CN111991362A - A kind of ticagrelor sustained-release tablet and preparation method thereof - Google Patents

Abstract

The invention belongs to the field of pharmaceutical technical preparations, and relates to a ticagrelor sustained-release tablet and a preparation method thereof, which are suitable for taking once a day. The present disclosure provides a ticagrelor sustained-release tablet and a preparation method thereof. Specifically, it is formed by compressing an immediate-release solid composition and a sustained-release solid composition. The dosage form is a double-layer tablet, and the immediate-release solid composition is in the stomach. Rapid release to achieve effective blood drug concentration helps to quickly relieve symptoms, sustained-release solid composition is helpful to maintain effective dose, control drug slow release and absorption, maintain stable blood drug concentration, can achieve once-a-day administration, reduce The number of doses is increased, the patient's medication compliance is improved, and the risk of myocardial infarction and stroke is reduced. The preparation method of the invention is simple, suitable for operation and suitable for industrial production.

Description

A kind of ticagrelor sustained-release tablet and preparation method thereof

technical field

The invention belongs to the field of pharmaceutical technical preparations, and relates to a ticagrelor sustained-release tablet and a preparation method thereof, which are suitable for taking once a day.

Background technique

According to data, there are currently about 290 million people suffering from cardiovascular disease in China, and the number of cardiovascular deaths from 1990 to 2016 increased from more than 2.5 million to nearly 4 million; from 1990 to 2016, the cardiovascular death rate increased from 220.8 /100,000 people rose to 2.908/100,000 people, ranking first, accounting for more than 40% of residents' disease deaths. In recent years, with the continuous acceleration of urbanization, the arrival of an aging society, and the prevalence of unhealthy lifestyles among residents due to a faster pace of life, the probability of Chinese residents suffering from cardiovascular diseases has been increasing. Anti-platelet aggregation is the treatment of cardiovascular and cerebrovascular diseases. one of the important measures. Ticagrelor is a novel, selective oral antiplatelet drug. The platelet inhibition and patient endpoint event study (PLATO study) has confirmed the clinical efficacy and safety of the drug.

The correlation between the pharmacokinetic and pharmacodynamic data of ticagrelor is reported in the existing literature, and it is reported that a certain plasma concentration of ticagrelor must be maintained in order to achieve a platelet inhibition rate of more than 90%. The currently listed ticagrelor tablets (specifications: 60mg and 90mg) are produced by AstraZeneca. The blood concentration of this immediate-release tablet fluctuates significantly. 12 hours, in order to ensure the efficacy, it needs to be administered twice a day.

According to data released at the European Society of Cardiology Annual Meeting, 50% of coronary heart disease patients miss taking medicine at least once a month. In order to reduce this risk and improve patient compliance with medication, it is necessary to develop a once-daily dosage form. Patent CN 110876750 A relates to a preparation method of a sustained-release composition containing ticagrelor or a pharmaceutically acceptable salt thereof. Then, the outer layer of the sustained-release tablet wraps the isolation layer, the immediate-release layer and the coating layer in turn. The preparation process is complicated, the production cycle is long, and the result is that the release is incomplete in the later stage. There are currently no ticagrelor extended-release products on the market.

The present disclosure provides a ticagrelor sustained-release tablet and a preparation method thereof. The dosage form is a double-layer tablet, which is compressed from an immediate-release solid composition and a sustained-release solid composition. Symptoms, sustained-release solid composition is helpful to maintain effective dose, realize the organic combination of quick-acting and long-acting, can achieve once-a-day dosing, so that the drug is slowly released and absorbed, while reducing the frequency of taking, preventing missed doses, and improving patients. Medication compliance reduces the risk of myocardial infarction and stroke.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a preparation method of ticagrelor sustained-release tablets.

The ticagrelor sustained-release tablet prepared by the present invention contains 180 mg of ticagrelor. The currently listed ticagrelor tablets (specifications: 60 mg and 90 mg) are only effective for 12 hours. In order to ensure the curative effect, they need to be administered twice a day. The number of doses is increased and the patient's compliance is improved.

The ticagrelor sustained-release tablet prepared by the present invention is a double-layered tablet, and the drug release mode combining the immediate-release solid composition and the sustained-release solid composition ensures that after taking the medicine, the immediate-release solid composition disintegrates rapidly, so that the blood drug can be disintegrated rapidly. The concentration can quickly reach the therapeutic window range, and the sustained-release solid composition can be slowly released to maintain the therapeutic effect for a long period of time, and effectively control the toxic and side effects.

To achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:

A ticagrelor sustained-release tablet, the sustained-release tablet comprises a tablet core component and a coating component, wherein the tablet core component includes an immediate-release solid composition and a sustained-release solid composition.

The components contained in the immediate-release solid composition of the present invention include: ticagrelor, lactose, anhydrous calcium hydrogen phosphate, polyvinylpyrrolidone, sodium carboxymethyl starch, red iron oxide and magnesium stearate.

The components contained in the sustained-release solid composition of the present invention include: at least one of fillers, binders, framework materials, glidants and lubricants. Wherein the skeleton material is selected from one or more of hydroxypropyl methylcellulose, sodium alginate, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyoxyethylene, carbomer, kinds, preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose; the models of hydroxypropyl cellulose described in the present disclosure include: HPC HF, HPC HXF, HPC MF, HPC MXF, HPC GF, HPC GXF, HPC JF , HPC JXF, HPC LF, HPC LXF, HPC EF, HPC EXF, HPC ELF, preferably HPC HXF and HPC GXF, the hypromellose types include: K100M, K15M, K4M, K100LV, preferably K4M and K100LV

In the ticagrelor sustained-release tablet of the present invention, the mass ratio of the immediate-release solid composition to the ticagrelor sustained-release solid composition is 5:1 to 1:5, preferably 3:1 to 1:3.

In the ticagrelor sustained-release tablet of the present invention, the immediate-release solid composition and the sustained-release solid composition are prepared into granules by using a wet mixing granulator, respectively, and other corresponding adjuvants are added to prepare the final granules, and then the two A laminator compresses the prepared granules into tablets, and finally wraps a color layer on the outside of the tablets to prepare the final ticagrelor sustained-release tablet.

The preparation method of the present invention comprises the following steps:

1) Weighing and premixing of raw and auxiliary materials: Weigh ticagrelor, lactose (mannitol), and anhydrous calcium hydrogen phosphate (microcrystalline cellulose) according to the mass ratio, and mix them evenly;

2) Preparation of adhesive: add polyvinylpyrrolidone into purified water, stir until the solution is clear, transparent and completely dissolved to obtain an adhesive.

Wherein the amount of purified water is preferably 4 to 9 times the mass of polyvinylpyrrolidone;

3) Granulation process: put ticagrelor, lactose (mannitol), anhydrous calcium hydrogen phosphate (microcrystalline cellulose) in a wet granulator and mix evenly, add a binder to make a soft material, and shape the soft material Then put it in a granulator and pass it through a 20-24 mesh sieve to granulate, and then dry it at 50℃～60℃, and control the moisture content to be less than or equal to 3%;

4) granulation: the dried granules obtained above are subjected to 20-30 mesh sieve granulation;

5) Mixing: the above-mentioned granules are respectively added in proportions with adjuvants, wherein the hypromellose needs a porogen such as mannitol, lactose, microcrystalline cellulose, and hypromellose E5 to be premixed and mixed evenly;

6) Detection: Detect the content of intermediate particles, and calculate the actual tablet weight that should be pressed;

7) Tablet compression: use a double-layer tablet press to perform tablet compression, fill the immediate-release component material and the sustained-release component material respectively, adjust the loading capacity and pressure of the tablet press, and control the overall tablet hardness to be 100±30N;

8) Coating: control the concentration of the coating liquid to be 15.0%, and start spraying the coating liquid when the temperature of the material reaches 45.0°C; control the temperature of the material to be 40.0°C ± 5.0°C, and the weight gain of the plain tablet is 2.0% of the weight of the plain tablet ～5.0%, stop coating; dry in a coating pan for 20-30 min to obtain ticagrelor sustained-release tablets.

The ticagrelor sustained-release tablet of the present invention ensures that the insoluble ticagrelor can be completely released, the immediate-release solid composition in the early stage helps to relieve symptoms quickly, and the sustained-release solid composition in the later stage helps to maintain an effective dose, It reduces the fluctuation of blood drug concentration, realizes the organic combination of quick-acting and long-acting, reduces the frequency of taking, and reduces the risk of myocardial infarction and stroke.

Description of drawings

Accompanying drawing 1 embodiment 1 different prescription release curve cumulative release (%) figure

Accompanying drawing 2 embodiment 2 different prescription release curves cumulative release (%) figure

Accompanying drawing 3 embodiment 3 different prescription release curves cumulative release (%) figure

Accompanying drawing 4 embodiment different prescription release curve contrast cumulative release (%) figure

Detailed ways

Next, the present invention can be further described in detail with reference to specific embodiments. The following descriptions are all practical examples, which are only used to describe the present invention in detail, rather than limiting the present invention.

Ticagrelor sustained-release tablet and preparation method thereof

Example 1

Prepare ingredients according to the recipes in the table above.

Weighing and premixing of raw and auxiliary materials: Weigh ticagrelor, lactose, and anhydrous calcium hydrogen phosphate according to the mass ratio, and mix them evenly;

Preparation of adhesive: add polyvinylpyrrolidone into purified water, stir until the solution is clear and completely dissolved, and then the adhesive is obtained;

Granulation process: Put ticagrelor, lactose, and anhydrous calcium hydrogen phosphate in a wet granulator to mix evenly, add a binder to make a soft material, and place the soft material in a granulator to pass through a 20-mesh sieve after molding. granulate, then dry at 50°C to 60°C, control the moisture content to be ≤2.00%, and perform dry granulation after the moisture is qualified to obtain a solid composition;

Granulation: the dried granules obtained above are sieved through a 30-mesh sieve for granulation;

Mixing: Add the above-mentioned granules in proportion to the external auxiliary materials, and mix them evenly;

Detection: Detect the content of intermediate particles, and calculate the actual tablet weight that should be pressed;

Tablet compression: use a double-layer tablet press, adjust the loading capacity and pressure of the tablet press, and control the overall tablet hardness to 100±30N;

Coating: control the concentration of the coating liquid to 15.0%, and start spraying the coating liquid when the material temperature reaches 45.0 °C; control the material temperature to be 40.0 °C ± 5.0 °C, and the weight gain of the plain tablet is 2.0% to 5.0% of the weight of the plain tablet %, stop coating; dry in a coating pan for 20-30 min to obtain ticagrelor sustained-release tablets.

Example 2

Example 3

Example 1 release profile

Example 2 release profile

Example 3 release profile

The results of the comparison of the release curves of the examples show that the release curves of prescriptions 1, 2, 3, 4, 6, 7, 8, 9, 11, 13, and 14 are good, and can be rapidly released to more than 30% within 2 hours in the early stage, and can Stable release for 18-20 hours.

The preparation methods in the above examples are all the same preparation steps as those in Example 1, and the proportions of raw and auxiliary materials are weighed according to their respective proportions to prepare ticagrelor sustained-release tablets.

Detection of indicators of ticagrelor sustained-release tablets

The tablet prepared in Example 2, Recipe 9 was used as the test product for quality research.

The key quality inspection items of ticagrelor sustained-release tablets include: properties, related substances, dissolution, content, etc.

Detection method of related substances: according to high performance liquid chromatography (Chinese Pharmacopoeia, 2010 edition, Part II, Appendix VD), with octadecylsilane-bonded silica gel as filler, phosphate buffer-acetonitrile (90:10) as flow In phase A, phosphate buffer-acetonitrile (30:70) was used as mobile phase B, the flow rate was 1.0 ml/min, the column temperature was 55°C, and the detection wavelength was 242 nm.

Content detection method: according to high performance liquid chromatography (Chinese Pharmacopoeia, 2010 edition, two appendix VD), with octadecylsilane bonded silica gel as filler, with phosphate buffer-acetonitrile (48:52) as mobile phase , the flow rate is 1.2ml/min, the column temperature is 55℃, and the detection wavelength is 242nm. The number of theoretical plates should not be less than 3000 calculated according to ticagrelor.

Dissolution detection method: 1000ml of 0.2% (w/v) Tween 80 solution was used as the dissolution medium, and the rotation speed was 75 revolutions per minute. , 12h, 18h, 24h, take 5ml each, and supplement the dissolution medium of the same volume and temperature at the same time. The absorbance was measured at a wavelength of 300 nm by UV-Vis spectrophotometry.

Influencing factor test: The ticagrelor sustained-release tablets prepared in Example 2 in formula 9 were packaged in aluminum-plastic packaging and placed in a stability box. Place under light (4500lx±500lx) conditions for 10 days, take samples at 0 days, 5 days and 10 days, and test the key quality items of ticagrelor sustained-release tablets.

The key quality test results of ticagrelor sustained-release tablets are as follows:

The test results of the in vitro dissolution profile of ticagrelor sustained-release tablets are as follows:

Claims (10)

1. a ticagrelor sustained release tablet comprises a tablet core component and a coating component; wherein the core component comprises a quick release solid composition and a slow release solid composition; the slow release solid composition is prepared by premixing framework materials including hypromellose, hyprolose and pore-forming agent, wherein the pore-forming agent is selected from mannitol, lactose, microcrystalline cellulose and hypromellose E5, and the dosage of the pore-forming agent is 1/5-1/1, preferably 1/2 of the framework materials.

2. A ticagrelor sustained release tablet according to claim 1, wherein the ticagrelor is milled using a jet mill, the milled ticagrelor having an average particle size of less than 30 microns, preferably an average particle size of less than 10 microns.

3. The ticagrelor sustained release tablet according to claim 1, wherein the sustained release solid composition sustained release component comprises a framework material, and the framework material is selected from one or more of hydroxypropyl methylcellulose, sodium alginate, hydroxyethyl cellulose, methylcellulose, hydroxypropyl cellulose, polyoxyethylene, carbomer and glyceryl behenate, preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose; wherein the hydroxypropyl methylcellulose is K4M or K100LV, the hydroxypropyl cellulose is HF (HXF) or GF (GXF), and the content of the framework material is 10-50 percent of the total weight of the composition, preferably 10-30 percent.

4. The ticagrelor sustained-release tablet according to claim 1, wherein the matrix material is further subjected to wet granulation by an internal addition method using a binder, wherein the binder is selected from an aqueous solution of hypromellose or povidone.

5. The ticagrelor sustained release tablet according to claim 1, wherein the ticagrelor starting material is first granulated using a wet granulation process using equipment comprising a fluidized bed and a high shear wet granulator, preferably a high shear wet granulator.

6. The ticagrelor sustained release tablet according to claim 1, wherein the wet granulation internal addition material is ticagrelor and pharmaceutically acceptable auxiliary materials such as filler, adhesive, disintegrant and the like, wherein the filler is selected from one or more of mannitol, lactose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch; the adhesive is selected from one or more of hydroxypropyl cellulose and povidone; the disintegrating agent is selected from carboxymethyl starch sodium, crospovidone, etc., and is prepared into granules by wet method with water as dissolving agent of binder.

7. The ticagrelor sustained release tablet according to claim 1, wherein a skeleton material, a pore-forming agent, a disintegrating agent, a glidant, a coloring agent and a lubricant are added after the ticagrelor raw material is granulated; wherein the quick-release component additional material is disintegrant, glidant, colorant and lubricant, and the slow-release component additional material is framework material, pore-forming agent, glidant, lubricant and the like; the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch.

8. The ticagrelor sustained release tablet according to claims 1 to 7, characterized in that the ticagrelor sustained release tablet is tableted in a manner selected from a double-layer tablet or a core-coated tablet, preferably a double-layer tablet; the double-layer tabletting punch dies with the shapes of round, oval, heart, capsule, triangle and the like can be selected for pressing.

9. The ticagrelor sustained release tablet of claims 1-8, wherein the coating is carried out using a high performance film coating machine, and the coating material is a gastric-soluble film coating premix.

10. The ticagrelor sustained release tablet according to claims 1-9, consisting of, and not limited to, the following components:

Images