CN106265557A - Pharmaceutical composition containing ticagrelor - Google Patents
Pharmaceutical composition containing ticagrelor Download PDFInfo
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- CN106265557A CN106265557A CN201510301972.9A CN201510301972A CN106265557A CN 106265557 A CN106265557 A CN 106265557A CN 201510301972 A CN201510301972 A CN 201510301972A CN 106265557 A CN106265557 A CN 106265557A
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Abstract
The invention discloses a kind of dispersible tablet containing ticagrelor, each adjuvant and crude drug are the most collaborative in specific components and amount ranges so that the rapid disintegrate of dispersible tablet of ticagrelor, and dissolution rate is high, and improves the bioavailability of ticagrelor.The preparation method of ticagrelor pharmaceutical composition of the present invention, technical process is simple, it is easy to operation realizes, and is suitable to industrial application.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of ticagrelor pharmaceutical composition and preparation method thereof.
Background technology
Ticagrelor (Ticagrelor), chemistry is entitled: (1S, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropyl amino]-5-(rosickyite base)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol.
Its structural formula is:
Molecular formula: C23H28F2N6O4S molecular weight: 522.57
Pharmacology type: ticagrelor is a member of chemical classification cyclopenta triazolo pyrimidine (CPTP), CPTP is a kind of selectivity adenosine diphosphate (ADP) (ADP) receptor antagonist, act on P2Y12ADP receptor, with platelet activation and the gathering of suppression ADP mediation, similar to the mechanism of action of Thienopyridines medicine (such as clopidogrel).
2010, EU Committee have approved an oral antidiabetic new drug ticagrelor of Astrazeneca AB's exploitation
(Ticagrelor), for acute coronary syndrome (ACS；Unstable angina pectoris, non-ST elevation acute myocardial infraction or ST section Elevation Myocardial Infarction) patient, gets involved, including accepting Drug therapy and percutaneous coronary, the patient that (PCI) treats, reduces the incidence rate of thrombotic cardiovascular event.This is that ticagrelor gets the Green Light first.Trade name: BRILINTA, listing dosage form is tablet.
Prior art is about the preparation technique research design several formulations form of ticagrelor, such as prior art CN201410801996.6 discloses a kind of ticagrelor sheet and preparation method thereof, selecting mannitol, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate is that tablet prepared by adjuvant, gained tablet has preferable dissolution rate, improve commercially available ticagrelor Dissolution of Tablet low, the problem that dissolution is uneven；It is ticagrelor dropping pill formulation that prior art CN201410779640.7 discloses a kind of ticagrelor novel formulation type；Prior art CN201310432438.2 provides a kind of ticagrelor solid dispersion form preparation, is scattered in carrier material by ticagrelor, makes ticagrelor be in the state of high degree of dispersion, solves the slightly solubility problem of ticagrelor；Prior art CN201310408327.8 discloses tablet composition of a kind of ticagrelor and preparation method thereof, wherein the composition of particle diameter, crystal formation and the adjuvant thereof of ticagrelor is illustrated, jointly prepare stable and controllable for quality, the ticagrelor tablet that efficacy and saferry is good.
Ticagrelor preparation is studied by the applicant further, because of the physicochemical property of ticagrelor material, still suffers from mobility of particle bad, sticking, poor stability, dissolution is relatively low, complex process, production cost is high, it be difficult to the problems such as industrialized big production, in order to improve production quality further, We conducted design and the research of substantial amounts of technical scheme, choose prescription and the technique of optimum, solve above-mentioned technological deficiency.
Ticagrelor tablet formulation prepared by the present invention, owing to having the rapid homodisperse effect of disintegrate in water, its disintegrate is not affected by physiological environment, therefore its dissolution is high, thus it is high to improve its bioavailability, improve the therapeutic effect of ticagrelor, and overcome complex manufacturing present in prior art, it is impossible to carry out the defect of large-scale production.
Summary of the invention
It is an object of the invention to provide a kind of pharmaceutical composition Han ticagrelor, mixed according to a certain percentage with mannitol and calcium hydrogen phosphate by ticagrelor, said composition formula is simple, and mature preparation process, result of extraction is good.
It is a further object to provide a kind of method preparing ticagrelor pharmaceutical composition.
The present invention is by the following technical solutions:
The pharmaceutical composition containing ticagrelor that the present invention relates to uses wet granule compression tablet, it is provided that the applicable prescription of tablet of preparing in addition to containing active component, possibly together with diluent and disintegrating agent, appropriate lubricant can be contained as required simultaneously.
Specifically, the ticagrelor dispersible tablet of the present invention, containing ticagrelor, diluent and disintegrating agent, wherein ticagrelor accounts for the percentage by weight of whole tablet weight is 20-50%, and it is 30-70% that diluent accounts for the percentage by weight of whole tablet weight.
Preferably, it is 30-40% that ticagrelor accounts for the percentage by weight of whole tablet weight, and it is 50-65% that diluent accounts for the percentage by weight of whole tablet weight.
Mannitol and calcium hydrogen phosphate are the diluent of pharmaceutical composition of the present invention, and the weight ratio of mannitol and calcium hydrogen phosphate is 1-5, it is therefore preferable to 1.5-2.5.Appropriate lubricant and disintegrating agent can be contained as required, lubricant is selected from one or more in magnesium stearate, Pulvis Talci and sodium stearyl fumarate, and disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, pregelatinized Starch and carboxymethylstach sodium.
Preferably, above-mentioned ticagrelor dispersible tablet, wherein said lubricant is magnesium stearate, and described disintegrating agent is carboxymethylstach sodium or polyvinylpolypyrrolidone.
The invention have the characteristics that the consumption to ticagrelor and diluent is controlled, further diluent kind is selected, find out ticagrelor and two kinds of necessary proportion relations of diluent, make the disintegration of tablet prepared rapid, there is preferable dissolution, good stability, the problem simultaneously also solving large-scale industrial production.Complete it is critical only that of the present invention: ticagrelor and the consumption of diluent, the ratio of ticagrelor and two kinds of diluent controls.
In the pharmaceutical composition of the present invention, each component accounts for the percentage by weight of whole tablet weight and is:
Ticagrelor 20-50%
Diluent 30-70%
Disintegrating agent 3-10%
Lubricant 1-4%
Preferably, in the pharmaceutical composition of the present invention, each component accounts for the percentage by weight of whole tablet weight and is:
Ticagrelor 30-40%
Mannitol 30-40%
Calcium hydrogen phosphate 16-25%
Disintegrating agent 8%
Lubricant 2%
Specifically, the preferred scheme of the present invention is, prescription forms:
Ticagrelor 30%
Mannitol 40%
Calcium hydrogen phosphate 20%
Disintegrating agent 8%
Lubricant 2%
It is a further object to provide a kind of method preparing above-mentioned ticagrelor pharmaceutical composition, comprise the following steps:
1) preparation of supplementary material and process: ticagrelor and other adjuvants are crossed 100 mesh sieves respectively standby；
2) weigh and mix: calculating inventory according to recipe quantity through double verification and weigh above-mentioned supplementary material respectively；
3) mixing: after the ticagrelor of recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, then mix with the mannitol of recipe quantity, be subsequently adding carboxymethylstach sodium so that it is be sufficiently mixed uniformly；
4) pelletizing: added by 1% hypromellose aqueous solution in the material of mix homogeneously, prepare the soft material of suitable stiff, use 20 eye mesh screens to pelletize, gained granule should lack fine powder, neat without strip；
5) it is dried: prepared granule is dried to moisture≤3.0% under the conditions of 60 DEG C ± 5 DEG C；
6) granulate: dried granule is used 20 eye mesh screen granulate；
7) always mix: mix disintegrating agent outside adding and mix lubricant is uniform, to be tested；
8) intermediate inspection: measure granule content, calculates loading amount；
9) tabletting: according to the actual tablet weight of result of calculation gained, regulates machine, tabletting.
Wherein, the addition sequence of disintegrating agent is to add in carboxymethylstach sodium, and polyvinylpolypyrrolidone is additional together with lubricant so that the dissolving out capability of dispersible tablet has obtained further improvement.
Below by concrete experimental program, the invention will be further described:
That follows tablet is typically prepared principle and existing technical scheme, and we devise pre-prescription:
Preparation technology:
The ticagrelor weighing recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, the mannitol and the carboxymethylstach sodium that add recipe quantity mixed 100 mesh sieves, so that it is sufficiently mixed, soft material processed, pelletize with 20 eye mesh screens, it is dried under the temperature conditions of 60 DEG C ± 5 DEG C, pelletize with 20 eye mesh screens again, add polyvinylpolypyrrolidone and magnesium stearate mix homogeneously, tabletting, coating, to obtain final product.
By the trial-production to prescription 1 ~ prescription 6, screen prescription from indexs of correlation such as character, hardness, friability, angle of repose, disintegration phenomenon respectively.
Table 1
Being shown by above result of the test, prescription 1-6 mobility of particle all meets the requirements, but the disintegration time of prescription 6 relatively prescription 1-5 disintegration time is long.
Prescription 1-6 is carried out dissolution determination:
Dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010) is with 900ml0.2% Tween 80 solution as dissolution medium, rotating speed is 75 turns per minute, operates in accordance with the law, takes solution at 5,10,15,20,30 minutes respectively appropriate, filter and fluid infusion, take subsequent filtrate as need testing solution；Separately take ticagrelor reference substance about 20mg, accurately weighed, put in 100ml measuring bottle, add that methanol is the most ultrasonic makes dissolving, adding dissolution medium to scale, shake up, precision measures 2ml and puts in 100ml measuring bottle, add dissolution medium to scale, shaking up, precision measures 5ml and puts in 100ml measuring bottle, adds dissolution medium to scale, shake up, compare product solution.Precision measures need testing solution and each 100 l of reference substance solution, is injected separately into chromatograph of liquid, records chromatogram, measures according to the chromatographic condition under assay item, the stripping quantity of the ticagrelor in going out every by external standard method with calculated by peak area.
Table 2
Separately being shown by above result of the test, prescription 1-5 relatively prescription 6 has preferable dissolution, and wherein the result of extraction of prescription 2 is optimum.
Additionally, pharmaceutical composition of the present invention can also be containing other anticoagulant, described anticoagulant is preferably aspirin.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, it should be understood that the non-scope being only limitted to these embodiments of the scope of the present invention.
Embodiment 1
(1) prescription
Ticagrelor 90g
Mannitol 120g
Calcium hydrogen phosphate 60g
Carboxymethylstach sodium 15g
Polyvinylpolypyrrolidone 9g
Magnesium stearate 6g
Make 1000
(2) preparation method
1) preparation of supplementary material and process: ticagrelor and other adjuvants are crossed 100 mesh sieves respectively standby；
2) weigh and mix: calculating inventory according to recipe quantity through double verification and weigh above-mentioned supplementary material respectively；
3) mixing: after the ticagrelor of recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, then mix with the mannitol of recipe quantity, be subsequently adding carboxymethylstach sodium so that it is be sufficiently mixed uniformly；
4) pelletizing: added by 1% hypromellose aqueous solution in the material of mix homogeneously, prepare the soft material of suitable stiff, use 20 eye mesh screens to pelletize, gained granule should lack fine powder, neat without strip；
5) it is dried: prepared granule is dried to moisture≤3.0% under the conditions of 60 DEG C ± 5 DEG C；
6) granulate: dried granule is used 20 eye mesh screen granulate；
7) always mix: outside adding, mix polyvinylpolypyrrolidone and magnesium stearate mix homogeneously, to be tested；
8) intermediate inspection: measure granule content, calculates loading amount；
9) tabletting: according to the actual tablet weight of result of calculation gained, regulates machine, tabletting.
Embodiment 2
(1) prescription
Ticagrelor 90g
Mannitol 105g
Calcium hydrogen phosphate 75g
Carboxymethylstach sodium 15g
Polyvinylpolypyrrolidone 9g
Magnesium stearate 6g
Make 1000
(2) preparation method is with embodiment 1.
Embodiment 3
(1) prescription
Ticagrelor 90g
Mannitol 76.5g
Calcium hydrogen phosphate 36g
Carboxymethylstach sodium 11.3g
Polyvinylpolypyrrolidone 6.7g
Magnesium stearate 4.5g
Make 1000
(2) preparation method is with embodiment 1.
Embodiment 4
Ticagrelor 90g
Aspirin 25g
Mannitol 100g
Calcium hydrogen phosphate 50g
Carboxymethylstach sodium 10g
Polyvinylpolypyrrolidone 10g
Magnesium stearate 5g
Make 1000
) ticagrelor, aspirin, mannitol, calcium hydrogen phosphate and carboxymethylstach sodium are dried, pulverize, cross 100 mesh sieves；
2) mannitol and the calcium hydrogen phosphate that take recipe quantity are mixed homogeneously with ticagrelor, add aspirin, add carboxymethylstach sodium, soft material processed, cross 20 eye mesh screens and pelletize, obtain the wet granular of compound recipe；
3) above-mentioned compound recipe wet granular is dried under the conditions of 60 DEG C to moisture less than 3%, obtains the dry granule of compound recipe；
4) dry for above-mentioned compound recipe granule is crossed 20 eye mesh screen granulate, add polyvinylpolypyrrolidone and magnesium stearate, mix homogeneously, tabletting, to obtain final product.
Test example 1
Embodiment 1,2 and 3 is had the detection of related substance, dissolution and uniformity of dosage units
From result above, each check item of embodiment 1,2 and 3 all meets regulation, formulation and technology simple possible, steady quality.
Test example 2
The dissolution determination of the embodiment of the present invention 4
According to 2010 editions dissolution methods of Chinese Pharmacopoeia (annex XC the second method), with the HCl solution 900mL of pH 1.2 as solvent, temperature is 37 ± 0.5 DEG C, rotating speed is 50r/min, solution 10mL is taken respectively at 0,5,10,15,30,45,60 min, filter with 0.45 μm microporous filter membrane, take subsequent filtrate, and immediately supplement pH 1.2 HCl solution 10mL in a reservoir.Take subsequent filtrate sample introduction 20 μ L, record chromatographic peak area, measurement result substitute into standard curve and try to achieve the stripping quantity of a time point Li Gelieting, calibrated after i.e. obtain accumulation dissolution.Take in subsequent filtrate 1mL to 10mL volumetric flask, sample introduction 20 μ L after constant volume, record chromatographic peak area, measurement result substitute into standard curve and try to achieve the stripping quantity of time point aspirin, calibrated after i.e. obtain accumulation dissolution.Medicine total release percentage is calculated as follows: wherein CiFor drug level (μ g mL-1)；For release medium volume (mL)；For fluid replacement volume (mL)；W is example weight (mg)；FPercentage composition (%) for preparation of Chinese medicine.
Ticagrelor, the dissolution test result of aspirin
Claims (9)
1. a ticagrelor dispersible tablet, it is characterised in that containing ticagrelor, diluent and disintegrating agent, wherein ticagrelor accounts for the percentage by weight of whole tablet weight is 20-50%, and it is 30-70% that diluent accounts for the percentage by weight of whole tablet weight.
Ticagrelor dispersible tablet the most according to claim 1, it is characterised in that it is 30-40% that ticagrelor accounts for the percentage by weight of whole tablet weight, it is 50-65% that diluent accounts for the percentage by weight of whole tablet weight.
Ticagrelor dispersible tablet the most according to claim 1, it is characterised in that described diluent is selected from mannitol and calcium hydrogen phosphate.
Ticagrelor dispersible tablet the most according to claim 3, and the weight ratio of mannitol and calcium hydrogen phosphate is 1-5.
Ticagrelor dispersible tablet the most according to claim 1, it is characterised in that possibly together with other anticoagulation medicines.
Ticagrelor dispersible tablet the most according to claim 3, it is characterised in that each component and account for the percentage by weight of whole tablet weight and be:
Ticagrelor 30-40%
Mannitol
30-40%
Calcium hydrogen phosphate 16-25%
Disintegrating agent 8%
Lubricant 2%.
Ticagrelor dispersible tablet the most according to claim 6, it is characterised in that each component and account for the percentage by weight of whole tablet weight and be:
Ticagrelor 30%
Mannitol 40%
Calcium hydrogen phosphate 20%
Disintegrating agent 8%
Lubricant 2%.
8. the method for the ticagrelor dispersible tablet that a kind is prepared as described in claim 6-7 any one, concretely comprise the following steps: take ticagrelor and adjuvant sieves, standby, the adjuvant of the ticagrelor and recipe quantity that weigh recipe quantity is mixed homogeneously, soft material processed, it is dried, granulate, additional lubricant and disintegrating agent mixing, tabletting, coating, to obtain final product.
Preparation method the most according to claim 7, it is characterised in that comprise the following steps:
1) preparation of supplementary material and process: ticagrelor and other adjuvants are crossed 100 mesh sieves respectively standby；
2) weigh and mix: calculating inventory according to recipe quantity through double verification and weigh above-mentioned supplementary material respectively；
3) mixing: after the ticagrelor of recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, then mix with the mannitol of recipe quantity, be subsequently adding carboxymethylstach sodium so that it is be sufficiently mixed uniformly；
4) pelletizing: added by 1% hypromellose aqueous solution in the material of mix homogeneously, prepare the soft material of suitable stiff, use 20 eye mesh screens to pelletize, gained granule should lack fine powder, neat without strip；
5) it is dried: prepared granule is dried to moisture≤3.0% under the conditions of 60 DEG C ± 5 DEG C；
6) granulate: dried granule is used 20 eye mesh screen granulate；
7) always mix: mix disintegrating agent outside adding and mix lubricant is uniform, to be tested；
8) intermediate inspection: measure granule content, calculates loading amount；
9) tabletting: according to the actual tablet weight of result of calculation gained, regulates machine, tabletting.
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|---|---|---|---|
| CN201510301972.9A CN106265557A (en) | 2015-06-05 | 2015-06-05 | Pharmaceutical composition containing ticagrelor |
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| CN201510301972.9A CN106265557A (en) | 2015-06-05 | 2015-06-05 | Pharmaceutical composition containing ticagrelor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110327305A (en) * | 2019-06-26 | 2019-10-15 | 慧生医学科技(徐州)有限公司 | A kind of ticagrelor piece and preparation method thereof |
| 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 |
| WO2022261735A1 (en) * | 2021-06-14 | 2022-12-22 | Libbs Farmacêutica Ltda | Pharmaceutical composition and use of the pharmaceutical composition |
-
2015
- 2015-06-05 CN CN201510301972.9A patent/CN106265557A/en active Pending
Cited By (3)
| 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 |
| CN110327305A (en) * | 2019-06-26 | 2019-10-15 | 慧生医学科技(徐州)有限公司 | A kind of ticagrelor piece and preparation method thereof |
| WO2022261735A1 (en) * | 2021-06-14 | 2022-12-22 | Libbs Farmacêutica Ltda | Pharmaceutical composition and use of the pharmaceutical composition |
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