EP4058025A1

EP4058025A1 - Pharmaceutical compositions comprising ticagrelor

Info

Publication number: EP4058025A1
Application number: EP19952515.5A
Authority: EP
Inventors: Ersin Yildirim; Bayram Kanik; Fatma ÖZTÜRK; Tansel AKTA; Filiz ÖZYÜREK
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2019-11-13
Filing date: 2019-11-13
Publication date: 2022-09-21
Also published as: EP4058025A4; WO2021096444A1

Abstract

The present invention relates to a pharmaceutical composition, comprising ticagrelor, wherein the pharmaceutical composition is manufactured by using wet granulation method improved flow character and compressibility properties wherein; the composition comprises microcrystalline cellulose, and silicon dioxide together in the extragranular phase and dibasic calcium phosphate in intragranular phase with optimized lubrication time range between 6 to 12 minutes.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING TICAGRELOR

Field of the Invention

The present invention relates to a pharmaceutical composition, comprising ticagrelor, wherein the pharmaceutical composition is in a solid dosage form having proper correlation between in vitro dissolution release profile and in vivo release profile.

Background of the Invention

Ticagrelor is a platelet aggregation inhibitor that acts by inhibition of adenosine 5- diphosphate. Ticagrelor is a reversible, selective P2Y 12-receptor antagonist. Its chemical name is (lS,2S,3R,5S)-3-(7-{[(lR,2S)-2-(3,4-Diflourophenyl)cyclopropyl]amino}-5- (propylsulfanyl)-3H-[l,2,3]triazol[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol and its chemical structure is given below. Its CAS Number is 274693-27-5.

Formula (I)

Ticagrelor has a low and pH-independent solubility in aqueous media as well as a low permeability. Ticagrelor may exist in various crystalline forms, including solvated forms. Ticagrelor presents polymorphic characteristic. In addition to various crystalline forms, amorphous form is also available. Ticagrelor is a reversible, selective P2Y 12-receptor antagonist (antiplatelet agent) being developed to reduce thromboembolic events in patients with atherosclerosis. It is orally active and does not require metabolic activation. Proposed and granted indication is: “Ticagrelor, co administered with acetylsalicylic acid (ASA), is indicated for the prevention of thrombotic events (cardiovascular death, myocardial infarction and stroke) in patients with Acute Coronary Syndromes (unstable angina, non ST elevation Myocardial Infarction [NSTEMI] or ST elevation Myocardial Infarction [STEMI]) including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery by pass grafting (CABG)”. The dosing regimen is an initial single 180 mg loading dose (two tablets of 90 mg) and then continued at 90 mg twice daily. Treatment is recommended for at least 12 months unless discontinuation of ticagrelor is clinically indicated.

Ticagrelor is a cyclo-pentyltriazolo-pyrimidine that reversibly inhibits the P2Y12 receptor which is a protein found mainly but not exclusively on the surface of blood platelets and which is an important regulator in blood clotting.

Ticagrelor has 6 stereocenters and due to that there are many crystalline and also amorphous forms. Especially, four non- solvated crystalline forms are available, named as Polymorph I, II, III and IV. They all present different physical and chemical properties.

Ticagrelor is marketed by AstraZeneca with trade names of Brilinta and Brilique.

BRILINTA is an oral antiplatelet treatment that works by inhibiting platelet activation. For at least the first 12 months following Acute Coronary Syndrome (ACS), it is superior to other antithrombotic agents like clopidogrel. BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for the treatment of ACS. In the management of ACS, the recommended maintenance dose of BRILINTA is 90mg twice daily during the first year after an ACS event. After one year, patients with a history of heart attack can now be treated with 60mg twice daily. BRILINTA should be used with a daily maintenance dose of aspirin of 75 - 100 mg.

WO9905143 discloses [4,5-d]pyrimidine compounds and its derivatives, including Ticagrelor. WOO 192262 discloses various crystalline forms I, II, III and IV and amorphous forms of Ticagrelor. Pharmaceutical compositions comprising ticagrelor are disclosed in W02008024044 and W02008024045. Oral pharmaceutical compositions which can comprise 20-45% by weight of the active ingredient are explained and they release all the active ingredient substantially. A pharmaceutical composition comprises active ingredient, a filler/diluent consisting essentially of a mixture of mannitol and dibasic calcium phosphate dihydrate, a binder consisting essentially of hydroxypropyl cellulose, a disintegrant consisting essentially of sodium starch glycolate, and one or more lubricants. Wet granulation process is preferred as the manufacturing method.

W02015001489 relates to oral pharmaceutical compositions comprising amorphous ticagrelor and processes for their preparation.

TR2017/15203 discloses a method of manufacture for a formulation comprising ticagrelor, characterized in that the step of granulating the solid mixture wherein the mixture comprises the active agent ticagrelor and at least one water-soluble binder and at least one water-soluble filler that is granulated with a suitable granulation solution. TR2016/01835 discloses a process for producing a formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, characterized in that the ticagrelor or pharmaceutically acceptable salt is dissolved and / or dispersed in a solvent or solvent mixture during manufacture.

EP3332769 relates to a solid oral pharmaceutical composition, comprising ticagrelor or a pharmaceutically acceptable salt thereof with at least one hydrophilic polymer wherein the composition is substantially free of calcium salts and their derivatives.

WO20 14059955 relates to a solid oral pharmaceutical formulation containing ticagrelor as the active pharmaceutical constituent wherein the pharmaceutical composition contains at least one the non-hygroscopic binder, at least one the non-hygroscopic filler and at least one lubricant and substantially no disintegrant.

WO20 18229785 relates to oral pharmaceutical compositions comprising ticagrelor and pharmaceutically acceptable polymer in a ratio of 1:0.1 to 1:1 in the form of solid dispersion. WO2015110952 relates to a composition comprising ticagrelor or salt thereof in an amount less than 20% of the weight of total composition, wherein the composition is devoid of water- insoluble fillers.

CN107397717 discloses a solid preparation of ticagrelor or a pharmaceutically acceptable salt thereof which comprises filler, disintegrant, lubricant, additive and high polymer. The solid preparation is prepared by mixing a filler and ticagrelor or its pharmacy or it is acceptable to salt, adding a lubricant and a disintegrant respectively and mixing the additive and the polymer to form a suitable solid preparation.

CN109700773 relates to a pharmaceutical composition comprising ticagrelor wherein the percentage the ticagrelor of weight at the formulation composition is 2%.

CN201310432438 discloses a solid dispersion comprising ticagrelor in which ticagrelor is dispersed in a carrier material to solve the problem of solubility.

CN106265557 discloses a dispersible tablet formulation comprising ticagrelor in which ticagrelor is in an amount of the total tablet weight 20 to 50% by weight.

WO201 1076749 numbered patent document discloses solid dosage forms comprising ticagrelor, characterized in that at least 90% by volume of ticagrelor particles have a particle size in the range of 1 pm to 150 pm. It further discloses that ticagrelor, being poorly soluble, presents a significant problem in the design of pharmaceutical compositions. Further, in order to exhibit good bioavailability, it is desirable to formulate dosage forms showing fast dissolution of the drug. However, it is stated that these effects are observable only if the ratio of ticagrelor is more that 50% by weight in the composition with the particle size of the drug and by the use of hydrophilic polymers/emulsifiers in the dosage form. Ticagrelor is classified as a BCS class IV compound, exhibiting low solubility and low permeability. This property leads to an undesirable dissolution profile and hence poor bioavailability. It also leads to high intra-subject and inter-subject variability following oral administration.

In the state of the art, the patent application no. EP2056832 discloses an oral pharmaceutical composition comprising ticagrelor and other excipients. The composition is presented as enhancing the bioavailability through increasing the release of the active agent due to the formulation comprising at least one filler, one disintegrant, one diluent, one binder and one lubricant. Ticagrelor has a low aqueous solubility and this characteristic property brings bioavailability and dissolution release profile problems regarding decreases in the solubility of solid formulations. In the state of the art, several methods are followed, different forms of ticagrelor and different excipients are composed to overcome some of these problems. However, there is a need for pharmaceutical preparations that have proper dissolution release profile in correlation with in vivo release profile with improved flow character and compressibility properties.

Summary of the Invention

In one general aspect of this invention is to provide solid pharmaceutical compositions comprising ticagrelor or salt thereof and one or more pharmaceutically acceptable excipients with proper dissolution release profile and in vivo release profile.

In another general aspect of the present invention is related to an oral dosage form composition in concurrent use of acetylsalicylic acid for the treatment of the prevention of atherothrombotic events in adult patients with - acute coronary syndromes (ACS) or

- a history of myocardial infarction (MI) and a high risk of developing an atherothrombotic event.

In another aspect of this invention is to develop an immediate-release solid pharmaceutical formulation comprising ticagrelor or a pharmaceutically acceptable salt thereof, which has improved blend properties prior to tablet compression or filling into the capsule.

In another aspect of this invention relates to an immediate release solid oral composition comprising only ticagrelor as active substance and one or more acceptable excipients manufactured by using optimised wet granulation process.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salt thereof, which composition is in the form of a tablet.

In another general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salt thereof, which composition is in the form of a capsule. One or more pharmaceutically acceptable excipients may be present in the tablets, e.g. at least one filler, at least one binder, at least one disintegrant, at least one glidant, and at least one lubricant, and optionally a coating comprising film forming polymer. In another general aspect, there is provided a solid oral pharmaceutical composition comprising ticagrelor or salt thereof with one or more pharmaceutically acceptable excipients, wherein the composition comprises no more than 80% pharmaceutically acceptable excipients by weight of the composition.

In a preferred embodiment of the present invention, the active agent is crystalline ticagrelor. Preferably, the active agent is ticagrelor polymorph II presenting X-ray powder diffraction pattern containing specific peaks at 5.5° (±0.1°), 6.8° (±0.1°), 10.6° (±0.1°), 13.5° (±0.1°), 14.9° (±0.1°), 18.3° (±0.1°), 19.2° (±0.1°), 22.7° (±0.1°), 24.3° (±0.1°) and 27.G (±0.1°) 2Q. In a preferred embodiment of the present invention, the active agent is ticagrelor polymorph II which is also used in innovator drug product and declared that it is the most stable crystalline form of ticagrelor hat has desired thermodinamic and chemical characteristics.

In another object of the present invention is provide a pharmaceutical compositions containing ticagrelor wherein the total weight of the ticagrelor is between 20 - 30% w/w per solid dosage form.

In another object of the present invention is to obtain a bioequivalent pharmaceutical composition with improved dissolution release profile containing ticagrelor with optimized amounts of excipients manufactured by using optimized parameters of wet granulation method. Detailed Description of the Invention

The present invention provides a solid oral dosage form comprising ticagrelor and optimized amounts of pharmaceutically acceptable excipients manufactured by using the most proper manufacturing method. The present invention relates to an immediate release solid oral composition comprising ticagrelor and one or more acceptable excipients manufactured by using optimised wet granulation process.

Another object of the present invention is to provide a preparation method of a pharmaceutical composition of ticagrelor wherein the pharmaceutical compositions herein disclosed can be manufactured into solid dosage forms, such as tablet, film coated tablet, sachet, capsule having improved granule characteristics and the desired dissolution profiles.

Another object of the present invention is to provide a pharmaceutical compositions containing ticagrelor manufactured by using wet granulation process wherein provided for the manufacture of tablets containing the active ingredient, filler(s), diluent(s), disintegrant(s), glidant(s), and lubricant(s) etc.

Basicly three types of manufactming methods are available in the prior art. Advantageous and disadvantageous of the manufacturing methods are evaluated based on the information and experimental data procured from prior art documents. More specifically the present invention is related to a pharmaceutical composition manufactured by using wet granulation method comprising Ticagrelor, Microcrystalline cellulose, Silicon dioxide in the extragranular phase, Dibasic calcium phosphate in the intragranular phase, wherein lubrication time is between 6 to 12 minutes.

In a preferred embodiment, the composition is in a solid dosage form. In another preferred embodiment, crystalline ticagrelor can be used as ticagrelor. Preferably, ticagrelor is in crystalline form. More preferably crystalline ticagrelor is in the form of polymorph II has a X-ray powder diffraction pattern containing specific peaks at 5.5°, 6.8° , 10.6°, 13.5°, 14.9°, 18.3°, 19.2° , 22.7°, 24.3° and 27.G (±0.1° 2Q).

Pharmaceutical composition preferably further comprises at least one excipient selected from fillers, diluents, disintegrants, binders and lubricants. In a preferred embodiment, the composition comprises mannitol as a diluent. Disintegrant is preferably selected from croscarmellose sodium, crospovidone, low- substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. More preferably the disintegrant is croscarmellose sodium.

Binder is preferably selected from hypromellose, hydroxypropyl cellulose, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. More preferably, the binder is hydroxypropyl cellulose.

Lubricant is preferably selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. More preferably, the lubricant is magnesium stearate.

In another embodiment, quantitative composition in %w/w by weight of the pharmaceutical composition of the invention is stated below:

Ticagrelor 20-30

Mannitol 30-40

Dibasic calcium phosphate 10-20 Hydroxypropyl cellulose 1-4 Croscarmellose sodium 2-4 (intragranular), 1-3 (extragranular) Microcrystalline cellulose 10-20 Silicon dioxide 0.1-2 Magnesium stearate 0.1-4 Deionized water q.s. Coating agent Coating 1-4

The present invention is also provides a wet granulation manufacturing process for the pharmaceutical composition comprising ticagrelor, preferably crystalline ticagrelor as polymorph II, comprising the following steps: a. Ticagrelor, mannitol, dibasic calcium phosphate, specified amount of croscarmellose sodium were stirred in high-shear granulator for 5 minutes. b. Hydroxypropyl cellulose was dissolved in deionised water and added on the powder blend in step a and granulation process was performed with stirring. c. Granule obtained in step b was sifted and dried at a specified temperature. d. Dried granule was sifted and silicon dioxide, microcrystalline cellulose and the remaining amount of croscarmellose sodium was added through screening. e. Powder blend obtained in step d was lubricated with magnesium stearate for 6 to 12 minutes. f. Final blend in step e was subjected to tablet compression process. g. Tablets obtained in step f were coated with a proper film coating agent.

Quality by Design (QbD) principles were applied to the development of the ticagrelor comprising pharmaceutical composition. The critical quality attributes that have the potential to affect product performance have been identified using the principles as outlined in ICH Q8 and Q9 guidelines.

Solubility of ticagrelor is very low (not ionised in the pysiological pH range) and exhibits a moderate intrinsic permeability, there is potentially a higher risk that changes in formulation and processing parameters can affect clinical performance, and this was taken into account during development. Moreover, this low aqueous solubility of ticagrelor leads to an increase of relevance of particle size. Solubility studies in human intestinal fluids, bulk-tapped density, compressibility index, Hausner ratio, flowability studies of drug substance were performed prior to beginning of the development process of pharmaceutical drug product.

As shown in table above, ticagrelor solubility is very low in pysiological pH range.

In addition, bulk density and tapped density values of ticagrelor was investigated. By using the results obtained, compressibility index, Hausner ratio calculated and flowability of drug substance was evaluated according to international pharmacopeias such as US Pharmacopeia.

Drug substances with poor aqueous solubility and poor dissolution in the GI fluids is a limiting factor to the in vivo bioavailability after oral administration. Therefore, in vitro dissolution has been recognized as an important element in drug development and thus increasing the dissolution rate of poorly soluble drugs and enhancing their bioavailability is an important challenge to formulation designation studies.

Ticagrelor containing pharmaceutical drug products are designed based on all investment studies explained above. Micronizing particle size values and designation of polymorphism are the main approaches to improve physicochemical and biopharmaceutical properties of the poorly soluble drugs, thereby improving their solubility. These approaches are used for ticagrelor also.

Moreover, particle size distribution analysis for ticagrelor was performed. Results are shown in the table below. Polymorphism is a direct impact on physical and chemical properties of drug substance. Based on this information XRD anaysis was performed and confirmed that the drug substance used was polymorph II as it is in the innovator drug product.

In a preferred embodiment, suitable fillers may comprise but not limited to dibasic calcium phosphate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. The most preferred filler is microcrystalline cellulose.

In a preferred embodiment, the pharmaceutical composition comprises at least a disintegrant, preferably, it is selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. More preferably, the disintegrant is croscarmellose sodium.

In a preferred embodiment, suitable diluents may comprise but not limited to dibasic calcium phosphate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. The most preferred diluent is mannitol, silicon dioxide and dibasic calcium phosphate or a mixture thereof, preferably is a mixture thereof. In a preferred embodiment, the binder may be, for example, hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. The binder is dissolved in a solvent, for instance, water, an alcohol, or mixtures thereof. In particularly advantageous embodiments of the present invention, the binder solution is hydroxypropyl cellulose dissolved in water.

In a preferred embodiment, the pharmaceutical composition comprises at least a lubricant, preferably, it is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. More preferably, the lubricant is magnesium stearate.

In order to obtain a targetted product profile, quality attributes have been defined and discussed, the manufacturing process has been selected based on these aspects and a control strategy has been defined.

Beginning from the well-known prior art documents and based on experimental studies, multiple formulations were designed to overcome challenges directly affects dissolution profile and granule characteristics of pharmaceutical compositions comprising ticagrelor. In a preferred embodiment, formulation design

Manufacturing method:

1. Ticagrelor, mannitol, dibasic calcium phosphate, croscarmellose sodium were stirred in high-shear granulator for 5 minutes.

2. Hydroxypropyl cellulose was dissolved in sufficient quantity of deionised water.

3. The solution obtained in step 2 was added on the powder blend in step 1 and granulation process was performed with stirring. 4. Granule obtained in step 3 was sifted and dried at a specified temperature.

5. Dried granule was lubricated with magnesium stearate by mixing for 3 minutes.

6. Final blend in step 5 was subjected to tablet compression process.

7. Tablets obtained in step 6 were coated with a proper film coating agent.

Regarding the disadvantages observed during investigating the active substance, ticagrelor, characteristics, Formulation I was analyzed for granule properties, such as bulk density, tapped-density. Moreover, Hausner ratio, Carr index (compressibility index) were calculated by using bulk density, tapped-density and specified.

Flowability is described and scaled based on compressibility index and Hausner ratio in US Pharmaceopeia. The parameters of compressibility index and Hausner ratio are calculated by using bulk and tapped density properties.

Bulk and tapped densities were analyzed according to analytical methods described in US pharmacopeia.

The results of analysis for bulk and tapped densities were presented in the table below and Hausner ratio and compressibility index parameters were calculated by using them based on the methods in US pharmacopeia: Evaluation of powder properties was done based on matching the results obtained with the proper compressibility index and Hausner ratio designated in the table taken form US pharmacopeia. Flow character of powder blend was found poor.

The flowability of granule was poor due to drug substance characteristics. Altough formulation I was designed to overcome the identified problems, flowability problem was not improved as it was targetted. Also, stickiness was observed during compression process.

Observations during and after manufacturing process:

Poor flowability of powder blend,

Stickiness during compression process,

Very fine particulate after drying process.

In order to overcome the problems mentioned above many modifications were planned to be performed.

To improve the flowability and prevent stickiness;

Diluents used in the formulation I, were dibasic calcium phosphate and mannitol. A third diluent was planned to be added into the granulation process which is silicon dioxide. It is known from the prior art that silicon dioxide helps to improve the flowability of powders by acting to counteract different mechanisms. The nature of silicon dioxide allows it to attract and preferentially bind moisture, helping to eliminate liquid bridges between solid particles that hinder powder flow.

Silicon dioxide incorporated in powder during the granulation means uniform flow through the equipment. This can boost consistency during the tabletting process and provide improvement in the physico-chemical properties like friability, hardness, structural stability with content uniformity, easy tabletting processes and high resistance to sticking. Moreover, the large internal porosity silicon dioxide provides greater capacity for water included in the formulation.

Moreover, use of silicon dioxide in tabletting process has advantageous regarding performing the process with lower compression force. Thus, physico-chemical properties of the next formulation was planned to be improved. To obtain drug product with proper disintegration and dissolution characteristics; Croscarmellose sodium used as disintegrant in the previous formulation was kept constant however it was planned to be added in both the wet and dry stages of the process (intra- and extragranularly) so that the wicking and swelling ability of the disintegrant is best utilized.

Regarding these modifications, hydroxypropyl cellulose that was used in the formulation as binder was planned to be in solution form as dissolving into the deionized water. Thus, while obtaining a powder blend with proper physico-chemical characteristics dissolution profile was also under control.

The amounts of excipients were also adjusted according to the modifications that were planned to be performed. For example,

Manufacturing method:

1. Ticagrelor, mannitol, dibasic calcium phosphate, specified amount of croscarmellose sodium were stirred in high-shear granulator for 5 minutes. 2. Hydroxypropyl cellulose was dissolved in deionised water and added on the powder blend in step 1 and granulation process was performed with stirring.

3. Granule obtained in step 2 was sifted and dried at a specified temperature. 4. Dried granule was sifted and silicon dioxide, microcrystalline cellulose and the remaining amount of croscarmellose sodium was added through screening.

5. Powder blend obtained in step 4 was lubricated with magnesium stearate for 3 minutes and then extra 6 minutes. Lubrication time was totally 9 minutes. 6. Final blend in step 5 was subjected to tablet compression process.

7. Tablets obtained in step 6 were coated with a proper film coating agent.

Observations during and after manufacturing process: flowability of powder blend was improved, - stickiness during compression process was improved, appearance of granule particulates after drying process was easier to process.

Results of bulk and tapped densities and calculated Hausner ratio and compressibility index were presented in the table below:

Evaluation of powder properties was done based on matching the results obtained with the proper flow character. Flow character of powder blend was found fair.

Obtained tablets were analyzed for disintegration time accroding to USP<701> Disintegration analytical method, the result is about 1 minute which is good for immediate release solid dosage forms. Thus, in vitro dissolution profile analysis was performed on the obtained tablets.

Dissolution conditions are as in the following:

Dissolution medium: Water + 0.2% Polysorbate 80

Volume of dissolution medium: 900 ml

Apparatus: Paddle

Temperature: 37±0.5°C

Time: 75 minutes

Rotation speed: 50 rpm In addition, disintegration time result is also the indication for dissolution rate and it is known from the prior arts that in vitro studies have lineer correlation with in vivo drug release.

Results of dissolution analysis Comparison of dissolution profiles is shown in the graph presented as Fig. 1.

During lubrication, it was observed that mixing time of magnesium stearate was the critical parameter to overcome stickiness at tablet compression process. Totally 9 minutes of lubrication time was perfomed in manufacturing of formulation II.

In another embodiment designated as Formulation III, was designed to optimize lubrication time in manufacturing process of formulation II. Manufacturing method: 1. Ticagrelor, mannitol, dibasic calcium phosphate, specified amount of croscarmellose sodium were stirred in high-shear granulator for 5 minutes.

2. Hydroxypropyl cellulose was dissolved in deionised water and added on the powder blend in step 1 and granulation process was performed with stirring. 3. Granule obtained in step 2 was sifted and dried at a specified temperature.

4. Dried granule was sifted and silicon dioxide, microcrystalline cellulose and the remaining amount of croscarmellose sodium was added through screening.

5. Powder blend obtained in step 4 was lubricated with magnesium stearate for a specied range of duration to get two more different types of the formulation. 6. Final blend in step 5 was subjected to tablet compression process.

7. Tablets obtained in step 6 were coated with a proper film coating agent. minutes. Formulation III_A; Same manufacturing method with Formulation III with lubrication time of 6 minutes.

Formulation III_B; Same manufacturing method with Formulation III with lubrication time of 12 minutes.

Comparison of dissolution profiles is shown in the graph presented as Fig. 2.

As it is observed from the graph, all of Formulation III modified accroding to lubrication time presents similar in vitro dissolution profiles with respect to innovator drug product with adjustment of lubrication time. The limiting factor for the appearance of the drug in the blood could be the pure permeability through the intestinal membrane the release from the drug dosage form, or the solubility of the active ingredient. In case of solubility-limited product, the absorption could be improved by physico-chemical characteristics of the drug product (such as solubility, disintegration time, dissolution rate) that is gained with formulation based modifications.

Based on this information, obtaining proper in vitro dissolution results will lead the formulation to achieve proper in vivo profile.

According to “Guideline on the Investigation on Bioequivalence” published by EMA, to establish bioequivalence of the test product with that of reference product, 90% Confidence Interval (Cl) for the ratio (Test/Reference) of Least Square Means of the Ln transformed PK parameters (AUQ and C_max) must fall between 80.00% to 125.00%.

In-vivo Bio-equivalence study results

PK parameters (AUQ and C_max) are in line with the specifications based on Guideline on the Investigation on Bioequivalence.

Both in-vitro and in-vivo release profile of the drug product comprising microcrystalline cellulose together with silicon dioxide manufactured by using high-shear granulator at optimized lubrication time.

It was surprisingly found that the use of microcrystalline cellulose together with silicon dioxide both in the extragranular and dibasic calcium phosphate in the intragranuar phases with optimized lubrication time range directly affects the compressibility process and in vitro dissolution profile of solid dosage form comprising ticagrelor as active ingredient. Optimized lubrication time is between 6 to 12 minutes. While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Brief description of the drawings:

Fig.l Comparative dissolution profiles of Formulation II and Innovator drug product

Fig.2 Comparative dissolution profiles of Formulation II, III_A, IIIB and Innovator drug product

Claims

1. A pharmaceutical composition manufactured by using wet granulation method comprising

- Ticagrelor, and

- Dibasic calcium phosphate in the intragranular phase, - Microcrystalline cellulose, and

- Silicon dioxide in the extragranular phase, wherein lubrication time is between 6 to 12 minutes.

2. A pharmaceutical composition according to claim 1, wherein the composition is in a solid dosage form.

3. A pharmaceutical composition according to any one of the preceding claims, wherein ticagrelor is in crystalline form.

4. A pharmaceutical composition according to claim 3, wherein crystalline ticagrelor is in the form of polymorph II has a X-ray powder diffraction pattern containing specific peaks at 5.5°, 6.8°, 10.6°, 13.5°, 14.9°, 18.3°, 19.2° , 22.7°, 24.3° and 27.1° (±0.1° 2Q).

5. A pharmaceutical composition according to any one of the preceding claims, wherein the composition further comprises at least one excipient selected from fillers, diluents, disintegrants, binders and lubricants.

6. A pharmaceutical composition according to claim 5, wherein the composition comprises mannitol as a diluent.

7. A pharmaceutical composition according to claim 5, wherein a disintegrant is selected from croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof, preferably the disintegrant is croscarmellose sodium.

8. A pharmaceutical composition according to claim 5, wherein binder is selected from hypromellose, hydroxypropyl cellulose, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof.

9. A pharmaceutical composition according to claim 8, wherein the binder is hydroxypropyl cellulose.

10. A pharmaceutical composition according to claim 5, wherein lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof, preferably the lubricant is the lubricant is magnesium stearate.

11. A pharmaceutical composition according to any one of the preceding claims wherein the quantitative composition in %w/w by weight of the pharmaceutical composition is as stated below:

Ticagrelor 20-30

Mannitol 30-40

12. A wet granulation manufacturing process for the pharmaceutical composition comprising crystalline ticagrelor as polymorph II, comprising the following steps: a. Ticagrelor, mannitol, dibasic calcium phosphate, specified amount of croscarmellose sodium were stirred in high-shear granulator for 5 minutes. b. Hydroxypropyl cellulose was dissolved in deionised water and added on the powder blend in step a and granulation process was performed with stirring. c. Granule obtained in step b was sifted and dried at a specified temperature. d. Dried granule was sifted and silicon dioxide, microcrystalline cellulose and the remaining amount of croscarmellose sodium was added through screening. e. Powder blend obtained in step d was lubricated with magnesium stearate for 6 to 12 minutes. f. Final blend in step e was subjected to tablet compression process. g. Tablets obtained in step f were coated with a proper film coating agent.