A stable immediate release ticagrelor tablet composition

Abstract

The present invention relates to an oral solid dosage form comprising ticagrelor as pharmaceutically active ingredient and at least one excipient. In particular, the present invention relates to a process for producing an immediate release ticagrelor tablet composition which is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant in order to produce stable in vitro dissolution profile throughout the shelf-life.

Description

[0001]A STABLE IMMEDIATE RELEASE TICAGRELOR TABLET COMPOSITION DESCRIPTION Technical field: The present invention interests an oral solid dosage form featuring ticagrelor as the active pharmaceutical ingredient. It describes a method for manufacturing an immediate- release ticagrelor tablet that maintains a consistent and satisfactory in vitro dissolution profile over its shelf-life. Prior Art: Ticagrelor is the most recent and most effective antiplatelet agent used to inhibit platelet aggregation via blocking the ADP receptors of the subtype P2Y12. It is a non- thienopyridine class drug. The drug was first discovered by Astra Zeneca and approved for use in 2011 by the FDA. Ticagrelor is the drug of choice for the prevention and treatment of thromboembolism in adult patients with acute coronary syndrome. Ticagrelor is a crystalline powder with low aqueous solubility of about 10 mg / L across the entire pH range. It is established that it has several polymorphs. Ticagrelor was first described in WO 99 / 05143 and can be prepared according to the methods disclosed in this patent. WO 01 / 92262 definitely states that ticagrelor exists in four different crystalline forms and an amorphous form. Ticagrelor has four non-solvated polymorphs (Polymorph I, II, III and IV) and a number of solvated crystalline modifications, which can be distinguished by X-ray powder diffraction. It does not convert to any other form when stored. Ticagrelor belongs to class IV compound according to the biopharmaceutical classification system (BCS), which means it has low solubility in water and low permeability. Its chemical name is 1S-[1α,2α,3β (1S*,2R*),5β]-3-(7-[2-(3,4- difluorophenyl)cyclopropyl]amino-5-(propylthio) -3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)- 5-(2-hydroxyethoxy)cyclopentane-1,2-diol. Its empirical formula is C23H28F2N6O4S, and its molecular weight is 522.57 Da. Ticagrelor structural formula is as follows; Ticagrelor is an oral, direct-acting P2Y12 receptor antagonist. In vitro studies have definitely shown that ticagrelor binds reversibly and non-competitively to the P2Y12 receptor at a site distinct from that of the endogenous agonist adenosine diphosphate (ADP). This antiplatelet drug helps blood flow through the veins, reducing the likelihood of dangerous blood clots. Ticagrelor is used to prevent strokes, heart attacks and other events in people with acute coronary syndrome, which is a problem with the blood supply to the coronary arteries. It is marketed under the brand names Brilinta® in the US and Brilique® in the EU in 60 mg and 90 mg oral tablets. The pharmaceutical compositions comprising ticagrelor are disclosed in WO 2008 / 024044 and WO 2008 / 024045. The compositions, which may contain up to 50% by weight of the active ingredient, are suitable for oral administration and release substantially all of the active ingredient. The compositions are prepared using a conventional wet granulation process. Ticagrelor faces challenges as a pharmaceutically active compound due to its low solubility. This poor solubility presents significant problems in formulating effective pharmaceutical products. Ticagrelor has minimal solubility in neutral media such as water. Therefore, water is the preferred medium for assessing non-bioequivalence in dissolution studies. The development of solid oral dosage forms containing ticagrelor will achieve formulations with high dissolution rates in water. These dosage forms must demonstrate strong dissolution properties in the first fluid, simulating gastric juice, during dissolution testing. Given ticagrelor's low solubility and moderate intrinsic permeability, it is clear that changes in formulation and processing parameters could affect its clinical efficacy. This has been given due consideration during development. Furthermore, the low aqueous solubility of the compound highlights the critical role of particle size in formulation. Studies have been conducted with the specific aim of improving the solubility of the active ingredient, ticagrelor. EP2515871 B1 reports the development of solid dosage forms of ticagrelor with a D90 value in the range of 1-150 µm, which have the desired solubility and bioavailability. For oral administration of such poorly soluble substances, the limiting factor in drug absorption is the dissolution rate. It therefore essential to improve the dissolution rate in pharmaceutical processing throughout the shelf life, as this has a significant impact on bioavailability. It is therefore desirable to provide a pharmaceutical composition which, in addition to releasing all of the active ingredient, provides rapid dissolution of the active ingredient while maintaining the desired release throughout the shelf life. Furthermore, it is essential to provide a pharmaceutical composition that is simple to prepare and stable over its shelf life retaining the beneficial properties of rapid solubility and bioavailability, particularly from the point of view of patient compliance. The present invention solves these problems. Description of the Invention: The objective of the present invention is to produce a stable solid oral pharmaceutical composition comprising therapeutically effective amount of ticagrelor and at least one excipient. According to one embodiment of the present invention, there is provided a stable pharmaceutical tablet composition comprising ticagrelor wherein said tablet composition comprises 4%-7% disintegrant by weight based on total weight of the composition which is present both in internal phase and in external phase. According to one embodiment of the present invention, there is provided a formulation for producing an immediate release tablet composition that ticagrelor is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant and at least one other excipient, wherein said tablet composition comprises 4%-7% disintegrant by weight based on total weight of the composition which is present both in the internal phase and in the external phase. According to one embodiment of the present invention, there is provided a formulation for producing an immediate release tablet composition that ticagrelor is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant and at least one other excipient, wherein said tablet composition comprises totally 4%-7% disintegrant by weight based on total weight of the composition and the disintegrant ratio in the internal phase and external phase is 1:1. According to one embodiment of the present invention, there is provided a formulation for producing an immediate release tablet composition with a ticagrelor active substance particle size of D90 between 5 µm and 50 µm. According to one embodiment of the present invention, there is provided a formulation for producing an immediate release tablet composition that ticagrelor is wet granulated with croscarmellose sodium or sodium starch glycolate as a disintegrant, hydroxypropyl cellulose as a binder and a mixture of mannitol and dibasic calcium phosphate as a filler / diluent to form the internal phase. When formulating a compound into a tablet or other solid dosage form, the objective is to develop a storage stable formulation that can withstand temperatures and relative humidity levels above those typically encountered. A formulation should also be designed to have other desirable properties, such as fast dissolution, so that the tablet quickly dissolves and the drug is available for absorption. Accordingly, the present invention aims to exhibit good storage stability and fast dissolution. The present invention produced a stable and solid oral pharmaceutical composition that contains ticagrelor. This composition has an in-vitro dissolution profile that is comparable to that of Brilique® Tablets. Pharmaceutical companies are committed to enhancing the quality of their products and accelerating drug development while simultaneously pursuing innovative strategies to reduce costs. There are three main processes for making compressed tablets: wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and choice of excipients are carefully selected to achieve the desired physical characteristics of the tablet formulation, allowing for efficient compression of the tablets. In one aspect the invention relates to a pharmaceutical composition prepared by wet granulation. Granulation is the process by which primary particles (powders) are made to adhere and form larger, multiparticulate entities called granules. Granulation normally commences after initial dry mixing of the powdered ingredients to ensure a uniform distribution of ingredients throughout the mix. Granulation methods can be divided into two types: wet granulation methods that utilise a liquid to form the granules and dry methods that do not. Wet granulation involves massing the primary powder particles using a granulating fluid. The fluid contains a solvent that can be removed by drying and is non-toxic. The granulating fluid can be used alone or more typically with a binding agent (binder) to ensure article adhesion in the dry state. Binding agents can be added to the system in two ways: as a binder solution (as part of the granulating fluid) or as dry material mixed with the primary powder particles. There are three main types of wet granulator: shear granulators, high shear mixer granulators and fluid bed granualtors. High shear wet granulation is a process that involves intensive dry mixing of primary powders and subsequent addition of granulating fluid, resulting in the formation of granules. The granulating fluid contains a volatile solvent (usually water) and may also include a binder; which ensures particle adhesion. Binders may also be added dry as powders to the bulk of the formulation to be granulated. Granules have significant advantages over powders in terms of improved flow properties, reduced risk of segregation and increased homogeneity. (Source: Aulton ME, Pharmaceutics- The Science of Dosage Form Design, 2nd Edition, 2002, Churchill Livingstone.) The term "active substance" or "active pharmaceutical ingredient" refers to any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active substance is ticagrelor or its pharmaceutically acceptable salts thereof, particularly ticagrelor. In the present invention, the active substance ticagrelor is present with a particle size of D90 between 5 µm and 50 µm. The use of a small particle size raw material is essential to promote the release of the compound’s low aqueous solubility. The most common approach to defining the distribution width is to cite three values on the x-axis as D10, D50 and D90. The D50, also known as the median, is the diameter where 50 percent of the distribution lies below this value. Similarly, D90 is defined as 90 percent of the distribution lying below, with 10 percent of the population lying below the D10. The term “therapeutically effective amount” refers to the amount of ticagrelor or its pharmaceutically acceptable salts, esters, and solvates thereof, that is sufficient to effect treatment when administered to a subject in need of such treatment, as defined herein. The tablet composition of the present invention comprises 90 mg and 60 mg of ticagrelor. The term "immediate release" as described herein refers to the release of the active ingredient immediately upon reaching the stomach. In this context, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other complications commensurate with a reasonable benefit / risk ratio. In addition to the active or therapeutic substances, tablets contain a number of inert materials known as excipients, which are essential for their function. The pharmaceutical compositions described herein can include one or more pharmaceutically acceptable excipients, if desired. The term "excipient" refers to any substance that is not itself a therapeutic agent. It can be used as a carrier or vehicle for the delivery of a therapeutic agent to a subject. It can also be combined with a therapeutic agent (e.g. to create a pharmaceutical composition) to improve its handling or storage properties. It can also be used to permit or facilitate the formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralising agents, if necessary), penetration enhancers, solubilising agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odour, fragrances or taste, and substances added to improve appearance or texture of the composition. Such excipients can be used in any dosage forms, as set forth in the present disclosure. The foregoing classes of excipients are not exhaustive. There are merely illustrative as a person of ordinary skill in the art would recognise that additional types and combinations of excipients could be used to achieve the desired goals for release and stability of ticagrelor tablet composition. The present invention relates to an oral solid dosage form comprising ticagrelor and at least one excipient. Preferably, ticagrelor tablet comprises at least one binder, at least one filler (diluent), at least one disintegrant and at least one lubricant. The excipients can be classified according to their role they play in the final tablet. Excipients are typically added to a formulation to impart good flow and compression characteristics to the material being compressed. The lubricant is typically added to prevent the tableting materials from sticking to punches, minimise friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts of less than 1% by weight. The composition comprises at least one lubricant selected from the group comprising magnesium stearate, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate or mixtures thereof. In the present invention, magnesium stearate is selected. The filler (diluents) is added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary when the dose of the drug is relatively small. According to one embodiment of the invention, the composition comprises at least one filler (diluent) selected from the group comprising microcrystalline cellulose, lactose, mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, inorganic phosphates, like dibasic calcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin , sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or mixtures thereof. In the present invention, mixture of mannitol and dibasic calcium phosphate is selected. The binders are agents, which impart cohesive qualities to the powdered material. According to one embodiment of the invention, the composition comprises at least one binder selected from the group comprising polyvinyl pyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacrylate, or mixtures thereof. In the present invention hydroxypropyl cellulose is selected. The disintegrants are included to decompose the tablet in the gastrointestinal fluid in order to ensure that the tablet has an acceptable rate of disintegration. According to one embodiment of the invention, the composition comprises at least one disintegrant selected from the group comprising croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycollate, starch, pregelatinised starch, alginic acid and alginates, ion exchange resins, magnesium aluminium silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof. In the present invention, sodium starch glycollate and croscarmellose sodium are selected for disintegrant. Croscarmellose sodium and sodium starch glycolate are superdisintegrants that promote tablet disintegration by swelling and wicking mechanisms. When in contact with water, the omni-directional increase in the croscarmellose sodium particle size pushes the tablet apart. The wicking action draws water into the tablet, which effectively disrupts the intermolecular forces between particles in the tablet. The disintegrant amount is set at 4 to 7% to ensure continuity of stability, given the moisture retention properties of the disintegrants. The pharmaceutical dosage form according to the present invention comprising ticagrelor may be present in form of a tablet which is coated with one or more coating materials. The coating materials are not limited and are known to the person skilled in the art. Finding suitable excipients for a particular active substance and determining the appropriate manufacturing process for the combination of excipient and active substance is a challenging task when designing a pharmaceutical product such as a tablet. The excipients may be distributed partly in the internal (granular) phase and partly in the external phase, as seen in the described invention. In the present invention, the disintegrant is distributed in the internal and external phase. The binder and filler / diluent are only part of the internal phase, whereas the lubricant is only part of the external phase. The internal phase excipients, e.g. filler / diluent, binder and part of disintegrant, and the drug substance are mixed and granulated with an aqueous solution. The granulate is then dried and sieved. The external phase, which contains, for example, part of the disintegrant and lubricant, is screened with the dried granulate and mixed. The mixture is compressed into tablets. The granulate phase is defined as the ‘internal phase’, the excipients added to the granulate are defined as the ‘external phase’ of the tabletting mixture. It is essential to develop a stable formulation that can withstand higher temperatures and relative humidity levels than those typically encountered when formulating a compound into a tablet or another solid dosage form. It is also important to consider other desirable properties, such as fast dissolution, to ensure that the drug is quickly available for absorption. The present invention achieves excellent storage stability and fast dissolution, along with other highly desirable characteristics. The following examples represent various embodiments of the present invention. The examples are provided for illustrative purposes only on and do not limit the scope of the present invention. There are numerous variations that fall within the spirit and scope of the invention. Examples: The present invention provides a stable pharmaceutical dosage form for oral administration comprising ticagrelor and exhibiting an immediate drug release profile. Furthermore, the pharmaceutical composition shall be bioequivalent to reference product and meet the acceptance criteria for generic products and must be stable under different storage conditions. Example 1. Compositions prepared by wet granulation process The present invention comprises a method of preparing a pharmaceutical composition comprising a pharmaceutically effective amount of ticagrelor or pharmaceutically ассерtаblе salts thereof, a filler which is a mixture of mannitol and dibasic calcium phosphate dihydrate; a binder which is hydroxyl propyl cellulose; a lubricant which is magnesium stearate, and a disintegrant which is sodium starch glycollate or croscarmellose sodium. In the present invention, internal phase was prepared with wet granulation of the required amounts of active ingredient ticagrelor, filler which is a mixture of mannitol and dibasic calcium phosphate dihydrate; binder which is hydroxyl propyl cellulose and part of disintegrant which is sodium starch glycollate or croscarmellose sodium. Once the granulation and drying processes were complete, the prepared granule was mixed with the external phase which comprised the rest of the disintegrant (sodium starch glycollate or croscarmellose sodium) and required amounts of lubricant (magnesium stearate). The final blends were compressed using a rotary tablet press. To demonstrate the relationship between the percentage ratios of disintegrant used in the internal and external phases of the final tablet, we have conducted a series of formulation trials. Table 1. Unit formula for Ticagrelor Tablet % Component F-01 F-02 F-03 F-04 F-05Internal phase Ticagrelor 30 30 30 30 30 Mannitol 41.5 40.5 39.5 38.5 41.5 Dibasic calcium phosphate 21 21 21 21 21 dihydrate Hydroxypropyl cellulose Sodium starch glycolate - - 3.0 3.5 4.0 Croscarmellose sodium 2.0 2.5 - - - External phase Sodium starch glycolate - - 3.0 3.5 - Croscarmellose sodium 2.0 2.5 - - - Magnesium stearate 1 1 1 1 1 Example 2. In-Vitro Dissolution Drug dissolution is a critical factor affecting the rate of systemic absorption. A variety of in vitro methods have been developed for assessing the dissolution properties of pharmaceutical formulations. Dissolution testing is sometimes used as a surrogate for the direct evaluation of drug bioavailability (Source Emmanuel et al., Pharmaceutics (2010), 2:351-363). Dissolution testing measures the percentage of the active substance released from the drug product (i.e., tablet or capsule) and dissolved in the dissolution medium under controlled testing conditions over a defined period of time. To maintain sink conditions, the saturation solubility of the drug in the dissolution media should be at least three times the drug concentration. For low solubility compounds, dissolution may sometimes be determined under non-sink conditions. Dissolution is affected by the properties of the active substance (e.g., particle size, crystal form, bulk density), the composition of the drug product (e.g., drug loading, excipients), the manufacturing process (e.g., compression forces) and the stability under storage conditions (e.g., temperature, humidity). In the present invention, the tablets were tested in a USP 2 apparatus with paddles spinning at 75 rpm, in 900 mL of 0.2% w / v Polysorbate 80 in water at a temperature of 37°C±0.5oC (FDA Dissolution Methods Database, 25.06.2015). An in-vitro comparative dissolution test was performed for test and reference products in accordance to the Guideline on Investigation of Bioequivalence, was performed using the chosen dissolution conditions (900 mL dissolution medium, paddle at 75 rpm at 37oC ±0.5oC at 0.2% w / v Polysorbate 80 in water medium). The above exemplified compositions (Formulations F-01 to F-05) comprising ticagrelor were tested in vitro and found to be comparable to a commercial reference product Brilique® Tablet. Comparative dissolution data were generated for the ticagrelor tablet of Example 1 (F- 01 to F-05) with reference product Brilique® Tablet. An example for the comparison of dissolution profile prepared by Example 1 (F-04) and reference product is shown in Figure 1. The dissolution profiles were compared and evaluated using the similarity factor (f2) (Helmy & Bedaiwy, 2013). An f2value between 50 and 100 indicates that the all- dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010). The similarity factor (f2) values of the test products (Formulations F-01 to F-05) and the reference product (Brilique® Tablet) for the different pH media are found between 50 and 100. Example 3. Stability Studies It is crucial to ensure that the stability of a drug substance in order to manufacture safe and effective pharmaceutical products. Any applicant seeking approval for a new pharmaceutical product must submit stability studies. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP / ICH / 2738 / 99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities. However, it is imperative to prevent or reduce degradation much as possible to avoid exposing patients to substances. The stability of a pharmaceutical dosage form is contingent upon the maintenance of its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, specifically within a designated container and environment. Physical stability means that the formulation is totally unchanged throughout its shelf-life and has not undergone any changes in appearance, organoleptic properties (colour, odour and taste), hardness, brittleness or particle size. Furthermore, physical stability affects the pharmaceutical product’s elegance, drug content uniformity and drug release rate. It is essential that the general appearance of a tablet, its visual identity and overall elegance, is maintained for consumer acceptance and lot-to-lot uniformity, general tablet-to-tablet uniformity, and for monitoring trouble-free manufacturing. The general appearance of tablets must be controlled by measuring a number of characteristics, including size, shape, colour, odour, taste, surface texture, physical flaws and consistency, and legibility of any identifying markings. Physical properties must remain stable during storage. Changes in physical properties, such as disintegration times, dissolution rates or tablet hardness, can affect product performance. Decreases in dissolution rate on storage under International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) stability testing conditions, used to assign product shelf life, will reduce the bioavailability of the active substance. USP methodologies for disintegration times and dissolution testing are the best way to measure physical property stability. The compositions must be chemically stable. Degradation by oxidation, hydrolysis, isomerisation, photolysis, polymerisation or any other method of degradation, either as a result of mixing with excipients or by any other method, will lead to a reduction in bioavailability. Chemical stability can be determined by a suitable, stability indicating chromatographic method for determining degradation products. It is well-established that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues. Even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable. It makes therapy with the drug less certain. Environmental factors such as humidity and temperature can cause stability issues. However, degradation will result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients or impurities contained in any of these excipients. The stability tests were performed in accordance with the EMEA Guideline on Stability Testing (CPMP / QWP / 122 / 02, rev 1). The product was maintained in its container at a temperature of 40°C ± 2°C and 75% ± 5% RH (Relative Humidity) for six months and at a temperature of 25°C ± 2°C and 60% ± 5% RH for twenty-four months. The stability studies demonstrated that no unexpected degradation or impurity formation occurred in the test and reference products. The resulting tablets demonstrated consistent content uniformity at the initial state and throughout the stability studies. The formulations have been proven to be chemically and physically stable under accelerated and long-term stability test conditions. The in-vitro release of the low solubility ticagrelor active substance was aimed to remain the same over time. The release of the test products and the reference product were analysed under time-dependent stability conditions (Table 2). Table 2. Comparison of in-vitro dissolution results for Test products (F-01 to F-05) and Reference product at accelerated and long term stability conditions Dissolution* (After 45 minutes) F-01 F-02 F-03 F-04 F-05 Reference Product Initial To 93 94 95 95 94 94 After 6 months at 40oC 86 92 93 93 82 78 After 6 months at 25oC 88 93 94 94 84 81 After 24 months 80 The stability results clearly show that the in-vitro release of the product is affected by the amount of disintegrant and the usage of internal phase / external phase in the formulation. It therefore evident that in vitro release shows a decrease in shelf-life stability, particularly in the compositions without disintegrant in the external phase. The results clearly showed that using the same amount of disintegrant in both the internal and external phases together solved the existing problem. This invention provides a solution to the challenge of ensuring that ticagrelor, a medication used to prevent blood clots, remains effective and reliable throughout its storage period. This process optimises the formulation and production techniques to deliver a high-quality tablet that consistently meets dissolution criteria. This enhances the therapeutic efficacy and stability of the ticagrelor dosage form. Example 4. Bioequivalence study As per USFDA guideline titled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study." The tablets produced with the present invention (F-04) are bioequivalent to the reference product Brilique® with the bioequivalence study conducted in normal, healthy, adult, female subjects under fasting conditions. FIGURES Figure 1. Comparison of in vitro dissolution profile for Test product (F-04) and Reference product (BriliqueTablet)

Claims

CLAIMS 1. A stable pharmaceutical tablet composition comprising pharmaceutically effective amount of ticagrelor or pharmaceutically ассерtаblе salts thereof, wherein said tablet composition comprises 4%-7% disintegrant by weight based on total weight of the composition which is present both in the internal phase and in the external phase.

2. The stable tablet composition according to claim 1, wherein the active substance is ticagrelor.

3. The stable tablet composition according to claim 1, wherein the composition is in the form of immediate release tablet.

4. The stable tablet composition according to claim 1, wherein the disintegrate is sodium starch glycolate.

5. The stable tablet composition according to claim 1, wherein the disintegrant is croscarmellose sodium.

6. The stable tablet composition according to claim 1, wherein the disintegrant ratio in the internal phase and external phase is 1:

1.

7. The stable tablet composition according to claim 4, wherein the composition comprises sodium starch glycolate 6%-7% by weight based on total weight of the composition.

8. The stable tablet composition according to claim 5, wherein the composition comprises croscarmellose sodium 4%-5% by weight based on total weight of the composition.

9. The stable tablet composition according to claim 2, wherein the active substance ticagrelor is present with a particle size of D90 between 5 µm to 50 µm.

10. The stable tablet composition according to claim 1, wherein the composition is prepared by wet granulation process.

11. The stable tablet composition according to claim 10, wherein the internal phase is prepared by granulating ticagrelor, filler / diluent, binder, and part of disintegrant with an aqueous solution.

12. The stable tablet composition according to claim 11, wherein the external phase comprising part of the disintegrant and lubricant are mixed with the internal phase and the mixture is compressed into tablets.

13. The stable tablet composition according to claim 10, wherein the binder is hydroxypropyl cellulose.

14. The stable tablet composition according to claim 10, wherein the filler / diluents are a mixture of mannitol and dibasic calcium phosphate.

15. The stable tablet composition according to claim 11, wherein the lubricant is magnesium stearate.

16. The stable tablet composition according to any proceeding claims, wherein the composition comprises 90 mg or 60 mg ticagrelor.

Images