect.
3. ticagrelor sustained release preparation of the present invention, including the sustained-release micro-spheres and there is anti-oxidant and anti-light degradation pair
The Butylated Hydroxyanisole of recast, further includes the calcium carbonate of mass fraction 5-15%, the microcrystalline cellulose of mass fraction 1-3% and remaining
The chitosan of amount, good with sustained-release micro-spheres compatibility, manufactured ticagrelor sustained release preparation had good sustained release effect, slow-release time is long, medicine
It is good that object discharges stability.
4. the preparation method of ticagrelor sustained release preparation of the present invention, simple process and low cost, service performance is more
It is good.
5. ticagrelor sustained-release micro-spheres of the present invention and affiliated sustained release preparation are used for the drug of Antiplatelet therapy, it is made
Medication medication release stablize completely, long action time, therapeutic effect is good.
Specific embodiment
There is provided following embodiments is to preferably further understand the present invention, it is not limited to the best embodiment party
Formula is not construed as limiting the contents of the present invention and protection scope, anyone under the inspiration of the present invention or by the present invention and its
The feature of his prior art is combined and any and identical or similar product of the present invention for obtaining, all falls within of the invention
Within protection scope.
Specific experiment step or condition person are not specified in embodiment, according to the literature in the art described routine experiment
The operation of step or condition can carry out.Reagents or instruments used without specified manufacturer, being can be by commercially available acquisition
Conventional reagent product.
Embodiment 1
A kind of specific embodiment of ticagrelor sustained release preparation is present embodiments provided, described in detail below:
18g ticagrelor is taken, 200 mesh are crushed to, is dissolved in 50ml ethyl acetate, 20g resistant starch microballoon, partial size is added
For 400-500nm, porosity 40%, aperture 30-50nm promotes to embed, ultrasonic power using ultrasonic guidance vacuum technique
For 500W, vacuum degree 0.1MPa, action time 25min, ethyl acetate is volatilized under ultrasonic state after effect, is made described
The extended-release core of sustained-release micro-spheres；
It is 10mM, heating stirring in the phosphate buffer solution that pH value is 7.0 that the extended-release core, which is dissolved in 50ml concentration,
It is uniformly mixed and forms solution, power is that 500W is ultrasonically treated 30min, and 25g carragheen is added, and heating stirring is uniformly mixed, power
It is ultrasonically treated 30min for 500W, high-pressure pulse electric is handled 3 times, and high-voltage pulse electric field intensity is 25kV/cm, electrode plate spacing
The sustained-release micro-spheres for being coated with slow release layer are made in 0.4cm；
By the sustained-release micro-spheres and 5g calcium carbonate, 1g microcrystalline cellulose, 0.01g magnesium stearate and 0.01g Butylated Hydroxyanisole are remaining
Amount is chitosan, and total 100g raw material is uniformly mixed, the mixture of the ticagrelor sustained release preparation is made；
Granulating mixture is obtained into 100 sustained release preparation labels, label is compressed into consolidation, increases weight 1% in coating pan, i.e.,
?.
Embodiment 2
A kind of specific embodiment of ticagrelor sustained release preparation is present embodiments provided, described in detail below:
24g ticagrelor is taken, 300 mesh are crushed to, is dissolved in 50ml ethyl acetate, 20g soybean protein isolate and fish is added
Gelatin mixes microballoon processed, partial size 600-800nm, porosity 60%, aperture 50-80nm, using ultrasonic guidance vacuum skill
Art promotes embedding, ultrasonic power 800W, vacuum degree 0.1MPa, action time 30min, by second under ultrasonic state after effect
Acetoacetic ester volatilization, is made the extended-release core of the sustained-release micro-spheres；
It is 10mM, heating stirring in the phosphate buffer solution that pH value is 7.0 that the extended-release core, which is dissolved in 50ml concentration,
It is uniformly mixed and forms solution, power is that 800W is ultrasonically treated 30min, and 30g sodium alginate is added, and heating stirring is uniformly mixed, function
Rate is that 500W is ultrasonically treated 30min, and high-pressure pulse electric is handled 10 times, and high-voltage pulse electric field intensity is 30kV/cm, between electrode plate
Away from 0.4cm, the sustained-release micro-spheres for being coated with slow release layer are made；
By the sustained-release micro-spheres and 15g calcium carbonate, 3g microcrystalline cellulose, 0.03g magnesium stearate and 0.02g Butylated Hydroxyanisole,
Surplus is chitosan, total 100g raw material, is uniformly mixed, the mixture of the ticagrelor sustained release preparation is made；
Granulating mixture is obtained into 100 sustained release preparation labels, label is compressed into consolidation, increases weight 3% in coating pan, i.e.,
?.
Embodiment 3
A kind of specific embodiment of ticagrelor sustained release preparation is present embodiments provided, described in detail below:
20g ticagrelor is taken, 200 mesh are crushed to, is dissolved in 50ml ethyl acetate, 15g resistant starch microballoon, partial size is added
For 500-600nm, porosity 50%, aperture 70-80nm promotes to embed, ultrasonic power using ultrasonic guidance vacuum technique
For 600W, vacuum degree 0.1MPa, action time 40min, ethyl acetate is volatilized under ultrasonic state after effect, is made described
The extended-release core of sustained-release micro-spheres；
It is 10mM, heating stirring in the phosphate buffer solution that pH value is 7.0 that the extended-release core, which is dissolved in 50ml concentration,
It is uniformly mixed and forms solution, power is that 700W is ultrasonically treated 30min, and 30g sodium alginate is added, and heating stirring is uniformly mixed, function
Rate is that 600W is ultrasonically treated 40min, and high-pressure pulse electric is handled 8 times, and high-voltage pulse electric field intensity is 30kV/cm, between electrode plate
Away from 0.4cm, the sustained-release micro-spheres for being coated with slow release layer are made；
By the sustained-release micro-spheres and 10g calcium carbonate, 2g microcrystalline cellulose, 0.02g magnesium stearate and 0.015g Butylated Hydroxyanisole,
Surplus is chitosan, total 100g raw material, is uniformly mixed, the mixture of the ticagrelor sustained release preparation is made；
Granulating mixture is obtained into 100 sustained release preparation labels, label is compressed into consolidation, increases weight 2% in coating pan, i.e.,
?.
Embodiment 4
A kind of specific embodiment of ticagrelor sustained release preparation is present embodiments provided, described in detail below:
22g ticagrelor is taken, 300 mesh are crushed to, is dissolved in 50ml ethyl acetate, 20g resistant starch microballoon or big is added
Beans protein isolate and isinglass mix microballoon processed, partial size 500-600nm, porosity 55%, aperture 70-80nm, use
Ultrasonic guidance vacuum technique promotes embedding, ultrasonic power 700W, vacuum degree 0.1MPa, action time 50min, after effect
Ethyl acetate is volatilized under ultrasonic state, the extended-release core of the sustained-release micro-spheres is made；
It is 10mM, heating stirring in the phosphate buffer solution that pH value is 7.0 that the extended-release core, which is dissolved in 50ml concentration,
It is uniformly mixed and forms solution, power is that 700W is ultrasonically treated 50min, and 20g carragheen, sodium alginate or carboxymethyl cellulose is added
Sodium, heating stirring are uniformly mixed, and power is that 700W is ultrasonically treated 40min, and high-pressure pulse electric is handled 5 times, high-pressure pulse electric
Intensity is 25kV/cm, electrode plate spacing 0.4cm, and the sustained-release micro-spheres for being coated with slow release layer are made；
By the sustained-release micro-spheres and 12g calcium carbonate, 2g microcrystalline cellulose, 0.01g magnesium stearate and 0.01g Butylated Hydroxyanisole,
Surplus is chitosan, total 100g raw material, is uniformly mixed, the mixture of the ticagrelor sustained release preparation is made；
Granulating mixture is obtained into 100 sustained release preparation labels, label is compressed into consolidation, increases weight 2% in coating pan, i.e.,
?.
Embodiment 5
A kind of specific embodiment of ticagrelor sustained release preparation is present embodiments provided, described in detail below:
20g ticagrelor is taken, 300 mesh are crushed to, is dissolved in 50ml ethyl acetate, 20g soybean protein isolate and fish is added
Gelatin mixes microballoon processed, partial size 500-600nm, porosity 55%, aperture 60nm, using ultrasonic guidance vacuum technique rush
Into embedding, ultrasonic power 600W, vacuum degree 0.1MPa, action time 30min, by acetic acid second under ultrasonic state after effect
Ester volatilization, is made the extended-release core of the sustained-release micro-spheres；
It is 10mM, heating stirring in the phosphate buffer solution that pH value is 7.0 that the extended-release core, which is dissolved in 50ml concentration,
It is uniformly mixed and forms solution, power is that 600W is ultrasonically treated 30min, and 15g sodium carboxymethylcellulose is added, and heating stirring mixing is equal
Even, power is that 600W is ultrasonically treated 30min, and high-pressure pulse electric is handled 6 times, and high-voltage pulse electric field intensity is 25kV/cm, electrode
The sustained-release micro-spheres for being coated with slow release layer are made in plate spacing 0.4cm；
By the sustained-release micro-spheres and 6g calcium carbonate, 3g microcrystalline cellulose, 0.03g magnesium stearate and 0.02g Butylated Hydroxyanisole are remaining
Amount is chitosan, and total 100g raw material is uniformly mixed, the mixture of the ticagrelor sustained release preparation is made；
Granulating mixture is obtained into 100 sustained release preparation labels, label is compressed into consolidation, increases weight 1% in coating pan, i.e.,
?.
Test case 1
Drug release determination: using and investigate 2h containing mass fraction for the dissolution medium of the HCL of the 0.1M of 0.2% Tween 80,
It is then transferred in the dissolution medium that pH that mass fraction is 0.2% Tween 80 is 6.8 and investigates to the drug release situation of 20h,
Test result is as follows shown in table 1
1 embodiment 1-5 ticagrelor sustained release preparation release test result of table
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| 2h | 20% | 22% | 25% | 18% | 12% |
| 4h | 45% | 45% | 50% | 35% | 30% |
| 8h | 58% | 60% | 65% | 55% | 40% |
| 12h | 70% | 72% | 75% | 70% | 50% |
| 16h | 80% | 82% | 85% | 80% | 61% |
| 20h | 88% | 90% | 90% | 90% | 70% |
Above embodiment is only intended to clearly illustrate example, and does not limit the embodiments.For
For those of ordinary skill in the art, other various forms of variations or change can also be made on the basis of the above description
It is dynamic.There is no necessity and possibility to exhaust all the enbodiments.And obvious variation extended from this or change
It moves still within the protection scope of the invention.
Claims (10)
1. a kind of ticagrelor sustained-release micro-spheres, which is characterized in that extended-release core and slow release layer including loading ticagrelor, it is described
Extended-release core includes nanosphere, and the nanosphere is selected from resistant starch microballoon or soybean protein isolate and isinglass mixing system
Microballoon, partial size 400-800nm, porosity 20-40%, aperture 30-80nm.
2. ticagrelor sustained-release micro-spheres according to claim 1, which is characterized in that the slow release layer is carragheen, seaweed
Sour sodium or sodium carboxymethylcellulose are coated on affiliated extended-release core outer surface.
3. a kind of preparation method of ticagrelor sustained-release micro-spheres as claimed in claim 1 or 2, which comprises the following steps:
Step 1: ticagrelor is crushed, and embeds into the nanosphere and extended-release core is made；
Step 2: the extended-release core surface is coated into slow release layer.
4. the preparation method of ticagrelor sustained-release micro-spheres according to claim 3, which is characterized in that in the extended-release core
The embedding of ticagrelor is mediated by ultrasonic guidance vacuum technique, and the slow release layer on the extended-release core surface is coated by high-voltage pulse electric
Field promotes.
5. a kind of ticagrelor sustained release preparation, which is characterized in that including ticagrelor sustained-release micro-spheres of any of claims 1 or 2
Or the ticagrelor sustained-release micro-spheres of the ticagrelor sustained-release micro-spheres preparation method preparation of claim 3 or 4.
6. ticagrelor sustained release preparation according to claim 5, which is characterized in that further include mass fraction be 0.01%-
0.02% Butylated Hydroxyanisole.
7. ticagrelor sustained release preparation according to claim 5 or 6, which is characterized in that the ticagrelor sustained release preparation
Per unit preparation contains ticagrelor 180-240mg.
8. according to the described in any item ticagrelor sustained release preparations of claim 4-7, which is characterized in that based on mass fraction, also
Calcium carbonate including 5-15%, the microcrystalline cellulose of 1-3%, the magnesium stearate of 0.01-0.03%, remaining is chitosan.
9. a kind of preparation method of any one of claim 5-8 ticagrelor sustained release preparation, which is characterized in that including that will replace
Ge Ruiluo sustained-release micro-spheres are mixed with remaining raw material, pelletize and are coated.
10. a kind of ticagrelor sustained-release micro-spheres of any of claims 1 or 2 or the ticagrelor sustained release of claim 3 or 4
The ticagrelor sustained-release micro-spheres or the described in any item ticagrelor sustained release preparations of claim 5-8 of method for preparing microsphere preparation,
Or the ticagrelor sustained release preparation of the preparation of ticagrelor sustained release preparation preparation method described in claim 9 is in Antiplatelet therapy medicine
Application in object.
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| CN117837763A (en) * | 2024-01-09 | 2024-04-09 | 中食安泓(广东)健康产业有限公司 | High-activity slow-release probiotic microcapsule and preparation method and application thereof |
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Application publication date: 20190503 |