Stable avatrombopag maleate compositions

Abstract

The present invention relates to stable pharmaceutical compositions comprising avatrombopag, a thrombopoietin receptor agonist, as an active pharmaceutical ingredient. The invention particularly addresses pharmaceutical compositions of avatrombopag maleate manufactured by using direct compression with specific weight ratio of disintegrant based on the total weight of the composition.

Description

[0001] DESCRIPTION

[0002] STABLE AVATROMBOPAG MALEATE COMPOSITIONS Technical Field

[0003] The present invention relates to stable pharmaceutical compositions comprising avatrombopag, a thrombopoietin receptor agonist, as an active pharmaceutical ingredient. The invention particularly addresses pharmaceutical compositions of avatrombopag maleate manufactured by using direct compression with specific weight ratio of disintegrant based on the total weight of the composition.

[0004] State of Art

[0005] Avatrombopag is a synthetic thrombopoietin receptor agonist (TPO-RA) that is primarily used to treat thrombocytopenia (a condition characterized by low platelet counts). It stimulates platelet production by activating the thrombopoietin receptor on megakaryocytes and their precursors, enhancing the production of platelets in the bone marrow.

[0006] Its chemical name is 2-{(2-{[4-(4-Chlorophenyl)-2-thiazolyl]amino}phenyl)formamido}-N-methylbenzamide with the following structure Formula I, the empirical formula C29H34C12N6O3S2 and a molecular weight of 652.66 g / mol.

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[0008]

[0009] The active substance is a non-hygroscopic white to off white powder freely soluble in 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide and N-methylpyrrolidone, slightly soluble in methanol and ethanol (dehydrated) and practically insoluble in water, acetonitrile, acetone, ethyl acetate, hexane, and tert-butyl methyl ether. The active substance has a non-chiral molecular structure.

[0010] Avatrombopag is available in the marketed reference product in the form of maleate salt. The name of reference product is Doptelet® and it is marketed by Swedish Orphan Biovitrum Ltd. company in the strength of 20 mg per film-coated tablet.Polymorphism has been observed for the active substance avatrombopag maleate. Three anhydrous crystal forms (Form-A, Form-B, and Form-C) of avatrombopag maleate have been declared in the scientific literature.

[0011] Avatrombopag and its pharmaceutically acceptable salts thereof were first described in patent document EP1466912 by Astellas Pharma Inc. This document discloses the preparation of avatrombopag and its salts, particularly focusing on its maleate form. Subsequently, pharmaceutical compositions containing avatrombopag for use in the treatment of thrombocytopenia.

[0012] Based on this knowledge, several patents or patent applications in the state of art aim to develop a solid oral composition comprising avatrombopag which are summarized below.

[0013] EP2739621 relates to a pharmaceutical composition for oral administration comprising; an immediate release comprising avatrombopag or a pharmaceutically acceptable salt thereof. In the document, the salt of avatrombopag is maleate which is described by declaring melting points. The form of the dedicated avatrombopag maleate is Form C. Patent protection will expire in 2032.

[0014] CN117582412 relates to a pharmaceutical formulation comprising an immediate-release avatrombopag maleate and at least one pharmaceutical excipients such as solubilizing agent. The 90% of the total particle size of avatrombopag maleate is below 4.5 microns which measured by using laser diffraction method.

[0015] W02020044364 relates to a composition comprising avatrombopag maleate in amorphous form and specific crystal forms with particular manufacturing process details.

[0016] Avatrombopag is a BCS Class IV drug and presents low solubility and low permeability properties. Therefore, there is a challenging issues about the activities which may contribute dissolution in contrast affect adversely with regards to stability.

[0017] Thus, these challenges are the critical parameters to investigate the formulation of the composition and the manufacturing process. However, achieving consistent performance, particularly in terms of dissolution versus polymorphic stability are outlined on priority.

[0018] The inventors, although avatrombopag belongs to BCS Class IV, designed a formulation comprising micronized form of avatrombopag and at least one pharmaceutically acceptable excipient to be manufactured by using direct compression.Summary of The Invention

[0019] The present invention relates to stable pharmaceutical compositions comprising avatrombopag or its pharmaceutically acceptable salts, particularly maleate salt thereof, and at least one pharmaceutically acceptable excipients.

[0020] The object of the present invention is to provide an immediate-release solid oral pharmaceutical composition comprising avatrombopag or its pharmaceutically acceptable salts, particularly maleate salt thereof, and at least two pharmaceutically acceptable excipient in immediate-release dosage form.

[0021] In the present invention, avatrombopag maleate is in Form B polymorph.

[0022] In the present invention, avatrombopag maleate belongs to BCS Class IV and presents low solubility and low permeability.

[0023] In the present invention, avatrombopag maleate is preferred in micronized particle size distribution to enhance dissolution properties and the size of 90% (D90) of avatromvopag maleate particles is below 10-microns with the measurement obtained by using laser diffraction method. The usage of micronized form avatrombopag maleate is aimed to enhance in vitro dissolution and overcome disadvantages sourced from the nature of active substance itself.

[0024] In the present invention, micronized form avatrombopag maleate as active substance is used along with a specific weight ratio of disintegrant.

[0025] Another object of the present invention is to provide a pharmaceutical composition comprising avatrombopag maleate, disintegrant and at least one pharmaceutically acceptable excipient manufactured by using direct compression method.

[0026] The present invention relates to pharmaceutical compositions comprising avatrombopag maleate, disintegrant and at least one pharmaceutically acceptable excipient manufactured by using direct compression method which have D90 value for powder blend particle size prior to tablet compression process as below 500-microns with the measurement by using laser diffraction method.In the present invention, micronized avatrombopag maleate in the pharmaceutical composition exhibits polymorphic stability under different stability conditions and stay stable as crystal Form B.

[0027] In a preferred embodiment, the present invention is to provide stable immediate-release oral pharmaceutical compositions comprising avatrombopag maleate in micronized form and a disintegrant along with at least one pharmaceutically acceptable excipient manufactured by using direct compression method.

[0028] Detailed Description of The Invention

[0029] The object of the present invention relates to a solid oral pharmaceutical composition comprising avatrombopag or a pharmaceutically acceptable salt, particularly avatrombopag maleate salt, and a disintegrant, manufactured with direct compression method and designed to achieve improved in-vitro dissolution profiles and polymorphic stability.

[0030] Avatrombopag is an active substance with low solubility in aqueous media (< 0.005 mg / ml) over the entire physiological pH range. Actually, it is reported in the literature that avatrombopag maleate is practically insoluble in pH 1-11. Thus, the particle size becomes an important issue to get the completed and desired dissolution profile.

[0031] In the preferred embodiment, avatrombopag maleate particles have a D90 value less than 10-microns.

[0032] The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter. The value of D90 refers to the particle size distribution of avatrombopag maleate particles by using laser diffraction method.

[0033] In the present invention, avatrombopag maleate constituted between 10% - 14% weight by the total weight of the composition.

[0034] Polymorphism is the phenomenon related to the occurrence of different crystal forms, wherein crystalline forms have different arrangements and / or conformations of the molecules in the crystal lattice. Those differences can have a direct effect on the ability to process and / or manufacture the drug product.

[0035] Thus, the stability of polymorph in the drug product for therapeutic use is very important to obtain the appropriate bioavailability and bioequivalence characteristics.Polymorphic stability refers to the ability of a specific polymorphic form, Form B herein, of a compound, avatrombopag maleate inhere, to maintain its physical and chemical structure under various environmental conditions, including temperature, humidity, pressure, and exposure to solvents. Polymorphism occurs when a substance can exist in more than one crystalline form, with each polymorph having distinct properties such as solubility, melting point, and stability. Polymorphic stability is critical in pharmaceutical products since it can influence a drug's bioavailability, manufacturability, and shelflife.

[0036] A difficulty in using polymorphic forms that are not the thermodynamically most stable form of a compound arises when the desired material spontaneously converts to the less desirable, more stable, form or when the polymorphic change occurs during formulation processing steps. In the preferred embodiment, avatrombopag maleate is in Form B polymorph without presenting any polymorphic change.

[0037] Manufacturing process has a critical role in polymorphic stability. The more the polymorph expose to environmental conditions such as pressure, temperature (drying) and solvent (humidity), the more the risk of losing polymorphic stability. Thus, various manufacturing processes are investigated to avoid environmental effectives in the pharmaceutical industry. The most proper processes are to remove solvent and prefer dry methods such as direct compression, dry granulation, hot-melt extrusion.

[0038] High pressure and mechanical stress can induce changes in crystal packing, leading to new polymorphic forms. Thus, the manufacturing stages of sieving and tableting may affect the polymorphic stability although direct compression is employed.

[0039] In the preferred embodiment of the invention, the manufacturing process is direct compression to be the most proper choice regarding not needing of multiple-steps with regards to be free of solvent throughout the process.

[0040] However, the solubility of avatrombopag maleate is very low and that is the reason inventors proposed micronized form of active substance employed in the preferred embodiment. On the other hand, in contrast to enhancing in vitro release characteristics, direct compression is highly challenging with micronized form materials.

[0041] In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising avatrombopag maleate by using direct compression method whereinprovided for the manufacture of tablets containing the active ingredient, diluents, disintegrant, lubricant and glidant selected as to be the most suitable ones with respect to the intended form of administration.

[0042] In a preferred embodiment, the pharmaceutical composition comprises at least two diluent can be selected from the group consisting of dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose monohydrate, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and mixtures thereof. Preferably, the diluent is lactose monohydrate and microcrystalline cellulose or a mixture thereof, more preferably is a mixture thereof. Preferably, the mixture of lactose monohydrate and microcrystalline cellulose is in weight range of 75.0% - 85.0%.

[0043] In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant can be selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid, hydrogenated castor oil and mixtures thereof. Preferably, the lubricant is magnesium stearate in amount range of 0.1% - 3.0%.

[0044] In a preferred embodiment, the pharmaceutical composition comprises at least two glidant can be selected from the group consisting of colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof. Preferably, the glidants are colloidal silicon dioxide and talc or a mixture thereof in the amount range of 1.0% - 3.0%.

[0045] Disintegrant(s) is one of the main excipients used in pharmaceutical compositions to ensure the rapid breakdown into their primary particles when they contact with the gastrointestinal tract. Thus, it is highly related to the dissolution or release of active substances.

[0046] The preferred embodiment is in immediate-release dosage form, which rely heavily on disintegrants to ensure rapid disintegration and onset of drug action. Moreover, since avatrombopag is a low-soluble drug effective disintegration is critical to ensure that the surface area available for dissolution is maximized. The weight ratio of disintegrant is directly related with type and efficiency of the disintegrant based on its relationship between active ingredient.

[0047] 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 crospovidone in amount range of 6.0% - 10.0%.Crospovidone has a highly porous nature which increases overall porosity of the composition. Hence, the interconnected pores allow liquid to penetrate deeply and evenly throughout the composition, accelerating the breakup into smaller fragments. On the other hand, it remains insoluble, retaining its structural integrity during disintegration.

[0048] Although crospovidone is known to be its oxidative nature, in the present invention the weight ratios of active ingredient and the manufacturing method are the main parameters to control the level of the impurities in the composition.

[0049] The embodiments in accordance with the present invention are designed with an adjusted quantitative compositions composed of pharmaceutically acceptable ingredients mentioned above by using the direct compression method.

[0050] The ratio between avatrombopag maleate and disintegrant amounts used in the composition is in a range of 1.2 to 1.4.

[0051] Further in Example- 1 and Example-2, the process for the preparation of a pharmaceutical composition manufactured by using direct compression, including the below steps:

[0052] a) Avatrombopag maleate, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, talc and magnesium stearate were screened through a proper sieve for a final D90 particle size value below 500 microns and stirred.

[0053] b) The powder blend in step a, was mixed for about 10 minutes.

[0054] c) Tablet compression was performed with powder blend in step b.

[0055] d) Optionally, the tablets were film coated.

[0056] In the present invention, stable pharmaceutical composition comprising micronized avatrombopag maleate, disintegrant and at least one pharmaceutically acceptable excipient manufactured by using direct compression process wherein;

[0057] the disintegrant is crospovidone within the weight ratio of 6.0%- 10.0% by weight of the composition.

[0058] The ratio between avatrombopag maleate and disintegrant in the composition is in a range of 1.4 to 1.6.

Claims

CLAIMS1. A stable pharmaceutical composition comprising micronized avatrombopag maleate, disintegrant and at least one pharmaceutically acceptable excipient manufactured by using direct compression process wherein;the disintegrant is crospovidone within the weight ratio of 6.0%- 10.0% by weight of the composition.the ratio between avatrombopag maleate and disintegrant is in a range of 1.4 to 1.6.

2. A stable pharmaceutical composition according to claim 1, wherein D90 value of avatrombopag maleate is below 10 microns measured by using laser diffraction method.

3. A stable pharmaceutical composition according to claim 1 or 2, wherein avatrombopag maleate is in Form B polymorph.

4. A stable pharmaceutical composition according to any one of the preceeding claims, wherein at least one pharmaceutically acceptable excipient is selected from the group comprising disintegrant, lubricant and glidant.

5. A stable pharmaceutical composition according to claim 4, wherein the lubricant is magnesium stearate.

6. A stable pharmaceutical composition according to claim 4, wherein the glidant is colloidal silicon dioxide, talc, or mixtures thereof.

7. A stable pharmaceutical composition according to any one of the preceeding claims, wherein D90 value of powder blend prior to tablet compression process is below 500 microns measured by using laser diffraction method.

8. A direct compression method for the preparation of a pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of; a) Avatrombopag maleate, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, talc and magnesium stearate were screened through a proper sieve for a final D90 particle size value below 500 microns and stirred. b) The powder blend in step a, was mixed for about 10 minutes.c) Tablet compression was performed with powder blend in step b.d) Optionally, the tablets were film coated.

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