Solid oral compositions of avatrombopag maleate

Abstract

The present invention relates to an immediate-release solid oral pharmaceutical composition comprising avatrombopag, a thrombopoietin receptor agonist, as an active pharmaceutical ingredient (API). The invention particularly addresses solid oral avatrombopag maleate compositions comprising at least two diluents in a specific range of weight ratio manufactured by using direct compression.

Description

[0001] DESCRIPTION

[0002] SOLID ORAL COMPOSITIONS OF AVATROMBOPAG MALEATE

[0003] Technical Field

[0004] The present invention relates to an immediate-release solid oral pharmaceutical composition comprising avatrombopag, a thrombopoietin receptor agonist, as an active pharmaceutical ingredient (API). The invention particularly addresses solid oral avatrombopag maleate compositions comprising at least two diluents in a specific range of weight ratio manufactured by using direct compression.

[0005] State of Art

[0006] 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.

[0007] 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.

[0008] 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-butylmethyl ether. The active substance has a non-chiral molecular structure.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] W02020044364 relates to a composition comprising avatrombopag maleate in amorphous form and specific crystal forms with particular manufacturing process details.

[0015] Avatrombopag being identified as BCS Class IV drug in the international guidelines, presents low solubility and low permeability properties. 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, polymorphic stability and blend uniformity, remains significant challenges.

[0016] In the state of the art, there is no information and / or any study, which focus on formulation design of avatrombopag maleate compositions, manufactured by using direct compression method with considering avatrombopag maleate belongs to BCS Class IV. The present invention overcome indicated problems by employing two diluents in specific ratio in the formulation.

[0017] Summary of The Invention

[0018] The present invention relates to a solid oral pharmaceutical composition comprising avatrombopag or its pharmaceutically acceptable salts, particularly maleate salt thereof, and at least two pharmaceutically acceptable excipients.

[0019] 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.

[0020] In the present invention, avatrombopag maleate is in Form B polymorph.

[0021] Another object of the present invention is to provide a solid oral pharmaceutical composition comprising avatrombopag maleate and at least two pharmaceutically acceptable excipients manufactured by using direct compression method.

[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% of avatromvopag maleate particles is below 20-microns with the measurement obtained by using laser diffraction method.

[0024] In the present invention, the solid oral pharmaceutical composition comprising micronized avatrombopag maleate is incorporated with powder blend homogeneity arising from flowability problem due to the use of avatrombopag maleate in micronized form.

[0025] In the present invention, the solid oral pharmaceutical composition comprising micronized avatrombopag maleate exhibits polymorphic stability throughout the shelf-life period.

[0026] In a preferred embodiment, the present invention is to provide a immediate-release solid oral pharmaceutical composition comprising avatrombopag maleate and at least two pharmaceutically acceptable diluents as the excipients manufactured by using direct compression method, wherein - the diluents are microcrystalline cellulose and lactose monohydrate,

[0027] - the weight ratio between microcrystalline cellulose and lactose monohydrate is from 1 : 1.5 to 1 :2.5.

[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 at least two diluents, manufactured with direct compression method and designed to achieve homogenous powder blend 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 20 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 12% - 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, as well as on drug product stability, dissolution, and bioavailability due to having different chemical and physical properties.

[0035] Thus, the selection of proper polymorph of drug substance for therapeutic use is very important to obtain the appropriate drug product with bioavailability and bioequivalence.

[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.

[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] In the preferred embodiment of the invention, the manufacturing process is direct compression.

[0039] 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 dissolution parameters, direct compression is highly challenging with micronized form materials.

[0040] The inventors surprisingly achieved to provide solid oral pharmaceutical composition comprising avatrombopag maleate manufactured by using direct compression method, presents proper dissolution profiles and polymorphic stability by including at least two diluents.

[0041] In another preferred embodiment of the present invention is to provide a pharmaceutical composition comprising avatrombopag maleate by using direct compression method wherein provided 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 the like and mixtures thereof. Preferably, the diluent is lactose monohydrate and microcrystalline cellulose or a mixture thereof, more preferably is a mixture thereof.

[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 weight range of 1.0% - 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 weight 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] 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 weight range of 3.0% - 8.0%.

[0047] 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.

[0048] The weights of excipients were used within the pharmaceutically acceptable ranges for immediate-release solid oral dosage form except lactose monohydrate and microcrystalline cellulose, which were in ratios on below table.

[0049] Table 1: Examples comprising different weight ratios of diluents

[0050] Further in Example- 1 and Example-2, the process for the preparation of a pharmaceutical composition manufactured by using direct compression, including the steps of: a) Avatrombopag maleate, microcrystalline cellulose, lactose monohydrate, crospovidone, colloidal silicon dioxide, talc and magnesium stearate were screened through a proper sieve 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.

[0051] After getting final blends, it was observed that the flowability of final blends were suitable for direct compression process even though it is not expected to be applicable for powder blends comprising micronized avatrombopag maleate due to it poor flowability. Additionally, bysolving the flowability problem homogeneity also obtained with the present invention.

[0052] Although, no technical document recommends or leads the technical person to use direct compression method for immediate-release solid oral pharmaceutical compositions comprising such an active substance as avatrombopag maleate in micronized form, the inventors are accomplished and provide the present invention with proper polymorphic stability and dissolution profile.

[0053] In the present invention, immediate-release solid oral pharmaceutical composition comprises comprising avatrombopag maleate and at least two pharmaceutically acceptable diluents wherein; the diluents are microcrystalline cellulose and lactose monohydrate, or mixtures thereof, the weight ratio between lactose monohydrate and microcrystalline cellulose is in the range of 1 : 1.5 - 1 :2.5, the manufacturing method is direct compression.

Claims

CLAIMS1. An immediate release solid oral pharmaceutical composition comprising micronized avatrombopag maleate and at least two pharmaceutically acceptable diluents, wherein; the diluents are lactose monohydrate and microcrystalline cellulose, or mixtures thereof, the weight ratio of lactose monohydrate and microcrystalline cellulose is in the range of 1 : 1.5 - 1 :2.5, the manufacturing method is direct compression.

2. An immediate release solid oral pharmaceutical composition according to claim 1, wherein, D90 value of Avatrombopag maleate is below 20 microns measured by using laser diffraction method.

3. An immediate release solid oral pharmaceutical composition according to claim 1 or 2, wherein avatrombopag maleate is in Form B polymorph.

4. An immediate release solid oral pharmaceutical composition according to any one of the preceeding claims, wherein the composition further comprises at least one pharmaceutically acceptable excipient is selected from the group comprising disintegrant, lubricant and glidant.

5. An immediate release solid oral pharmaceutical composition according to claim 4, wherein the disintegrant is crospovidone.

6. An immediate release solid oral pharmaceutical composition according to claim 4, wherein the lubricant is magnesium stearate.

7. An immediate release solid oral pharmaceutical composition according to claim 4, wherein the glidants are selected from the group consisting of colloidal silicon dioxide, talc and mixtures thereof.

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 are screened through a proper sieve and stirred. b) The powder blend in step a, is mixed for about 10 minutes. c) Tablet compression is performed with powder blend in step b. d) Optionally, the tablets are film coated.

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