CN111450072B

CN111450072B - Ticagrelor controlled release tablet and preparation method thereof

Info

Publication number: CN111450072B
Application number: CN202010386979.6A
Authority: CN
Inventors: 舒欣; 董海红; 陈磊; 陆平波
Original assignee: Jiangsu Ailikang Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Ailikang Pharmaceutical Technology Co ltd
Priority date: 2020-05-07
Filing date: 2020-05-09
Publication date: 2022-07-15
Anticipated expiration: 2040-05-09
Also published as: CN111450072A; WO2021223480A1

Abstract

The invention provides a ticagrelor controlled release tablet and a preparation method thereof, wherein the controlled release tablet comprises a tablet core and a membrane-controlled coating system, the tablet core comprises ticagrelor accounting for 30-60 wt% of the total weight of the tablet core, and the controlled release tablet is provided with more than two drug release holes. The ticagrelor controlled release tablet provided by the invention is mild and lasting in release, can be basically and completely released in 20 hours, can have a good release effect on ticagrelor with different crystal forms, is stable in performance, can be stored for a long time, is simple in preparation process, and is suitable for industrial production.

Description

Ticagrelor controlled release tablet and preparation method thereof

Technical Field

The invention relates to a ticagrelor oral controlled release preparation and a preparation method thereof.

Background

Ticagrelor is a novel selective anticoagulant, is also the first reversible binding type P2Y12 adenosine diphosphate receptor (ADP) antagonist, can reversibly act on a purine 2 receptor subtype P2Y12 on Vascular Smooth Muscle Cells (VSMC), has obvious inhibition effect on platelet aggregation caused by ADP, can effectively improve the symptoms of patients with acute coronary heart disease, and has a chemical structure shown as formula I:

ticagrelor is an oral anti-platelet aggregation drug developed by AstraZeneca (AstraZeneca) and approved for marketing by the european union 12 months 2010 with the trade name Brilique, us FDA approved for marketing 7 months 2011, and in 2016 in japan. The clinical curative effect and safety of the clopidogrel are obviously superior to those of clopidogrel, so that the clopidogrel is recommended by a plurality of domestic and foreign guidelines, and the recommended level of the ticagrelor is recommended by the European guidelines in two years before the clopidogrel, so that patients who cannot take the ticagrelor can use the clopidogrel.

Ticagrelor is rapidly absorbed after oral administration, and has a median T_maxAbout 1.5 hours. Since ticagrelor is a non-prodrug and directly acts on a P2Y12 receptor, the main circulating metabolite ARC124910XX can be rapidly generated without being activated by liver metabolism. The medicament and the metabolite thereof have activity, so the medicament not only can quickly and strongly inhibit ADP-mediated platelet aggregation, but also has effectiveness not influenced by the polymorphism of the liver CYP2C19 gene. The pharmacokinetics of ticagrelor were linear (within 1260mg dose), and ticagrelor and active metabolite (ARC124910XX) exposure were substantially proportional to dose. Although ticagrelor showed superiority over clopidogrel in clinical studies, a significant disadvantage is the mean T of ticagrelor_1/2About 7 hours, the active metabolite was 9 hours, each less than 12 hours, so the dose of ticagrelor and active metabolite decreased to half after 12 hours, so it was administered twice a day.

Correlation of pharmacokinetic and pharmacodynamic data for ticagrelor has been reported in the literature and studies have shown that maintaining a certain plasma concentration level of ticagrelor provides platelet inhibition rates of 90% or greater. The blood concentration of the current marketed quick-release preparation fluctuates obviously, and in order to reduce the peak blood concentration, the marketed dosage can only maintain the drug effect for 12 hours, and the twice-daily administration is required to ensure the curative effect of the drug. For a rapidly reversible drug, too high a dose increases the incidence of Ventricular pause (venticular pauss), while missed doses may result in too low a blood level which is likely to increase the risk of acute thrombosis in the patient, resulting in myocardial infarction or stroke.

Ticagrelor is a white or off-white to light pink powder. Log P (n-octanol/water) at pH7.4 is around 4.5. The solubility of the compound is not influenced by pH in a physiological pH environment between pH1.0 and pH7.4, is about 10 mu g/ml, and belongs to an insoluble drug; the study showed that the product has a permeability of about 51% in vivo, which is medium permeability, but less than 90%, which is BCSIV (low solubility and low permeability). The dose of a conventional formulation of ticagrelor was 90mg twice a day. If a once-a-day controlled release formulation is designed, the dose is 180mg and the dose number (dose number) is 72 based on biological dosimetry. Generally, the formulation products with the number of doses of oral drugs exceeding 20 are difficult to develop, and the controlled release formulation products thereof are more difficult to develop.

Patent CN101505754A discloses a composition suitable for oral administration comprising triazolo [4,5-d ] pyrimidine derivatives, said pharmaceutical composition comprising ticagrelor and other pharmaceutically acceptable excipients. The original preparation which is sold on the market at present is prepared by adopting the examples in the patent, and the auxiliary materials comprise: mannitol, calcium hydrogen phosphate dihydrate, hydroxypropyl cellulose, sodium starch glycolate and magnesium stearate, wherein the preparation adopts a wet granulation process, and the specification is 90 mg.

The patent CN102657629A discloses a ticagrelor controlled release tablet system and a preparation method thereof, in the invention, a matrix type controlled release tablet is prepared by controlling the particle size of the raw material drug, simultaneously mixing with a certain amount of high molecular polymer and performing wet granulation. However, since ticagrelor is insoluble in water, the high molecular polymer can further retard drug release, and is not suitable for preparing controlled release preparations of insoluble drugs. Patent CN103860504A provides a ticagrelor sustained-release preparation for oral administration, which is prepared into matrix type controlled-release tablets, controlled-release coated tablets, controlled-release pellet capsules by adding a matrix material or by a coating technology, and describes a method for evaluating the release degree and determining the release degree, but does not disclose the release degree results of each example.

Patents CN103520164A and CN105998026A relate to controlled release preparations comprising ticagrelor, medicinal controlled release materials and other medicinal excipients. The controlled release preparation is divided into a quick release part and a controlled release part, can be a double-layer tablet pressed by a double-layer tablet press, or a tablet taking a controlled release medicine as a tablet core and taking a quick release medicine as an outer coating, or a controlled release capsule consisting of quick release and controlled release pellets. Patent CN103520164A also relates to the use of beta-cyclodextrin inclusion to improve drug solubility and improve bioavailability. The controlled release preparation of the invention can lead the medicine to take effect quickly, can maintain the effective concentration of the medicine for a long time and has more ideal treatment effect, but the technical prescription process is complex, needs high-end equipment such as a double-layer tablet press or a double-station capsule filling agent and the like, and is not beneficial to large-scale production.

Patent CN108210498A discloses a breakable ticagrelor controlled release preparation, which is suitable for once-a-day oral administration, and simultaneously the tablet can achieve the effect of quick drug release after being damaged, the tablet core adopts the same prescription as the original patent, and a controlled release layer, an enteric layer and a drug-containing layer are respectively coated on the outer layer, the technology is very complex, the whole procedure time is long, and the large-scale production is not facilitated.

The Ticagrelor is an insoluble drug, the solubility of the Ticagrelor needs to be improved and the bioavailability needs to be improved when the controlled release preparation is prepared, the dosage of the designed controlled release preparation is large, the beta-cyclodextrin inclusion or solid dispersion technology is adopted, the required dosage of the beta-cyclodextrin or solid solvent is 1-10 times of the weight of the active ingredient, and the preparation size of the product is overlarge, which is obviously unsuitable. Osmotic pump formulations of poorly soluble drugs generally employ a bi-chambered osmotic pump formulation, i.e., consisting of a drug layer and a push layer, typically a drug layer: the weight ratio of the push layer is 1: 2-1: 3, so that the expected size of the preparation cannot be achieved, and the double-chamber osmotic pump preparation is more suitable for small-dose insoluble medicines. Therefore, there is a need to develop a controlled release formulation suitable for large dose of poorly soluble drug ticagrelor to achieve a desired stable slow release rate.

Meanwhile, the existing ticagrelor preparation has the defects of too high release speed, short duration, incomplete release, multiple daily administration times, large dosage, incapability of keeping consistent release effect on ticagrelor with different crystal forms, instability, incapability of long-term storage, complex preparation process and inconvenience for industrial mass production.

Disclosure of Invention

Problems to be solved by the invention

In order to solve the technical problems, the invention provides a ticagrelor controlled release tablet which is mild and durable in release, can release completely in 20 hours basically, has a good release effect on ticagrelor with different crystal forms, is stable in performance, can be stored for a long time, is simple in preparation process, and is suitable for industrial production.

Means for solving the problems

In order to solve the technical problems, the invention provides a ticagrelor controlled release tablet which comprises a tablet core and a membrane controlled coating system, wherein the tablet core comprises 30-60 wt% of ticagrelor based on the total weight of the tablet core, and the controlled release tablet is provided with more than two drug release holes.

Preferably, the tablet core further comprises a penetration enhancer and an osmotic pressure active agent.

Preferably, the content of the ticagrelor is 150-200 mg, and the particle size is less than 50 mu m.

Preferably, the film-control coating system comprises a film-forming material and a plasticizer, wherein the film-forming material accounts for 1-30% of the controlled release tablet by mass, and the plasticizer accounts for 0.1-10% of the controlled release tablet by mass. More preferably, the film forming material is selected from one or more of cellulose acetate, ethyl cellulose and polyacrylic resin, and preferably is cellulose acetate; the plasticizer is selected from one or more of polyethylene glycol, oleic acid and triethyl citrate, and preferably polyethylene glycol.

Preferably, the penetration enhancer is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, non-cellulose polysaccharide, polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose and salts thereof, alginic acid and salts thereof, polyoxyethylene and hydroxymethyl cellulose, and preferably is hydroxyethyl cellulose.

Preferably, the osmotic pressure active agent is selected from sugar osmotic pressure active agents and/or salt osmotic pressure active agents, the sugar osmotic pressure active agents are selected from one or more of mannitol, xylitol, glucose, sorbitol, fructose, sucrose and starch oligomeric pond, and sorbitol is preferred; the salt osmotic pressure active agent is one or a mixture of more than two of sodium chloride, potassium chloride, sulfate and phosphate.

Preferably, the tablet core further comprises a binder and a lubricant, wherein the binder is one or more selected from cellulose ether, polyvinylpyrrolidone and hydroxypropyl methyl cellulose succinate, and is preferably copovidone; the lubricant is one or more selected from stearic acid, magnesium stearate and calcium stearate, and preferably magnesium stearate.

Preferably, the drug release holes are positioned on the front surface, the back surface or the side surface of the controlled release tablet, and only one drug release hole is arranged on the same surface, and the aperture of the drug release hole is 0.3-1.2 mm.

Preferably, the controlled release tablet is a ticagrelor single-chamber osmotic pump controlled release tablet.

The invention also provides a preparation method of the ticagrelor controlled release tablet, which comprises the following steps:

(1) uniformly mixing ticagrelor, penetration enhancer, osmotic pressure promoter and adhesive, adding ethanol or alcohol water solution to prepare soft material, drying, granulating, adding lubricant, mixing, and tabletting to obtain a medicine tablet core;

(2) preparing semipermeable membrane coating liquid containing a film forming material and a plasticizer by taking an acetone-water solution as a coating solvent, and spraying the coating liquid onto the medicine tablet core obtained in the step (1) to form a coated tablet;

(3) and (4) aging the coated tablet, and performing laser drilling to obtain the finished product.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention adopts a single-chamber osmotic pump technology, controls the speed of water entering a tablet core through a membrane control coating system, and after the water enters the tablet core, the osmotic pressure inside the tablet core is higher than the external medium environment after the osmotic pressure promoter absorbs water, so that the osmotic pressure difference is generated, the permeation of the water is further promoted, the osmotic pressure promoter absorbs water and expands, the medicine forms a suspension to be pushed out from a medicine release hole, and the medicine release is controlled. Because the dosage of the controlled release preparation related to the invention is larger, the design of multiple drug release holes is adopted, the complete release of the drug is ensured as far as possible, and the overlarge osmotic pressure in the tablet core is relieved, so that the coating film can be prevented from cracking.

Meanwhile, the ticagrelor controlled release tablet provided by the invention is mild and durable in release, can be basically and completely released in 20 hours, can have a good release effect on ticagrelor with different crystal forms, is stable in performance, can be stored for a long time, is simple in preparation process, and is suitable for industrial production.

Drawings

Fig. 1X-ray powder diffraction pattern of form i ticagrelor;

figure 2 an X-ray powder diffraction pattern of form ii ticagrelor;

figure 3 an X-ray powder diffraction pattern of form iii ticagrelor;

figure 4 is an X-ray powder diffraction pattern of form iv ticagrelor;

figure 5X-ray powder diffraction pattern of ticagrelor in form a.

Detailed Description

The invention provides a ticagrelor controlled release tablet which comprises a tablet core and a membrane controlled coating system, wherein the tablet core comprises ticagrelor accounting for 30-60 wt% of the total weight of the tablet core, and the controlled release tablet is provided with more than two drug release holes.

In a preferred embodiment, the ticagrelor can exist in four different fully crystalline forms, i.e. polymorphic forms i, ii, iii, iv, which differ from each other and from the amorphous form in melting point, solubility, bioavailability, wherein form ii is the original form of the study. The ticagrelor sustained-release tablet is selected from a crystal or amorphous form, and the content of ticagrelor in the sustained-release tablet is 150-200 mg, preferably 160-190 mg, and more preferably 180 mg.

In a preferred embodiment, the solubility and bioavailability of the active ingredient ticagrelor is improved by reducing the particle size of the active ingredient, which is controlled to be below 50 μm, preferably below 15 μm (particle size D90 calculated on a volume basis).

In a preferred embodiment, the core further comprises a penetration enhancer and an osmotically active agent.

The penetration enhancer can expand after contacting water to push out liquid medicine or medicine suspension from a medicine release hole, and can be a water-soluble or water-insoluble penetration enhancer, wherein the penetration enhancer accounts for 10-50% of the total weight of the tablet core, and preferably 10-30%.

The osmotically active agent is a mixture of one or more compounds that produces a higher osmotic pressure upon absorption of water. The osmotic pressure active agent accounts for 20-80% of the total weight of the tablet core, and preferably 30-50%.

In a more preferred embodiment, the penetration enhancer is selected from one or more of hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, non-cellulosic polysaccharides (e.g., acacia, trehalose gum, pregelatinized starch, etc.), polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose and its salts, alginic acid and its salts, polyoxyethylene, hydroxymethyl cellulose, etc., preferably hydroxyethyl cellulose. The osmotic pressure active agent is selected from one or more of saccharide osmotic pressure active agents and/or salt osmotic pressure active agents, the saccharide osmotic pressure active agents are selected from mannitol, xylitol, glucose, sorbitol, fructose, sucrose and starch oligomeric pond, the salt osmotic pressure active agents are selected from one or more of sodium chloride, potassium chloride, sulfate and phosphate, and sorbitol is preferred.

In a preferred embodiment, the film-forming material is preferably water-insoluble, and the film-forming material is present in an amount of 1 to 30%, preferably 2 to 15%, more preferably 3 to 10% by weight of the controlled release tablet, and a plasticizer. The mass percentage of the plasticizer in the controlled release tablet is 0.1-10%, preferably 0.5-5%, and more preferably 1-3%.

In a more preferred embodiment, the film forming material is selected from one or more of cellulose acetate, ethyl cellulose, polyacrylic resin and the like, preferably cellulose acetate. The plasticizer is selected from one or more of polyethylene glycol, oleic acid, triethyl citrate and the like, and preferably polyethylene glycol. According to the dissolution characteristics of the film-forming material, the semipermeable membrane coating solution is generally selected from organic solvents, such as acetone, ethanol, isopropanol or aqueous solution thereof, preferably acetone, more preferably 90-99% acetone-aqueous solution, and the solid content of the coating solution is generally 3-15% (w/v,%), preferably 5-8% (w/v,%).

In a preferred embodiment, the tablet core further comprises a binder and a lubricant, wherein the binder is selected from one or more of cellulose ether, polyvinylpyrrolidone, hydroxypropyl methyl cellulose succinate and the like, preferably copovidone, and the binder accounts for 0.5-10%, preferably 1-5% of the total weight of the tablet core; the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate and the like, preferably magnesium stearate, and accounts for 0.1-10% of the total weight of the tablet core, preferably 0.5-5% of the total weight of the tablet core.

In a preferred embodiment, in order to solve the problem of drug release residue at the tail end of a large-dose insoluble drug single-chamber osmotic pump preparation, the invention adopts a multi-drug-release hole technology, the number of the drug-release holes is two or more, the punching positions can respectively select the front surface, the back surface and the side surface of the tablet, but different drug-release holes are arranged on different surfaces, one surface is provided with only one drug-release hole, and the pore diameter of the drug-release hole is generally 0.3-1.2 μm, preferably 0.5-0.8 μm.

In a preferred embodiment, the controlled release tablet is a ticagrelor single compartment osmotic pump controlled release tablet.

Another object of the present invention is to provide a method for preparing ticagrelor controlled release tablets, comprising:

(3) aging the coated tablet, and laser drilling.

The technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention should not be construed as limiting the implementable scope of the present invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.

The active ingredient ticagrelor used in the following examples is selected from crystalline or amorphous form, and the particle size (particle size D90 calculated by volume) is controlled to be below 50 μm.

EXAMPLE 1 active ingredient polymorphism study

The melting point and saturation solubility measurement results of each polymorph are shown in table 1:

TABLE 1 melting Point and saturated solubility of polymorphic forms

Polycrystalline form	Melting point/melting range	Saturated solubility
			Ι	151℃(146～152℃)	10.89μg/ml
Ⅱ	137.5℃(136～139℃)	16.78μg/ml
			Ⅲ	132℃(127～132℃)	23.10μg/ml
Ⅳ	139℃	22.54μg/ml
			Alpha form	/	554.67μg/ml

Wherein, the X-ray powder diffraction patterns of ticagrelor with the polymorphic forms i, ii, iii, iv and α in table 1 are respectively shown in fig. 1 to 5.

EXAMPLE 2 initial prescription Process study (Single well)

The composition of the initial recipe is shown in table 2:

table 2 recipe ingredients and contents

The preparation method of the ticagrelor controlled release tablet comprises the following steps:

(1) uniformly mixing ticagrelor with polymorphic form II, a penetration enhancer, an osmotic pressure promoter and an adhesive, adding ethanol or an alcohol-water solution to prepare a soft material, drying, granulating, adding a lubricant, mixing and tabletting to obtain a medicine tablet core;

(2) preparing semipermeable membrane coating solution containing film-forming material and plasticizer by using acetone-water solution as coating solvent, and spraying the coating solution onto the tablet core to obtain coated tablet;

(3) aging the coated tablet in a 40 deg.C oven, and laser drilling hole with aperture of 0.6mm at the center of the front surface of the coated tablet.

Example 3 penetration enhancer species investigation

Table 3 recipe ingredients and contents

Composition of	Dosage (mg)	Ratio (%)
			Ticagrelor	180	42.9
Sorbitol	153	36.4
			Polyethylene oxide	55	13.1
Co-polyvidone	8	1.9
			Magnesium stearate	4	0.9
Cellulose acetate	14	3.3
			Polyethylene glycol	6	1.4
Is totaled	420	/

(1) uniformly mixing ticagrelor with a penetration enhancer, an osmotic pressure promoter and an adhesive, adding ethanol or an alcohol water solution to prepare a soft material, drying, granulating, adding a lubricant, mixing, and tabletting to obtain a medicine tablet core;

(3) aging the coated tablet in an oven at 40 deg.C, and laser drilling at the center of the front surface of the coated tablet to obtain a product with a hole diameter of 0.6 mm.

EXAMPLE 4 semipermeable Membrane coating formulation inspection

Table 4 prescription composition and content

Composition of	Dosage (mg)	Ratio (%)
			Ticagrelor	180	42.9
Sorbitol	153	36.4
			Hydroxyethyl cellulose	55	13.1
Copovidone	8	1.9
			Magnesium stearate	4	0.9
Cellulose acetate	15.8	3.8
			Hydroxypropyl methylcellulose	4.2	1.0
Is totaled	420	/

Example 5 evaluation of in vitro Release degree

The chromatographic conditions for the release determination were: octadecylsilane chemically bonded silica is used as a chromatographic column filler, 10ml of phosphate buffer solution (1.0 mol/L sodium dihydrogen phosphate solution (pH value is adjusted to 3.0 by phosphoric acid) is taken, water is added to 480ml, and even shaking-up-acetonitrile (48:52) is used as a mobile phase; the column temperature was 55 ℃; the detection wavelength was 242 nm. The tailing factor of the ticagrelor peak is not more than 1.5, and the number of theoretical plates is not less than 13500 according to the ticagrelor peak. Release Rate measurements drug release was observed for 20h using 0.2% Tween 80 in phosphate dissolution media pH6.8, and is shown in Table 5.

TABLE 5 Release of controlled Release tablets of examples 2 to 4

As can be seen from Table 5, the controlled release tablets of ticagrelor obtained by selecting the secondary ingredients and contents of example 2 have mild and lasting release and the highest release rate.

EXAMPLE 6 comparative study of multiple drug-releasing wells

Respectively preparing the ticagrelor with polycrystal forms I, II, III, IV and alpha according to the prescription in the embodiment 2 and the steps (1) and (2) in the preparation method, respectively drilling double-release holes with the diameter of 0.6mm at the central positions of the front and back surfaces of the coated tablet, and aging to obtain the ticagrelor tablet. The effect of single and double-sided aperturing on different crystal forms of examples 2 and 6 was evaluated according to the method for determining the degree of release in example 5, the release profile being shown in table 6.

TABLE 6 Release of controlled Release tablets of examples 2 and 6

As can be seen from Table 6, the single-release holes are adopted in example 2, the obtained single-chamber osmotic pump sustained-release tablets are not completely released, the release of the mixed crystal containing part of alpha form in the raw material drug is relatively quick, while the double-release holes are adopted in example 6, the release of the controlled-release tablets is mild and lasting, the release in 20h is more than 90%, and the release is basically complete. The polymorphic forms of different ticagrelor in example 6 had no effect on the release profile, which indicates that the single-compartment osmotic pump controlled release tablet can eliminate the effect of different solid forms on solubility and achieve effective controlled release effect.

EXAMPLE 7 Release Rate stability Studies

The samples of example 6, form II, were subjected to accelerated conditions (40 deg.C/RH 75%) and prolonged conditions (25 deg.C/RH 65%) for one month, and the evolution of the in vitro release rate was examined according to the release rate evaluation method of example 5, and the release rate is shown in Table 7.

TABLE 7 in vitro Release

Time (h)/Release (%)	0 month	Accelerated for 1 month	Long term of 1 month
				2	17	11	12
4	38	41	37
				6	55	52	54
8	69	70	65
				12	86	85	89
16	94	95	93
				20	98	97	100

As can be seen from table 7, the release profiles of the ticagrelor controlled release tablets in example 6-form ii of the present invention under accelerated conditions and long-term conditions do not change significantly from the release profiles of the ticagrelor controlled release tablets under 0 month conditions, and thus it can be seen that the ticagrelor controlled release tablets in example 6 of the present invention have good stability and do not change significantly under accelerated conditions and long-term storage conditions.

Claims

1. A ticagrelor controlled release tablet, which is characterized in that the controlled release tablet comprises a tablet core and a membrane controlled coating system, wherein the tablet core comprises 30-60 wt% of ticagrelor based on the total weight of the tablet core;

the tablet core also comprises a penetration enhancer and an osmotic pressure active agent, wherein the penetration enhancer accounts for 10-30 wt% of the total weight of the tablet core, and the osmotic pressure active agent accounts for 30-50 wt% of the total weight of the tablet core;

the penetration enhancer is hydroxyethyl cellulose, and the osmotic pressure active agent is sorbitol;

the controlled release tablet is a ticagrelor single-chamber osmotic pump controlled release tablet, and the controlled release tablet is provided with more than two drug release holes.

2. The ticagrelor controlled release tablet of claim 1, wherein the ticagrelor content is 150-200 mg, and the particle size is 50 μm or less.

3. The ticagrelor controlled release tablet of claim 1, wherein the film-forming coating system comprises 1-30% by mass of a film-forming material and 0.1-10% by mass of a plasticizer.

4. The ticagrelor controlled release tablet of claim 3, wherein the film forming material is selected from one or more of cellulose acetate, ethyl cellulose and polyacrylic resin; the plasticizer is selected from one or more of polyethylene glycol, oleic acid and triethyl citrate.

5. The controlled-release tablet of ticagrelor according to claim 3 or 4, wherein the film-forming material is cellulose acetate and the plasticizer is polyethylene glycol.

6. The controlled release tablet of ticagrelor of claim 1, wherein the tablet core further comprises a binder and a lubricant, the binder being selected from one or more of cellulose ether, polyvinylpyrrolidone and hydroxypropylmethylcellulose succinate; the lubricant is selected from one or more of stearic acid, magnesium stearate and calcium stearate.

7. The controlled release tablet of ticagrelor according to claim 6, wherein the binder is copovidone and the lubricant is magnesium stearate.

8. The ticagrelor controlled release tablet of claim 1, wherein the drug release holes are located on the front, back or side of the controlled release tablet, and only one drug release hole is located on the same surface, and the pore diameter of the drug release hole is 0.3-1.2 mm.

9. A method for preparing a ticagrelor controlled release tablet, the method comprising:

(3) aging the coated tablet, and laser drilling.