Avatrombopag maleate compositions manufactured by using dry granulation

Abstract

The present invention relates to a pharmaceutical composition comprising avatrombopag maleate or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using dry granulation with improved pharmaceutical characteristics to obtain proper release profiles in three different physiological media of gastrointestinal tract.

Description

[0001] DESCRIPTION

[0002] AVATROMBOPAG MALEATE COMPOSITIONS MANUFACTURED BY USING DRY GRANULATION

[0003] Field of Invention

[0004] The present invention relates to a pharmaceutical composition comprising avatrombopag maleate or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using dry granulation with improved pharmaceutical characteristics to obtain proper release profiles in three different physiological media of gastrointestinal tract.

[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]

[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-butylmethyl ether. The active substance has a non-chiral olecular structure.

[0010] Avatrombopag is available in the marketed reference product in the form of maleate salt. The name of reference product is Doptelef® 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 detailed search of prior art given above, not many formulation strategies have been carried out to overcome the poor solubility, low absorbability and in the gastrointestinal tract of avatrombopag maleate and at least one pharmaceutically acceptable excipient to get a stableformulation. Moreover the studies related with avatrombopag maleate, dissolution releases of avatrombopag maleate both in three different gastrointestinal pH media simulating gastrointestinal (GI) tract isn’t explained in any immediate release pharmaceutical composition design manufactured by using dry granulation process.

[0019] Moreover, the inventors of the present invention have developed a pharmaceutical composition comprising avatrombopag maleate and at least one pharmaceutically acceptable excipient in the immediate release dosage form manufactured by using dry granulation to obtain suitable release profiles in three different physiological media of gastrointestinal tract with improved pharmaceutical characteristics of solubility and flowability.

[0020] Summary Of The Invention

[0021] The object of this invention is to develop a pharmaceutical composition comprising a therapeutically effective amount of avatrombopag maleate in the immediate release dosage form, with a dedicated manufacturing process.

[0022] According to state of the art, avatrombopag maleate is known to be poorly soluble in physiological pH range. Thus, it is the objective of the present invention is to provide a pharmaceutical composition comprising avatrombopag maleate in Form B crystal form with improved solubility.

[0023] The utilization of the Form B avatrombopag maleate can increase the solubility of tolvaptan in physiological pH range. However, any action may cause deviation in polymorphic nature.

[0024] Another object of the present invention is related to a pharmaceutical composition comprising avatrombopag maleate and at least one pharmaceutically acceptable excipient manufactured by using dry granulation where obtained granules are manufactured without using moisture, solvents and heat and a pre-treatment to get a solid dispersion or composite.

[0025] Another object of the present invention is related to a pharmaceutical composition comprising the active ingredient, diluents, binder, disintegrant, lubricant and glidant with respect to the intended form of administration.

[0026] Avatrombopag maleate itself has another restriction during development pharmaceutical such as having quite poor flowability property. Thus, to overcome its flowability problem, colloidalsilicon dioxide is used as glidant and the composition is manufactured by using the dry granulation process.

[0027] The, pressure applied during dry granulation manufacturing process is also critical parameter. Thus, a specified range should be investigated to obtain the most proper release profile in the considered GI tract.

[0028] Another object of the present invention is to provide a pharmaceutical composition comprising avatrombopag maleate and at least one pharmaceutically acceptable excipient manufactured by using dry granulation process.

[0029] Detailed Description Of The Invention

[0030] The present invention provides a pharmaceutical composition comprising Form B avatrombopag maleate and at least one pharmaceutically acceptable excipients developed in the immediate release dosage form wherein the prepared composition is manufactured with the most proper manufacturing process with critical parameters.

[0031] It is known that, three different conventional manufacturing process are utilized for preparation of the mix before performing the compression that are direct compression, dry granulation and wet granulation. The selection of proper manufacturing process is determined by taking into consider of the physical properties of active substance such as solubility and flowability.

[0032] This study is also confirmed the information that tolvaptan is poorly soluble and in addition, permeability is low as to be expected due to BCS IV drug characterisation. In the present invention, avatrombopag maleate is preferred to be used in Form B crystalline form.

[0033] Avatrombopag maleate is in BCS Class IV with presenting low-solubility and low-permeability and these are critical characteristics to be considered while designing the composition and manufacturing process.

[0034] After investigation of active substance characterization and a detailed search of prior art, the development studies were initiated to compose a pharmaceutical product manufactured by using the most proper conventional manufacturing processes.

[0035] Wet granulation couldn’t be preferred since any further manufacturing process includes solvent has the highest potential for unstable conditions which can cause the composition to bedecompose. The next manufacturing step after exposing the powder blend with solvent and granulate is drying process. Drying is another manufacturing process that may generate different polymorphic forms. Hence, it is not applicable.

[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 present invention, a pharmaceutical composition comprising avatrombopag maleate and at least one pharmaceutically acceptable excipient was designed to be able use dry granulation manufacturing process.

[0040] In a preferred embodiment of the present invention is a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablets, capsules, granules, powders, and pellet or unit dose packets, preferably the solid oral dosage form is tablet.

[0041] In the preferred embodiment, a pharmaceutical composition containing avatrombopag maleate manufactured by using dry granulation process in tablet dosage form to comprise pharmaceutically acceptable excipients in function of diluent, disintegrant, glidant and lubricants selected as to be the most suitable ones with respect to the intended form of administration.In the preferred embodiment of the present invention, the diluent may include, but are not limited to dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, diluents are lactose and microcrystalline cellulose.

[0042] In the preferred embodiment of the present invention, the disintegrant may include, but is not limited to calcium, croscarmellose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is crospovidone.

[0043] 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 glidant is colloidal silicon dioxide.

[0044] In the preferred embodiment of the present invention, the lubricants may include, but are not limited to sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricants are talc and magnesium stearate.

[0045] Further, the preferred embodiment, a diluent mixture of microcrystalline cellulose and lactose monohydrate was in the weight ratio of at least 70.0% by weight of the composition.

[0046] Further, the preferred embodiment, a diluent mixture of microcrystalline cellulose and lactose monohydrate was in the weight ratio between 70.0% - 85% by weight of the composition. Preferably, the weight ratio between lactose monohydrate and microcrystalline cellulose is in the range of 1:1.8 - 1:2.5,

[0047] In the preferred embodiment, avatrombopag maleate particles have a D90 value less than 10-microns to improve dissolution release profiles.

[0048] 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.

[0049] Another object of the present invention is to provide a pharmaceutical compositions containing avatrombopag maleate wherein the total weight of the avatrombopag maleate is between 10.0% - 14.0% w / w by total weight of the composition.The proposed embodiment based on the invention provides an immediate release pharmaceutical composition wherein the values in w / w% by weight of the total composition are as stated in the Table 1 below:

[0050] Table 1: Unit Formula of Example 1

[0051]

[0052] The detailed manufacturing steps of Example 1 for immediate release pharmaceutical were presented below:

[0053] i. Avatrombopag maleate, specified amount of microcrystalline cellulose, talc and lactose monohydrate were weighed and screened through a proper sieve and then transferred into mixer to stir,

[0054] ii. The prepared powder blend in Step (i) was compressed by slugging process,

[0055] iii. The granules in Step (ii) were sifted through a proper sieve,

[0056] iv. Remaining amount of microcrystalline cellulose, crospovidone, colloidal silicon dioxide was weighed and screened through a proper sieve and added in prepared granules in Step (iii),

[0057] v. Magnesium stearate was screened through a proper sieve and added to the granules prepared in Step (iv).

[0058] vi. Tablet compression was performed with the granules in Step v.

[0059] It was observed that, the flowability of the final blend was suitable for the tablet compression process where the compressibility index and Hauser ratio were classified as “good”.

[0060] Then, the final blend with improved processability was compressed into tablets by applying between 50 kP to 90 kP pressure and subjected to the in-vitro dissolution study.

[0061] The inventors surprisingly found that when the compression pressure is below 50 kP during slugging process, compaction process was not performed successfully. No proper compaction was obtained.Further, the inventors surprisingly found that when the compression pressure applied above 90 kP during slugging process, compaction process was performed successfully. However, a polymorphic change was observed. This means that polymorphic stability not maintained, based on that dissolution behaviour and physicochemical properties change due to this phenomenon.

[0062] Thus, chemical characteristics such as the most critical ones polymorphic stability and stable dissolution release profile through a successful slugging process can be provided by performing the slugging process on applied compression pressure between 50 kP to 90 kP.

Claims

CLAIMS1. A pharmaceutical composition comprising avatrombopag maleate and at least one pharmaceutically acceptable excipient manufactured by using dry granulation method, wherein the compression pressure during slugging process is between 50 kP and 90 kP.

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

3. A pharmaceutical composition according to Claim 1, wherein at least one pharmaceutically acceptable excipient is selected from diluents, disintegrant, glidant, lubricant.

4. A stable pharmaceutical composition according to claim 3, wherein the glidants are colloidal silicon dioxide and talc, and mixtures thereof.

5. A stable pharmaceutical composition according to claim 3, wherein the diluents are the mixture of lactose monohydrate and microcrystalline cellulose.

6. A stable pharmaceutical composition according to claim 3, wherein the disintegrant is crospovidone.

7. A stable pharmaceutical composition according to claim 3, wherein the lubricant is magnesium stearate.

8. A pharmaceutical composition according to any one of the preceding claims, wherein the composition is compressed into a tablet dosage form.

9. A pharmaceutical composition according to any one of the preceding claims; wherein the composition is:

10. A dry granulation method for pharmaceutical composition comprising avatrombopag maleate comprises the steps of;i. Avatrombopag maleate, specified amount of microcrystalline cellulose, talc and lactose monohydrate are weighed and screened through a proper sieve and then transferred into mixer to stir,ii. The prepared powder blend in Step (i) is compressed by slugging process,iii. The granules in Step (ii) are sifted through a proper sieve,iv. Remaining amount of microcrystalline cellulose, crospovidone, colloidal silicon dioxide is weighed and screened through a proper sieve and added in prepared granules in Step (iii),v. Magnesium stearate is screened through a proper sieve and added to the granules prepared in Step (iv).vi. Tablet compression is performed with the granules in Step v.

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