A kind of ticagrelor dispersible tablet and preparation method thereofTechnical 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 formulaShow：
Ticagrelor belongs to cyclopenta triazolopyrimidines, is first reversible P2Y12 platelet suppressant drugs, is BritainAstraZeneca（AstraZeneca）A kind of new platelet aggregation inhibitor of company's research and development, is the activity for being not required to liver activationMedicine, effect starting are fast；And the combination of itself and platelet receptor is reversible, this is for Acute Coronary Syndrome Patients hemorrhage riskThe reduction of property is highly beneficial；Ticagrelor has validity in the patient to clopidogrel low reaction；In curing thrombus mistakeIn journey in adjoint bleeding problems, compared with clopidogrel, the increase of massive haemorrhage does not occur for ticagrelor treatment, simplyCause some non-CABG related hemorrhages and the fatal increase intracranialed hemorrhage；Although ticagrelor treatment is gone back with other notThe 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 throughInterrupt treatment and terminate.Obviously, ticagrelor is a very promising medicine, with good Clinical efficacy and rationallySecurity, 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 4.5It 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 solubilityMedicine；Its permeability is 51% or so at the same time（Less than 90%）, belong to hypotonicity medicine.By biopharmacy BCS classification for cardGray belongs to IV classes（That is low-solubility hypotonicity）.Because Ticagrelor belongs to low-solubility hypotonicity medicine, its preparationDissolution and permeability are to influence the crucial speed limit process that Ticagrelor absorbs in vivo.The human-body biological of Ticagrelor piece utilizesSpend 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, specificationFor 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 addSolubilizer；The dissolution rate of ticagrelor insoluble drug can be improved, is suitable for taking.Piece is made for the difficult medicine of disintegrationIt 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, secondaryEffect 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 lifeThe 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 absorbThe 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 examinationTest, 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 moreThe 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 fiberThe 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, hydroxypropylThe 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 80The 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 time10 ~ 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, mixes10 ~ 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, mixes10 ~ 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 fillingAgent, 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 tabletTechnique 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 timeKa 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, underIt is illustrative to state embodiment, be not limited, it is impossible to limits protection scope of the present invention with following embodiments.It is everyMade any modification, equivalent replacement and improvement etc. within the spirit and principles in the present invention, should be included in the present invention'sWithin 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 speedClock, 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 speedClock, 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 speedClock, obtains mixture（3）
5）Magnesium stearate, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer10 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 10Rev/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 speedClock, 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 speedClock, obtains mixture（3）；
5）Magnesium stearate, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer10 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 speedClock, 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 speedClock, 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 speedClock, obtains mixture（3）；
5）Magnesium stearate, dodecyl sodium sulfate are added into step 4 gained mixture（3）In, incorporation time 10 minutes, mixer10 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 speedClock, 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 mixed10 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, mixer10 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 caseIt 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 minutesMore 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