CN108078944A - Solid composite containing ticagrelor and preparation method thereof - Google Patents

Solid composite containing ticagrelor and preparation method thereof Download PDF

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Publication number
CN108078944A
CN108078944A CN201611025315.7A CN201611025315A CN108078944A CN 108078944 A CN108078944 A CN 108078944A CN 201611025315 A CN201611025315 A CN 201611025315A CN 108078944 A CN108078944 A CN 108078944A
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CN
China
Prior art keywords
ticagrelor
solid composite
diluent
lubricant
disintegrant
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Application number
CN201611025315.7A
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Chinese (zh)
Inventor
叶敏
罗礼平
刘小伟
商露
陈波
朱月伟
肖玉梅
廖兴婷
勾娟
Original Assignee
重庆植恩药业有限公司
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Priority to CN201611025315.7A priority Critical patent/CN108078944A/en
Publication of CN108078944A publication Critical patent/CN108078944A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

The invention discloses the solid composite containing ticagrelor, the component of weight percent is:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%, disintegrant 2% ~ 8%, lubricant 0.5% ~ 5%, wherein, adhesive is hydroxypropyl methylcellulose.In addition, additionally provide the preparation method of the solid composite for containing ticagrelor:Bulk pharmaceutical chemicals crush, mixing, granulation, dry, total mixed, tabletting and coating.The ticagrelor piece dissolution rate of the present invention is high, and single impurity and total impurities content are lower, and stability is high, it is ensured that product quality.

Description

Solid composite containing ticagrelor and preparation method thereof

Technical field

The invention belongs to field of pharmaceutical preparations, and in particular to solid composite containing ticagrelor and preparation method thereof.

Background technology

Ticagrelor is a kind of new, selective small molecule anticoagulant.The medicine invertibity vasoactive Smooth muscle cell(VSMC)On 2 receptor subtype P2Y12 of purine, have apparent inhibitory action to platelet aggregation caused by ADP, And it is rapid to work after being administered orally, therefore can effectively improve the symptom of acute coronary patient.

Ticagrelor is developed by Astrazeneca AB, English name:Ticagrelor, chemical name:(1S,2S,3R,5S)- 3-[7-{[(1R,2S) -2- (3,4- difluorophenyls) ring third] amino -5- (thiopropyl) -3H- [1,2,3]-triazole [4,5-d] phonetic Pyridine -3- bases] -5- (2- hydroxyl-oxethyls) pentamethylene -1,2- glycol, structural formula is:

The ticagrelor dosage form listed at present be tablet, specification be 90mg and 60mg, trade name " Brilique ".For lattice Rui Luo is insoluble drug, at room temperature solubility in water be 10 μ g/mL, Biopharmaceutics Classification system(BCS)For IV class: Low-solubility, hypotonicity.Therefore, it is necessary to screen the bulk pharmaceutical chemicals of appropriate particle size, auxiliary material and preparation process to have ticagrelor piece There are better dissolution rate and homogeneity.

In addition, import commercially available product(Trade name:Times Linda, specification:90mg)Single impurity and total impurities are larger, are placing The possibility of limit is had more than in journey.

The content of the invention

The present invention provides the solid composites containing ticagrelor, improve for the auspicious dissolution rate of lattice and homogeneity, single A impurity and total impurities are smaller, and stability is good, it is ensured that the security of product;Meanwhile preparation method provided by the invention, technique letter It is single, securely and reliably, it can be mass-produced.

The object of the present invention is to provide the solid composites containing ticagrelor.

It is a further object of the present invention to provide the preparation methods of the solid composite containing ticagrelor.

Technical solution of the present invention is as follows:

In one embodiment of the present invention, the present invention provides the solid composite containing ticagrelor, described contains The solid weight composition percent composition of ticagrelor is:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%th, disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;Wherein, the adhesive is hydroxypropyl methylcellulose.

In embodiments of the invention, the solid composite containing ticagrelor is orally available tablet;More preferably Ground, the solid composite containing ticagrelor are the orally available tablet of coating.

In a kind of preferred embodiment of the present invention, the present invention provides the solid composite containing ticagrelor, In, the solid weight composition percent composition containing ticagrelor is:Ticagrelor 20% ~ 50%, diluent 40% ~ 70%th, adhesive 2% ~ 6%, disintegrant 2% ~ 6% and lubricant 0.5% ~ 3%;Wherein, the adhesive is hydroxypropyl methylcellulose.

In a kind of more preferred of the present invention, the present invention provides the solid composite containing ticagrelor, Wherein, the solid weight composition percent composition containing ticagrelor is:Ticagrelor 20% ~ 40%, diluent 50% ~ 70%, adhesive 2% ~ 4%, disintegrant 2% ~ 5% and lubricant 1% ~ 2%;Wherein, the adhesive is hydroxypropyl methylcellulose.

In the solution of the present invention, the present invention provides the solid composite containing ticagrelor, wherein, the dilution The one kind of agent in Parteck deltaM, microcrystalline cellulose PH101, starch, Icing Sugar, calcium phosphate dibasic dihydrate, pregelatinized starch Or several, preferably Parteck deltaM, calcium phosphate dibasic dihydrate and microcrystalline cellulose PH101.

In the solution of the present invention, the present invention provides the solid composite containing ticagrelor, wherein, the disintegration The one kind or several of agent in croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxyrnethyl starch sodium Kind, preferably carboxyrnethyl starch sodium.

In the solution of the present invention, the present invention provides the solid composite containing ticagrelor, wherein, the lubrication Agent includes one or more of magnesium stearate, Compritol 888 ATO, talcum powder, superfine silica gel powder, preferably magnesium stearate.

In a kind of preferred embodiment of the present invention, the present invention provides the solid composite containing ticagrelor, it Component containing following weight percents:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%, disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;

Here, the diluent is selected from Parteck deltaM, microcrystalline cellulose PH101, starch, Icing Sugar, two hypophosphite monohydrate hydrogen One kind in calcium, pregelatinized starch and more than;Adhesive is selected from hydroxypropyl methylcellulose;Disintegrant is selected from cross-linked carboxymethyl cellulose Sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxyrnethyl starch sodium;Lubricant include magnesium stearate, Compritol 888 ATO, Talcum powder, superfine silica gel powder.

In the solution of the present invention, the present invention provides the solid composite containing ticagrelor, wherein, described contains The solid weight composition percent composition of ticagrelor is:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%th, disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;

Here, the diluent is selected from Parteck deltaM, calcium phosphate dibasic dihydrate and microcrystalline cellulose PH101;Described adhesive Selected from hydroxypropyl methylcellulose;The disintegrant is selected from carmethose;The lubricant is selected from magnesium stearate.

In a kind of preferred embodiment of the present invention, the present invention provides the solid composite containing ticagrelor, it Component containing following weight percents:Ticagrelor 20% ~ 50%, diluent 40% ~ 70%, adhesive 2% ~ 6%, disintegrant 2% ~ 6% and lubricant 0.5% ~ 3%;

Here, one kind in Parteck deltaM, calcium phosphate dibasic dihydrate and microcrystalline cellulose PH101 of the diluent and More than, adhesive is selected from hydroxypropyl methylcellulose, disintegrant is selected from carboxyrnethyl starch sodium, lubricant is selected from magnesium stearate.

In a kind of preferred embodiment of the present invention, the present invention provides the solid composite containing ticagrelor,

It contains the component of following weight percents:Ticagrelor 20% ~ 40%, diluent 50% ~ 70%, adhesive 2% ~ 4%, disintegration Agent 2% ~ 5% and lubricant 1% ~ 2%.The diluent is selected from Parteck deltaM, calcium phosphate dibasic dihydrate and microcrystalline cellulose One kind in PH101 and more than;Adhesive is selected from hydroxypropyl methylcellulose, disintegrant is selected from carboxyrnethyl starch sodium, lubricant is selected from firmly Fatty acid magnesium.

The present invention provides the solid composite containing ticagrelor, the solid composite containing ticagrelor is Thin membrane coated tablet, the coating material used is Opadry full formula thin film coating system, and using water as solvent, it contains following group Part:Hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talcum powder.

On the other hand, the present invention provides the preparation method of the above-mentioned solid composite containing ticagrelor, including following Step:

(1)By ticagrelor air-flow crushing, granularity is measured with Malvern particle size analyzer(Wet method, D9050 μm of <), obtain micro mist The ticagrelor of change;

(2)By weight proportion, by the ticagrelor, diluent, disintegrant of micronizing in mixer, stirring at low speed mixing 5 ~ 10 Minute, obtain dry-mixed powder;

(3)Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh nylon mesh Net)Granulation, obtains wet granular;

(4)Wet granular is dried under the conditions of 50 ~ 60 DEG C, drying terminates particle crushed 40 mesh sieves, obtains intermediate products 1;

(5)The lubricant of intermediate products 1 and weight ratio is added in mixer to mix 15 ~ 20 minutes, obtains intermediate products 2;

(6)Intermediate products 2 are subjected to tabletting, slice, thin piece 7 ~ 10kg of hardness is controlled, obtains ticagrelor plain piece.

In embodiments of the invention, the preparation side of the above-mentioned solid composite containing ticagrelor provided by the invention Method further comprises the following steps after ticagrelor plain piece is obtained:

By the plain piece with 8%(w/w)Coating solution is coated, and it is 2% ~ 4% to control coating weight gain, obtains ticagrelor piece.

In the solid composite preparation method provided by the invention containing ticagrelor, wherein, described contains for lattice The solid weight composition percent composition of auspicious Lip river is:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%, Disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;Wherein, the adhesive is hydroxypropyl methylcellulose.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the solid weight composition percent composition containing ticagrelor is:Ticagrelor 20% ~ 50%, diluent 40% ~ 70%, adhesive 2% ~ 6%, disintegrant 2% ~ 6% and lubricant 0.5% ~ 3%;Wherein, the adhesive is hypromellose Element.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the solid weight composition percent composition containing ticagrelor is:Ticagrelor 20% ~ 40%, diluent 50% ~ 70%, adhesive 2% ~ 4%, disintegrant 2% ~ 5% and lubricant 1% ~ 2%.The diluent is selected from Parteck deltaM, two water Close calcium monohydrogen phosphate and one kind in microcrystalline cellulose PH101 and more than;Wherein, the adhesive is hydroxypropyl methylcellulose.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the disintegrant is selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, carboxylic first One or more of sodium starch, preferably carboxyrnethyl starch sodium.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the lubricant includes one or more of magnesium stearate, Compritol 888 ATO, talcum powder, superfine silica gel powder, It is preferred that magnesium stearate.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the solid composite of ticagrelor of the invention, it contains the component of following weight percents:Ticagrelor 10% ~ 60%th, diluent 30% ~ 80%, adhesive 1% ~ 10%, disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;

Here, the diluent be selected from Parteck deltaM, microcrystalline cellulose PH101, starch, Icing Sugar, calcium phosphate dibasic dihydrate, Pregelatinized starch;Described adhesive is selected from hydroxypropyl methylcellulose;The disintegrant is selected from croscarmellose sodium, crosslinking gathers Tie up ketone, low-substituted hydroxypropyl cellulose, carboxyrnethyl starch sodium;The lubricant is selected from magnesium stearate, Compritol 888 ATO, talcum Powder, superfine silica gel powder.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the solid weight composition percent composition containing ticagrelor is:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%, disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;

Here, the diluent is selected from Parteck deltaM, calcium phosphate dibasic dihydrate and microcrystalline cellulose PH101, adhesive and is selected from Hydroxypropyl methylcellulose, disintegrant are selected from carboxyrnethyl starch sodium, lubricant is selected from magnesium stearate.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the solid composite of ticagrelor of the invention, it contains the component of following weight percents:Ticagrelor 20% ~ 50%th, diluent 40% ~ 70%, adhesive 2% ~ 6%, disintegrant 2% ~ 6% and lubricant 0.5% ~ 3%;

Here, the diluent is selected from Parteck deltaM/and microcrystalline cellulose PH101 calcium phosphate dibasic dihydrates, and adhesive is selected from Hydroxypropyl methylcellulose, disintegrant are selected from carboxyrnethyl starch sodium, lubricant is selected from magnesium stearate.

In the solid composite preparation method provided by the invention containing ticagrelor, as one kind side of being preferably implemented Case, wherein, the solid composite of ticagrelor of the invention, it contains the component of following weight percents:Ticagrelor 20% ~ 40%th, diluent 50% ~ 70%, hydroxypropyl methylcellulose 2% ~ 4%, carboxyrnethyl starch sodium 2% ~ 5%, magnesium stearate 1% ~ 2%.The diluent One kind in Parteck deltaM, calcium phosphate dibasic dihydrate and microcrystalline cellulose PH101 and more than;Adhesive is selected from hydroxypropyl Methylcellulose.

The ticagrelor piece of the present invention and commercially available ticagrelor piece(Trade name:Times Linda)It compares, dissolution rate higher, One property is more preferable, and single impurity and total impurities are lower, and product stability is more preferable.

Specific embodiment:

The present invention is described in further details with reference to embodiment, but not limited to this.

Embodiment 1:It is prepared with 20,000 tablet recipe amounts

Product prescription:

Ticagrelor 1200g Parteck deltaM 2550g Calcium phosphate dibasic dihydrate 1650g Hydroxypropyl methylcellulose 240g Carboxyrnethyl starch sodium 300g Magnesium stearate 60g In batches 20000

Preparation process:

1st, the crushing of bulk pharmaceutical chemicals:By ticagrelor air-flow crushing to granularity(D90)It is auspicious for lattice after being crushed less than 50 μm Lip river;

2nd, mix:By ticagrelor, Parteck deltaM, calcium phosphate dibasic dihydrate, the hydroxypropyl methylcellulose after the crushing of recipe quantity It is mixed with carboxyrnethyl starch sodium in postposition wet granulator, stirring at low speed stirs 5 minutes, obtains dry-mixed powder;

3rd, pelletize:Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh Buddhist nuns Imperial sieve)Granulation, obtains wet granular;

4th, it is dry:By wet granular when drying 2 is small under the conditions of 50 ~ 60 DEG C, particle be crushed into 40 mesh sieves after drying, in obtaining Between product 1;

5th, it is total mixed:Intermediate products 1 and recipe quantity magnesium stearate are added in mixer to mix 15 minutes, obtain intermediate products 2;

6th, tabletting:Piece weight is determined according to intermediate products 2, and the loading amount for adjusting tablet press machine carries out tabletting, the tableting processes control sheet method of double differences It is different(±5%)And hardness(7~10kg), ticagrelor plain piece is made;

7th, it is coated:By plain piece with 8%(w/w)Coating solution(Opadry full formula thin film coating system)It is coated, control coating It increases weight as 2% ~ 4%, obtains ticagrelor piece.

Above-mentioned production process strict implement China drug's GMP specification, strict implement technological procedure and operating instruction, strictly hold Row clean operation regulation.

The granularity of bulk pharmaceutical chemicals after being crushed in embodiment 1 is measured, to ticagrelor piece and import commercially available product(Commodity Name:Times Linda, specification:90mg)It carries out hot test and high wet test carries out stability comparison.

The particle size detection method of the crushing of above-mentioned raw materials medicine is laser scattering method(Wet method), testing result is shown in Table 1;Above-mentioned two Kind preparation is placed 10 days under the conditions of 60 DEG C of high temperature and high humidity RH75% and sampled, to emphasis index(Character, related substance, dissolution rate And content)It is detected, detection method is import standard.Testing result is shown in Table 2.

Raw material powder degree measurement result in 1 embodiment 1 of table

2 embodiment 1 of table and times Linda's Detection of Stability result

Embodiment 2:It is prepared with 20,000 tablet recipe amounts

Product prescription:

Ticagrelor 1200g Parteck deltaM 2640g Calcium phosphate dibasic dihydrate 1560g Hydroxypropyl methylcellulose 180g Carboxyrnethyl starch sodium 300g Magnesium stearate 120g In batches 20000

Preparation process:

1st, the crushing of bulk pharmaceutical chemicals:By ticagrelor air-flow crushing to granularity(D90)It is auspicious for lattice after being crushed less than 50 μm Lip river;

2nd, mix:By ticagrelor, Parteck deltaM, microcrystalline cellulose pH101, the hypromellose after the crushing of recipe quantity In element and carboxyrnethyl starch sodium mixing postposition wet granulator, stirring at low speed stirs 5 minutes, obtains dry-mixed powder;

3rd, pelletize:Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh Buddhist nuns Imperial sieve)Granulation, obtains wet granular;

4th, it is dry:By wet granular when drying 2 is small under the conditions of 50 ~ 60 DEG C, particle be crushed into 40 mesh sieves after drying, in obtaining Between product 1;

5th, it is total mixed:Intermediate products 1 and recipe quantity magnesium stearate are added in mixer to mix 15 minutes, obtain intermediate products 2;

6th, tabletting:Piece weight is determined according to intermediate products 2, and the loading amount for adjusting tablet press machine carries out tabletting, the tableting processes control sheet method of double differences It is different(±5%)And hardness(7~10kg), ticagrelor plain piece is made;

7th, it is coated:By plain piece with 8%(w/w)Coating solution(Opadry full formula thin film coating system)It is coated, control coating It increases weight as 2% ~ 4%, obtains ticagrelor piece.

The granularity of bulk pharmaceutical chemicals after being crushed in embodiment 2 is measured, to ticagrelor piece and import commercially available product(Commodity Name:Times Linda, specification:90mg)It carries out hot test and high wet test carries out stability comparison.

The particle size detection method of the crushing of above-mentioned raw materials medicine is laser scattering method(Wet method), testing result is shown in Table 3;Above-mentioned two Kind preparation is placed 10 days under the conditions of 60 DEG C of high temperature and high humidity RH75% and sampled, to emphasis index(Character, related substance, dissolution rate And content)It is detected, detection method is import standard (standard No.:JX20110193).Testing result is shown in Table 4.

Raw material powder degree measurement result in 3 embodiment 2 of table

4 embodiment 2 of table and times Linda's Detection of Stability result

Embodiment 3:It is prepared with 20,000 tablet recipe amounts

Product prescription:

Ticagrelor 1800g Parteck deltaM 2460g Calcium phosphate dibasic dihydrate 1290g Hydroxypropyl methylcellulose 120g Carboxyrnethyl starch sodium 240g Magnesium stearate 90g In batches 20000

Preparation process:

1st, the crushing of bulk pharmaceutical chemicals:By ticagrelor air-flow crushing to granularity(D90)It is auspicious for lattice after being crushed less than 50 μm Lip river;

2nd, mix:By ticagrelor, Parteck deltaM, calcium phosphate dibasic dihydrate, the hydroxypropyl methylcellulose after the crushing of recipe quantity It is mixed with carboxyrnethyl starch sodium in postposition wet granulator, stirring at low speed stirs 5 minutes, obtains dry-mixed powder;

3rd, pelletize:Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh Buddhist nuns Imperial sieve)Granulation, obtains wet granular;

4th, it is dry:By wet granular when drying 2 is small under the conditions of 50 ~ 60 DEG C, particle be crushed into 40 mesh sieves after drying, in obtaining Between product 1;

5th, it is total mixed:Intermediate products 1 and recipe quantity magnesium stearate are added in mixer to mix 15 minutes, obtain intermediate products 2;

6th, tabletting:Piece weight is determined according to intermediate products 2, and the loading amount for adjusting tablet press machine carries out tabletting, the tableting processes control sheet method of double differences It is different(±5%)And hardness(7~10kg), ticagrelor plain piece is made;

7th, it is coated:By plain piece with 8%(w/w)Coating solution(Opadry full formula thin film coating system)It is coated, control coating It increases weight as 2% ~ 4%, obtains ticagrelor piece.

The granularity of bulk pharmaceutical chemicals after being crushed in embodiment 3 is measured, to ticagrelor piece and import commercially available product(Commodity Name:Times Linda, specification:90mg)It carries out hot test and high wet test carries out stability comparison.

The particle size detection method of the crushing of above-mentioned raw materials medicine is laser scattering method(Wet method), testing result is shown in Table 5;Above-mentioned two Kind preparation is placed 10 days under the conditions of 60 DEG C of high temperature and high humidity RH75% and sampled, to emphasis index(Character, related substance, dissolution rate And content)It is detected, detection method is import standard (standard No.:JX20110193).Testing result is shown in Table 6.

Raw material powder degree measurement result in 5 embodiment 3 of table

6 embodiment 3 of table and times Linda's Detection of Stability result

Embodiment 4:It is prepared with 20,000 tablet recipe amounts

Product prescription:

Ticagrelor 1800g Parteck deltaM 2490g Calcium phosphate dibasic dihydrate 1410g Hydroxypropyl methylcellulose 120g Carboxyrnethyl starch sodium 120g Magnesium stearate 60g In batches 20000

Preparation process:

1st, the crushing of bulk pharmaceutical chemicals:By ticagrelor air-flow crushing to granularity(D90)It is auspicious for lattice after being crushed less than 50 μm Lip river;

2nd, mix:By ticagrelor, Parteck deltaM, calcium phosphate dibasic dihydrate, the hydroxypropyl methylcellulose after the crushing of recipe quantity It is mixed with carboxyrnethyl starch sodium in postposition wet granulator, stirring at low speed stirs 5 minutes, obtains dry-mixed powder;

3rd, pelletize:Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh Buddhist nuns Imperial sieve)Granulation, obtains wet granular;

4th, it is dry:By wet granular when drying 2 is small under the conditions of 50 ~ 60 DEG C, particle be crushed into 40 mesh sieves after drying, in obtaining Between product 1;

5th, it is total mixed:Intermediate products 1 and recipe quantity magnesium stearate are added in mixer to mix 15 minutes, obtain intermediate products 2;

6th, tabletting:Piece weight is determined according to intermediate products 2, and the loading amount for adjusting tablet press machine carries out tabletting, the tableting processes control sheet method of double differences It is different(±5%)And hardness(7~10kg), ticagrelor plain piece is made;

7th, it is coated:By plain piece with 8%(w/w)Coating solution(Opadry full formula thin film coating system)It is coated, control coating It increases weight as 2% ~ 4%, obtains ticagrelor piece.

The granularity of bulk pharmaceutical chemicals after being crushed in embodiment 4 is measured, to ticagrelor piece and import commercially available product(Commodity Name:Times Linda, specification:90mg)It carries out hot test and high wet test carries out stability comparison.

The particle size detection method of the crushing of above-mentioned raw materials medicine is laser scattering method(Wet method), testing result is shown in Table 7;Above-mentioned two Kind preparation is placed 10 days under the conditions of 60 DEG C of high temperature and high humidity RH75% and sampled, to emphasis index(Character, related substance, dissolution rate And content)It is detected, detection method is import standard (standard No.:JX20110193).Testing result is shown in Table 8.

Raw material powder degree measurement result in 7 embodiment 4 of table

8 embodiment 4 of table and times Linda's Detection of Stability result

Embodiment 5:It is prepared with 20,000 tablet recipe amounts

Product prescription:

Ticagrelor 2400g Parteck deltaM 1920g Calcium phosphate dibasic dihydrate 1080g Hydroxypropyl methylcellulose 240g Carboxyrnethyl starch sodium 300g Magnesium stearate 60g In batches 20000

Preparation process:

1st, the crushing of bulk pharmaceutical chemicals:By ticagrelor air-flow crushing to granularity(D90)It is auspicious for lattice after being crushed less than 50 μm Lip river;

2nd, mix:By ticagrelor, Parteck deltaM, calcium phosphate dibasic dihydrate, the hydroxypropyl methylcellulose after the crushing of recipe quantity It is mixed with carboxyrnethyl starch sodium in postposition wet granulator, stirring at low speed stirs 5 minutes, obtains dry-mixed powder;

3rd, pelletize:Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh Buddhist nuns Imperial sieve)Granulation, obtains wet granular;

4th, it is dry:By wet granular when drying 2 is small under the conditions of 50 ~ 60 DEG C, particle be crushed into 40 mesh sieves after drying, in obtaining Between product 1;

5th, it is total mixed:Intermediate products 1 and recipe quantity magnesium stearate are added in mixer to mix 15 minutes, obtain intermediate products 2;

6th, tabletting:Piece weight is determined according to intermediate products 2, and the loading amount for adjusting tablet press machine carries out tabletting, the tableting processes control sheet method of double differences It is different(±5%)And hardness(7~10kg), ticagrelor plain piece is made;

7th, it is coated:By plain piece with 8%(w/w)Coating solution(Opadry full formula thin film coating system)It is coated, control coating It increases weight as 2% ~ 4%, obtains ticagrelor piece.

The granularity of bulk pharmaceutical chemicals after being crushed in embodiment 5 is measured, to ticagrelor piece and import commercially available product(Commodity Name:Times Linda, specification:90mg)It carries out hot test and high wet test carries out stability comparison.

The particle size detection method of the crushing of above-mentioned raw materials medicine is laser scattering method(Wet method), testing result is shown in Table 9;Above-mentioned two Kind preparation is placed 10 days under the conditions of 60 DEG C of high temperature and high humidity RH75% and sampled, to emphasis index(Character, related substance, dissolution rate And content)It is detected, detection method is import standard (standard No.:JX20110193).Testing result is shown in Table 10.

Raw material powder degree measurement result in 9 embodiment 5 of table

10 embodiment 5 of table and times Linda's Detection of Stability result

Result above shows that the ticagrelor piece of preparation of the invention impurity more single than times Linda and total impurities are small;High temperature and High humidity stability result shows that the single impurity of ticagrelor piece of the invention and total impurities are lower than Linda again.Illustrate the present invention The obtained ticagrelor piece of composition and preparation method thereof than commercially available times of Linda stable quality.

Solid composite containing ticagrelor of the present invention and preparation method thereof, sharpest edges are ticagrelor piece Single impurity, total impurities compare commercially available product(Times Linda)It is small, and stability is good, it is ensured that the security of this product.

Claims (7)

1. the solid composite containing ticagrelor as claimed in claim 1, the component of weight percent are:Ticagrelor 10% ~ 60%, diluent 30% ~ 80%, adhesive 1% ~ 10%, disintegrant 2% ~ 8% and lubricant 0.5% ~ 5%;Wherein, it is described viscous Mixture is selected from hydroxypropyl methylcellulose.
2. according to the solid composite of claims 1, wherein, ticagrelor 20% ~ 50%, diluent 40% ~ 70%, adhesive 2% ~ 6%, disintegrant 2% ~ 6% and lubricant 0.5% ~ 3%.
3. the solid composite as any one of claims 1 or 2, wherein the diluent is selected from mannitol 200SD, microcrystalline cellulose PH101, starch, Icing Sugar, calcium phosphate dibasic dihydrate, pregelatinized starch;Preferably, it is mannitol 200SD, calcium phosphate dibasic dihydrate and microcrystalline cellulose PH101.
4. the solid composite as any one of claims 1 or 2, wherein the disintegrant is selected from cross-linked carboxymethyl Sodium cellulosate, crospovidone, low-substituted hydroxypropyl cellulose, carboxyrnethyl starch sodium;Preferably, it is carboxyrnethyl starch sodium.
5. the solid composite as any one of claims 1 or 2, wherein the lubricant be selected from magnesium stearate, Compritol 888 ATO, talcum powder, superfine silica gel powder;Preferably, it is magnesium stearate.
6. the solid composite containing ticagrelor, the component of weight percent are:Ticagrelor 20% ~ 40%, diluent 50% ~ 70%th, hydroxypropyl methylcellulose 2% ~ 4%, carboxyrnethyl starch sodium 2% ~ 5%, magnesium stearate 1% ~ 2%.
7. the preparation method of the solid composite containing ticagrelor, comprises the following steps described in claims 1:
(1)By ticagrelor air-flow crushing, granularity is measured with Malvern particle size analyzer(Wet method, D9050 μm of <), obtain micro mist The ticagrelor of change;
(2)By weight proportion, by the ticagrelor, diluent, disintegrant of micronizing in mixer, stirring at low speed mixing 5 ~ 10 Minute, obtain dry-mixed powder;
(3)Purified water is added in dry-mixed powder under stirring at low speed, softwood processed;By softwood oscillating granulator(16 mesh nylon mesh Net)Granulation, obtains wet granular;
(4)Wet granular is dried under the conditions of 50 ~ 60 DEG C, drying terminates particle crushed 40 mesh sieves, obtains intermediate products 1;
(5)The lubricant of intermediate products 1 and weight ratio is added in mixer to mix 15 ~ 20 minutes, obtains intermediate products 2;
(6)Intermediate products 2 are subjected to tabletting, slice, thin piece 7 ~ 10kg of hardness is controlled, obtains ticagrelor plain piece.
CN201611025315.7A 2016-11-22 2016-11-22 Solid composite containing ticagrelor and preparation method thereof CN108078944A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104940204A (en) * 2014-03-27 2015-09-30 广东东阳光药业有限公司 Ticagrelor solid preparation and preparation method thereof
CN105832683A (en) * 2015-01-15 2016-08-10 成都国弘医药有限公司 Tablet containing ticagrelor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104940204A (en) * 2014-03-27 2015-09-30 广东东阳光药业有限公司 Ticagrelor solid preparation and preparation method thereof
CN105832683A (en) * 2015-01-15 2016-08-10 成都国弘医药有限公司 Tablet containing ticagrelor

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* Cited by examiner, † Cited by third party
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方亮: "《药剂学》", 31 March 2016, 中国医药科技出版社 *

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