WO2021197451A1

WO2021197451A1 - Multiple formulation of ticagrelor

Info

Publication number: WO2021197451A1
Application number: PCT/CN2021/085154
Authority: WO
Inventors: 张强; 陈昊; 曹秀秀; 何花; 王捷; 卢韵
Original assignee: 江苏恒瑞医药股份有限公司
Priority date: 2020-04-02
Filing date: 2021-04-02
Publication date: 2021-10-07
Also published as: TW202143972A

Abstract

A multiple formulation for once-a-day administration of ticagrelor or a pharmaceutically acceptable salt thereof, said multiple formulation comprising an immediate-release multiple unit portion and a sustained-release multiple unit portion, the immediate-release multiple unit portion consisting of separate immediate-release units and the sustained-release multiple unit portion consisting of separate sustained-release units, each unit comprising the multiple formulation having a maximum diameter of less than 5.0 mm.

Description

A multivariate preparation of ticagrelor

Technical field

A multi-component preparation containing ticagrelor or its pharmaceutically acceptable salt for once-a-day administration belongs to the field of pharmacy.

Background technique

Ticagrelor tablet is an immediate-release preparation produced by AstraZeneca. Its mechanism of action is a platelet aggregation inhibitor, which can reversibly interact with platelet P2Y12ADP receptors and block signal transduction and platelet activation. It needs to be combined with aspirin It is used in patients with acute coronary syndrome, patients with a history of myocardial infarction, or patients at high risk of atherosclerotic thrombotic events to reduce the incidence of thrombotic cardiovascular events.

The marketed specifications of ticagrelor are 90mg and 60mg. The first dose of ticagrelor is 180mg, the maintenance dose is 90mg, twice a day. After one year, ticagrelor (60mg, one day) Twice) to prevent cardiovascular events. Since the marketed immediate-release preparations need to be taken twice a day, patients who missed taking ticagrelor during long-term medication are likely to cause acute thrombosis and lead to the risk of myocardial infarction or stroke. Therefore, it is necessary to develop a once-a-day sustained-release preparation to reduce the number of patients taking it, thereby improving medication compliance, and further reducing the risk of myocardial infarction or stroke caused by acute thrombosis caused by missed medication.

CN106074357A discloses a once-a-day formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, wherein the formulation exhibits the following characteristics after being administered to a subject in need of its treatment: a ) In a subject, a plasma concentration of ticagrelor greater than about 0.2 μg/mL can be reached within 2 hours; and b) In a subject, a plasma concentration of ticagrelor greater than about 0.2 μg/mL can be reached after 12 hours. mL of the plasma concentration of ticagrelor; and c) the maximum plasma concentration of ticagrelor or a pharmaceutically acceptable salt thereof that produces between about 0.2 μg/mL and about 0.8 μg/mL in a subject (Cmax).

CN110507624A discloses a controlled-release preparation of ticagrelor, which solves the problem of incomplete release of the sustained-release component after the formulation is enlarged in batches in CN106074357A by adding sodium carboxymethyl cellulose to the sustained-release component.

Summary of the invention

The present disclosure provides a multi-component preparation for once-a-day administration, which comprises ticagrelor or a pharmaceutically acceptable salt thereof. The maximum diameter of the unit is less than 5.0mm, optionally less than 3.0mm, and optionally less than 2.5mm.

In an alternative embodiment, the maximum diameter of each unit constituting the multi-component formulation is 0.1-5.0 mm, optionally 0.5-3.0 mm, optionally 1-2.5 mm.

In an alternative embodiment, the immediate-release multi-unit part of the multi-component preparation provided in the present disclosure is composed of a plurality of independent immediate-release units, the number of units is ≥3, optional ≥4, and optional ≥5.

In an alternative embodiment, the sustained-release multi-unit part of the multi-component formulation provided by the present disclosure is composed of a plurality of independent sustained-release units, the number of units is ≥5, optional ≥8, and optional ≥10.

In an alternative embodiment, the content of ticagrelor or its pharmaceutically acceptable salt in the multi-component preparation taken by the patient in a single dose is taken by the patient daily

1-1.2 times the content of ticagrelor.

In an alternative embodiment, the content of ticagrelor or its pharmaceutically acceptable salt in one or two multi-component preparations is taken by the patient daily

1-1.2 times the content of ticagrelor.

The multi-component preparation provided by the present disclosure, taking the multi-component preparation once a day and the patient taking it orally twice a day

The effect of bioequivalence (prototype drug).

The bioequivalence evaluation of chemical pharmaceutical preparations usually adopts the average bioequivalence (Average bioequivalence, ABE) method. The equivalence standard is the ratio of the geometric mean of the main pharmacokinetic parameters (AUC and Cmax) of the test preparation and the reference preparation The 90% confidence interval falls within the range of 80.00%-125.00%.

The CV value refers to the coefficient of variation, the RSD value refers to the relative standard deviation, and the CV value of inter-individual differences, that is, the RSD. In this disclosure, the RSD value is used to represent the size of individual differences.

_{Specifically, the RSD value of AUC 0-t} of the multi-component preparation provided in the present disclosure is less than 42, optionally less than 40, and optionally less than 38. _{The RSD value of AUC 0-∞} of the multi-component preparation provided in the present disclosure is less than 40, optionally less than 38, optionally less than 36; the RSD value of the Cmax of the multi-component preparation provided in the present disclosure is less than 44, optionally less than 42, and optionally less than 40 .

_{In an alternative embodiment, the RSD value of the AUC 0-t} of the multi-component formulation provided in the present disclosure is less than 42, optionally less than 40, optionally less than 38; the RSD value of the Cmax of the multi-component formulation provided in the present disclosure is less than 44, optionally Less than 42, optional less than 40.

In an alternative embodiment, in the multi-component formulation provided by the present disclosure, any sustained-release unit contains a drug-containing core and a sustained-release material coating layer.

In an optional embodiment, the sustained-release material is selected from ethyl cellulose, sodium alginate, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, Sodium carboxymethyl cellulose, chitin, galactomannan, povidone, polyvinyl alcohol.

In an optional embodiment, the sustained-release material is selected from acrylic resins, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS) , Cellulose acetate phthalate (CAP), polyvinyl phthalate (PVAP), cellulose acetate trimellitate (CAT) one or more of enteric materials.

In an optional embodiment, in the multi-component formulation provided by the present disclosure, any sustained-release unit contains a core and a coating layer of a sustained-release material, and the sustained-release material is selected from acrylic resins, hydroxypropyl methylcellulose Intestines of one or more of phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, polyvinyl phthalate, and cellulose acetate trimellitate The coating layer of the soluble material and the sustained-release material is the coating layer of the enteric material.

In an alternative embodiment, in the multi-component preparation provided by the present disclosure, any sustained-release unit contains a core and an enteric material coating layer, and the enteric material is selected from acrylic resins, such as Udtech L100, Udtech One or more of S100 and Utraki L30D-55.

In an alternative embodiment, in the multi-component formulation provided by the present disclosure, any sustained-release unit contains a core and an enteric material coating layer, and the enteric material is Udage L100.

In an optional embodiment, in the multi-component formulation provided by the present disclosure, the weight of the coating layer of the sustained-release material is 1%-50% of the total weight of the core, and optionally 10%-35% (mass percentage).

In the multi-component preparation provided by the present disclosure, the immediate release unit and/or sustained release unit are selected from granules, pellets or microtablets, and microtablets are optional.

In an alternative embodiment, the multi-component formulation provided by the present disclosure, wherein the content of ticagrelor or ticagrelor pharmaceutically acceptable salt in terms of ticagrelor is 45 mg-220 mg.

In an optional embodiment, the content of ticagrelor or a pharmaceutically acceptable salt of ticagrelor in the multi-component formulation is 60 mg, 90 mg, 100 mg, 108 mg, 120 mg, 133 mg, 144 mg, 180 mg , 200mg or 216mg.

In an optional embodiment, the content of ticagrelor or a pharmaceutically acceptable salt of ticagrelor in the multi-component formulation is 100 mg, 108 mg, 133 mg, 144 mg, 200 mg or 216 mg. .

The multi-component preparation provided by the present disclosure, wherein the weight ratio of ticagrelor or its salt in the immediate-release multi-unit part and the sustained-release multi-unit part is 1:0.5-1:10, and 1:1-1:8 can be selected. Choose 1:2.

In the multi-component preparation provided by the present disclosure, the immediate-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and at least one auxiliary material optionally selected from diluents, binders, disintegrants, and lubricants.

In an optional embodiment, the content of ticagrelor or its pharmaceutically acceptable salt in the immediate-release unit is 5%-60% of the total weight of the immediate-release unit, optionally 10%-50%, and optionally 20%. %-45% (mass percentage).

In an optional embodiment, the diluent of the immediate release unit is selected from one of lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Several kinds, optional mannitol and dibasic calcium phosphate.

In an optional embodiment, the content of the diluent in the immediate-release unit is 10%-80% of the total weight of the immediate-release unit, optional 30%-70%, optional 45%-75% (mass percentage) .

In an optional embodiment, the binder of the immediate release unit is selected from one or more of polyvinylpyrrolidone, starch, carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, Optional hydroxypropyl cellulose.

In an optional embodiment, the content of the binder in the immediate-release unit is 0.1%-20% of the total weight of the immediate-release unit, optionally 1%-10% (mass percentage).

In an optional embodiment, the disintegrant of the immediate release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, One or more of pregelatinized starch, which can be sodium carboxymethyl starch or croscarmellose sodium.

In an optional embodiment, the content of the disintegrant in the immediate-release unit is 0.1%-20% of the total weight of the immediate-release unit, optionally 1%-10% (mass percentage).

In an optional embodiment, the lubricant of the immediate release unit is selected from one of magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, calcium stearate, micronized silica gel, and sodium stearate fumarate Or several, optional magnesium stearate.

In an optional embodiment, the content of the lubricant in the immediate-release unit is 0.1%-10% of the total weight of the immediate-release unit, optionally 1%-5% (mass percentage).

In the multi-component preparation provided by the present disclosure, the sustained-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and at least one auxiliary material optionally selected from diluents, disintegrants, glidants, and lubricants.

In an optional embodiment, the content of ticagrelor or its pharmaceutically acceptable salt in the sustained-release unit is 5%-70% of the total weight of the sustained-release core, optionally 10%-45% (mass percentage) .

In an optional embodiment, the diluent of the sustained-release unit is selected from one or more of lactose, microcrystalline cellulose, mannitol, and dibasic calcium phosphate, and microcrystalline cellulose is optional.

In an optional embodiment, the content of the diluent in the sustained-release unit is 1%-80% of the total weight of the sustained-release core, optionally 5%-60% (mass percentage).

In an optional embodiment, the disintegrant of the sustained-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, One or more kinds of pregelatinized starch, croscarmellose sodium can be selected.

In an optional embodiment, the content of the disintegrant in the sustained-release unit is 1%-35% of the total weight of the sustained-release core, optionally 5%-25% (mass percentage).

In an optional embodiment, the glidant of the sustained-release unit is selected from talc or silicon dioxide, and silicon dioxide is optional.

In an optional embodiment, the content of the glidant in the sustained-release unit is 0.1%-15% of the total weight of the sustained-release core, optionally 0.5%-5% (mass percentage).

In an optional embodiment, the lubricant of the sustained-release unit is selected from one or more of magnesium stearate, calcium stearate, glyceryl behenate, and hydrogenated vegetable oil, and magnesium stearate can be selected.

In an optional embodiment, the content of the lubricant in the sustained-release unit is 0.1%-15% of the total weight of the sustained-release core, optionally 0.5%-5% (mass percentage).

In an optional embodiment, in the multi-component formulation provided by the present disclosure, ticagrelor or a pharmaceutically acceptable salt thereof in the sustained-release unit is selected from povidone, copovidone, polyethylene glycol, and poloxamer. , Acrylic resin, hydroxypropyl methyl cellulose or a mixture thereof into a solid dispersion, and the carrier may be copovidone. The weight ratio of ticagrelor or its salt to the carrier is 1:0.2 to 5, optional 1:0.5 to 2, and optional 1:1.

The solid dispersion described in the present disclosure can be prepared by conventional processes, such as solvent method, melting method, solid phase deposition evaporation method, ball mill grinding, spray drying method, hot melt extrusion method, and the like. In the present disclosure, a spray drying method can be selected to prepare the solid dispersion, that is, the drug and the carrier are dissolved in a suitable solvent, and then the organic solvent is removed by spray drying to obtain the solid dispersion. Wherein, the solvent is selected from absolute ethanol, acetone, ethyl acetate, dichloromethane, etc., and further optional solvent in the present disclosure is absolute ethanol.

In an alternative embodiment, the multi-component formulation provided by the present disclosure is a capsule.

In an optional embodiment, in the multi-component formulation provided by the present disclosure, the sustained-release unit is composed as follows:

Core (based on the total weight of the core)

Ticagrelor 10%-45% (mass percentage);

Copovidone 10%-45% (mass percentage);

Microcrystalline cellulose 5%-60% (mass percentage);

Croscarmellose sodium 5%-25% (mass percentage);

Micro-powder silica gel 0.5%-5% (mass percentage);

Magnesium stearate 0.5%-5% (mass percentage);

In addition, it contains 15%-35% (mass percentage) of the slow-release material coating of the total weight of the core.

In an alternative embodiment, the multi-component formulation provided by the present disclosure has the following composition:

Quick release unit (based on the total weight of the quick release unit):

Ticagrelor 20%-45% (mass percentage);

Mannitol 20%-60% (mass percentage);

Calcium hydrogen phosphate 10%-45% (mass percentage);

Sodium carboxymethyl starch 1%-10% (mass percentage);

Hydroxypropyl cellulose 1%-10% (mass percentage);

Magnesium stearate 1%-5% (mass percentage);

Sustained release unit

Core (based on the total weight of the sustained-release unit core)

Ticagrelor 10%-45% (mass percentage);

Copovidone 10%-45% (mass percentage);

Microcrystalline cellulose 5%-60% (mass percentage);

Croscarmellose sodium 5%-25% (mass percentage);

Micro-powder silica gel 0.5%-5% (mass percentage);

Magnesium stearate 0.5%-5% (mass percentage);

In an alternative embodiment, Opadry is selected for the coating of the sustained-release material.

The multi-component preparations provided in the present disclosure were tested in accordance with the release test method (Chinese Pharmacopoeia 2015 Edition IV 0931 Method 2). First, 750 mL of 0.2% Tween pH 1.0 was used as the dissolution medium, and after 2 hours, 250 mL of anhydrous phosphoric acid was added. The adjustment medium of sodium solution is 0.2% Tween pH6.8, and then the release degree is measured by UV-Vis spectrophotometry, not less than 10% of the total content, 20% optional; 12 hours release not less than 80% of the total content , Optional 85%, optional 90%.

With the multi-component preparation provided by the present disclosure, the plasma drug concentration peak time Tmax in the patient after a single oral administration is 4-12 hours after self-administration.

In an alternative embodiment, the patient takes orally a multi-component preparation containing 200 mg of ticagrelor or ticagrelor pharmaceutically acceptable salts in a single oral dose, and C _2h and C _12h are both greater than 200 ng/mL.

The present disclosure provides a use of the above-mentioned multi-component preparation in the preparation of drugs for preventing or treating myocardial infarction, thrombosis, stroke, transient ischemic attack and/or peripheral vascular disease, unstable or stable angina pectoris, and platelet aggregation disease.

In an alternative embodiment, the present disclosure provides a use of the aforementioned multi-component preparation in the preparation of a medicament for the prevention or treatment of acute coronary syndrome.

The present disclosure provides a method for treating acute coronary syndrome, which includes administering the above-mentioned multi-component preparation to a patient.

The present disclosure provides a method for preparing the above-mentioned multi-component preparation, which includes the step of wet granulating ticagrelor or its pharmaceutically acceptable salt and at least one of the auxiliary materials in the immediate-release unit and then compressing the tablet.

In an alternative embodiment, the method for preparing multiple formulations provided in the present disclosure includes 1) adding ticagrin

The step of dry granulation of the solid dispersion of Luo or its pharmaceutically acceptable salt and at least one of the auxiliary materials in the sustained-release unit, followed by tablet compression, and 2) the step of coating the sustained-release material.

In an alternative embodiment, the method for preparing a multi-component preparation provided in the present disclosure includes the step of filling granules, pellets, microtablets, etc. into capsules according to effective doses.

Because the marketed immediate-release preparations need to be administered twice a day, patients who missed taking ticagrelor during long-term medication may easily cause acute thrombosis and lead to the risk of myocardial infarction or stroke. The multi-component preparations administered once a day provided in the present disclosure It can reduce the frequency of taking, thereby improving the compliance of patients with medication, and reducing the risk of myocardial infarction or stroke caused by acute thrombosis caused by missed medication.

The present disclosure provides a method for reducing the risk of a patient's myocardial infarction or stroke by administering the multi-component preparation provided by the present disclosure to the patient.

The present disclosure provides a method for reducing the individual variability of medication patients, including administering the multiple formulations provided in the present disclosure to patients in need of treatment. The multi-component preparation provided by the present disclosure provides more uniform absorption of ticagrelor or its pharmaceutically acceptable salt and provides smaller pharmacokinetic distribution fluctuations between and within individuals.

In the present disclosure, those preparations composed of many small units contained in, for example, capsules, such as granules, pellets, or microtablets, are named multi-component preparations.

The pharmacokinetic parameters involved in this disclosure are data obtained from a group of individuals, specifically, the area under the plasma concentration-time curve (AUC0-t) from zero to t, and the plasma concentration-time from zero to infinite time The area under the curve (AUC0- _∞ ) and the maximum plasma concentration (Cmax) use GeoLSM (the value is equivalent to the geometric mean), the Tmax is the median, the plasma concentration at 2 hours (C _2h ), at 12 hours The blood drug concentration (C _12h ) is the arithmetic mean.

The maximum diameter in the present disclosure is understood to mean that the average diameter of the smallest unit is in the range of 0.1-5.0 mm.

Detailed ways

The present disclosure can be further described through the following specific examples, but they do not limit the content of the present disclosure.

Example 1. Preparation and dissolution test of ticagrelor capsules

Preparation method of immediate-release microtablets: mix ticagrelor with mannitol, calcium hydrogen phosphate, sodium carboxymethyl starch, and hydroxypropyl cellulose, then wet granulate, mix with magnesium stearate, and press φ2mm), you can;

The preparation method of enteric-coated sustained-release microtablets: Dissolve ticagrelor and copovidone in absolute ethanol, and spray-dry them to prepare a solid dispersion of ticagrelor; combine the solid dispersion of ticagrelor and the micro After mixing crystalline cellulose, croscarmellose sodium, and micronized silica gel, dry granulation is carried out, and after total mixing with magnesium stearate, tableting (punching die φ2mm), film coating premix (enteric-coated type) ) For coating, that's it;

The immediate-release microtablets and the enteric-coated sustained-release microtablets are filled into the capsules according to a certain ratio to prepare the ticagrelor sustained-release capsules.

Table 1. Prescription composition

2. Dissolution test

The sustained-release capsules were subjected to the dissolution test according to the release test method (Chinese Pharmacopoeia 2015 Edition Sibu 0931 Second Method). First, 750mL of 0.2% Tween pH1.0 was used as the dissolution medium, and after 2h, 250mL of anhydrous sodium phosphate solution was added. The adjustment medium is 0.2% Tween pH 6.8, and then the release degree is measured by ultraviolet-visible spectrophotometry. The results are shown in Table 2.

Table 2. Capsule release results in different media

It can be seen from the above data that the immediate-release part of the sustained-release capsule can dissolve quickly in the medium, and the enteric-coated part begins to slowly release after 2 hours of adding lye, and the cumulative release of the drug is above 90% by 12 hours.

Example 2. Pharmacokinetic data test

The prescriptions in the above examples were performed to analyze the relationship between in vitro release and pharmacokinetics (PK) of human pharmacokinetics (blood drug concentration), and to explore the in vivo and in vitro correlation of ticagrelor.

A randomized, crossover, single-center, and controlled trial study was conducted on healthy volunteers with different prescriptions. The study evaluated the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects (8 subjects). In this study, the prescription of the present invention is 180 mg and 200 mg once a day, and the commercially available immediate-release preparation is 90 mg twice a day. Collect plasma samples to determine the blood concentration of ticagrelor and platelet inhibition. The samples were analyzed by HPLC/MS/MS.

Table 3. Pharmacokinetic parameters of prescription 1

Table 4. Pharmacokinetic parameters of prescription 2

Comparative example,

The prescription 6 in the example of CN110507624A was tested for pharmacokinetic data (8 healthy subjects), and the specific values are shown in Table 5.

Table 5. Pharmacokinetic parameters

From the above data, it can be seen that the preparation composed of φ2mm microtablets has the characteristics of slow-release kinetics, and compared with the preparation of φ6.0mm, the individual variability is significantly reduced.

Claims

A multi-component preparation for once-a-day administration, comprising ticagrelor or a pharmaceutically acceptable salt thereof. The multi-component preparation contains an immediate-release multi-unit part and a sustained-release multi-unit part. The sustained-release multi-unit part is composed of independent sustained-release units, and the maximum diameter of each unit constituting the multi-component preparation is less than 5.0 mm, preferably less than 3.0 mm, and most preferably less than 2.5 mm.
The multi-component preparation according to claim 1, wherein the content of ticagrelor or its pharmaceutically acceptable salt in the multi-component preparation taken by the patient daily is the same as that of Belinda taken by the patient daily.
1-1.2 times the content of ticagrelor.
The multi-component preparation according to claim 1, wherein the content of ticagrelor or its pharmaceutically acceptable salt in one or two multi-component preparations is the same as that of Belinda taken by the patient daily.
1-1.2 times the content of ticagrelor.
The multi-component preparation according to any one of claims 2 or 3, wherein the patient takes the multi-component preparation once a day and the patient takes Belinda twice a day.
Bioequivalent.
The multi-component preparation according to claim 1, wherein any sustained-release unit contains a drug-containing core and a coating layer of sustained-release material.
The multi-component preparation according to claim 5, wherein the sustained-release material is selected from the group consisting of ethyl cellulose, sodium alginate, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and hydroxypropyl ethyl Cellulose, sodium carboxymethyl cellulose, chitin, galactomannan, povidone, polyvinyl alcohol, and selected from acrylic resins, hydroxypropyl methyl cellulose phthalate, hydroxy acetate Enteric materials of one or more of propyl methyl cellulose succinate, cellulose acetate phthalate, polyvinyl phthalate, and cellulose acetate trimellitate, preferably acrylic resins, hydroxy One of propyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, polyvinyl phthalate, cellulose acetate trimellitate One or more types, most preferably acrylic resins, particularly preferably one or more of Eudragit L100, Eudragit S100, and Eudragit L30D-55.
The multi-component formulation according to claim 5, wherein the weight of the coating of the sustained-release material is 1%-50% of the total weight of the core, preferably 10%-35%.
The multi-component formulation according to any one of claims 1-7, wherein the immediate release unit and/or sustained release unit are selected from granules, pellets or microtablets, preferably microtablets.
The multi-component preparation according to claim 8, wherein the content of ticagrelor or ticagrelor pharmaceutically acceptable salt in terms of ticagrelor is 45mg-220mg, preferably 60mg, 90mg, 100mg, 108mg, 120mg, 133mg , 144mg, 180mg, 200mg or 216mg, most preferably 100mg, 108mg, 133mg, 144mg, 200mg or 216mg.
The multi-component formulation according to any one of claims 8 or 9, wherein the weight ratio of ticagrelor or its salt in the immediate-release multi-unit part and the sustained-release multi-unit part is 1:0.5-1:10, preferably 1: 1-1:8, most preferably 1:2.
The multi-component preparation according to claim 6, wherein the immediate-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and at least one excipient optionally selected from diluents, binders, disintegrants, and lubricants .
The multi-component formulation of claim 11, wherein the diluent of the immediate-release unit is selected from lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate One or more, preferably a mixture of mannitol and dibasic calcium phosphate.
The multi-component preparation according to claim 11, wherein the binder of the immediate-release unit is selected from one of polyvinylpyrrolidone, starch, carboxymethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Several kinds, preferably hydroxypropyl cellulose.
The multi-component formulation according to claim 11, wherein the disintegrant of the immediate-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked poly One or more of vinylpyrrolidone and pregelatinized starch, preferably sodium carboxymethyl starch or croscarmellose sodium.
The multi-component preparation according to claim 11, wherein the lubricant of the immediate release unit is selected from magnesium stearate, glyceryl behenate, hydrogenated vegetable oil, calcium stearate, micronized silica gel, and sodium stearate fumarate One or more of them, preferably magnesium stearate.
The multi-component formulation according to claim 11, wherein the sustained-release unit contains ticagrelor or a pharmaceutically acceptable salt thereof and at least one auxiliary material selected from diluents, disintegrants, glidants, and lubricants .
The multi-component formulation according to claim 16, wherein the diluent of the sustained-release unit is selected from lactose, starch, pregelatinized starch, mannitol, microcrystalline cellulose, glucose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate One or more, preferably microcrystalline cellulose.
The multi-component formulation according to claim 17, wherein the disintegrant of the sustained-release unit is selected from the group consisting of croscarmellose sodium, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked poly One or more of vinylpyrrolidone and pregelatinized starch, preferably croscarmellose sodium.
The multi-component formulation according to claim 17, wherein the glidant of the sustained-release unit is selected from talc or silicon dioxide, preferably silicon dioxide.
The multi-component formulation according to claim 17, wherein the lubricant of the sustained-release unit is selected from one or more of magnesium stearate, calcium stearate, glyceryl behenate, and hydrogenated vegetable oil, preferably stearic acid magnesium.
The multi-component preparation according to claim 8, wherein ticagrelor or its pharmaceutically acceptable salt in the sustained-release unit is selected from povidone, copovidone, polyethylene glycol, poloxamer, acrylic resin The carrier of hydroxypropyl methylcellulose or its mixture is a solid dispersion, and the carrier is preferably copovidone.
The multi-component preparation according to any one of claims 1-21, which is a capsule.
The multi-component preparation according to claim 22, the sustained-release unit is composed as follows:

Core (based on the total weight of the core)

Ticagrelor 10%-45%;

Copovidone 10%-45%;

Microcrystalline cellulose 5%-60%;

Croscarmellose sodium 5%-25%;

Micro-powder silica gel 0.5%-5%;

Magnesium stearate 0.5%-5%;

It also contains 1%-50% of the total core weight of the sustained-release material coating.
The multi-component preparation according to claim 23, which has the following composition:

Quick release unit (based on the total weight of the quick release unit):

Ticagrelor 20%-45%;

Mannitol 20%-60%;

Calcium hydrogen phosphate 10%-45%;

Sodium carboxymethyl starch 1%-10%;

Hydroxypropyl cellulose 1%-10%;

Magnesium stearate 1%-5%;

Sustained release unit

Core (based on the total weight of the sustained-release unit core)

Ticagrelor 10%-45%;

Copovidone 10%-45%;

Microcrystalline cellulose 5%-60%;

Croscarmellose sodium 5%-25%;

Micro-powder silica gel 0.5%-5%;

Magnesium stearate 0.5%-5%;

It also contains 1%-50% of the total core weight of the sustained-release material coating.
The multi-component formulation according to any one of claims 1-24, the maximum diameter of each unit constituting the multi-component formulation is 0.1-5.0 mm, preferably 0.5-3.0 mm, most preferably 1-2.5 mm.
The multi-component formulation according to any one of claims 1-25, wherein the number of units of the immediate-release multi-unit in each multi-component formulation is ≥3, preferably ≥4, most preferably ≥5; the number of units of the sustained-release multi-unit ≥5, preferably ≥8, most preferably ≥10.
The multi-component preparation according to any one of claims 1-26, the dissolution test is carried out in accordance with the release determination method (Chinese Pharmacopoeia 2015 Edition Four Part 0931 Method 2), first using 750 mL of 0.2% Tween pH 1.0 as the dissolution medium, After 2 hours, add 250 mL of anhydrous sodium phosphate solution to adjust the medium to 0.2% Tween pH 6.8, and then measure the release degree by ultraviolet-visible spectrophotometry, which is not less than 10% of the total content, preferably 20%; 12 hours does not release Less than 80% of the total content, preferably 85%, most preferably 90%.
According to the multi-component preparation according to any one of claims 1-26, the plasma drug concentration peak time Tmax in the patient's body after a single oral administration is 4-12 hours after self-administration.
The multi-component preparation according to any one of claims 1-26, the RSD value of AUC0-t is less than 42, preferably less than 40, and most preferably less than 38.
According to the multi-component formulation of claim 29, the RSD value of Cmax is less than 44, preferably less than 42, and most preferably less than 40.
The multi-component preparation according to any one of claims 1-26, the patient contains 200 mg of ticagrelor or ticagrelor as the ticagrelor salt in a single oral administration, and C 2h and C 12h are both greater than 200 ng/mL .
A method for preparing the multi-component preparation of any one of claims 1-26, comprising the step of wet granulating ticagrelor or its pharmaceutically acceptable salt with at least one of the auxiliary materials in the immediate-release unit and then compressing the tablet.
The method for preparing a multi-component preparation according to claim 32, comprising: 1) dry granulation of a solid dispersion of ticagrelor or its pharmaceutically acceptable salt and at least one of the auxiliary materials in the sustained-release unit and then press the tablet into a core Step, 2) the step of coating the sustained-release material.
The multi-component preparation according to any one of claims 1-26 is used in the preparation of drugs for the prevention or treatment of myocardial infarction, thrombosis, stroke, transient ischemic attack and/or peripheral vascular disease, unstable or stable angina pectoris, platelet aggregation disease In the use.
A method for reducing the risk of myocardial infarction or stroke in a patient by administering the multi-component preparation according to any one of claims 1-26 to the patient once a day.
A method for reducing the variability between individual patients taking medication, comprising administering the multi-component preparation according to any one of claims 1-26 to patients in need of treatment.