EP3761965A1

EP3761965A1 - Ticagrelor-containing tablet formulation

Info

Publication number: EP3761965A1
Application number: EP18711270.1A
Authority: EP
Inventors: Panagiotis PANAGOPOULOS; Konstantinos-Emmanouil PANITSAS; Konstantinos KOMPOROZOS; Dimosthenis KANTAS; Sofia GEORGAKAKOU; Ioanna PARELI
Original assignee: Pharmaceutical Oriented Services Ltd; Rontis Hellas SA
Current assignee: Pharmaceutical Oriented Services Ltd; Rontis Hellas SA
Priority date: 2018-03-08
Filing date: 2018-03-08
Publication date: 2021-01-13
Also published as: WO2019170244A1

Abstract

The present invention relates to a tablet containing ticagrelor, starch and pregelatinized starch. The tablet is prepared by wet-granulation.

Description

Ticagrelor-containing tablet formulation

The present invention relates to a tablet containing ticagrelor, wherein the tablet is prepared by wet-granulation.

Ticagrelor is marketed under the tradename Brilique^® in the form of film-coated tablets, which contain 60 mg or 90 mg ticagrelor. Brilique^® is indicated for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) or with a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event. Brilique^® treatment should be initiated with a single 180 mg loading dose and then continued at 90 mg twice daily for twelve months in ACS-patients. Brilique^® 60 mg twice daily is the recommended dose when an extended treatment is required for patients with a history of MI of at least one year and a high risk of an atherothrombotic event. The tablets should be administered with a daily maintenance dose of acetylsalicylic acid of 75-100 mg.

Ticagrelor has a low and pH-independent solubility in aqueous media as well as a low permeability, so that the drug is classified as a class IV compound according to the Biopharmaceutics Classification System (BCS). Ticagrelor may exist in various crystalline forms, including solvated forms. WO 01/92262 describes the crystalline forms I-IV of ticagrelor as well as an amorphous form that may be prepared by freeze-drying or spray-drying of a solution containing the drug. In addition, tablets are described containing ticagrelor, lactose, croscarmellose sodium, magnesium stearate, and maize starch paste or maize starch and polyvinylpyrrolidone (povidone).

The commercially available Brilique^® tablet contains, besides ticagrelor, mannitol and calcium hydrogen phosphate (dibasic calcium phosphate) as fillers, sodium starch glycolate as a disintegrant, hydroxypropylcellulose as a binder and magnesium stearate as a lubricant. The tablet is prepared by wet-granulation and is further film- coated. WO 2008/024044 and WO 2008/024045 describe the wet-granulation process used for the preparation of the Brilique^® tablets. It is stated in these applications that the drug release from the formulation and the stability of the formulation affects the bioavailability of ticagrelor, and that it is important that the formulation releases substantially all of the drug. According to WO 2008/024044 and WO 2008/024045, a tablet that releases substantially all of the drug and that has sufficiently high stability may be obtained if it contains, besides the drug, a water-soluble filler, e.g., mannitol, sorbitol, maltodextrin, maltose and dextrin, a water-insoluble filler, e.g., dibasic calcium phosphate (dihydrate or anhydrous), pregelatinized starch and tribasic calcium phosphate, a binder, e.g., hydroxypropylcellulose, alginic acid, carboxymethyl- cellulose sodium, a vinylpyrrolidone/vinyl acetate copolymer (copovidone) and methylcellulose, a superdisintegrant selected from sodium starch glycolate, croscarmellose sodium and crospovidone, as well as a lubricant. The tablet is prepared by wet-granulation using, e.g., a high-shear wet-granulator. WO 2014/059955 discloses that a disintegrant is not necessary in order to release substantially all of the drug, if the main excipient of the tablet is a non-hygroscopic but water-soluble filler. Preferred fillers are sugars and sugar alcohols such as lactose (monohydrate or anhydrous), xylitol, mannitol, isomaltose, maltose, maltitol and lactitol. The tablet may be prepared by wet-granulation, dry-granulation or direct compression, wherein a non-hygroscopic binder should be present if wet-granulation is used. As suitable binders, povidone, copovidone, microcrystalline cellulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, starch, pregelatinized starch and polymethacrylates are mentioned. According to WO 2015/110952, the drug release may be further improved if the tablet contains only a low amount of ticagrelor, i.e. less than 20 % by weight based on the total weight of the tablet, and if the filler, which constitutes the major portion of the tablet composition, is not a water-insoluble filler. The filler is preferably a sugar or sugar alcohol, e.g., mannitol, whereby the tablet is preferably prepared by wet-granulation using an aqueous povidone-containing granulation liquid. The tablet may contain sodium starch glycolate as extragranular component.

WO 2011/076749 discloses that the formulations described in WO 2008/024044 and WO 2008/024045 may only contain up to 50 % by weight of ticagrelor, because otherwise, the unit dosage form may not release substantially all of the active ingredient. WO 2011/076749 suggests as a solution to the problem of providing a tablet containing a high drug-load and releasing substantially all of drug, the co- grinding of ticagrelor and a hydrophilic polymer and/or an emulsifier, and the adjustment of the particle size of the ticagrelor particles. The unit dosage form, e.g., a tablet, which can be prepared by wet-granulation, melt-granulation or direct compression, should contain ticagrelor with a particle size distribution of D_v90 of 1 mm to 150 mm.

WO 2015/001489 suggests the use of ticagrelor in amorphous form, which includes a solid dispersion or solid solution (molecularly dispersed) of ticagrelor within a hydrophilic matrix, in order to provide a sufficiently high dissolution rate.

It was an objective of the present invention to provide an immediate-release tablet for oral administration containing ticagrelor, which releases substantially all of the drug and which has sufficiently high stability, so that the high bioavailability of the drug is maintained after storage. This objective is attained by the subject matter as defined in the claims.

The tablet of the present invention is an immediate-release tablet, preferably a film- coated tablet. This tablet is prepared by wet-granulation and contains starch as disintegrant, pregelatinized starch as binder, a filler and optionally further pharmaceutical excipients.

Starch, e.g., maize starch, may be used as both a binder and disintegrant. If used as a binder, the starch needs to be converted to a paste. However, starch loses its disintegration properties when it gelatinizes in the preparation of the starch paste. Gelatinized starch contains amylose and amylopectin, which are set free in the preparation of starch paste. The free amylopectin is responsible for the binding.

In the present invention, the starch is not converted to starch paste, because otherwise, it cannot function as a disintegrant. Instead, pregelatinized starch is used as a binder. Either fully or partially pregelatinized starch may be used. A preferred partially pregelatinized starch is Starch 1500^®. Typically, pregelatinized starch contains 5 % of free amylose, 15 % of free amylopectin and 80 % unmodified starch.

It is preferred that the tablet of the present invention does not contain a disintegrant and a binder other than starch and pregelatinized starch. In particular, the tablet of the present invention does not contain a superdisintegrant as sodium starch glycolate, croscarmellose sodium or crospovidone. It was found that ticagrelor is not stable in a tablet prepared by wet-granulation that contains sodium starch glycolate as a disintegrant and povidone as a binder.

The release profile of ticagrelor may be adjusted by the weight ratio of starch to pregelatinized starch. Typically, the weight ratio of starch to pregelatinized starch is 4 : 1 to 1 : 4, preferably 3 : 1 to 1 : 3, more preferred 2 : 1 to 1 : 2, and most preferably 1 : 1, If fully pregelatinized starch is used, more starch needs to be contained in the tablet in order to compensate the higher amount of binder. Typically, the tablet or, if film-coated, the tablet core of the present invention contains ticagrelor in an amount of 20-40 % by weight, starch in an amount of 5-20 % by weight and pregelatinized starch in an amount of 5-20 % by weight. According to a preferred embodiment of the present invention, the tablet or the tablet core consists of ticagrelor in an amount of 20-40 % by weight, starch in an amount of 5-20 % by weight, pregelatinized starch in an amount of 5-20 % by weight, a filler in an amount of 20-70 %, and further pharmaceutical excipients in an amount of 0-5 % by weight.

The further pharmaceutical excipient may be selected from a lubricant, a glidant and a surfactant.

The tablet of the present invention may be obtained by a process comprising the method steps: i) mixing ticagrelor, starch, at least a part of the pregelatinized starch, a filler, and optionally a first further pharmaceutical excipient,

ii) subjecting the mixture obtained in step (i) to wet-granulation,

iii) optionally mixing the granules obtained in step (ii) with a second further pharmaceutical excipient and with the remaining part of the pregelatinized starch, and

iv) subjecting the granules obtained in step (ii) or the mixture obtained in step (iii) to compression to obtain the tablet or the tablet core.

Usually, water is used as granulating liquid. The tablet may contain a first further pharmaceutical excipient selected from a glidant and a surfactant. The second further pharmaceutical excipient may be selected from a glidant and a lubricant. It is preferred that the tablet of the present invention does not contain a first further pharmaceutical excipient and, as a second further pharmaceutical excipient, only a lubricant.

Examples of fillers include microcrystalline cellulose, calcium hydrogen phosphate (anhydrous or dihydrate), lactose (anhydrous or monohydrate), calcium carbonate, magnesium carbonate, silicified microcrystalline cellulose, powder cellulose, mannitol, sorbitol, maltitol and lactitol. Mannitol, optionally in admixture with calcium hydrogen phosphate, is preferably used in the present invention. Examples of glidants include silicon dioxide (silica) and magnesium silicate.

Examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, talc, sodium stearyl iumarate and glyceryl dibehenate. The tablet preferably contains talc and sodium stearyl fumarate.

Examples of surfactants include polyoxyethylene stearate, sodium lauryl sulfate, sorbitan fatty acid esters (e.g. sorbitan palmitate or sorbitan stearate) and polyoxyethylene sorbitan fatty acid esters (e.g. polysorbate 80). The tablets of the present invention may optionally be coated with a film-coating. Commercially available film-coating systems containing polyvinyl alcohol as coating polymer, which are marketed under the tradename Opadry^®, may be used.

The drug contained in the tablet of the present invention is preferably crystalline ticagrelor, wherein the crystalline form II disclosed in WO 01/92262 is particularly suitable for the present invention.

Typically, the utilized ticagrelor has a particle size distribution D_v90 of 80 mm or below, preferably of 5-70 mm and more preferred of 10-60 mm (determined by using Mastersizer 2000). The tablet of the present invention is suitable for preventing an atherothrombotic event in a patient, usually having acute coronary syndromes or being at risk of developing an atherothrombotic event. The following examples are intended to further illustrate the present invention.

Examples

In the examples, crystalline ticagrelor having a particle size distribution of D_v90 = 10-60 mm was used. D_v90 corresponds to the particle size at 90 % of the cumulative volume distribution.

The dissolution tests were performed according to the FDA recommended dissolution method for ticagrelor tablets, i.e. in 900 ml purified water with 0.2 % (w/v) polysorbate 80, using USP apparatus II (paddle), speed: 75 rpm, temperature: 37 ± 0.5°C.

The Brilique^® 90 mg film-coated tablet was used as reference product. Comparative Example

1) Dispensing & Sifting

All the ingredients were dispensed in individual polybags, labelled properly and sifted through appropriate sieves.

2) Dry Mix

The total amount of Ticagrelor API was introduced into a high shear mixer along with Mannitol, Calcium hydrogen phosphate dihydrate and part of Sodium Starch Glycolate and mixed for sufficient time.

3) Wet granulation

The mixture of step 2 was granulated with water for sufficient time until granules are formed and was further dried in a fluid bed granulator. 4) Sizing step

The granules of step 3 were sized through an appropriate screen.

5) Pre-Lubrication

The granules of step 4 were added in a blender along with the remaining quantity of Sodium Starch Glycolate and were mixed for sufficient time.

6) Lubrication

Magnesium Stearate was added to the blender containing the mixture of step 5 and was mixed for sufficient time.

7) Compression

Compression was initiated using the blend of step 6 using suitable round biconvex punches. All the physical parameters of the core tablets presented in the following table were found to be satisfactory. Table 1: Physical characteristics of the tablet core

The tablets were further coated and tested for dissolution and compared to the reference product Brilique^®.

Table 2: Dissolution profile of the film-coated tablet

The tablet had acceptable physical characteristics comparable to the reference product and a similar dissolution.

The tablets were packed in PVC blisters and charged on stability study in the accelerated conditions.

Table 3: Stability of the film-coated tablet

The related substances after one-month storage under accelerated conditions indicate that the formulation is not stable. For comparison purposes, the results obtained with the reference product are reported below.

Examples 1 and 2

1) Dispensing & Sifting

All the ingredients were dispensed in individual polybags, labelled properly and sifted through appropriate sieves. 2) Dry Mix

The total amount of Ticagrelor API was introduced into a high shear mixer along with Mannitol, optionally Calcium hydrogen phosphate dihydrate, Maize Starch and part of Pregelatinized Starch and mixed for sufficient time.

3) Wet granulation

The granules of step 3 were sized through an appropriate screen.

5) Pre-Lubrication

The granules of step 4 were added in a blender along with the remaining quantity of Pregelatinized Starch and Talc and were mixed for sufficient time.

6) Lubrication

Sodium Stearyl Fumarate was added to the blender containing the mixture of step 5 and was mixed for sufficient time.

7) Compression

Compression was initiated using the blend of step 6 using suitable round biconvex punches. All the physical parameters of the core tablets were found to be satisfactory and comparable to the reference product. Table 4: Physical characteristics of the tablet cores

The tablets were further coated and tested for dissolution in 900 mL purified water with 0.2%w/v Polysorbate 80 and compared to the reference product Brilique^®90mg. The comparative tables are presented below.

Table 5: Dissolution profile of the film-coated tablets

The tablets had acceptable tablet characteristics comparable to the reference product and similar dissolution profiles.

The tablets were packed in PVC blisters and charged on stability study in the accelerated conditions. Tables 6: Stability of the film-coated tablets

The related substances after one-month storage under accelerated conditions indicate that the formulations are stable and comparable to Brilique^®.

Claims

1. An optionally film-coated tablet containing ticagrelor, starch as disinte- grant, pregelatinized starch as binder, a filler and optionally further pharmaceutical excipients, wherein the tablet is prepared by wet-granulation.

2. The tablet according to claim 1, wherein the tablet or the tablet core contains ticagrelor in an amount of 20-40 % by weight.

3. The tablet according to claim 1 or 2, wherein the tablet or the tablet core contains starch in an amount of 5-20 % by weight.

4, The tablet according any one of the preceding claims, wherein the tablet or the tablet core contains pregelatinized starch in an amount of 5-20 % by weight.

5. The tablet according to claim 4, wherein the tablet or the tablet core consists of:

ticagrelor in an amount of 20-40 % by weight,

starch in an amount of 5-20 % by weight,

pregelatinized starch in an amount of 5-20 % by weight,

a filler in an amount of 20-70%, and

further pharmaceutical excipients in an amount 0-5 % by weight.

6. The tablet according any one of the preceding claims, wherein the further pharmaceutical excipient is selected from a lubricant, a glidant and a surfactant.

7. The tablet according any one of the preceding claims, wherein the pregelatinized starch is fully or partially pregelatinized starch.

8. The tablet according any one of the preceding claims, wherein the weight ratio of starch to pregelatinized starch is 4 : 1 to 1 : 4, preferably 3 : 1 to 1 : 3, more preferred 2 : 1 to 1 : 2, and most preferably 1 : 1.

9. The tablet according to any one of the preceding claims, wherein the tablet is obtained by a process comprising the method steps: i) mixing ticagrelor, starch, at least a part of the pregelatinized starch, a filler, and optionally a first further pharmaceutical excipient,

ii) subjecting the mixture obtained in step (i) to wet-granulation,

10. The tablet according to claim 9, wherein the tablet contains a first further pharmaceutical excipient selected from a glidant and a surfactant.

11. The tablet according to claim 9 or 10, wherein the tablet contains a second further pharmaceutical excipient selected from a glidant and a lubricant.

12. A process for preparing a tablet according to any one of the preceding claims, comprising the method steps: i) mixing ticagrelor, starch, at least a part of the pregelatinized starch, a filler, and optionally a first further pharmaceutical excipient,

ii) subjecting the mixture obtained in step (i) to wet-granulation, iii) optionally mixing the granules obtained in step (ii) with a second further pharmaceutical excipient and with the remaining part of the pregelatinized starch, and

13. The tablet according to any one of claims 1-11 for use in preventing an atherothrombotic event in a patient.

14. The use as defined in claim 13, wherein the patient is a patient with acute coronary syndromes or a patient at risk of developing an atherothrombotic event.