CN107260700A - A kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation - Google Patents
A kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation Download PDFInfo
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- CN107260700A CN107260700A CN201610215761.8A CN201610215761A CN107260700A CN 107260700 A CN107260700 A CN 107260700A CN 201610215761 A CN201610215761 A CN 201610215761A CN 107260700 A CN107260700 A CN 107260700A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
- A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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Abstract
The present invention relates to a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation, the compound oral solid pharmaceutical preparation is that the content of ticagrelor in per unit preparation is selected from 60 ~ 180mg, preferably 60 ~ 90mg；The content of aspirin or its pharmaceutically acceptable salt or ester is selected from 35 ~ 75mg, preferably 35 ~ 50mg in per unit preparation.The compound oral solid pharmaceutical preparation is made up of ticagrelor, aspirin, capsule core material, adhesive, thin film coating material, enteric-coating material, diluent, disintegrant, lubricant.By separately preparing ticagrelor particle or micropill or piece; and aspirin Intestine-soluble micro-pill or enteric coatel tablets; the ticagrelor and aspirin for remixing pack, or encapsulated or tabletting to reach are not directly contacted with and kept the purpose of stability in drug combination preparation product.
Description
Technical field
The invention belongs to art of pharmaceutical industry, and in particular to a kind of preparation side of ticagrelor compound oral solid pharmaceutical preparation
Method, specifically, to prepare ticagrelor particle or micropill or piece respectively, and aspirin or its pharmaceutically acceptable salt or
Enteric coated particles, enteric-coated micro-pill or the enteric coatel tablets of ester, mix pack or encapsulated or tabletting to reach ticagrelor and Ah in proportion
A department woods or its pharmaceutically acceptable salt or ester are not directly contacted with compound preparation product and increase the purpose of stability.
Background technology
Acute coronary（Coronary artery）Syndrome（Acute coronary syndrome, ACS）It is clinically common
One of cardiovascular emergency case, case fatality rate and the incidence of disease are high, and the medicine of platelet aggregation-against clinically is classified as into treatment ACS's
Routine administration.
Ticagrelor (ticagrelor) also known as Ticagrelor, are a kind of selective P2Y12 acceptor inhibitors, by suppressing
The formation of new blood clot, helps patient to reduce the generation of atheroma thrombosis event.The chemical name of ticagrelor is
(1S, 2S, 3R, 5S) -3- [7- { [(1R, 2S) -2- (3,4- difluorobenzenes) cyclopropyl] amino } -5- (propylthiouracil) -3H-
[1,2,3]-Hostathion [4,5-D] pyrimidin-3-yl] -5- (2- ethoxys) pentamethylene -1,2- glycol, molecular formula:
C23H28F2N6O4S, molecular weight：522.57, molecular structural formula is：
Ticagrelor is crystalline powder, insoluble in water, and the solubility in water is 10 ~ 20 μ g/mL at room temperature, low molten hypotonic,
The 4th class is listed in BCS；Fusing point is 140 ~ 142 DEG C, and with polymorphic, the crystal formation fusing point in patent protection is judged as
Crystal formation IV；European Union's approval is obtained in December, 2010, for adult acute coronary syndrome（ACS）Patient's atherosclerosis
Thrombosis event is prevented.In January, 2011, ticagrelor was formally sold in all member states of European Union, trade name Brilique,
Its specification is 90mg/ pieces, and 60 is on chip.On July 20th, 2011, AstraZeneca announces that FDA approveds ticagrelor is used to reduce urgency
Property coronary syndrome（ACS）The cardiovascular death of patient and heart attack.Plus the current approval for obtaining FDA, ticagrelor
Nowadays it is approved listing in 41 countries, and incorporates wherein 7 countries（Such as Britain）Medical compensation range.
Ticagrelor（Ticagrelor）It is first oral, reversible action that chemical constitution is the Hostathion pyrimidine of ring penta
Adp receptor antagonist, can be done directly on P2Y12 acceptors, without metabolic activation.Studies have shown that Ticagrelor and clopidogrel
Compare, can substantially reduce the primary endpoints such as patient's heart infarction, palsy or cardiovascular death, and severe haemorrhage complication does not increase
Plus Ticagrelors are non-precursor medicine, can directly it be worked without liver metabolism activation, with P2Y12 adp receptor invertibity knots
Close.PLATO results of study show that Ticagrelor treats 12 months in the case where not increasing main bleeding, enters compared with clopidogrel
One step significantly reduces cardiovascular death/myocardial infarction/palsy composite end points event risk of ACS patient up to 16%, while significantly drop
Low cardiovascular death is up to 21%.Ticagrelor is different with the mode of action of clopidogrel, and clopidogrel causes irreversible to blood platelet
Turn influence, blood platelet was all remained stationary in one week, but stop after Ticagrelor treatment, the effect is weakened or reversed quickly,
Blood platelet can rise in two days.Patient's Excessive bleedings are very important in this species diversity opponent's art.It is more suitable for after quick reverse
Coronary artery bypass surgery medication, or possess multivessel disease and by-pass operation patient may be received.
Ticagrelor is a kind of oral anti-diabetic agent thing, anti-to ACS patient with good clinical efficacy and safety
Anti-platelet therapy is highly beneficial.Therefore, American Society of Cardiology's foundation and American Heart Association's percutaneous coronary intervention are controlled
Treating guide recommends ticagrelor to select (recommended stage as the Antiplatelet therapy for planning to implement percutaneous coronary intervention (pci) patient
Other Ib).American Society of Cardiology's foundation in 2012 and American Heart Association's unstable angina pectoris and the non-sT sections of elevation heart
Flesh infarct treatment guidelines recommend ticagrelor can as clopidogrel alternative medicine (recommend rank Ib).
Aspirin（Aspirin）Also acetylsalicylic acid is, chemical name is：2- (acetoxyl group) benzoic acid, molecularization
Formula is:C9H8O4, molecular weight is:180.16, molecular structural formula is：
Aspirin is a kind of white crystals or crystalline powder；Odorless or micro-strip acetic acid stink, taste are slightly sour；Water is slightly soluble in, it is molten
In ethanol, ether, chloroform, alkali hydroxide solution or carbon acid solution also are soluble in, is decomposed simultaneously.The less stable of aspirin,
Facile hydrolysis is into salicylic acid and acetic acid under super-humid conditions.Contain ester bond in molecular structure, facile hydrolysis can be catalyzed into salicylic acid, soda acid
Hydrolysis.
Aspirin is one of medicine the most frequently used in non-steroidal Antiplatelet therapy, has been established as treating the acute heart
Flesh infarct（AMI）, unstable angina and myocardial infarction（MI）The classical medication of Secondary prevention, can suppress platelet aggregation, have
Effect prevents thrombosis.Its mechanism of action mainly passes through selective depression Cycloxygenase 1（COX-1）, so as to prevent thromboxane A2
Formation, and then prevent platelet aggregation and release reaction.
European Society of Cardiology（ESC）2012 on high acute myocardial infarction AMI（STEMI）I classes are recommended in diagnosis guide
A grades of evidences show：Receive the patient of PCI treatments, it is recommended to use aspirin is combined or aspirin and pula with ticagrelor
The united DAPT treatments of Gray, its curative effect is better than aspirin and Clopidogrel.Clinical research also indicates that, ticagrelor
Joint aspirin for treatment can significantly reduce the incidence of disease and case fatality rate of ACS patient, reduce the generation of angiocardiopathy.
The patient for incorporating 21162 heart infarctions morbidities altogether in 1 ~ 3 year is studied in PEGASUS-TIMI 54.All patients
Receive low dosage（75~150mg）Aspirin for treatment, and by 1：1：1 ratio is randomly assigned using the mg of ticagrelor 90, for lattice
The auspicious mg of Lip river 60 and placebo, 2 times/day.Primary efficacy endpoint is the composite end points of cardiovascular death, heart infarction or palsy.Main peace
Full terminal is TIMI major bleeding events.Follwing-up in average 33 months.Data display, the curative effect of the mg groups of ticagrelor 90 at 3 years
Endpoints incidence is 7.85%, and the mg groups of ticagrelor 60 are 7.77%, placebo 9.04%.Compared with placebo, replace
The mg groups of Ge Ruiluo 90（HR =0.85；95% CI, 0.75 ~ 0.96）With 60 mg groups（HR=0.84；95% CI, 0.74 ~ 0.95）'s
Primary efficacy endpoint occurrence risk is relatively low.Plus with after ticagrelor, endpoints curve is initially separated in early stage, is pushed away over time
Move and continue to separate, further demonstrate that aspirin is combined the sight that long-term dual anti-treatment can benefit heart infarction patient with ticagrelor
Point is correct.
Domestic clinical study results [Chinese Medicine Leader, 2014；16（8）：1243-1246] also point out, with exclusive use
Aspirin compares, and clinical efficacy total effective rate and electrocardiogram improve notable after ticagrelor joint aspirin group treatment
Higher than independent aspirin group, the statistically significant (P of difference<0.05), and two groups do not occur serious adverse reaction, not in
Disconnected treatment, illustrates that ticagrelor joint aspirin can significantly improve ACS clinical efficacies and sign, therapeutic effect is notable.
In the researchs of CURRENT OASIS 7, researcher includes more than 25000 ACS patients, than relatively low dose
Measure aspirin（75~100mg）With high dose（≥300mg）Curative effect, as a result show first month after stenter to implant, two kinds of agent
Amount acts on similar in terms of ischemic events and main bleeding, but the secondary bleeding event of low dose group is relatively low.Then, 2013
U.S. ST sections of elevation myocardial infarction（STEMI）Guide recommends aspirin maintenance dose to be 81 ~ 325mg, and points out and replace
When Ge Ruiluo is combined, aspirin best maintained dosage is 81mg.And 2014 European myocardial blood transport reconstruction guides are explicitly pointed out
Aspirin maintenance dose is 75 ~ 100mg.
The A of Chinese patent CN 104434931 disclose a kind of compound oral solid comprising ticagrelor and aspirin
The content of ticagrelor is selected from 80 ~ 180mg, preferably 80 ~ 100mg in agent, per unit preparation；In per unit preparation aspirin or
The content of its pharmaceutically acceptable salt or ester is selected from 50 ~ 120mg, preferably 70 ~ 100mg.According to clinical research, ticagrelor
Maintaining treatment ACS, patient needs daily 2 times, when being combined with ticagrelor, and aspirin maintenance dose, which is more than 100mg, to drop
Low ticagrelor reduces the clinical efficacy of composite end points event, therefore when aspirin and ticagrelor combination, it maintains daily dose
No more than 100mg.So the prescription described in patent does not have reasonability in clinical practice.
This patent discloses a kind of compound oral solid pharmaceutical preparation containing ticagrelor, ticagrelor contains in per unit preparation
Amount is selected from 60 ~ 180mg, preferably 60 ~ 90mg；The content of aspirin or its pharmaceutically acceptable salt or ester in per unit preparation
Selected from selected from 35 ~ 75mg, preferably 35 ~ 50mg.By the specification of ticagrelor piece, the day maintaining treatment dosage of ticagrelor is
180mg or 120mg（FDA ratifies the maintenance dose after medication is treated 1 year）, it is oral in two times daily, such as take answering for this patent
Square oral solid formulation, also needs to take that 2 times a day, and the day maintaining treatment dosage equivalent to ticagrelor is 180mg or 120mg,
It is consistent with the taking dose of approval；The day taking dose of aspirin is then 70 ~ 100mg simultaneously, with 2014 European myocardial blood transports
Reconstruction guide explicitly points out aspirin and maintains 75 ~ 100mg of agent consistent.
Facile hydrolysis is into salicylic acid and acetic acid under the less stable of aspirin, super-humid conditions.Contain ester in molecular structure
Key, facile hydrolysis is into salicylic acid, and soda acid can catalytic hydrolysis reaction.And ticagrelor is alkaline drug（Pka=12.94）, Liang Zhezhi
Contact can cause the degraded of acetylsalicylic acid, the problem of stability reduction occur, so as to influence medication validity and security.
The A of Chinese patent CN 104434931 disclose a kind of compound oral solid comprising ticagrelor and aspirin
Agent preparation method, mainly pelletizes by being coated, separately or separately mixing causes ticagrelor and aspirin in final solid formulation
It is not directly contacted with product.Technique is mainly to mix aspirin and suitable auxiliary material, granulation or coating；Again by ticagrelor
It is well mixed with suitable auxiliary material, then two parts are prepared by mixing into finished product.But particle or coating can not completely cut off two groups completely
The exposure contact divided, and the difficulty of granule coating is very big, and technological feasibility difficulty is larger.
It is auspicious for lattice to prepare respectively that this patent discloses a kind of preparation method of the compound oral solid pharmaceutical preparation containing ticagrelor
Lip river particle or micropill or piece, and aspirin or its pharmaceutically acceptable salt or ester enteric-coated micro-pill or enteric coatel tablets, by than
Example mixing pack or encapsulated or tabletting, make ticagrelor and aspirin or its pharmaceutically acceptable salt or ester in compound
It is adequately isolated out in formulation products, is not directly contacted with to increase the purpose of stability.
Due to ticagrelor in water it is insoluble, at room temperature the solubility in water be 10 ~ 20 μ g/mL.Belong to biopharmacy
Categorizing system (BCS) IV class medicines, its solubility and permeability are all very low, and dissolution is the speed limit process absorbed, oral bio profit
Expenditure is low, it is likely that cause dosage regimen to fail because blood concentration is too low.The present invention passes through Universalpulverizer, ball mill, air-flow
The granularity requirements that ticagrelor bulk drug is crushed to by the crushing such as pulverizer means are D90<85 μm, preferably D90For 5~50 μm, more
It is preferred that D90For 5~30 μm, the dissolution rate of ticagrelor is substantially increased, its oral administration biaavailability is improved.
Aspirin orally has stomach irritation, and the incidence of gastrointestinal side effect can increase when research display routine is used
Plus.Aspirin is prepared into enteric coated preparations by the compound oral solid pharmaceutical preparation of the present invention, goes far towards to prevent from taking acetyl water
The patient of poplar acid treatment has a stomach upset or stimulated, and reduces the generation of its adverse reaction.
Compound oral solid pharmaceutical preparation of the present invention containing ticagrelor and aspirin can improve curative effect, reduce single
Adverse drug reaction caused by one survival dose is excessive, improves the Compliance of patient, increases drug safety.
The content of the invention
It is an object of the invention to provide a kind of compound oral solid pharmaceutical preparation containing ticagrelor, further, the present invention
Purpose also reside in a kind of answering for stability for avoiding the directly contact of ticagrelor and aspirin and keeping solid pharmaceutical preparation be provided
The preparation method of square oral solid dose.
Ticagrelor in a kind of compound oral solid pharmaceutical preparation containing ticagrelor disclosed in the present invention, per unit preparation
Content is selected from 60 ~ 180mg, preferably 60 ~ 90mg；Aspirin or its pharmaceutically acceptable salt or ester in per unit preparation
Content is selected from 35 ~ 75mg, preferably 35 ~ 50mg.
It is auspicious for lattice in further disclosed a kind of preparation method of the compound oral solid pharmaceutical preparation containing ticagrelor of the invention
The granularity requirements of Lip river bulk drug are D90<85 μm, preferably D90For 5~50 μm, more preferably D90It is 5~30 μm of mainly by omnipotent
The crushing such as pulverizer, ball mill, airslide disintegrating mill means are to reach requirement.
The present invention further discloses a kind of preparation method of the compound oral solid pharmaceutical preparation containing ticagrelor, mainly pass through
Prepare ticagrelor particle or micropill or piece respectively, and aspirin or its pharmaceutically acceptable salt or ester enteric
Grain, enteric-coated micro-pill or enteric coatel tablets, then mixing pack or encapsulated or tabletting in proportion, its step are as follows：
A. the preparation of aspirin enteric-coated preparation：
Aspirin and capsule core material are mixed, active drugs capsule core is prepared using pastille micropill preparation method, then again will
Active medicine piller carries out film coating, then carries out enteric coating, and aspirin Intestine-soluble micro-pill is made；
Or medicine accommodation layer piller will be made in aspirin medicine-feeding to blank capsule core, medicine-feeding piller is then subjected to film coating again,
Enteric coating is carried out again, and aspirin Intestine-soluble micro-pill is made；
Or will be pelletized after aspirin and suitable auxiliary materials and mixing, small pieces are pressed into, first bag isolated film is coated enteric coated again, system
Into
Enteric coatel tablets；
B. the preparation of ticagrelor solid pharmaceutical preparation：
Ticagrelor and capsule core material are mixed and use pastille micropill preparation method, active drugs capsule core is prepared, then again will
Active medicine piller carries out isolated film coating, and ticagrelor micropill is made；
Ticagrelor is added medicine to onto blank capsule core, then isolated film is carried out to medicine-feeding piller and is coated to obtain ticagrelor micropill；
Or will be pelletized after ticagrelor and suitable auxiliary materials and mixing, ticagrelor particle is made；
Or will be pelletized after ticagrelor and suitable auxiliary materials and mixing, small pieces are pressed into, ticagrelor piece is made；
C. mix
Both particles or micropill are mixed by a certain percentage, additional auxiliary materials and mixing is added again；
D. finished product is prepared using suitable mould
Both particles or micropill mixture is filling into granule, capsule, or it is pressed into full wafer or double-layer tablets or interior outer core piece.
Or both small pieces are filling in capsule, into capsule；
Or without blend step, directly incited somebody to action using Autocapsulefillingmachine in both micropills or micropill+granule filling capsule, into
Capsule.
The step a and b of the present invention active medicine capsule core or the preparation method of blank capsule core be fluidization, rotary
Pill, centrifugation-fluidized bed coating, extrusion-spheronization, the preparation of rotating cutting type granulator, intra-liquid desiccation method, spheroidal crystal skill
Art, any method of vibrating nozzle forming technique.
The present invention step a and step b Blank Pellets medicine-feeding method be powder add medicine to method, solution medicine-feeding method it is any
Method.
Step a and step b of the present invention coating preparation thereof are fluidized bed coating equipment, are coated pan coating, centrifugation-fluidisation
Bed granulation pan coating, porous centrifugal device are coated, any method of pressed coated, preferably fluidized bed coating and high-efficiency coating
Pan coating.
The preparation method of the step a of present invention acetylsalicylic acid tablet is wet granulation, dry granulation, any of direct tablet compressing
Plant, preferably dry granulation and direct tablet compressing.
The step b of present invention ticagrelor particle or the preparation method of piece are wet granulation, dry granulation, hot-melt extruded
That pelletizes is any, preferably wet granulation.
Capsule core material of the present invention includes diluent, adhesive, disintegrant, wetting agent；Diluent be sucrose, starch,
Microcrystalline cellulose, lactose, one or more kinds of mixtures of beta-schardinger dextrin；Adhesive is that described adhesive is syrup, shallow lake
Slurry, polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivative（Hydroxypropyl methylcellulose, hydroxypropyl cellulose, Methyl cellulose
Element, sodium carboxymethylcellulose）One or more kinds of mixtures；Disintegrant is starch, sodium carboxymethyl starch, crosslinking carboxylic first
Base sodium cellulosate, low-substituted hydroxypropyl cellulose, one or more kinds of mixtures of PVPP；Wetting agent be water,
One or more kinds of mixtures of ethanol；
The thin film coating material is forming thin film material and additive, and the forming thin film material is carbohydrate, polyethylene glycol, gathered
Vinyl alcohol, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose or Opadry are thin
One or more kinds of mixtures of film clothing product, the additive includes plasticizer, opacifier, colouring agent, antiplastering aid, anti-
Electrostatic agent；Plasticizer is glycerine, propane diols, polyethylene glycol, rutgers（DMP）, diethyl phthalate（DEP）、
Dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, glycerol triacetate（GTA）, triethyl citrate（TEC）, lemon
Lemon acid tributyl（TBC）, CitroflexA-2, citroflex A-4（TBAC）, castor oil one kind or one
Plant the mixture of the above；Opacifier is titanium dioxide；Colouring agent is iron oxide；It is hard that antitack agent includes magnesium stearate, talcum powder, list
One or more kinds of mixtures of glycerol；
The enteric-coating material includes enteric coating layer polymer, plasticizer, opacifier, antiplastering aid, and the polymer includes poly-
Acrylic resin type enteric material（Utech L30D-55, Eudragit L100-55, Utech L100, Utech S100, Utech
NE30D, No. I acrylic resin, No. II acrylic resin, No. III acrylic resin）, Hydroxypropyl Methylcellulose Phathalate
Ester（HPMCP）, HPMC-AS（HPMCAS）, poly- acetate phthalate vinyl acetate (PVAP), benzene two
Formic acid cellulose acetate（CAP）, acetic acid benzenetricarboxylic acid cellulose, carboxymethylethylcellulose, phthalate, cellulose, shellac
One or more kinds of solution or dispersion liquid；The plasticizer is glycerine, propane diols, polyethylene glycol, rutgers
（DMP）, diethyl phthalate（DEP）, dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, glycerol triacetate
（GTA）, triethyl citrate（TEC）, ATBC（TBC）, CitroflexA-2, the fourth of acetyl citrate three
Ester（TBAC）, castor oil one or more kinds of mixtures；
The opacifier is titanium dioxide；Colouring agent is iron oxide；Antitack agent is magnesium stearate, talcum powder, glycerol monostearate
One or more kinds of mixtures of ester；
The diluent is cornstarch, pregelatinized starch, lactose, microcrystalline cellulose, calcium monohydrogen phosphate, mannitol, sucrose, paste
Essence, calcium sulfate, calcium sulphate dihydrate, calcium carbonate, one or more kinds of mixtures of sorbierite；
Described adhesive is syrup, starch slurry, polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivative（Hypromellose
Element, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose）, polyethylene glycol, pregelatinized starch, gelatin, the one of sucrose
Plant or more than one mixture；
The disintegrant is starch, sodium carboxymethyl starch, Ac-Di-Sol, low-substituted hydroxypropyl cellulose, crosslinking
One or more kinds of mixtures of PVP；
The lubricant is magnesium stearate, stearic acid, talcum powder, superfine silica gel powder, sodium stearyl fumarate, hydrogenated vegetable oil, poly-
Glycols（PEG4000、PEG6000）, the one or more kinds of mixture of lauryl sodium sulfate.
The invention provides a kind of preparation method of the particularly preferred compound oral solid pharmaceutical preparation containing ticagrelor, with showing
There is technology to compare, its remarkable advantage：1）By the way that two folk prescriptions of clinical often combination treatment are made into compound, hence it is evident that improve patient's use
The compliance of medicine；2）This compound is compared with the same compound of patent report before, and it is more reasonable that this compound specification is set, and meets and faces
Bed medication guide；3）Preparation method disclosed in this patent more science, feasible, reliable, and environmental protection.
Brief description of the drawings
Hereinafter, embodiment of the present invention is described in detail with reference to accompanying drawing, wherein：
Fig. 1 is 0 day dissolution rate figure with accelerating June of sample and times Linda of case study on implementation.
Fig. 2 is 0 day relevant material figure with accelerating June of sample and times Linda of case study on implementation.
The dissolution rate figure that Fig. 3 is the sample of case study on implementation and visits aspirin 0 day with accelerating June.
Fig. 4 is the sample of case study on implementation and the relevant material figure for visiing aspirin 0 day with accelerating June.
Embodiment
The present invention will be further illustrated by specific embodiment below, it should be understood, however, that, these embodiments are only
It is to be used to specifically describe in more detail to be used, and is not to be construed as limiting the present invention in any form.
Embodiment 1（Tablet-preparation A）
Preparation method：
A. the preparation of aspirin enteric coated tablet
Direct tablet compressing after aspirin is well mixed with microcrystalline cellulose, pregelatinized starch, stearic acid；By Opadry film bag
Clothing powder prepares isolation coat layer solution；By Utech L30D-55（30% aqueous dispersion）In be separately added into glycerin monostearate,
Triethyl citrate stirs, and is configured to enteric layer solution.Using high-efficiency coating pot plain piece is wrapped respectively isolation coat and
Enteric coating, 40 DEG C of oven dryings are produced for 24 hours.
B. the preparation of ticagrelor particle：
Ticagrelor is crushed to granularity D90<85 μm, then after being well mixed with mannitol, calcium monohydrogen phosphate, sodium carboxymethyl starch,
Using hydroxypropyl cellulose solution as adhesive wet granulation, dry, then mixed with additional magnesium stearate, obtain ticagrelor particle.
C. tabletting
Using aspirin enteric coated tablet as kernel, ticagrelor aspirin composite sheet is suppressed.
Embodiment 2（Capsule-preparation B）
Preparation method：
A. the preparation of aspirin Intestine-soluble micro-pill
Aspirin and microcrystalline cellulose are mixed, using hydroxypropyl methylcellulose and PVP as adhesive, extrusion spheronization work is used
Skill prepares active drugs capsule core.Then Opadry film coating powder is configured to film coating liquid；Eudragit L100-55 is molten
Solution adds triethyl citrate and stirred in 95% ethanol, then the suspension of talcum powder is poured into L100-55 solution,
Enteric layer solution is configured to, based calcium and enteric coat layer are then sprayed to medicine-feeding respectively using bed spray technology
Aspirin Intestine-soluble micro-pill is made on piller, 40 DEG C of oven dryings are produced for 24 hours.
B. the preparation of ticagrelor micropill：
Ticagrelor is crushed to granularity D90<85 μm, then mixed with microcrystalline cellulose, sodium carboxymethyl starch, it is fine with hydroxypropyl
Dimension element is adhesive, and active drugs capsule core is prepared using extrusion spheronization technique.Then Opadry film coating powder is configured to
Film isolation coat liquid；Film isolation coat layer solution is sprayed on pastille piller with bed spray technology afterwards and is made for lattice
Auspicious Lip river micropill, 40 DEG C of oven dryings are produced for 24 hours.
C. two kinds of micropills are well mixed
Both are well mixed by a certain percentage, then additional mix lubricant is uniform.
D. finished product is prepared using suitable mould
By the filling capsule of micropill mixture.
Embodiment 3（Tablet-formulation C）
Preparation method：
A. the preparation of blank capsule core
Microcrystalline cellulose blank capsule core is used as Blank Pellets capsule core.
B. the preparation of aspirin Intestine-soluble micro-pill
Aspirin is dissolved in the ethanol solution of PVP, medicated layer solution is configured to.By Utech L30D-55（30% water
Dispersion）, Utech NE30D（30% aqueous dispersion）Mix in proportion, then be separately added into glycerin monostearate, citric acid three
Ethyl ester stirs, and is configured to enteric layer solution.By Opadry film coating powder with made membrane isolation coat layer solution.Using stream
Medicated layer solution is sprayed in Blank Pellets capsule core by change bed spray technique is made medicine accommodation layer piller.Then by spacer layer coating liquid
It is sprayed on medicine-feeding piller, then aspirin Intestine-soluble micro-pill is made in enteric coat layer of spraying, then spacer layer coating liquid is sprayed to
Play protection enteric coat layer on aspirin enteric-coated piller, 40 DEG C of oven dryings are produced for 24 hours.
C. the preparation of ticagrelor micropill：
Ticagrelor is crushed to granularity D90<85 μm, then stirring is suspended in hydroxypropyl cellulose solution, is configured to pastille
Suspension solution.Opadry film coating powder is prepared into isolation coat layer solution.Using bed spray technology by medicated layer solution
It is sprayed in Blank Pellets capsule core and medicated layer piller is made.Then isolation coat layer solution is sprayed to bed spray technology
Ticagrelor micropill is made on pastille piller, 40 DEG C of oven dryings are produced for 24 hours.
D. two kinds of micropills and additional auxiliary material are well mixed
Two kinds of micropills are mixed by a certain percentage, then additional microcrystalline cellulose, sodium carboxymethyl starch and magnesium stearate are well mixed.
E. finished product is prepared using suitable mould
Mixture is pressed into tablet shaping.
Case study on implementation 4：Stability（Ticagrelor part）
The sample and reference preparation of case study on implementation are taken respectively（Times Linda）, by chemicals stability study technological guidance's principle
Accelerated test（40℃±2℃/75%RH±5%RH）Investigate 6 months, enter by import registration quality standard by under the conditions of commercially available back
Row dissolution rate detects that leaching condition is four 0931 dissolutions of Chinese Pharmacopoeia 2015 edition and the method for release detection method second（Paddle method）,
0.2%（W/v）Polyoxyethylene sorbitan monoleate solution 900ml is dissolution medium, and rotating speed is 75 turns per minute, detection time 45 minutes.
0 day dissolution data with accelerating June of the sample of the case study on implementation of table 1 and times Linda
| Sample | 0.2%（W/v）Polyoxyethylene sorbitan monoleate solution 45 minutes |
| Times Linda 0 day | 91.20 |
| Times Linda June | 87.56 |
| Preparation A（%）0 day | 93.71 |
| Preparation A（%）June | 91.03 |
| Preparation B（%）0 day | 92.04 |
| Preparation B（%）June | 88.65 |
| Formulation C（%）0 day | 95.71 |
| Formulation C（%）June | 95.24 |
Shown by the result of table 1 and Figure of description 1, case study on implementation and reference preparation-times Linda（AstraZeneca pharmacy is limited
Company produces）0 day and accelerate June sample 0.2%（W/v）The polyoxyethylene sorbitan monoleate solution dissolution rate of 45 minutes is satisfied by 45 points
Quality standard is registered in the import that 70% is at least discharged in clock, illustrates that the dissolution under the conditions of June is accelerated of case study on implementation sample is kept
It is stable.
The sample and reference preparation of case study on implementation are taken respectively（Times Linda）, it is former by chemicals stability study technological guidance
Accelerated test then（40℃±2℃/75%RH±5%RH）Investigated 6 months by under the conditions of commercially available back, it is detected by quality standard
About the change of material.
0 day relevant substance data with accelerating June of the sample of the case study on implementation of table 2 and times Linda
| Sample | Impurity H | Impurity J | Impurity L-A | Impurity L-B | Impurity N | Impurity O | TG-Ⅲ | It is maximum single miscellaneous | It is total miscellaneous |
| Times Linda 0 day | 0.015 | 0.007 | 0.013 | 0.021 | 0.04 | 0.026 | 0.096 | 0.02 | 0.25 |
| Times Linda June | 0.022 | 0.017 | 0.033 | 0.031 | 0.09 | 0.036 | 0.15 | 0.09 | 0.48 |
| Preparation A 0 day | 0.018 | 0 | 0 | 0.015 | 0.018 | 0.045 | 0.019 | 0.04 | 0.17 |
| Preparation A June | 0.028 | 0 | 0 | 0.034 | 0.028 | 0.045 | 0.039 | 0.07 | 0.25 |
| Preparation B 0 day | 0.015 | 0 | 0 | 0.023 | 0.024 | 0.05 | 0.032 | 0.05 | 0.21 |
| Preparation B June | 0.025 | 0 | 0 | 0.033 | 0.031 | 0.09 | 0.042 | 0.1 | 0.36 |
| Formulation C 0 day | 0.006 | 0 | 0 | 0.025 | 0.038 | 0.015 | 0.028 | 0.03 | 0.15 |
| Formulation C June | 0.016 | 0 | 0 | 0.035 | 0.046 | 0.025 | 0.048 | 0.12 | 0.30 |
The impurity spectrum of the sample of case study on implementation and reference preparation knowable to result from table 2 and Figure of description 2 is basically identical, 6
The moon, the impurity growth trend of accelerated test was basically identical, and total miscellaneous amount of sample is below reference preparation, and impurity level meets single miscellaneous
Less than 0.2%, the limit of total miscellaneous quality standard for being less than 0.5%.Show that the sample of case study on implementation is placed 6 months under acceleration conditions
Ticagrelor keeps stable.
Case study on implementation 5：Study on the stability (aspirin part)
The sample and reference preparation of case study on implementation are taken respectively（Visit aspirin）, it is former by chemicals stability study technological guidance
Accelerated test then（40℃±2℃/75%RH±5%RH）Investigated 6 months by under the conditions of commercially available back.Using Chinese Pharmacopoeia 2015
Four 0931 dissolutions of version and the method for release detection method first（Basket method）, detection is by dissolution in 0.1 mol/L hydrochloric acid, two hours acid
Amount and the afterwards stripping quantity in buffer solution (pH=6.8).
The sample of the case study on implementation of table 3 and the dissolution data for visiing aspirin 0 day with accelerating June
| Sample | Acidproof 2 hours | PH6.8 buffer solutions 45 minutes |
| Visit aspirin 0 day | 1.01 | 98.82 |
| Visit aspirin June | 3.45 | 95.23 |
| Preparation A（%）0 day | 1.1 | 99.14 |
| Preparation A（%）June | 3.21 | 95.56 |
| Preparation B（%）0 day | 1.2 | 98.34 |
| Preparation B（%）June | 2.45 | 96.86 |
| Formulation C（%）0 day | 0.92 | 98.75 |
| Formulation C（%）June | 2.23 | 95.16 |
Shown by table 3 and the result of Figure of description 3, case study on implementation and reference preparation-visit aspirin（Bayer medicines and health protection has
Limit company produces）0 day and accelerate June sample be satisfied by after the acidproof experiment in two hours of 0.1 N hydrochloric acid it is molten in 2 hours acid
Go out the limit for the quality standard for being less than 10%.In buffer solution (pH=6.8), it is satisfied by 45 minutes at least discharging 80% water
The quality standard of poplar acid, keeps stable.
The sample and reference preparation of case study on implementation are taken respectively（Visit aspirin）, refer to by chemicals stability study technology
Lead the accelerated test of principle（40℃±2℃/75%RH±5%RH）Investigate 6 months, examined by quality standard by under the conditions of commercially available back
Survey the change of its free salicylic acid.
The sample of the case study on implementation of table 4 and the relevant substance data for visiing aspirin 0 day with accelerating June
| Sample | Free salicylic acid |
| Visit aspirin 0 day | 0.11 |
| Visit aspirin June | 2.31 |
| Preparation A 0 day | 0.19 |
| Preparation A June | 1.88 |
| Preparation B 0 day | 0.12 |
| Preparation B June | 2.46 |
| Formulation C 0 day | 0.13 |
| Formulation C June | 1.42 |
The sample of case study on implementation and the free water of 6 months accelerated tests of reference preparation are understood from the result of table 4 and Figure of description 4
The content growth trend of poplar acid is basically identical, and the content of free salicylic acid is respectively less than the limit of 3% USP quality standards.Show reality
The sample for applying case places the aspirin holding stabilization of 6 months under acceleration conditions.
Case study on implementation 6：Stripping curve（Ticagrelor part）
The sample and reference preparation of case study on implementation are taken respectively（Times Linda）, stripping curve detection is carried out, leaching condition is middle traditional Chinese medicines
Four 0931 dissolutions of allusion quotation 2015 edition and the method for release detection method second（Paddle method）, dissolution medium：0.2%（W/v）Polyoxyethylene sorbitan monoleate is molten
Liquid 900ml, 0.2% polyoxyethylene sorbitan monoleate hydrochloric acid solution（pH1.2）900ml, 0.2% polyoxyethylene sorbitan monoleate phosphate buffer
（pH4.5）, 0.2% polyoxyethylene sorbitan monoleate phosphate buffer（pH6.8）For dissolution medium, rotating speed is 75 turns per minute, during detection
Between for 5,10,15,30,45,60,90,120 minutes.Assay method：HPLC
Evaluation method：
According to《Normal oral solid pharmaceutical preparation Dissolution Rate Testing technological guidance's principle》Described in " take respectively tested（After change）And ginseng
Compare product（Before changing）Each 12（Grain）, determine its stripping curve；Take the average Dissolution Value at each time point on two curves, root
Similar factors are calculated according to formula（f2）；F2 values are closer to 100, then it is assumed that two curves are similar.Generally, f2 values are higher than
50, it is believed that two curves have similitude, tested（After change）With Reference Product（Before changing）With equivalence..
f2=50·log{[1+（1/n）∑nt=1（Rt -Tt）2]-0.5100}
N is time point in above-mentioned formula（n≥3）, Rt is reference sample（Or product before changing）In the Dissolution Value of t,
Tt is experiment batch（Sample after change）In the Dissolution Value of t.
If medicine dissolution in 15min reaches more than 85%, it is believed that product dissolved corrosion is similar, is not required to
Data analysis is judged by statistical method.
Table 5 0.2%（W/v）Accumulation stripping curve in polyoxyethylene sorbitan monoleate aqueous medium
| Time（min） | 5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 | f2 |
| Times Linda（%） | 61.7 | 75.5 | 80.9 | 88.3 | 91.2 | 92.9 | 94.4 | 95.4 | / |
| Preparation A（%） | 54.0 | 69.1 | 78.1 | 90.4 | 93.7 | 95.1 | 97.4 | 96.6 | 63 |
| Preparation B（%） | 54.2 | 72.4 | 79.5 | 89.7 | 94 | 96.6 | 97 | 97 | 68 |
| Formulation C（%） | 53 | 70.7 | 82.3 | 90.5 | 94.7 | 95.7 | 96.8 | 97.5 | 64 |
Note：f2Take 5,10,15, the dissolution point such as 20min compared with commercially available product
The hydrochloric acid solution of the polyoxyethylene sorbitan monoleate of table 6 0.2%（pH1.2）Accumulation stripping curve
| Time（min） | 5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 | f2 |
| Times Linda（%） | 58.6 | 73.2 | 79.1 | 87.8 | 91.1 | 92.7 | 95.0 | 95.7 | / |
| Preparation A（%） | 63.0 | 77.4 | 84.7 | 92.9 | 96.5 | 97.6 | 97.4 | 97.5 | 65 |
| Preparation B（%） | 63.5 | 70.7 | 87.0 | 93.7 | 96.7 | 98.5 | 97.5 | 98.2 | 62 |
| Formulation C（%） | 60.1 | 65.6 | 85.3 | 94.9 | 97.5 | 98.6 | 98.5 | 99.2 | 60 |
Note：f2Take 5,10,15, the dissolution point such as 20min compared with commercially available product
The phosphate buffer of the polyoxyethylene sorbitan monoleate of table 7 0.2%（pH4.5）Accumulation stripping curve
| Time（min） | 5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 | f2 |
| Times Linda（%） | 59.5 | 74.4 | 80.7 | 88.6 | 92.5 | 94.4 | 95.6 | 96.4 | / |
| Preparation A（%） | 59.3 | 76.9 | 84.0 | 94.7 | 98.6 | 98.9 | 100.8 | 100.6 | 71 |
| Preparation B（%） | 62.3 | 73.7 | 86.7 | 95.7 | 100.0 | 101.3 | 102.5 | 103.0 | 65 |
| Formulation C（%） | 53.1 | 67.9 | 84.1 | 94.4 | 97.1 | 98.4 | 99.2 | 99.0 | 62 |
Note：f2Take 5,10,15, the dissolution point such as 20min compared with commercially available product
The phosphate buffer of the polyoxyethylene sorbitan monoleate of table 8 0.2%（pH6.8）Accumulation stripping curve
| Time（min） | 5 | 10 | 15 | 30 | 45 | 60 | 90 | 120 | f2 |
| Times Linda（%） | 56.7 | 71.8 | 78.2 | 87.3 | 90.6 | 92.3 | 94.2 | 95.1 | / |
| Preparation A（%） | 53.9 | 63.1 | 81.4 | 93.3 | 97.5 | 98.8 | 100.5 | 100.2 | 62 |
| Preparation B（%） | 58.1 | 78.9 | 83.8 | 96.0 | 98.9 | 100.9 | 102.4 | 102.7 | 60 |
| Formulation C（%） | 57.1 | 77.4 | 85.9 | 96.9 | 100.1 | 102.4 | 103.2 | 104.4 | 58 |
Note：f2Take 5,10,15, the dissolution point such as 20min compared with commercially available product
As a result show：The sample and reference preparation of case study on implementation（Times Linda）Stripping curve in four kinds of dissolution mediums it is similar
Factor f2Value is all higher than 50, and both stripping curves are similar.
Case study on implementation 7：Stripping curve（Aspirin part）
The sample and reference preparation of case study on implementation are taken respectively（Visit aspirin）, stripping curve detection is carried out, during leaching condition is
Four 0931 dissolutions of state's pharmacopeia 2015 edition and the method for release detection method first（Basket method）, dissolution medium：600ml0.1 is passed through in detection
Stripping quantity and the stripping quantity in buffer solution (pH=6.8) 800ml afterwards in two hours acid of mol/L hydrochloric acid.
Rotating speed is 100 turns per minute, and it is 52 hours in acid, in pH6.8 media that detection time, which is, 10,15,30,45,60 points
Clock.Assay method：HPLC
Evaluation method：
According to《Normal oral solid pharmaceutical preparation Dissolution Rate Testing technological guidance's principle》Described in " take respectively tested（After change）And ginseng
Compare product（Before changing）Each 12（Grain）, determine its stripping curve；Take the average Dissolution Value at each time point on two curves, root
Similar factors are calculated according to formula（f2）；F2 values are closer to 100, then it is assumed that two curves are similar.Generally, f2 values are higher than
50, it is believed that two curves have similitude, tested（After change）With Reference Product（Before changing）With equivalence..
f2=50·log{[1+（1/n）∑nt=1（Rt -Tt）2]-0.5100}
N is time point in above-mentioned formula（n≥3）, Rt is reference sample（Or product before changing）In the Dissolution Value of t,
Tt is experiment batch（Sample after change）In the Dissolution Value of t.
If medicine dissolution in 15min reaches more than 85%, it is believed that product dissolved corrosion is similar, is not required to
Data analysis is judged by statistical method.
Table 9 is after 0.1mol/L hydrochloric acid discharges 2 hours in pH6.8 phosphate buffers
| Time（min） | 0 | 5 | 10 | 15 | 30 | 45 | 60 | f2 |
| Visit aspirin（%） | 1.01 | 0.64 | 4.5 | 13.2 | 90.1 | 98.8 | 102.3 | / |
| Preparation A（%） | 1.1 | 2.34 | 6.52 | 17.4 | 93.3 | 99.1 | 100.2 | 75 |
| Preparation B（%） | 1.2 | 1.23 | 10.21 | 20.1 | 96.0 | 98.3 | 98.9 | 63 |
| Formulation C（%） | 0.92 | 1.52 | 7.12 | 15.9 | 96.9 | 98.8 | 99.8 | 70 |
Note：f2Take 5,10,15,20,30, the dissolution point such as 45min compared with commercially available product
As a result show, case study on implementation and reference preparation-visit aspirin（Bayer HealthCare Co produces）By 0.1 N
The limit that dissolution in 2 hours acid is less than 10% quality standard, and and reference preparation are satisfied by after hydrochloric acid acidproof experiment in two hours
Stripping quantity is quite, less in acid（Less than 2.0%）.In buffer solution (pH=6.8), similar factors f2Value is all higher than 50, two
Person's stripping curve is similar.
Claims (10)
1. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation, it is characterised in that the compound oral solid pharmaceutical preparation bag
Contain：Ticagrelor, aspirin or its pharmaceutically acceptable salt or ester；And by preparing ticagrelor particle or micropill respectively
Or piece, and aspirin or its pharmaceutically acceptable salt or ester enteric-coated micro-pill or enteric coatel tablets, in proportion mixing pack or
Encapsulated or tabletting is to reach ticagrelor and aspirin or its pharmaceutically acceptable salt or ester in compound preparation product
It is not directly contacted with and increases the purpose of stability.
2. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claim 1, it is characterised in that institute
In the compound oral solid pharmaceutical preparation stated, the unit content of ticagrelor is 60 ~ 180mg, preferably 60 ~ 90mg；Aspirin or its
The unit content of pharmaceutically acceptable salt or ester is：35 ~ 75mg, preferably 35 ~ 50mg.
3. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claim 1, it is characterised in that institute
The preparation method that the ticagrelor and aspirin stated are not directly contacted with final solid pharmaceutical preparation product is as follows：
A. the preparation of aspirin enteric-coated preparation：
Aspirin and capsule core material are mixed and are prepared into pastille micropill capsule core, it is then again that the progress isolation of active medicine piller is thin
Film coating, then enteric coating is carried out, aspirin Intestine-soluble micro-pill is made；Or blank capsule core is first prepared, then aspirin is added medicine to
Medicine accommodation layer piller is made on to blank capsule core, medicine-feeding piller is then subjected to isolated film coating again, then carries out enteric coating, makes
Into aspirin Intestine-soluble micro-pill；Or will be pelletized after aspirin and suitable auxiliary materials and mixing, small pieces are pressed into, first bag isolated film bag
Clothing is enteric coated again, and enteric coatel tablets are made；
B. the preparation of ticagrelor solid pharmaceutical preparation：
Ticagrelor and capsule core material are mixed and are prepared into pastille micropill capsule core, it is then again that the progress isolation of active medicine piller is thin
Film coating, is made ticagrelor common pellets；Or blank capsule core is first prepared, then ticagrelor is added medicine to onto blank capsule core, then
Isolated film is carried out to medicine-feeding piller and is coated to obtain ticagrelor micropill；Or will be pelletized after ticagrelor and suitable auxiliary materials and mixing,
Ticagrelor particle is made；Or will be pelletized after ticagrelor and suitable auxiliary materials and mixing, small pieces are pressed into, ticagrelor piece is made；
C. mix：
Both particles or micropill are mixed by a certain percentage, additional auxiliary materials and mixing is added again；
D. finished product is prepared using suitable mould
Both particles or micropill mixture is filling into granule, capsule, or it is pressed into full wafer or double-layer tablets or interior outer core piece；
Or both small pieces are filling in capsule, into capsule；Or without blend step, directly will using Autocapsulefillingmachine
In both micropills or micropill+granule filling capsule, into capsule.
4. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claims 1, it is characterised in that replace
Ge Ruiluo bulk drug granularity requirements D90<85 μm, preferably D90 is 5~50 μm, more preferably 5~30 μm.
5. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claims 1, it is characterised in that should
Compound component is included：Ticagrelor, aspirin or its pharmaceutically acceptable salt or ester, capsule core material, thin film coating material,
Enteric-coating material, diluent, adhesive, disintegrant, lubricant.
6. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claim 5, it is characterised in that：
The capsule core material includes diluent, adhesive, disintegrant, wetting agent；Diluent be sucrose, starch, microcrystalline cellulose,
One or more kinds of mixtures of lactose, beta-schardinger dextrin；Adhesive is syrup, starch slurry, polyvinylpyrrolidone, poly- second
Enol, cellulose derivative（Hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose）One kind
Or more than one mixture；Disintegrant is starch, sodium carboxymethyl starch, Ac-Di-Sol, low substituted hydroxy-propyl
One or more kinds of mixtures of cellulose, PVPP；Wetting agent is water, the one or more kinds of of ethanol mix
Compound；
The thin film coating material is forming thin film material and additive, and the forming thin film material is carbohydrate, polyethylene glycol, gathered
Vinyl alcohol, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose or Opadry are thin
One or more kinds of mixtures of film clothing product, the additive includes plasticizer, opacifier, colouring agent, antiplastering aid, anti-
Electrostatic agent；Plasticizer is glycerine, propane diols, polyethylene glycol, rutgers（DMP）, diethyl phthalate（DEP）、
Dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, glycerol triacetate（GTA）, triethyl citrate（TEC）, lemon
Lemon acid tributyl（TBC）, CitroflexA-2, citroflex A-4（TBAC）, castor oil one kind or one
Plant the mixture of the above；Opacifier is titanium dioxide；Colouring agent is iron oxide；It is hard that antitack agent includes magnesium stearate, talcum powder, list
One or more kinds of mixtures of glycerol；
The enteric-coating material includes enteric coating layer polymer, plasticizer, opacifier, antiplastering aid, and the polymer includes poly-
Acrylic resin type enteric material（Utech L30D-55, Eudragit L100-55, Utech L100, Utech S100, Utech
NE30D, No. I acrylic resin, No. II acrylic resin, No. III acrylic resin）, Hydroxypropyl Methylcellulose Phathalate
Ester（HPMCP）, HPMC-AS（HPMCAS）, poly- acetate phthalate vinyl acetate (PVAP), benzene two
Formic acid cellulose acetate（CAP）, acetic acid benzenetricarboxylic acid cellulose, carboxymethylethylcellulose, phthalate, cellulose, shellac
One or more kinds of solution or dispersion liquid；The plasticizer is glycerine, propane diols, polyethylene glycol, rutgers
（DMP）, diethyl phthalate（DEP）, dibatyl phithalate（DBP）, SA dibutyl ester（DBS）, glycerol triacetate
（GTA）, triethyl citrate（TEC）, ATBC（TBC）, CitroflexA-2, the fourth of acetyl citrate three
Ester（TBAC）, castor oil one or more kinds of mixtures；Opacifier is titanium dioxide；Colouring agent is iron oxide；It is anti-sticking
Agent is magnesium stearate, talcum powder, one or more kinds of mixtures of glycerin monostearate；
The diluent is cornstarch, pregelatinized starch, lactose, microcrystalline cellulose, calcium monohydrogen phosphate, mannitol, sucrose, paste
Essence, calcium sulfate, calcium sulphate dihydrate, calcium carbonate, one or more kinds of mixtures of sorbierite；
Described adhesive is syrup, starch slurry, polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivative（Hypromellose
Element, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose）, polyethylene glycol, pregelatinized starch, gelatin, the one of sucrose
Plant or more than one mixture；
The disintegrant is starch, sodium carboxymethyl starch, Ac-Di-Sol, low-substituted hydroxypropyl cellulose, crosslinking
One or more kinds of mixtures of PVP；
The lubricant is magnesium stearate, stearic acid, talcum powder, superfine silica gel powder, sodium stearyl fumarate, hydrogenated vegetable oil, poly-
Glycols（PEG4000、PEG6000）, the one or more kinds of mixture of lauryl sodium sulfate.
7. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claims 3, it is characterised in that
Step a and b active medicine capsule core or the preparation method of blank capsule core are fluidization, rotary pelletizer, centrifugation-fluid bed
Coating, extrusion-spheronization, the preparation of rotating cutting type granulator, intra-liquid desiccation method, spheroidal crystal technology, vibrating nozzle shaping skill
Any method of art.
8. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claim 3, it is characterised in that step
Rapid a, step b Blank Pellets medicine-feeding method are powder medicine-feeding method, any method of solution medicine-feeding method.
9. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claims 3, it is characterised in that
Step a, step b coating preparation thereof be fluidized bed coating equipment, be coated pan coating, centrifugation-fluidized bed prilling pan coating, many
Hole centrifugal device is coated, any method of pressed coated, preferably fluidized bed coating and high-efficiency coating pan coating.
10. a kind of preparation method of ticagrelor compound oral solid pharmaceutical preparation according to claims 3, it is characterised in that
The preparation method of step a acetylsalicylic acid tablet is any, preferably dry method system of wet granulation, dry granulation, direct tablet compressing
Grain and direct tablet compressing;Step b ticagrelor particle or the preparation method of piece are wet granulation, dry granulation, hot-melt extruded system
Any, preferably wet granulation of grain.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109498594A (en) * | 2019-01-07 | 2019-03-22 | 甘肃瑞和祥生物科技有限公司 | A kind of oxytetracycline calcium enteric-coated micro-pill and preparation method thereof |
| CN109700784A (en) * | 2019-03-11 | 2019-05-03 | 梁江丽 | Ticagrelor sustained-release micro-spheres and its preparation and application |
| CN111939136A (en) * | 2020-09-07 | 2020-11-17 | 乐普（北京）医疗器械股份有限公司 | Compound preparation containing ticagrelor and aspirin and preparation method thereof |
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| CN112451531A (en) * | 2020-12-09 | 2021-03-09 | 乐普药业股份有限公司 | Aspirin and rivaroxaban compound preparation and preparation method thereof |
| CN113855799A (en) * | 2021-10-21 | 2021-12-31 | 天津市人民医院 | Application of combination of cideramide and rituximab in treatment of senile relapse refractory B cell lymphoma disease |
| CN114533694A (en) * | 2020-11-26 | 2022-05-27 | 乐普（北京）医疗器械股份有限公司 | Compound capsule preparation containing ticagrelor and aspirin and preparation method thereof |
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| CN109498594A (en) * | 2019-01-07 | 2019-03-22 | 甘肃瑞和祥生物科技有限公司 | A kind of oxytetracycline calcium enteric-coated micro-pill and preparation method thereof |
| CN109700784A (en) * | 2019-03-11 | 2019-05-03 | 梁江丽 | Ticagrelor sustained-release micro-spheres and its preparation and application |
| CN111939136A (en) * | 2020-09-07 | 2020-11-17 | 乐普（北京）医疗器械股份有限公司 | Compound preparation containing ticagrelor and aspirin and preparation method thereof |
| CN111991399A (en) * | 2020-09-07 | 2020-11-27 | 乐普（北京）医疗器械股份有限公司 | Compound packaging preparation containing ticagrelor and aspirin |
| CN114533694A (en) * | 2020-11-26 | 2022-05-27 | 乐普（北京）医疗器械股份有限公司 | Compound capsule preparation containing ticagrelor and aspirin and preparation method thereof |
| CN114533744A (en) * | 2020-11-26 | 2022-05-27 | 乐普（北京）医疗器械股份有限公司 | Ticagrelor-aspirin compound pellet preparation and preparation method thereof |
| CN112451531A (en) * | 2020-12-09 | 2021-03-09 | 乐普药业股份有限公司 | Aspirin and rivaroxaban compound preparation and preparation method thereof |
| CN112451531B (en) * | 2020-12-09 | 2022-01-07 | 乐普药业股份有限公司 | Aspirin and rivaroxaban compound preparation and preparation method thereof |
| CN113855799A (en) * | 2021-10-21 | 2021-12-31 | 天津市人民医院 | Application of combination of cideramide and rituximab in treatment of senile relapse refractory B cell lymphoma disease |
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