CN105998026A - Ticagrelor pharmaceutical composition and preparing method thereof - Google Patents
Ticagrelor pharmaceutical composition and preparing method thereof Download PDFInfo
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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- 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
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Abstract
The invention relates to a sustained-release preparation composition of an anticoagulant drug ticagrelor (also called brilinta) and a preparing method thereof. The composition comprises ticagrelor and other pharmaceutical accessories. The composition is characterized in that the composition can be quick in acting, also can ensure persistent effectivity within 24 hours, and further can reduce Cmax based on guarantee of the effective plasma concentration, thereby improving patient compliance and reducing drug safety problem in the premise without reduction of curative effect.
Description
Technical field
The invention belongs to technical field of medicine, oral slow more particularly to a kind of Ticagrelor (having another name called ticagrelor)
Release formulation pharmaceutical composition and preparation method thereof.
Background technology
Ticagrelor (Ticagrelor), has another name called ticagrelor, chemistry entitled (1S, 2S, 3R, 5S)-3-[7-{ [(1R,
2S)-2-(3,4-difluorophenyl) cyclopropyl] amino }-5-rosickyite base-3H-1,2,3-triazol [4,5-d] pyrimidin-3-yl]-5-
(2-hydroxyl-oxethyl)-1,2-ring pentanediol, chemical constitution shown in formula I:
Ticagrelor belongs to cyclopenta triazolopyrimidines, is first reversible P2Y12Platelet suppressant drug, main
It is used for reducing acute coronary syndrome (ACS) and (includes that unstable angina pectoris, non-ST section myocardial infarction, ST section are raised
Myocardial infarction) incidence rate of thrombotic cardiovascular event (cardiovascular death, myocardial infarction and apoplexy) of patient.Can also be used for subtracting
Include less accepting Drug therapy and accept percutaneous coronary to get involved (PCI) or coronary artery bypass grafting (CABG) blood afterwards
The incidence rate that bolt is formed;Can be additionally used in that to reduce its cardiovascular (more than 50 years old) in the patient being diagnosed as peripheral arterial disease dead
Die, myocardial infarction and Ischemic Stroke.
Ticagrelor is developed by AstraZeneca (AstraZeneca), trade name Brilique, and dosage form is conventional tablet,
Specification is 90mg.In December, 2010 obtains listing approval first in European Union;In July, 2011 is approved listing approval in the U.S.,
In the country's listing of more than 40, the whole world.This product is administered orally 1 day 2 times, rapid-action, and clinical efficacy is obvious, and safety is good, is oral anticoagulant
Clinical efficacy in blood medicine is notable, one of good medicine of market prospect.
It is currently used for the incidence rate of the thrombotic cardiovascular event of prevention of acute coronary syndromes (ACS) patient, existing
Column criterion Therapeutic Method is the bigeminy antiplatelet therapeutic alliance of clopidogrel and aspirin.Although clopidogrel is every day one
Secondary administration, but still there is the ACS patient of about 11% that serious cardiovascular (CV) event recurrence occurs, and great majority occur at ACS
Occur in some months after index event.Simultaneously because of clopidogrel there is also onset time slowly, to hematoblastic inhibitory action
Many safety issues such as not exclusively, antiplatelet effects individual variation is big, antiplatelet effects is irreversible.
In July, 2009, Lilly Co., Eli. research and development prasugrel be approved listing, prasugrel compared with clopidogrel,
It is a little that onset effect is very fast, relatively strong to hematoblastic inhibitory action, antiplatelet effects individual variation is less, can reduce the heart
Flesh infarction and the artery thrombosis risk of percutaneous coronary intervention (PCI) patient.But equally exist problems, as in treatment
During to increase the bleeding risk of big patient, antiplatelet effects irreversible, need could to recover blood in 5~7 days after drug withdrawal little
The coagulation function of plate, to needing, the patient carrying out CABG or other operation is unfavorable.
The successful listing of Ticagrelor compensate for many deficiencies of clopidogrel and prasugrel.It is oral rear rapid-action
(about 2h), antiplatelet effects individual variation is less, and clinical efficacy is notable, and is first reversible P2Y12Platelet suppresses
Agent, after drug withdrawal, in 1~3 day, platelet function can recover normal, can be used for needing to carry out CABG or the patient of other operation,
And can substantially reduce the mortality rate of cardiovascular patient.Meanwhile, long-term taking bleeding risk is less, and safety is high.
Use P2Y12Platelet suppressant drug is during treatment acute coronary syndrome (ACS), and its treatment cycle is relatively
Long, need long-term taking P2Y12Platelet suppressant drug.Although Ticagrelor has many excellent compared with clopidogrel and prasugrel
Point, but 2 administrations in 1 day can reduce the compliance of patient.During Long-term taking medicine, miss phenomenon inevitable, because replacing simultaneously
Card Gray is reversible P2Y12Platelet suppressant drug, therefore miss phenomenon and may result in safety issue.There is research display, for card
Gray's taking dose and Cmax are strict linear relationship, and Ticagrelor is administered about 200mg 1 day 1 time, and effective blood drug concentration can
To maintain 24 hours, although 1 day 1 time administration of high dose will not increase its bleeding risk.But its high dose can increase ventricular pause
The incidence rate of (Ventricular pauses).Therefore exploitation one can to reach onset time fast, can reduce again administration number of times and
The sustained-release preparation of the Ticagrelor of Cmax can be reduced, thus improve compliance and the clinical safety of patient, its clinical meaning
Great.
Ticagrelor is white or off-white color is to pale pink powder.PH 7.4 times, log P (n-octanol/water) is 4.5
Left and right.In physiological pH environment between pH1.0~pH7.4, its dissolubility is not affected by pH, all at 10 μ about g/ml, belongs to
Insoluble drug;Having research display this product permeability in vivo is about 51%, belongs to medium permeability, but because of less than 90%,
Therefore belong to IV class (i.e. low-solubility hypotonicity) by biopharmaceutics BCS classification Ticagrelor.Because Ticagrelor belongs to low molten
Solution property hypotonicity medicine, the release behavior of its preparation and permeability are affects the crucial speed limit that Ticagrelor absorbs in vivo
Process.
The most existing many document pharmaceutical compositions disclosing Ticagrelor sustained-release preparation and preparation method thereof, the most specially
Profit CN102657629B, patent CN103860504A and patent CN103520164B.Through above-mentioned patented technology being carried out point
Analysis, its Patent CN102657629B and patent CN103860504A, although can with action time in extension body, but can not
Reach quick acting.Although patent CN103520164B can realize quick acting, but 1 day 1 time administration is unable to maintain that 24 hours
Continuous and effective.Finding through research, the pharmaceutical composition that the present invention provides, 1 day 1 time administration both can reach quick acting, again
Can ensure that continuous and effective in 24 hours, Cmax can also be reduced on the basis of guaranteeing effective blood drug concentration simultaneously, thus solve
On the premise of not lessening the curative effect, improve patient compliance and reduce drug safety sex chromosome mosaicism.
Summary of the invention
An object of the present invention is to provide a kind of pharmaceutical composition containing Ticagrelor, this pharmaceutical composition 1 day 1
Secondary administration, both can reach quick acting, can ensure that again continuous and effective in 24 hours, can also guarantee that effective blood medicine is dense simultaneously
Reduce Cmax on the basis of degree, thus solve and on the premise of not lessening the curative effect, improve patient compliance and reduce medication
Safety issue.
Further object is that the preparation method that a kind of Ticagrelor slow release is provided.
Can be achieved through the following technical solutions to realize goal of the invention:
The invention provides a kind of Ticagrelor sustained release pharmaceutical composition, said composition includes medicine-releasing system I and selected from releasing
Medicine system II or the medicine-releasing system of medicine-releasing system III, wherein:
Medicine-releasing system I includes Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and optional
The isolated material selected;
Medicine-releasing system II includes Ticagrelor, slow-release material, porogen, binding agent, lubricant and/or antiplastering aid;
Medicine-releasing system III include Ticagrelor, slow release isolated material, filler, disintegrating agent, binding agent, lubricant and/or
Antiplastering aid.
In one embodiment, the Ticagrelor sustained release pharmaceutical composition that the present invention provides includes medicine-releasing system I and release
System II, wherein: medicine-releasing system I includes Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and
Selectable isolated material;Medicine-releasing system II includes Ticagrelor, slow-release material, porogen, binding agent, lubricant and/or resists
Stick.
In one embodiment, the Ticagrelor sustained release pharmaceutical composition that the present invention provides includes medicine-releasing system I and release
System III, wherein: medicine-releasing system I includes Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, with
And selectable isolated material;Medicine-releasing system III include Ticagrelor, slow release isolated material, filler, disintegrating agent, binding agent,
Lubricant and/or antiplastering aid.
In one embodiment, the Ticagrelor sustained release pharmaceutical composition that the present invention provides includes medicine-releasing system I, release system
System II and medicine-releasing system III, wherein: medicine-releasing system I include Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/or
Antiplastering aid, and selectable isolated material;Medicine-releasing system II includes Ticagrelor, slow-release material, porogen, binding agent, profit
Lubrication prescription and/or antiplastering aid;Medicine-releasing system III includes Ticagrelor, slow release isolated material, filler, disintegrating agent, binding agent, profit
Lubrication prescription and/or antiplastering aid.
In aforementioned pharmaceutical compositions, the amount of Ticagrelor is 155mg~230mg, preferably 170mg~200mg.Implement one
In scheme, Ticagrelor selected from 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg, 178mg,
179mg、180mg、181mg、182mg、183mg、184mg、185mg、186mg、187mg、188mg、189mg、190mg、
191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg, 199mg or 200mg.
In aforementioned pharmaceutical compositions, the particle diameter of Ticagrelor is distributed as D90Less than 200 μm, preferably D90Less than 100 μm, more
Preferably D90Less than 50 μm.
In aforementioned pharmaceutical compositions, medicine-releasing system I include Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/
Or antiplastering aid;
The amount of the Ticagrelor in above-mentioned medicine-releasing system I is 40mg~90mg, preferably 45mg~70mg;
The Ticagrelor in above-mentioned medicine-releasing system I weight content in medicine-releasing system I is 15%~60%, preferably 25%
~50%.
Filler in above-mentioned medicine-releasing system I is selected from microcrystalline Cellulose, lactose, mannitol, pregelatinized Starch, phosphoric acid hydrogen
One or more in calcium, calcium sulfate;The wherein one or many in preferably microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate
Kind.Selected filler loading weight content in medicine-releasing system I is 10%~70%, preferably 15%~50%.
Disintegrating agent in above-mentioned medicine-releasing system I is selected from carboxymethyl starch sodium, sodium starch glycolate, low substituted hydroxy-propyl fibre
One or more in dimension element, crospolyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium;Wherein preferably carboxymethyl starch sodium,
One or more in crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose.Selected disintegrating agent consumption is at medicine-releasing system I
In weight content be 0.5%~10%, preferably 1.5%~7%.
Binding agent in above-mentioned medicine-releasing system I is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidine
One or more in ketone;Wherein one or more in preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose.Selected bonding
Agent consumption weight content in medicine-releasing system I is 0.5%~5%, preferably 1%~4%.
Lubricant in above-mentioned medicine-releasing system I, including usually said fluidizer, selected from micropowder silica gel, Pulvis Talci, tristearin
One or more in acid magnesium, calcium stearate, fumaric acid sodium stearate;Wherein in preferred micropowder silica gel, Pulvis Talci, magnesium stearate
One or more.Selected lubricant quantity weight content in medicine-releasing system I is 0.2%~6%, preferably 0.5%~
3%.
Antiplastering aid in above-mentioned medicine-releasing system I, one or more in micropowder silica gel, Pulvis Talci, starch;The most excellent
Select one or more in micropowder silica gel, Pulvis Talci.Selected anti-stick agent level weight content in medicine-releasing system I is 0.2%
~6%, preferably 0.5%~3%.
In aforementioned pharmaceutical compositions, medicine-releasing system II includes Ticagrelor, slow-release material, porogen, binding agent, lubricant
And/or antiplastering aid;
The amount of the Ticagrelor in above-mentioned medicine-releasing system II is 55mg~160mg, preferably 60mg~140mg.
The Ticagrelor in above-mentioned medicine-releasing system II weight content in medicine-releasing system II is 10%~50%, preferably
15%~40%.
Slow-release material in above-mentioned medicine-releasing system II is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Methyl cellulose
Element, ethyl cellulose, hydroxyethylmethyl-cellulose, polyoxyethylene, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone,
Acrylic copolymer, chitin, sodium alginate, potassium alginate, tragcanth, butyl stearate, stearic acid, Brazil wax,
One or more in glyceryl stearate, cellulose acetate, Polyethylene Glycol, wherein preferred hydroxypropyl methyl cellulose, hydroxypropyl
Base cellulose, methylcellulose, ethyl cellulose, polyoxyethylene, hydroxyethyl cellulose, polyvinyl alcohol, acrylic resin copolymerization
One or more in thing, cellulose acetate, sodium alginate, Polyethylene Glycol.Selected slow-release material consumption is in medicine-releasing system II
Weight content be 10%~75%, preferably 20%~70%.
One or more in mannitol, lactose, sucrose, glucose of porogen in above-mentioned medicine-releasing system II, its
In preferred one or more in mannitol, sucrose, lactose.Selected porogen consumption weight content in medicine-releasing system II is
1%~15%, preferably 2%~10%.
Binding agent in above-mentioned medicine-releasing system II is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrole
One or more in alkanone;Wherein one or more in preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose.Selected viscous
Mixture consumption weight content in medicine-releasing system II is 0.5%~15%, preferably 1.5%~10%.
Lubricant in above-mentioned medicine-releasing system II, including usually said fluidizer, selected from micropowder silica gel, Pulvis Talci, hard
One or more in fatty acid magnesium, stearic acid, cetylate, calcium stearate, fumaric acid sodium stearate;Wherein preferred micropowder silicon
One or more in glue, Pulvis Talci, magnesium stearate.Selected lubricant quantity weight content in medicine-releasing system II is
0.2%~6%, preferably 0.5%~5%.
Antiplastering aid in above-mentioned medicine-releasing system II, one in micropowder silica gel, Pulvis Talci, magnesium stearate, starch or
Multiple;Wherein one or more in preferred micropowder silica gel, Pulvis Talci.Selected anti-stick agent level weight in medicine-releasing system II
Content for for 0.2%~6%, preferably 0.5%~5%.
In above-mentioned composition, medicine-releasing system III includes Ticagrelor, slow release isolated material, filler, disintegrating agent, bonding
Agent, lubricant and/or antiplastering aid
The amount of the Ticagrelor in above-mentioned medicine-releasing system III is 55mg~160mg, preferably 60mg~140mg.
The Ticagrelor in above-mentioned medicine-releasing system III weight content in medicine-releasing system III is 10%~50%, preferably
15%~40%.
Slow release isolated material in above-mentioned medicine-releasing system III is selected from methylcellulose, ethyl cellulose, hydroxy propyl cellulose
One or more in element, acrylic resin copolymer, cellulose acetate;Wherein preferred acrylic resins copolymer, ethyl fibre
One or more in dimension element, cellulose acetate.Selected slow release isolated material weight content in medicine-releasing system III be 20%~
70%, preferably 25%~65%;
Filler in above-mentioned medicine-releasing system III is selected from microcrystalline Cellulose, lactose, mannitol, pregelatinized Starch, phosphoric acid hydrogen
One or more in calcium, calcium sulfate;The wherein one or many in preferably microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate
Kind.Selected filler loading weight content in medicine-releasing system III is 5%~40%, preferably 10%~35%;
Binding agent in above-mentioned medicine-releasing system III is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrole
One or more in alkanone;Wherein one or more in preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose.Selected viscous
Mixture consumption weight content in medicine-releasing system III is 1%~15%, preferably 2%~10%;
Lubricant (including usually said fluidizer) in above-mentioned medicine-releasing system III is selected from micropowder silica gel, Pulvis Talci, hard
Fatty acid magnesium, stearic acid, one or more in cetylate, calcium stearate, fumaric acid sodium stearate;Wherein preferred micropowder silicon
One or more in glue, Pulvis Talci, magnesium stearate.Selected lubricant quantity weight content in medicine-releasing system III is
0.2%~6%, preferably 0.5%~5%;
The antiplastering aid in above-mentioned medicine-releasing system III one in micropowder silica gel, Pulvis Talci, magnesium stearate, the starch or
Multiple;Wherein one or more in preferred micropowder silica gel, Pulvis Talci.Selected anti-stick agent level weight in medicine-releasing system III
Amount content is 0.2%~6%, preferably 0.5%~5%;
Disintegrating agent in above-mentioned medicine-releasing system III is selected from carboxymethyl starch sodium, sodium starch glycolate, low substituted hydroxy-propyl
One or more in cellulose, crospolyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium;Wherein preferred carboxymethyl starch
One or more in sodium, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose.Selected disintegrating agent consumption is in release system
Weight content in system III is 0.5%~10%, preferably 1.5%~5%.
Aforementioned pharmaceutical compositions as required, can select the coating material of suitable available in non-time-release effect to be coated to change
Its outward appearance kind, its coating material is selected from hydroxypropyl methyl cellulose, Polyethylene Glycol, arabic gum, Opadry II, Opadry
One or more in 200 grades;Wherein preferred hydroxypropyl methyl cellulose, Opadry II;Above-mentioned coating material can also and its
He is used in combination medicinal antiplastering aid, plasticizer, thickening agent, coloring agent, defoamer, opacifier etc..Selected coating material accounts for medicine
The 0.5%~10% of composition weight, preferably 1%~5%.
Medicine-releasing system I~III in aforementioned pharmaceutical compositions can make rule or irregular by conventional formulation technologies
Granule or powder, the spherical or granule of almost spherical or micropill, rule or irregular small pieces etc., the most again by medicine-releasing system I,
II and/or III makes tablet, capsule, granule etc. for oral suitable dosage forms, wherein preferred tablet and capsule.In system
During standby above-mentioned composition, used solvent one in purified water, the ethanol of variable concentrations, isopropanol, acetone
Or multiple, wherein preferred purified water or the ethanol of variable concentrations.
Further, the invention provides the preparation method of aforementioned pharmaceutical compositions, the method can be according to following technology
Scheme realizes:
A: medicine-releasing system I and II is respectively adopted appropriate solvent and makes dry granule or powder, then use many laminations
Sheet machine is pressed into multilayer tablet, and this tablet can be coated as required, sees Fig. 1;Or above-mentioned granule or powder are loaded capsule
Shell is made capsule.
Or:
B, by medicine-releasing system I, II or III, use conventional formulation technologies, as extrusion spheronization technology, centrifugal make ball technology or
Fluidizations etc. are respectively prepared the spherical or granule of almost spherical or micropill, or use pressed-disc technique to be respectively prepared rule or not
The small pieces of rule, then the granule of medicine-releasing system III, micropill or small pieces are used slow-release material coating.As required can be to upper
State the granule of medicine-releasing system I or II, micropill or small pieces and be coated isolation, see Fig. 2, then by above-mentioned medicine-releasing system I and II, or
Person medicine-releasing system I and III, or the granule of medicine-releasing system I and II and III, micropill or small pieces loading softgel shell make capsule;
Or it being pressed into tablet after above-mentioned granule, micropill or small pieces being mixed with appropriate filler, this tablet can select bag as required
Clothing.
Or:
C: medicine-releasing system II is used conventional formulation technologies, such as extrusion spheronization technology, is centrifuged and makes ball technology or fluid bed skill
Arts etc. make the spherical or granule of almost spherical or micropill, above-mentioned granule or micropill can be coated isolation as required,
The material in medicine-releasing system I is coated on medicine-releasing system II surface again and makes the spherical or granule of almost spherical or micropill, see figure
3, finally above-mentioned granule or micropill are loaded in softgel shell and make capsule;Or above-mentioned granule or micropill are mixed with appropriate filler
After be pressed into tablet, this tablet can select coating as required.
Or:
D: medicine-releasing system III is used conventional formulation technologies, such as extrusion spheronization technology, is centrifuged and makes ball technology or fluid bed skill
Arts etc. make the spherical or granule of almost spherical or micropill, then use slow-release material to be coated every more above-mentioned granule or micropill
Material in medicine-releasing system I is coated on medicine-releasing system III surface and makes the spherical or granule of almost spherical or micropill, see Fig. 4,
Finally above-mentioned granule or micropill are loaded in softgel shell and make capsule;Or after above-mentioned granule or micropill are mixed with appropriate filler
Being pressed into tablet, this tablet can select coating as required.
Or:
E: medicine-releasing system III is used conventional formulation technologies, such as extrusion spheronization technology, is centrifuged and makes ball technology or fluid bed skill
Arts etc. make the spherical or granule of almost spherical or micropill, more above-mentioned granule or micropill are used slow-release material be coated every
From, then make spherical or almost spherical by being coated on medicine-releasing system III surface after the material mix homogeneously in medicine-releasing system II
Granule or micropill, the above-mentioned granule comprising medicine-releasing system II and III or micropill can be coated isolation as required, finally will
It is coated on the granule comprising medicine-releasing system II and III after material mix homogeneously in medicine-releasing system I or micropill surface is made and comprised
The granule of the spherical or almost spherical of medicine-releasing system I, II and III or micropill, be shown in Fig. 5.Finally by above-mentioned comprise medicine-releasing system I,
The granule of the spherical or almost spherical of II and III or micropill load in softgel shell makes capsule;Or after mixing with appropriate filler
Being pressed into tablet, this tablet can select coating as required.
The sustained release pharmaceutical composition of above-mentioned Ticagrelor, its vitro release is: 1 hour between 25~35%, 2 hours
Between 35~45%, within 6 hours, between 45~65%, 12 hours more than 75%.
The sustained release pharmaceutical composition of the Ticagrelor that the present invention provides, is administered, both can reach quick acting, again for 1 day 1 time
Can ensure that continuous and effective in 24 hours, Cmax can also be reduced on the basis of guaranteeing effective blood drug concentration simultaneously, thus solve
On the premise of not lessening the curative effect, improve patient compliance and reduce drug safety sex chromosome mosaicism.
Accompanying drawing explanation
Fig. 1 is to comprise medicine-releasing system I and the bilayer tablet of medicine-releasing system II.
Fig. 2 is for comprising medicine-releasing system I and medicine-releasing system II, or medicine-releasing system I and medicine-releasing system III, or medicine-releasing system is released
Medicine system I and medicine-releasing system II and the mixture of medicine-releasing system III.
Fig. 3 is the single micropill comprising medicine-releasing system I and medicine-releasing system II.
Fig. 4 is the single micropill comprising medicine-releasing system I and medicine-releasing system III.
Fig. 5 is the single micropill comprising medicine-releasing system I, medicine-releasing system II and medicine-releasing system III.
Fig. 6 is the sample of embodiment 5 preparation stripping curve in 0.2% Tween 80 medium.
Fig. 7 is the sample of embodiment 18 preparation stripping curve in 0.2% Tween 80 medium.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described, can make professional and technical personnel in the field more fully
Understand the present invention, but limit the scope of the present invention never in any form.
Embodiment 1
Ticagrelor pharmaceutical composition (specification 160mg):
Embodiment 2
Ticagrelor pharmaceutical composition (specification 175mg):
Embodiment 3
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 4
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 5
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 6
Ticagrelor pharmaceutical composition (specification 175mg):
Embodiment 7
Ticagrelor pharmaceutical composition (specification 178mg):
Embodiment 8
Ticagrelor pharmaceutical composition (specification 190mg):
Embodiment 9
Ticagrelor pharmaceutical composition (specification 200mg):
Embodiment 10
Ticagrelor pharmaceutical composition (specification 220mg):
Above-described embodiment 1~10 preparation method: by each supplementary material in release system I and release system II (except lubricant or
Fluidizer is outer) respectively after mix homogeneously, then use water as wetting agent soft material respectively, 20 mesh sieves are pelletized, and do under the conditions of 60 DEG C
Dry, control moisture and be less than 5.0%, with 20 mesh sieve granulate, additional lubricant or fluidizer mix homogeneously, use many laminate respectively
Machine is pressed into double-layer tablet, to obtain final product.
Embodiment 11
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 12
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 13
Ticagrelor pharmaceutical composition (specification 185mg):
Embodiment 14
Ticagrelor pharmaceutical composition (specification 180mg):
Above-described embodiment 11~14 preparation method: by each supplementary material in release system I and release system II (except lubricant or
Fluidizer is outer) respectively after mix homogeneously, then use water as wetting agent soft material respectively, 20 mesh sieves are pelletized, and do under the conditions of 60 DEG C
Dry, control moisture and be less than 5.0%, with 20 mesh sieve granulate, additional lubricant or fluidizer mix homogeneously, use many laminate respectively
Machine is pressed into double-layer tablet, or makes capsule by loading in softgel shell after the mixing of above two granule, to obtain final product.
Embodiment 15
Ticagrelor pharmaceutical composition (specification 190mg):
Embodiment 16
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 17
Ticagrelor pharmaceutical composition (specification 180mg):
Above-described embodiment 15~17 preparation method: (1), by each adjuvant mix homogeneously in above-mentioned release system II, uses water
Make wetting agent soft material, use extrusion spheronization to be prepared as uniform granule or micropill, be dried under the conditions of 60 DEG C, control moisture
Less than 5.0%, select granule or the micropill of release system II of 16 mesh~30 mesh, standby;(2), by above-mentioned release system I
Each adjuvant mix homogeneously, makees solvent with water and makes suspension solution, standby, and above-mentioned suspension solution is coated with by (3), employing fluid unit
Overlay on the surface of release system II, make internal layer is release system II and outer layer is release system I single-size or micropill.Will
Above-mentioned granule or micropill load in softgel shell makes capsule, to obtain final product.
Embodiment 18
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 18 preparation method: (1), by each auxiliary except other of acrylic resin copolymer in above-mentioned release system III
Material mix homogeneously, uses water as wetting agent soft material, uses extrusion spheronization to be prepared as uniform granule or micropill, 60 DEG C of conditions
Lower dry, control moisture and be less than 5.0%, select granule or the micropill of release system III of 16 mesh~30 mesh, standby;(2)、
Acrylic resin copolymer addition suitable quantity of water is made aqueous dispersion, uses fluid unit to be coated on above-mentioned release system III
Granule or micropill surface be coated isolation;(3), by each adjuvant mix homogeneously in above-mentioned release system 1, make molten of water
Suspension solution is made in agent, uses fluid unit that above-mentioned suspension solution is coated in the granule of release system III or micropill
Surface;Finally include that the spherical of medicine-releasing system I, II and III or the granule of almost spherical or micropill load system in softgel shell by above-mentioned
Become capsule, to obtain final product.
Embodiment 19
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 19 preparation method: (1), by each auxiliary except other of acrylic resin copolymer in above-mentioned release system III
Material mix homogeneously, uses water as wetting agent soft material, uses extrusion spheronization to be prepared as uniform granule or micropill, at 60 DEG C of bars
It is dried under part, controls moisture and be less than 5.0%, select granule or the micropill of release system III of 16 mesh~30 mesh, standby;
(2), acrylic resin copolymer addition suitable quantity of water is made aqueous dispersion, use fluid unit to be coated on above-mentioned release system
Granule or the micropill surface of III are coated isolation;(3), by each adjuvant mix homogeneously in above-mentioned release system II, water is used
Make solvent and make suspension solution, use fluid unit that above-mentioned suspension solution is coated in the granule of release system III or micro-
The surface of ball;(4), by each adjuvant mix homogeneously in above-mentioned release system I, make solvent with water and make suspension solution, use stream
Above-mentioned suspension solution is coated on and includes that the granule of medicine-releasing system II and III or micropill surface are made and included release system by change bed apparatus
The granule of the spherical or almost spherical of system I, II and III or micropill.Finally include that medicine-releasing system I, II and III's is spherical by above-mentioned
Or the granule of almost spherical or micropill load in softgel shell and make capsule, to obtain final product.
Embodiment 20
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 20 preparation method: (1), by each auxiliary except other of acrylic resin copolymer in above-mentioned release system III
Material mix homogeneously, uses water as wetting agent soft material, uses extrusion spheronization to be prepared as uniform granule or micropill, 60 DEG C of conditions
Lower dry, control moisture and be less than 5.0%, select granule or the micropill of release system III of 16 mesh~30 mesh, standby;(2)、
Acrylic resin copolymer addition suitable quantity of water is made aqueous dispersion, uses fluid unit to be coated on above-mentioned release system III
Granule or micropill surface be coated isolation;(3), by each adjuvant mix homogeneously in above-mentioned release system II, use from
The heart is made ball equipment and above-mentioned release system II mixed material is coated in the granule of release system III or the surface of micropill;(4)、
Above-mentioned release system I will be removed microcrystalline Cellulose and each adjuvant mix homogeneously of mannitol, use to be centrifuged and makes ball equipment by above-mentioned
Release system I mixed material be coated on include the granule of medicine-releasing system II and III or micropill surface make include medicine-releasing system I,
The granule of the spherical or almost spherical of II and III or micropill.Finally include that medicine-releasing system I, II and III's is spherical or near by above-mentioned
Spheroidal granule or micropill are pressed into tablet after mixing with microcrystalline Cellulose and mannitol, to obtain final product.
Embodiment 21
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 21 preparation method: (1), by each auxiliary except other of acrylic resin copolymer in above-mentioned release system III
Material mix homogeneously, uses water as wetting agent soft material, uses extrusion spheronization to be prepared as uniform granule or micropill, 60 DEG C of conditions
Lower dry, control moisture and be less than 5.0%, select granule or the micropill of release system III of 16 mesh~30 mesh, standby;(2)、
Acrylic resin copolymer addition suitable quantity of water is made aqueous dispersion, uses fluid unit to be coated on above-mentioned release system III
Granule or micropill surface be coated isolation;(3), by each adjuvant mix homogeneously in above-mentioned release system II, use from
The heart is made ball equipment and above-mentioned release system II mixed material is coated in the granule of release system III or the surface of micropill;(4)、
By each adjuvant mix homogeneously in above-mentioned release system I, use and centrifugal make ball equipment above-mentioned release system I mixed material is coated
Make in the granule or micropill surface including medicine-releasing system II and III and include the spherical of medicine-releasing system I, II and III or approximation ball
The granule of shape or micropill.Finally include the spherical of medicine-releasing system I, II and III or the granule of almost spherical or micropill dress by above-mentioned
Enter and softgel shell is made capsule, to obtain final product.
Embodiment 22
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 22 preparation method: (1), by adjuvant mix homogeneously each in above-mentioned release system III, uses water as wetting agent system
Soft material, uses and centrifugal make ball equipment and make uniform granule or micropill, be dried, control moisture and be less than under the conditions of 60 DEG C
5.0%, select granule or the micropill of release system III of 18 mesh~40 mesh, standby;(2), by above-mentioned release system II
Each adjuvant mix homogeneously, use centrifugal make ball equipment above-mentioned release system II mixed material is coated in release system III
Grain or the surface of micropill;(3), by adjuvant mix homogeneously each in above-mentioned release system I, use and centrifugal make ball equipment and release above-mentioned
Place system I mixed material is coated on and includes that the granule of medicine-releasing system II and III or micropill surface are made and included medicine-releasing system I, II
With the spherical of III or the granule of almost spherical or micropill.Finally include the spherical of medicine-releasing system I, II and III or approximation by above-mentioned
Spherical granule or micropill load in softgel shell makes capsule, to obtain final product.
Embodiment 23
Ticagrelor pharmaceutical composition (specification 180mg):
Embodiment 23 preparation method: (1), by adjuvant mix homogeneously each in above-mentioned release system I, II, III, uses water as profit
Humectant soft material, is respectively adopted extrusion spheronization equipment and makes uniform granule or micropill, is dried under the conditions of 60 DEG C, controls water
Divide less than 5.0%, select release system I of 18 mesh~30 mesh, the granule of II, III or micropill respectively.Finally by above-mentioned release
Load in softgel shell after system I, the granule of spherical or almost spherical of II and III or micropill mixing and make capsule, to obtain final product.
Embodiment 24
The Ticagrelor sustained-release preparation prepared according to embodiment 5, embodiment 12 and embodiment 18 is administered for 1 day 1 time, and replaces
Card Gray's ordinary tablet (AstraZeneca produces, trade name Brilique, and specification is 90mg) is administered bioequivalence 1 day 2 times.Now will be real
The results are shown in Table 24 to execute the sample stripping curve in 0.2% Tween 80 medium of example 5 and embodiment 18 preparation.
Claims (10)
1. a Ticagrelor medicament slow release pharmaceutical composition, said composition include medicine-releasing system I and selected from medicine-releasing system II or
The medicine-releasing system of medicine-releasing system III, wherein:
Medicine-releasing system I includes Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and selectable
Isolated material;
Medicine-releasing system II includes Ticagrelor, slow-release material, porogen, binding agent, lubricant and/or antiplastering aid;
Medicine-releasing system III includes Ticagrelor, slow release isolated material, filler, disintegrating agent, binding agent, lubricant and/or anti-stick
Agent.
Pharmaceutical composition the most according to claim 1, it is characterised in that:
Described pharmaceutical composition includes medicine-releasing system I and medicine-releasing system II, and wherein, medicine-releasing system I includes Ticagrelor, filling
Agent, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and selectable isolated material, medicine-releasing system II includes for card lattice
Thunder, slow-release material, porogen, binding agent, lubricant and/or antiplastering aid;Or,
Described pharmaceutical composition includes medicine-releasing system I and medicine-releasing system III, and wherein, medicine-releasing system I includes Ticagrelor, filling
Agent, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and selectable isolated material, medicine-releasing system III includes for card lattice
Thunder, slow release isolated material, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid;Or,
Described pharmaceutical composition includes medicine-releasing system I, medicine-releasing system II and medicine-releasing system III, and wherein, medicine-releasing system I includes replacing
Card Gray, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and selectable isolated material, medicine-releasing system II
Including Ticagrelor, slow-release material, porogen, binding agent, lubricant and/or antiplastering aid, medicine-releasing system III includes for card lattice
Thunder, slow release isolated material, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid.
Pharmaceutical composition the most according to claim 1 and 2, it is characterised in that the amount of wherein said Ticagrelor be 155mg ~
230mg, preferably 170mg ~ 200mg.
4. according to the pharmaceutical composition described in any one in claims 1 to 3, it is characterised in that wherein said Ticagrelor
Particle diameter is distributed as D90Less than 200 μm, preferably D90Less than 100 μm, more preferably D90Less than 50 μm.
5. according to the pharmaceutical composition described in any one in Claims 1 to 4, it is characterised in that wherein said medicine-releasing system I
Including Ticagrelor, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, and selectable isolated material, its
In:
Described Ticagrelor is 40mg~90mg, preferably 45mg ~ 70mg, and the weight content in medicine-releasing system I is 15% ~ 60%,
Preferably 25% ~ 50%;
Described filler one in microcrystalline Cellulose, lactose, mannitol, pregelatinized Starch, calcium hydrogen phosphate, the calcium sulfate or
Multiple, wherein one or more in preferably microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate, selected filler loading is being released
Weight content in medicine system I is 10% ~ 70%, preferably 15% ~ 50%;
Described disintegrating agent is selected from carboxymethyl starch sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrrole
One or more in pyrrolidone, cross-linked carboxymethyl cellulose sodium, wherein preferred carboxymethyl starch sodium, crosslinked polyethylene pyrrolidine
One or more in ketone, cross-linking sodium carboxymethyl cellulose, selected disintegrating agent consumption weight content in medicine-releasing system I is
0.5% ~ 10%, preferably 1.5% ~ 7%;
One or more in hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone of described binding agent,
Wherein one or more in preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose, selected binder dosage is at medicine-releasing system I
In weight content be 0.5% ~ 5%, preferably 1% ~ 4%;
Described lubricant one in micropowder silica gel, Pulvis Talci, magnesium stearate, calcium stearate, the fumaric acid sodium stearate or
Multiple, wherein one or more in preferred micropowder silica gel, Pulvis Talci, magnesium stearate, selected lubricant quantity is at medicine-releasing system I
In weight content be 0.2% ~ 6%, preferably 0.5% ~ 3%;
One or more in micropowder silica gel, Pulvis Talci, starch of described antiplastering aid, wherein preferred micropowder silica gel, Pulvis Talci
In one or more, selected anti-stick agent level weight content in medicine-releasing system I is 0.2% ~ 6%, preferably 0.5% ~ 3%.
6. according to the pharmaceutical composition described in any one in Claims 1 to 4, it is characterised in that wherein said medicine-releasing system II
Including Ticagrelor, slow-release material, porogen, binding agent, lubricant and/or antiplastering aid, wherein:
The amount of described Ticagrelor is 55mg~160mg, preferably 60mg ~ 140mg, and the weight content in medicine-releasing system II is
10% ~ 50%, preferably 15% ~ 40%;
Described slow-release material is selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxyl second
Ylmethyl cellulose, polyoxyethylene, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, acrylic copolymer, shell are many
Sugar, sodium alginate, potassium alginate, tragcanth, butyl stearate, stearic acid, Brazil wax, glyceryl stearate, acetic acid
One or more in cellulose, Polyethylene Glycol, wherein preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Methyl cellulose
Element, ethyl cellulose, polyoxyethylene, hydroxyethyl cellulose, polyvinyl alcohol, acrylic resin copolymer, cellulose acetate, Sargassum
One or more in acid sodium, Polyethylene Glycol, selected slow-release material consumption weight content in medicine-releasing system II is 10% ~
75%, preferably 20% ~ 70%;
One or more in mannitol, lactose, sucrose, the glucose of described porogen, wherein preferably mannitol, sucrose,
One or more in lactose, selected porogen consumption weight content in medicine-releasing system II is 1% ~ 15%, preferably 2% ~ 10%;
One or more in hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone of described binding agent;
Wherein one or more in preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose, selected binder dosage is at medicine-releasing system
Weight content in II is 0.5% ~ 15%, preferably 1.5% ~ 10%;
Described lubricant is hard selected from micropowder silica gel, Pulvis Talci, magnesium stearate, stearic acid, cetylate, calcium stearate, fumaric acid
One or more in fat acid sodium, wherein one or more in preferred micropowder silica gel, Pulvis Talci, magnesium stearate, selected lubrication
Agent consumption weight content in medicine-releasing system II is 0.2% ~ 6%, preferably 0.5% ~ 5%;
One or more in micropowder silica gel, Pulvis Talci, magnesium stearate, starch of described antiplastering aid, wherein preferred micropowder silicon
One or more in glue, Pulvis Talci, selected anti-stick agent level weight content in medicine-releasing system II is for for 0.2% ~ 6%, excellent
Select 0.5% ~ 5%.
7. according to the pharmaceutical composition described in any one in Claims 1 to 4, it is characterised in that wherein said medicine-releasing system
III includes Ticagrelor, slow release isolated material, filler, disintegrating agent, binding agent, lubricant and/or antiplastering aid, wherein:
The amount of described Ticagrelor is 55mg~160mg, preferably 60mg ~ 140mg, and the weight content in medicine-releasing system III is
10% ~ 50%, preferably 15% ~ 40%;
Described slow release isolated material selected from methylcellulose, ethyl cellulose, hydroxypropyl cellulose, acrylic resin copolymer,
One or more in cellulose acetate, wherein in preferred acrylic resins copolymer, ethyl cellulose, cellulose acetate
Planting or multiple, selected slow release isolated material weight content in medicine-releasing system III is 20% ~ 70%, preferably 25% ~ 65%;
Described filler one in microcrystalline Cellulose, lactose, mannitol, pregelatinized Starch, calcium hydrogen phosphate, the calcium sulfate or
Multiple, wherein one or more in preferably microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate, selected filler loading is being released
Weight content in medicine system III is 5% ~ 40%, preferably 10% ~ 35%;
One or more in hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone of described binding agent,
Wherein one or more in preferred hydroxypropyl methyl cellulose, hydroxypropyl cellulose, selected binder dosage is at medicine-releasing system
Weight content in III is 1% ~ 15%, preferably 2% ~ 10%;
Described lubricant is hard selected from micropowder silica gel, Pulvis Talci, magnesium stearate, stearic acid, cetylate, calcium stearate, fumaric acid
One or more in fat acid sodium, wherein one or more in preferred micropowder silica gel, Pulvis Talci, magnesium stearate, selected lubrication
Agent consumption weight content in medicine-releasing system III is 0.2% ~ 6%, preferably 0.5% ~ 5%;
One or more in micropowder silica gel, Pulvis Talci, magnesium stearate, starch of described antiplastering aid, wherein preferred micropowder silicon
One or more in glue, Pulvis Talci, selected anti-stick agent level weight content in medicine-releasing system III is 0.2% ~ 6%, preferably
0.5%~5%;
Described disintegrating agent is selected from carboxymethyl starch sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrrole
One or more in pyrrolidone, cross-linked carboxymethyl cellulose sodium, wherein preferred carboxymethyl starch sodium, crosslinked polyethylene pyrrolidine
One or more in ketone, cross-linking sodium carboxymethyl cellulose, selected disintegrating agent consumption weight content in medicine-releasing system III is
0.5% ~ 10%, preferably 1.5% ~ 5%.
8. according to the pharmaceutical composition described in any one in claim 1~7, it is characterised in that select suitable available in non-time-release to make
Coating material be coated, described coating material is selected from hydroxypropyl methyl cellulose, Polyethylene Glycol, arabic gum, Europe
Bar for one or more in II, Opadry 200, wherein preferably hydroxypropyl methyl cellulose, Opadry II, selected coating material
Account for the 0.5% ~ 10% of pharmaceutical composition weight, preferably 1% ~ 5%.
9. the preparation method of pharmaceutical composition described in any one in a claim 1~8, it is characterised in that this preparation method
It is selected from:
A: medicine-releasing system I and II is respectively adopted appropriate solvent and makes dry granule or powder, then use multilamellar tablet machine
Being pressed into multilayer tablet, this tablet can be coated as required, sees Fig. 1;Or above-mentioned granule or powder are loaded in softgel shell
Make capsule;Or,
B, by medicine-releasing system I, II or III, use conventional formulation technologies, such as extrusion spheronization technology, centrifugal make ball technology or fluidisation
Bed techniques etc. are respectively prepared the spherical or granule of almost spherical or micropill, or use pressed-disc technique to be respectively prepared rule or irregular
Small pieces, then by the granule of medicine-releasing system III, micropill or small pieces use slow-release material coating;Can release above-mentioned as required
Medicine system I or the granule of II, micropill or small pieces are coated isolation, see Fig. 2, and above-mentioned granule, micropill or small pieces are loaded softgel shell
In make capsule;Or it being pressed into tablet after above-mentioned granule, micropill or small pieces being mixed with appropriate filler, this tablet is according to need
Want to select coating;Or,
C: medicine-releasing system II is used conventional formulation technologies, such as extrusion spheronization technology, is centrifuged and makes ball technology or fluidization etc.
Make the spherical or granule of almost spherical or micropill, above-mentioned granule or micropill can be coated isolation as required, then will
Material in medicine-releasing system I is coated on medicine-releasing system II surface and makes the spherical or granule of almost spherical or micropill, sees Fig. 3,
After above-mentioned granule or micropill are loaded in softgel shell and make capsule;Or press after above-mentioned granule or micropill are mixed with appropriate filler
Making tablet, this tablet can select coating as required;Or,
D: medicine-releasing system III is used conventional formulation technologies, such as extrusion spheronization technology, is centrifuged and makes ball technology or fluidization etc.
Make the spherical or granule of almost spherical or micropill, then use slow-release material to be coated every releasing again above-mentioned granule or micropill
Material in medicine system I is coated on medicine-releasing system III surface and makes the spherical or granule of almost spherical or micropill, sees Fig. 4, finally
Above-mentioned granule or micropill are loaded in softgel shell and makes capsule;Or suppress after above-mentioned granule or micropill are mixed with appropriate filler
Piece agent, this tablet can select coating as required;Or,
E: medicine-releasing system III is used conventional formulation technologies, such as extrusion spheronization technology, is centrifuged and makes ball technology or fluidization etc.
Make the spherical or granule of almost spherical or micropill, then use slow-release material to be coated isolation above-mentioned granule or micropill, then
By be coated on after the material mix homogeneously in medicine-releasing system II medicine-releasing system III surface make the spherical or granule of almost spherical or
Micropill, the above-mentioned granule comprising medicine-releasing system II and III or micropill can be coated isolation as required, finally by release system
It is coated on, after material mix homogeneously in system I, the granule comprising medicine-releasing system II and III or micropill surface is made and comprised release system
The granule of the spherical or almost spherical of system I, II and III or micropill, be shown in Fig. 5;Finally comprise medicine-releasing system I, II and III by above-mentioned
The spherical or granule of almost spherical or micropill load in softgel shell and make capsule;Or tabletted after mixing with appropriate filler
Agent, this tablet can select coating as required.
10. prepare according to preparation method described in the pharmaceutical composition described in any one in claim 1~8 or claim 9
Pharmaceutical composition, it is characterised in that the vitro release of this pharmaceutical composition is: 1 hour between 25~35%, 2 hours
Between 35~45%, within 6 hours, between 45~65%, 12 hours more than 75%.
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US20220331255A1 (en) * | 2016-04-29 | 2022-10-20 | University Of Central Lancashire | Solid Dosage Form |
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CN109700784A (en) * | 2019-03-11 | 2019-05-03 | 梁江丽 | Ticagrelor sustained-release micro-spheres and its preparation and application |
CN109806261A (en) * | 2019-03-11 | 2019-05-28 | 梁江丽 | A kind of ticagrelor sustained release preparation and its preparation and application |
CN113181140A (en) * | 2021-05-07 | 2021-07-30 | 苏州康恒研新药物技术有限公司 | Ticagrelor skeleton sustained-release pellet and preparation method thereof |
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