CN107913254A - A kind of ticagrelor dispersible tablet and preparation method thereof - Google Patents

A kind of ticagrelor dispersible tablet and preparation method thereof Download PDF

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Publication number
CN107913254A
CN107913254A CN201610877954.XA CN201610877954A CN107913254A CN 107913254 A CN107913254 A CN 107913254A CN 201610877954 A CN201610877954 A CN 201610877954A CN 107913254 A CN107913254 A CN 107913254A
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CN
China
Prior art keywords
ticagrelor
dispersible tablet
minutes
revs
rotating speed
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610877954.XA
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Chinese (zh)
Inventor
杨苗苗
沙薇
米攀义
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Zhengzhou Taifeng Pharmaceutical Co Ltd
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Zhengzhou Taifeng Pharmaceutical Co Ltd
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Priority to CN201610877954.XA priority Critical patent/CN107913254A/en
Publication of CN107913254A publication Critical patent/CN107913254A/en
Pending legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Abstract

The present invention relates to a ticagrelor Disket, for Acute Coronary Syndrome Patients, including receives drug therapy and percutaneous coronary intervention（PCI）The patient for the treatment of.Using ticagrelor as raw material, auxiliary material is added, is prepared into ticagrelor dispersible tablet.Disket disintegration of the present invention is fast, absorbs fast, bioavilability height；It is convenient to take；Enteron aisle residual is few, few side effects；It is sweet, it is particularly easy to improve patient's drug compliance, improves the mouthfeel of preparation, and be not in that sticking shows during pelletizing press sheet, it is advantageously implemented industrialized production.

Description

A kind of ticagrelor dispersible tablet and preparation method thereof
Technical field
The invention belongs to ticagrelor formulation art, and in particular to ticagrelor dispersible tablet and preparation method thereof.
Background technology
Ticagrelor (Ticarelor), also known as ticagrelor, chemical name are（1S, 2S, 3R, 5S）- 3- [7- (1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl] amino } -5- rosickyite base -3H-1,2,3- triazols [4,5-d] pyrimidin-3-yl] -5- （2- hydroxyl-oxethyls）- 1,2 ring pentanediols.Molecular formula：C23H28F2N6O4S, molecular weight：522.57 the following institute of chemical structural formula Show：
Ticagrelor belongs to cyclopenta triazolopyrimidines, is first reversible P2Y12 platelet suppressant drugs, is Britain AstraZeneca（AstraZeneca）A kind of new platelet aggregation inhibitor of company's research and development, is the activity for being not required to liver activation Medicine, effect starting are fast；And the combination of itself and platelet receptor is reversible, this is for Acute Coronary Syndrome Patients hemorrhage risk The reduction of property is highly beneficial；Ticagrelor has validity in the patient to clopidogrel low reaction；In curing thrombus mistake In journey in adjoint bleeding problems, compared with clopidogrel, the increase of massive haemorrhage does not occur for ticagrelor treatment, simply Cause some non-CABG related hemorrhages and the fatal increase intracranialed hemorrhage；Although ticagrelor treatment is gone back with other not The generation of good reaction, but the generation of these adverse reactions it is most of be it is of short duration, what patient can be resistant to, and can pass through Interrupt treatment and terminate.Obviously, ticagrelor is a very promising medicine, with good Clinical efficacy and rationally Security, the Antiplatelet therapy of ACS will be had a huge impact.
Ticagrelor is white or off-white color to pale pink powder, and under pH7.4, logP (n- octanol/waters) is left for 4.5 It is right.Dissolubility influences from pH in physiological pH environment between pH1.0 ~ pH7.4, in 10 μ g/ml or so, belongs to slightly solubility Medicine；Its permeability is 51% or so at the same time（Less than 90%）, belong to hypotonicity medicine.By biopharmacy BCS classification for card Gray belongs to IV classes（That is low-solubility hypotonicity）.Because Ticagrelor belongs to low-solubility hypotonicity medicine, its preparation Dissolution and permeability are to influence the crucial speed limit process that Ticagrelor absorbs in vivo.The human-body biological of Ticagrelor piece utilizes Spend for 36% or so, illustrate that this drug bioavailability is relatively low.
Ticagrelor piece has an AstraZeneca exploitation, and ratifies to list in FDA in May, 2011, and formulation is tablet, specification For 90mg, trade name：Brilinta.
Dispersible tablet is a kind of quick-effective preparation, due to its distinctive advantage, has been had been to be concerned by more and more people.It can add Solubilizer；The dissolution rate of ticagrelor insoluble drug can be improved, is suitable for taking.Piece is made for the difficult medicine of disintegration It can be conducive to absorb.The characteristics of piece：Disintegration is fast, it is fast to absorb, bioavilability height；It is convenient to takeEnteron aisle residual is few, secondary Effect is few.
The content of the invention
It is an object of the invention to provide a kind of ticagrelor dispersible tablet and preparation method thereof, it is intended to solves ticagrelor life The problem of thing availability is relatively low, the dissolution rate and poor patient's compliance of ticagrelor.
Objects of the present invention are achieved through the following technical solutions：.
Ticagrelor dispersible tablet of the present invention is made of following component（Percentage by weight）：
It is above the basic prescription of the present invention, suitably can be adjusted or deleted according to being actually needed；
Since dispersible tablet requirement can be disintegrated rapidly dispersed in water, have that convenient to take, disintegration is rapid, it is fast and raw to absorb The features such as thing availability is high.Therefore the selection to supplementary product kind and its performance is to prepare the key of piece.Inventor is by repeatedly examination Test, it is determined that be adapted to the pharmaceutic adjuvant and its dosage of ticagrelor dispersible tablet.；
It is active ingredient for Ge Ruiluo in above-mentioned ticagrelor dispersible tablet, its weight content is 15% ~ 40%, preferably 20% ~ 35%.
In above-mentioned ticagrelor dispersible tablet, filler in microcrystalline cellulose, lactose, mannitol any one or it is more The combination of kind.Selected filler weight content is 50% ~ 80%, preferably 60% ~ 70%.
In above-mentioned ticagrelor dispersible tablet, disintegrant is selected from microcrystalline cellulose, sodium carboxymethyl starch, cross-linked carboxymethyl fiber The combination of any one or more in plain sodium, crosslinked polyvinylpyrrolidone.Selected disintegrant weight content for 0.5% ~ 10.0%, preferably 1% ~ 8%.
In above-mentioned ticagrelor dispersible tablet, lubricant, including usually said glidant, selected from talcum powder, magnesium stearate, One or more combinations in differential silica gel.Selected lubricant weight content is 0.2% ~ 5%, preferably 0.5% ~ 1.5%.
In above-mentioned ticagrelor dispersible tablet, it is fine that adhesive is selected from microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl The combination of any one or more in dimension element.The weight content of selected adhesive is 0.5% ~ 10%, is preferably 1% ~ 5%.
In above-mentioned ticagrelor dispersible tablet, solubilizer is appointed in dodecyl sodium sulfate, Macrogol 4000, Tween 80 The combination for one or more of anticipating.The weight content of selected solubilizer for 0.1 ~ ~ 5%, preferably 0.1% ~ 3%.
Another object of the present invention is to provide a kind of preparation method of ticagrelor dispersible tablet, include the following steps：
Ticagrelor is carried out micronization processes, 20 μm of control ticagrelor particle diameter ＜ by step 1. using air-flow crushing mode；.
Disintegrant and/or adhesive are uniformly mixed by step 2 with appropriate filler using the equivalent mode of progressively increasing, incorporation time 10 ~ 15 minutes, 10 ~ 15 revs/min of mixer rotating speed；
Step 3. adds ticagrelor in the mixture obtained by step 2, and is uniformly mixed, incorporation time 10 ~ 15 minutes, mixes 10 ~ 15 revs/min of machine rotating speed；
Step 4. adds remaining filler in the mixture obtained by step 3, and is uniformly mixed, incorporation time 10 ~ 15 minutes, 10 ~ 15 revs/min of mixer rotating speed；
Step 5. adds lubricant, solubilizer in step 4 gained mixture, is uniformly mixed, incorporation time 10 ~ 15 minutes, mixes 10 ~ 15 revs/min of conjunction machine rotating speed；
Step 6. takes the mixture direct tablet compressing obtained by step 5；
Above-mentioned direct tablet compressing technique, in order to increase the mobility of its mixed material, selects microcrystalline cellulose PH102 as filling Agent, crosslinked polyvinylpyrrolidone are disintegrant.
It is provided by the invention to replace Ka Ruiluo dispersible tablets, using direct tablet compressing after supplementary material is mixed, with wet granule compression tablet Technique is compared, and the preparation method operating procedure is simple, and technological parameter controllability is good, and technique reappearance is good；It can avoid replacing at the same time Ka Ruiluo may cause transformation of crystal and impurity increase during damp and hot.
Embodiment
Below in conjunction with the embodiments, one kind of the present invention is further illustrated for Ka Ruiluo dispersible tablets and preparation method thereof, under It is illustrative to state embodiment, be not limited, it is impossible to limits protection scope of the present invention with following embodiments.It is every Made any modification, equivalent replacement and improvement etc. within the spirit and principles in the present invention, should be included in the present invention's Within protection domain.
Embodiment 1
Ticagrelor dispersible tablet is formulated by following components, by 1000 dosages
Its preparation method includes the following steps：
1）Ticagrelor is micronized, to 20 μm of particle diameter ＜；
2）Sodium carboxymethyl starch and mannitol are progressively increased 3 times using equivalent, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（1）
3）Ticagrelor is added into the mixture obtained by step 2（1）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（2）
4）Microcrystalline cellulose is added into the mixture obtained by step 3（2）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（3）
5）Magnesium stearate, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer 10 revs/min of rotating speed, obtains mixture（4）
6）Take the mixture obtained by step 5（4）Direct tablet compressing, control tablet weight variation is in ± 5%.
Embodiment 2
Ticagrelor dispersible tablet is formulated by following components, by 1000 dosages
Its preparation method includes the following steps：
1）Ticagrelor is micronized, to 20 μm of particle diameter ＜；
2）Ac-Di-Sol and mannitol are progressively increased 2 times using equivalent, incorporation time 10 minutes, mixer rotating speed 10 Rev/min, obtain mixture（1）；
3）Ticagrelor is added into the mixture obtained by step 2（1）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（2）；
4）Microcrystalline cellulose is added into the mixture obtained by step 3（2）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（3）；
5）Magnesium stearate, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer 10 revs/min of rotating speed, obtains mixture（4）；
6）Take the mixture obtained by step 5（4）Direct tablet compressing, control tablet weight variation is in ± 5%.
3 ticagrelor dispersible tablet of embodiment is formulated by following components, by 1000 dosages
Its preparation method includes the following steps：
1）Ticagrelor is micronized, to 20 μm of particle diameter ＜；
2）Sodium carboxymethyl starch and mannitol are progressively increased 2 times using equivalent, incorporation time 10 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（1）；
3）Ticagrelor is added into the mixture obtained by step 2（1）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（2）；
4）Microcrystalline cellulose is added into the mixture obtained by step 3（2）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（3）；
5）Magnesium stearate, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer 10 revs/min of rotating speed, obtains mixture（4）；
6）Take the mixture obtained by step 5（4）Direct tablet compressing, control tablet weight variation is in ± 5%.
4 ticagrelor dispersible tablet of embodiment is formulated by following components, by 1000 dosages
Its preparation method includes the following steps：
1）Ticagrelor is micronized, to 20 μm of particle diameter ＜；
2）Sodium carboxymethyl starch and 10% mannitol are progressively increased 1 time using equivalent, incorporation time 10 minutes, 10 turns of mixer rotating speed/ Minute, obtain mixture（1）；
3）Ticagrelor is added into the mixture obtained by step 2（1）In, incorporation time 15 minutes, 10 revs/min of mixer rotating speed Clock, obtains mixture（2）；
4）Microcrystalline cellulose and remaining mannitol are added to the mixture obtained by step 3（2）In, incorporation time 15 minutes, is mixed 10 revs/min of conjunction machine rotating speed, obtains mixture（3）；
5）Superfine silica gel powder, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer 10 revs/min of rotating speed, obtains mixture（4）；
6）Take the mixture obtained by step 5（4）Direct tablet compressing, control tablet weight variation is in ± 5%.
Sample prepared by embodiment 1, embodiment 2, embodiment 3 and embodiment 4 is respectively placed in stability test case It is interior, accelerated test is carried out under conditions of temperature is 40 DEG C, relative humidity is 75%, using dissolution rate as inspection target, 30 minutes More than 85% should be reached, it was demonstrated that the scattered tablet recipe and the scientific rationality of technique invented：
1 accelerated stability test dissolution results of table

Claims (8)

1. the present invention designs a kind of preparation method of ticagrelor dispersible tablet, it is characterised in that the ticagrelor dispersible tablet Preparation method includes the following steps：
Ticagrelor is carried out micronization processes, 20 μm of control ticagrelor particle diameter ＜ by step 1. using air-flow crushing mode；
Disintegrant and/or adhesive are uniformly mixed by step 2 with appropriate filler using the equivalent mode of progressively increasing, and incorporation time 10 ~ 15 minutes, 10 ~ 15 revs/min of mixer rotating speed；
Step 3. adds ticagrelor in the mixture obtained by step 2, and is uniformly mixed, incorporation time 10 ~ 15 minutes, mixes 10 ~ 15 revs/min of machine rotating speed；
Step 4. adds remaining filler in the mixture obtained by step 3, and is uniformly mixed, incorporation time 10 ~ 15 minutes, 10 ~ 15 revs/min of mixer rotating speed；
Step 5. adds lubricant, solubilizer in step 4 gained mixture, is uniformly mixed, incorporation time 10 ~ 15 minutes, mixes 10 ~ 15 revs/min of conjunction machine rotating speed；
Step 6. takes the mixture direct tablet compressing obtained by step 5.
2. ticagrelor dispersible tablet according to claim 1, is mainly made of ticagrelor and other auxiliary materials.
3. ticagrelor dispersible tablet according to claim 1, it is characterised in that filler be selected from microcrystalline cellulose, lactose, The combination of any one or more in mannitol.
4. ticagrelor dispersible tablet according to claim 1, it is characterised in that disintegrant is selected from microcrystalline cellulose, carboxylic first The combination of any one or more in base sodium starch, Ac-Di-Sol, crosslinked polyvinylpyrrolidone.
5. ticagrelor dispersible tablet according to claim 1, it is characterised in that lubricant, including usually said help stream Agent, one or more combinations in talcum powder, magnesium stearate, differential silica gel.
6. ticagrelor dispersible tablet according to claim 1, it is characterised in that adhesive is selected from microcrystalline cellulose, hydroxypropyl The combination of any one or more in ylmethyl cellulose, hydroxypropyl cellulose.
7. ticagrelor dispersible tablet according to claim 1, it is characterised in that lubricant is selected from magnesium stearate, talcum powder With the one or more in superfine silica gel powder.
8. ticagrelor dispersible tablet according to claim 1, it is characterised in that solubilizer be selected from dodecyl sodium sulfate, The combination of any one or more in Macrogol 4000, Tween 80.
CN201610877954.XA 2016-10-09 2016-10-09 A kind of ticagrelor dispersible tablet and preparation method thereof Pending CN107913254A (en)

Priority Applications (1)

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Application Number Priority Date Filing Date Title
CN201610877954.XA CN107913254A (en) 2016-10-09 2016-10-09 A kind of ticagrelor dispersible tablet and preparation method thereof

Publications (1)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111450067A (en) * 2019-01-18 2020-07-28 北京万全德众医药生物技术有限公司 Ticagrelor dispersible tablet and preparation method thereof
CN112315918A (en) * 2019-08-05 2021-02-05 北京福元医药股份有限公司 Ticagrelor pharmaceutical preparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111450067A (en) * 2019-01-18 2020-07-28 北京万全德众医药生物技术有限公司 Ticagrelor dispersible tablet and preparation method thereof
CN112315918A (en) * 2019-08-05 2021-02-05 北京福元医药股份有限公司 Ticagrelor pharmaceutical preparation
CN112315918B (en) * 2019-08-05 2022-05-17 北京福元医药股份有限公司 Ticagrelor pharmaceutical preparation

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