CN104940204A - Ticagrelor solid preparation and preparation method thereof - Google Patents

Ticagrelor solid preparation and preparation method thereof Download PDF

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Publication number
CN104940204A
CN104940204A CN201510136454.6A CN201510136454A CN104940204A CN 104940204 A CN104940204 A CN 104940204A CN 201510136454 A CN201510136454 A CN 201510136454A CN 104940204 A CN104940204 A CN 104940204A
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Prior art keywords
ticagrelor
solid preparation
weight
according
mannitol
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CN201510136454.6A
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Chinese (zh)
Inventor
奉水旺
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广东东阳光药业有限公司
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Priority to CN2014101208261 priority
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Priority to CN201510136454.6A priority patent/CN104940204A/en
Publication of CN104940204A publication Critical patent/CN104940204A/en

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Abstract

The invention relates to a ticagrelor solid preparation and a preparation method thereof. The solid preparation contains active pharmaceutical ingredients including ticagrelor and a diluent, wherein the diluent is a combination of mannitol and microcrystalline cellulose; and furthermore, the weight proportion of mannitol to microcrystalline cellulose is 0.2:1 to 3:1. The solid preparation provided by the invention is capable of promoting drugs to dissolve out completely while accelerating drugs to dissolve out; therefore, the solid preparation is high in bioavailability and good in storage stability; furthermore, the invention further provides a preparation method of the ticagrelor solid preparation; and the preparation method is simple and feasible and low in production cost and is applied to industrial production.

Description

A kind of ticagrelor solid preparation and preparation method thereof

Technical field

The present invention relates to a kind of ticagrelor solid preparation, particularly relate to a kind of release fast, stable ticagrelor tablet and preparation method thereof, belongs to field of pharmaceutical preparations.

Background technology

Ticagrelor (Ticagrelor), listing is researched and developed by Astrazeneca AB, a kind of novel, Reversible binding type P2Y12 adenosine diphosphate receptor (ADP) antagonist, can purine 2 receptor subtype P2Y12 on reversibility vasoactive smooth muscle cell (VSMC), for anti-platelet aggregation and prevention with improve acute coronary artery syndrome shape.Ticagrelor obtains European Union's approval in December, 2010 and is used for the treatment of adult's acute coronary artery syndrome, and commodity are called Brilique; In February, 2011 is in Britain and Germany's listing; Obtain FDA approval in July, 2011, commodity are called Brilinta.

Chemistry (the 1S by name of ticagrelor, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) Pentamethylene .-1,2-glycol, structural formula is as follows:

Ticagrelor is as lower in the dissolubility in water at neutral medium, is 10 μ g/mL, the low process not only affecting preparation and prepare of dissolubility, and further, after medicine enters human body, stripping is slow, and stripping is incomplete, and then has influence on the bioavailability of medicine.The ticagrelor mainly tablet form of current listing, wherein containing ticagrelor 90mg.

The multiple ticagrelor preparation containing various adjuvant is disclosed in prior art, CN 200780031137.1 discloses a kind of solid preparation of ticagrelor, wherein ticagrelor and diluent, binding agent, lubricant and disintegrating agent mixing, adopt wet granulation method preparation can discharge medicine completely, the ticagrelor preparation of bioavailability may be improved, wherein, the diluent used in said preparation is mannitol and dicalcium phosphate dehydrate, lubricant adopts magnesium stearate, but there is the deficiency of several aspect, dicalcium phosphate dehydrate is as medicinal diluent on the one hand, expensive, medicinal cost is very high, on the other hand, applicant finds that dicalcium phosphate dehydrate easily occurs puckery in ticagrelor tablet compression process, and applicant also finds that preparation of Chinese medicine active component of the prior art has slack-off trend in the stripping later stage, causes drug-eluting incomplete.In order to effectively reduce production cost, economize on resources, simultaneously can effective prophylactic treatment disease, raising quality of life of patients, therefore develop a kind of production cost low, the preparation that bioavailability is high is particularly important.

Summary of the invention

Summary of the invention

First aspect present invention provides a kind of solid pharmaceutical preparation comprising ticagrelor, and while quickening drug-eluting, promote the complete stripping of medicine, bioavailability is high, and storage stability is good.

Second aspect present invention provides the preparation method of the ticagrelor solid preparation described in a kind of first aspect, and the method is simple, and production cost is low, is suitable for suitability for industrialized production.

Term definition

Term " comprises " or " comprising " is open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.

In the context of the present invention, no matter whether use the wording such as " approximately " or " about ", all numerals disclosed at this are approximation.The numerical value of each numeral likely there will be difference or the rational difference thought of those skilled in the art of less than 10%, as the difference of 1%, 2%, 3%, 4% or 5%.

Detailed Description Of The Invention

Based on the deficiencies in the prior art, we, through deeply investigating and research, select the combination of mannitol and microcrystalline Cellulose as diluent: on the one hand, use microcrystalline Cellulose compared to using dicalcium phosphate dehydrate and can reduce 3-5 production cost doubly, economize on resources; On the other hand, use the combination of mannitol and microcrystalline Cellulose smooth and easy as diluent tabletting in preparation technology, the generation of puckery situation can be reduced; And the ticagrelor tablet of preparation, wherein sustained drug stripping quickly, and then drug-eluting is complete, effectively improves bioavailability.

The invention provides a kind of solid preparation of ticagrelor, comprise ticagrelor and the diluent of active constituents of medicine, wherein said diluent is the combination of mannitol and microcrystalline Cellulose.

A solid preparation for ticagrelor, wherein, the part by weight of mannitol and microcrystalline Cellulose is 0.2:1 to 3:1.Be 0.25:1 in certain embodiments; Be 1:1 in certain embodiments; Be 2:1 in certain embodiments; Be 3:1 in further embodiments.

A solid preparation for ticagrelor, wherein, ticagrelor exists with the form of crystal form II or crystal form II I substantially; In some embodiments, ticagrelor comprises crystal form II or the crystal form II I of at least 90%; In some embodiments, ticagrelor comprises crystal form II or the crystal form II I of at least 95%; In some embodiments, ticagrelor comprises crystal form II or the crystal form II I of at least 99%; In some embodiments, ticagrelor comprises crystal form II or the crystal form II I of at least 99.9%.

A solid preparation for ticagrelor, relative to tablet total weight amount, calculate according to percentage by weight, the weight of the ticagrelor comprised is 10%-50%; In certain embodiments, the weight of the ticagrelor comprised is 25%-35%.

A solid preparation for ticagrelor, it also comprises binding agent, disintegrating agent and lubricant.Wherein, described binding agent is hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), sodium carboxymethyl cellulose (CMC-Na), methylcellulose, polyethylene glycol 6000 (PEG6000), arabic gum or its combination; In certain embodiments, described binding agent is hydroxypropyl cellulose.Wherein, described disintegrating agent is cross-linking sodium carboxymethyl cellulose (CC-Na), carboxymethyl starch sodium (CMS-Na), polyvinylpolypyrrolidone (PVPP), dried starch or its combination; In certain embodiments, described disintegrating agent is carboxymethyl starch sodium.Described lubricant is magnesium stearate, calcium stearate, sodium lauryl sulphate, titanium dioxide, Pulvis Talci, micropowder silica gel or its combination; In certain embodiments, described lubricant is magnesium stearate.Wherein, described ticagrelor solid preparation, in certain embodiments, relative to tablet total weight amount, calculates according to percentage by weight, comprises binding agent 2%-6%, disintegrating agent 2%-6%, lubricant 0.5%-2%; In some embodiments, relative to tablet total weight amount, calculate according to percentage by weight, comprise binding agent 3%-6%, disintegrating agent 2%-4%, lubricant 1%-2%.

A kind of solid preparation of ticagrelor, it comprises coating further, described coating material is selected from hydroxypropyl methylcellulose or Opadry, wherein, containing one or both in lactose, hydroxypropyl cellulose, titanium dioxide, triacetate and pigment in the formula of described Opadry.In some embodiments, coating material is 1%-4% relative to the percentage by weight of plain sheet, and in other embodiments, coating material is 3% relative to the percentage by weight of plain sheet.

A solid preparation for ticagrelor,

In some embodiments, it comprises:

1) ticagrelor 10%-50%;

2) mannitol 10%-55%;

3) microcrystalline Cellulose 16%-50%;

4) carboxymethyl starch sodium 2%-6%;

5) hydroxypropyl cellulose 2%-6%;

6) magnesium stearate 0.5%-2%.

In some embodiments, it comprises:

1) ticagrelor 25%-35%;

2) mannitol 15%-45%;

3) microcrystalline Cellulose 15%-40%;

4) carboxymethyl starch sodium 2%-4%;

5) hydroxypropyl cellulose 3%-6%;

6) magnesium stearate 1%-2%.

A kind of ticagrelor solid preparation, in some embodiments, the content of ticagrelor in per unit dose solid preparation is 50mg-300mg; In some embodiments, the content of ticagrelor in per unit dose solid preparation is 70mg-240mg; In other embodiments, ticagrelor is 90mg-180mg at the content of per unit dose solid preparation.

Ticagrelor solid preparation of the present invention is oral tablet.

The present invention additionally provides a kind of preparation method of ticagrelor solid preparation on the other hand, and described method comprises and ticagrelor, diluent, binding agent, disintegrating agent being mixed; Sieve, add binder solution soft material; To sieve drying, granulate; Add lubricant, always mix, tabletting, coating.

In some embodiments, ticagrelor solid preparation can be prepared in accordance with the following methods:

1) ticagrelor of recipe quantity, diluent, binding agent and disintegrating agent after mix homogeneously, add appropriate purified water and granulate in wet granulator;

2) wet granular made is crossed Comil pelletizing machine granulate;

3) wet granular after granulate is dry in fluid bed, inlet temperature is set to 50 DEG C-70 DEG C, during dried material loss on drying < 1.5%, stops dry, again dry granule is crossed Comil pelletizing machine granulate;

4) by after the mix lubricant of the dried particles after granulate and recipe quantity according to target patch weight sheet, control hardness;

5) Opadry is mixed with coating suspensions, and film coating is carried out to above-mentioned plain sheet.

Ticagrelor solid preparation energy fater disintegration provided by the invention, ensures the quick and complete stripping of medicine, improves the bioavailability of medicine; Solid preparation good stability provided by the invention simultaneously, convenient storage; The preparation method provided is simple, adopts the adjuvant of low cost, is conducive to reducing production cost, is suitable for suitability for industrialized production.

Detailed description of the invention

In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.

Reagent used in the present invention all can be buied from the market.

In the present invention, mg represents milligram, and g represents gram.

Prepared by embodiment 1 ticagrelor crystal form II

Ticagrelor crystal form II prepares according to prior art US Patent No. 7265124, and the ticagrelor crystal form II that following embodiment 2-embodiment 6 adopts is prepared by said method.

Embodiment 2 prescription and preparation technology

Component Every sheet content (mg) Ratio (%) 3000 tablet recipes amount (g) Ticagrelor crystal form II 90.0 30.0 270.0 Mannitol 36.0 12.0 108.0 Microcrystalline Cellulose 150.0 50.0 450.0 Carboxymethyl starch sodium 9.0 3.0 27.0 Hydroxypropyl cellulose 12.0 4.0 36.0 Magnesium stearate 3.0 1.0 9.0 Total amount 300.0 100.0 900.0 Opadry 9.0 3.0% of element sheet weight 27.0

Preparation method is as follows:

After the mannitol of recipe quantity, microcrystalline Cellulose, carboxymethyl starch sodium, hydroxypropyl cellulose and active component mix 10min in Glatt wet granulator, by peristaltic pump add account in add the purified water of supplementary material ratio 30% amount, the liquid feeding time is 5min.Liquid feeding terminates rear granulation 3min.

Wet granular is crossed Comil pelletizing machine granulate after granulation terminates.Wet granular after granulate is dry in GPCG fluid bed, and inlet temperature is set to 60 DEG C.Be dried to temperature of charge and reach 45 DEG C, and during dry materials weightlessness < 1.5%, stop dry.Dry granule is crossed Comil pelletizing machine granulate.

According to target patch weight sheet after being mixed with the magnesium stearate of recipe quantity by dried particles after granulate, hardness range is 50-130N.

Opadry is mixed with the suspension of 15%, and carries out film coating to above-mentioned plain sheet, coating weight gain is 3%.

Embodiment 3 prescription and preparation technology

Component Every sheet content (mg) Ratio (%) 3000 tablet recipes amount (g) Ticagrelor crystal form II 90.0 30.0 270.0 Mannitol 141.0 47.0 423.0 Microcrystalline Cellulose 48.0 16.0 144.0 Carboxymethyl starch sodium 9.0 3.0 27.0 Hydroxypropyl cellulose 9.0 3.0 27.0 Magnesium stearate 3.0 1.0 9.0 Total amount 300.0 100.0 900.0 Opadry 9.0 3.0% of element sheet weight 27.0

Preparation method is as follows:

After the mannitol of recipe quantity, microcrystalline Cellulose, carboxymethyl starch sodium, hydroxypropyl cellulose and active component mix 10min in Glatt wet granulator, by peristaltic pump add account in add the purified water of supplementary material ratio 26% amount, the liquid feeding time is 3min.Liquid feeding terminates rear granulation 2min.

Wet granular is crossed Comil pelletizing machine granulate after granulation terminates.Wet granular after granulate is dry in GPCG fluid bed, and inlet temperature is set to 60 DEG C.Be dried to temperature of charge and reach 45 DEG C, and during dry materials weightlessness < 1.5%, stop dry.Dry granule is crossed Comil pelletizing machine granulate.

According to target patch weight sheet after being mixed with the magnesium stearate of recipe quantity by dried particles after granulate, hardness range is 50-130N.

Opadry is mixed with the suspension of 15%, and carries out film coating to above-mentioned plain sheet, coating weight gain is 3%.

Embodiment 4 prescription and preparation technology

Component Every sheet content (mg) Ratio (%) 3000 tablet recipes amount (g) Ticagrelor crystal form II 90.0 30.0 270.0 Mannitol 120.0 40.0 360.0 Microcrystalline Cellulose 60.0 20.0 180.0 Carboxymethyl starch sodium 6.0 2.0 18.0 Hydroxypropyl cellulose 18.0 6.0 54.0

Magnesium stearate 6.0 2.0 18.0 Total amount 300.0 100.0 900.0 Opadry 9.0 3.0% of element sheet weight 27.0

Preparation method is as follows:

After the mannitol of recipe quantity, microcrystalline Cellulose, carboxymethylstach sodium, hyprolose and active component mix 10min in Glatt wet granulator, by peristaltic pump add account in add the purified water of supplementary material ratio 25% amount, the liquid feeding time is 5min.Liquid feeding terminates rear granulation 3min.

Wet granular is crossed Comil pelletizing machine granulate after granulation terminates.Wet granular after granulate is dry in GPCG fluid bed, and inlet temperature is set to 60 DEG C.Be dried to temperature of charge and reach 45 DEG C, and during dry materials weightlessness < 1.5%, stop dry.Dry granule is crossed Comil pelletizing machine granulate.

According to target patch weight sheet after being mixed with the magnesium stearate of recipe quantity by dried particles after granulate, hardness range is 50-130N.

Opadry is mixed with the suspension of 15%, and carries out film coating to above-mentioned plain sheet, coating weight gain is 3%.

Embodiment 5 prescription and preparation technology

Component Every sheet content (mg) Ratio (%) 3000 tablet recipes amount (g) Ticagrelor crystal form II 90.0 30.0 270.0 Mannitol 93.0 31.0 279.0 Microcrystalline Cellulose 93.0 31.0 279.0 Carboxymethyl starch sodium 9.0 3.0 27.0 Hydroxypropyl cellulose 9.0 3.0 27.0 Magnesium stearate 6.0 2.0 18.0 Total amount 300.0 100.0 900.0 Opadry 9.0 3.0% of element sheet weight 27.0

Preparation method is as follows:

After the mannitol of recipe quantity, microcrystalline Cellulose, carboxymethylstach sodium, hyprolose and active component mix 10min in Glatt wet granulator, by peristaltic pump add account in add the purified water of supplementary material ratio 20% amount, the liquid feeding time is 5min.Liquid feeding terminates rear granulation 3min.

Wet granular is crossed Comil pelletizing machine granulate after granulation terminates.Wet granular after granulate is dry in GPCG fluid bed, and inlet temperature is set to 60 DEG C.Be dried to temperature of charge and reach 45 DEG C, and during dry materials weightlessness < 1.5%, stop dry.Dry granule is crossed Comil pelletizing machine granulate.

According to target patch weight sheet after being mixed with the magnesium stearate of recipe quantity by dried particles after granulate, hardness range is 50-130N.

Opadry is mixed with the suspension of 15%, and carries out film coating to above-mentioned plain sheet, coating weight gain is 3%.

Embodiment 6 is with reference to preparation prescription and technique

Component Every sheet content (mg) Ratio (%) Ticagrelor crystal form II 90.0 30.0 Mannitol 126.0 42.0 Calcium phosphate dibasic dihydrate 63.0 21.0 Carboxymethyl starch sodium 9.0 3.0 Hydroxypropyl cellulose 9.0 3.0 Magnesium stearate 3.0 1.0 Total amount 300.0 100.00 Opadry 9.0 3.0% of element sheet weight

Preparation technology is with embodiment 5.

Embodiment 7 In Vitro Dissolution is tested

Each 6 of Example 2-embodiment 5 ticagrelor tablet, adopts dissolution method II method: paddle method, medium is 900mL, 0.1M HCl+0.2%Tween solution, records actual dissolution rate, the results are shown in following table 1.

Table 1. ticagrelor tablet stripping result (mean ± SD, n=6)

Discuss:

As can be seen from the above results, embodiment 2-embodiment 5 all maintains stripping faster after 10 minutes, and after 1 hour, stripping all reaches platform, meets the Fast Stripping requirement of medicine.

Embodiment 8 stability experiment

Two the annex XIXC medicine stability test guideline designs of laboratory reference " Chinese Pharmacopoeia " version in 2010.

Test item: dissolution, related substance and content.

Detection method: in stability, related substance detection method is HPLC method, this method is for checking related substance (maximum list is assorted and total assorted).

Accelerated test: relative humidity 75% put into by the reference preparation of the ticagrelor sheet and embodiment 6 of choosing the embodiment of the present invention 5, and temperature is that 40 DEG C of calorstats place 6 months, detects indices, the results are shown in Table 2 and table 3 in sampling in 1,2,3,6 month.

Table 2. Acceleration study (40 DEG C, 75%RH) stripping data

Table 3. related substance result

Discuss: table 2 and the display of table 3 result, this product maintains stripping faster in acceleration after 1-6 month, and stripping quantity is greater than 90%, is obviously better than with reference to preparation, and compares with reference to preparation stripping faster, and has with reference to preparation the trend slowed down in later stage stripping.Find out from single assorted and total assorted variation tendency, this product and the list with reference to preparation are mixed and are all had slight increase, always assortedly all to increase along with the increase of accelerated test time, and with reference to preparation always assorted increase trend be greater than this product.Draw from stripping and stability test interpretation of result, ticagrelor tablet of the present invention has stripping faster and good stability.

Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.

Claims (15)

1. a solid preparation for ticagrelor, comprises active constituents of medicine ticagrelor and diluent, and wherein said diluent is the combination of mannitol and microcrystalline Cellulose.
2. solid preparation according to claim 1, wherein, the part by weight of mannitol and microcrystalline Cellulose is 0.2:1 to 3:1.
3. solid preparation according to claim 1, wherein, ticagrelor exists with the form of crystal form II or crystal form II I substantially.
4. solid preparation according to claim 1, relative to tablet total weight amount, calculate according to percentage by weight, the weight of the ticagrelor comprised is 10%-50%, or weight is 25%-35%.
5. solid preparation according to claim 1, it also comprises binding agent, disintegrating agent and lubricant.
6. solid preparation according to claim 5, relative to tablet total weight amount, calculate according to percentage by weight, comprise binding agent 2%-6%, disintegrating agent 2%-6% and lubricant 0.5%-2%, or comprise binding agent 3%-6%, disintegrating agent 2%-4% and lubricant 1%-2%.
7. solid preparation according to claim 5, wherein, described binding agent is hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methylcellulose, polyethylene glycol 6000, arabic gum or its combination.
8. solid preparation according to claim 5, wherein, described disintegrating agent is cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, dried starch or its combination.
9. solid preparation according to claim 5, wherein, described lubricant is magnesium stearate, calcium stearate, sodium lauryl sulphate, titanium dioxide, Pulvis Talci, micropowder silica gel or its combination.
10. solid preparation according to claim 5, it comprises coating further, and described coating material is selected from hydroxypropyl methylcellulose or Opadry, and wherein coating material is 1%-4% relative to the percentage by weight of plain sheet.
11. solid preparations according to any one of claim 1-10, calculate according to percentage by weight, it comprises:
1) ticagrelor 10%-50%,
2) mannitol 10%-55%,
3) microcrystalline Cellulose 16%-50%,
4) carboxymethyl starch sodium 2%-6%,
5) hydroxypropyl cellulose 2%-6%,
6) magnesium stearate 0.5%-2%.
12. solid preparations according to any one of claim 1-10, calculate according to percentage by weight, it comprises:
1) ticagrelor 25%-35%,
2) mannitol 15%-45%,
3) microcrystalline Cellulose 15%-40%,
4) carboxymethyl starch sodium 2%-4%,
5) hydroxypropyl cellulose 3%-6%,
6) magnesium stearate 1%-2%.
13. solid preparations according to claim 1, wherein, described solid preparation is tablet.
14. solid preparations according to claim 1, wherein, the content of ticagrelor in per unit dose solid preparation is 50 mg-300 mg.
15. 1 kinds of methods preparing solid preparation as claimed in claim 1, comprising:
1) ticagrelor of recipe quantity, diluent, binding agent and disintegrating agent after mix homogeneously, add appropriate purified water by peristaltic pump and granulate in wet granulator;
2) wet granular made is crossed Comil pelletizing machine granulate;
3) wet granular after granulate is dry in fluid bed, inlet temperature is set to 50-70 DEG C, during dried material loss on drying < 1.5%, stops dry, again dry granule is crossed Comil pelletizing machine granulate;
4) by after the mix lubricant of the dried particles after granulate and recipe quantity according to target patch weight sheet, control hardness;
5) Opadry is mixed with coating suspensions, and film coating is carried out to above-mentioned plain sheet.
CN201510136454.6A 2014-03-27 2015-03-26 Ticagrelor solid preparation and preparation method thereof CN104940204A (en)

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