A pharmaceutical composition comprising avatrombopag maleate

Abstract

The present invention relates to a pharmaceutical composition comprising avatrombopag maleate in amorphous or crystalline form, and at least one filler, wherein the filler is lactose monohydrate having a d(0.9) particle size of less than 250 µm. The present invention also relates to a simple and cost-effective process for preparing the pharmaceutical composition.

Description

[0001] DESCRIPTION

[0002] A PHARMACEUTICAL COMPOSITION COMPRISING AVATROMBOPAG MALEATE

[0003] Field of Invention

[0004] The present invention relates to a pharmaceutical composition comprising avatrombopag maleate in amorphous or crystalline form, and at least one filler, wherein the filler is lactose monohydrate having a d(0.9) particle size of less than 250 pm. The present invention also relates to a simple and cost-effective process for preparing the pharmaceutical composition.

[0005] Background of the Invention

[0006] Avatrombopag, sold under the brand name Doptelet, is a medication that used for certain conditions that lead to thrombocytopenia (low platelets) such as thrombocytopenia associated with chronic liver disease in adults who are to undergo a planned medical or dental procedure.

[0007] The chemical name of avatrombopag maleate is 4-piperidinecarboxylic acid, 1-[3-chloro-5-[[[4-(4-chloro-2-thienyl)-5-(4-cyclohexyl-1-piperazinyl)-2 -thiazolyl] amino] carbonyl]-2-pyridinyl]-, (2Z)-2-butenedioate (1:1). It has the molecular formula C29H34CI2N6O3S2 C4H4O4. The molecular weight is 765.73 and its structural formula(l) is as follows:

[0008]

[0009] Formula IAvatrombopag is a white to off-white powder having a non-chiral structure and is non-hygroscopic. The compound exhibits very low aqueous solubility and is practically insoluble in water. The pharmaceutically acceptable salt form, avatrombopag maleate, also shows very poor aqueous solubility and is almost insoluble in water and in 0.1 M hydrochloric acid. Solubility measurements further indicate that avatrombopag maleate remains practically insoluble over a wide pH range, particularly between pH 1 and pH 11.

[0010] Avatrombopag maleate is an oral, small molecule thrombopoietin (TPO) receptor (c-Mpl) agonist, which can simulate the biological effect of TPO, stimulate platelet production, improve platelet count, belonging to the clinical urgent need medicine. The patent CN112022825A discloses avatrombopag maleate tablet and its preparation method. In this patent, the crystalline form of avatrombopag maleate is form C.

[0011] The patent CN118453530A discloses an avatrombopag maleate tablet and a preparation method of the avatrombopag maleate tablet. The avatrombopag maleate tablet comprises a tablet core and a film coating layer, the tablet core part of the medicine comprises avatrombopag maleate (the particle size D90 is less than or equal to 85.6 pm), a filler is anhydrous lactose and lactose in a ratio of (4.6: 1)-(3: 1), a disintegrating agent and a lubricating agent adopt two modes of internal and external addition, the internal and external addition ratio of the disintegrating agent is (2: 1)-(4: 1), and the internal and external addition ratio of the lubricating agent is (1: 1)-(1: 2.4). In this patent, the crystalline form of avatrombopag maleate is form C.

[0012] Avatrombopag maleate is an active ingredient that presents certain technical challenges in formulation development. Its low solubility in water is a significant disadvantage that complicates the development of oral solid dosage forms, potentially leading to limited dissolution rates and consequently reduced bioavailability. In addition, the fact that avatrombopag maleate is generally a low-dose active ingredient in formulations makes it difficult to ensure its homogeneous distribution in the powder mixture, which can cause problems in terms of content uniformity.

[0013] Although there are various patent applications related to avatrombopag maleate in the prior art, none of these applications simultaneously provide a solution to both theproblems arising from the low solubility of the active ingredient and the content uniformity problems arising from its low-dose use.

[0014] Therefore, there is a need for an improved formulation in pharmaceutical compositions comprising avatrombopag maleate that both ensures the homogeneous distribution of the active ingredient within the mixture and helps overcome the limitations associated with low solubility. We overcame these problems by selecting lactose monohydrate with a d(0.9) particle size of less than 250 pm.

[0015] Detailed description of the Invention

[0016] The main object of the present invention is to provide a pharmaceutical composition comprising avatrombopag maleate desired dissolution profile, content uniformity and flowability.

[0017] Another object of the present invention is to provide a simple and cost-effective process for preparing the pharmaceutical composition.

[0018] Avatrombopag maleate having low water solubility constitutes an important disadvantage that complicates the development of oral solid dosage forms. Due to its low water solubility, the dissolution rate of the active substance may remain limited, which may lead to reduced bioavailability.

[0019] In addition, since avatrombopag maleate is generally present in the formulation at a low dose, ensuring its homogeneous distribution within the powder mixture also constitutes an important technical challenge. In active substances present at low doses, particle segregation may occur during mixing, which may lead to serious problems in terms of content uniformity. Furthermore, poor flow properties of the mixture may lead to irregular die filling during tableting and consequently increase the risk of weight variation.

[0020] Within the scope of the present invention, lactose monohydrate having specific particle characteristics is used as a filler to overcome the disadvantages described above. In particular, the use of lactose monohydrate having a particle size smaller than 250 pm improves the flow properties of the powder mixture and enables more homogeneous die filling during manufacturing.Furthermore, the particle size and surface characteristics of lactose monohydrate facilitate the adsorption of low-dose avatrombopag maleate particles onto the surface of lactose, thereby contributing to a more homogeneous distribution of the active substance within the mixture and reducing the risk of segregation. In this way, a pharmaceutical composition with improved manufacturability and content uniformity is obtained for avatrombopag maleate, which has low solubility and is present at a low dosage level.

[0021] As used herein, “particle size” means the cumulative volume size distribution as tested by any conventionally accepted method such as the laser diffraction method (i.e. Malvern analysis). The term d(0.9) means, the size at which 90% by volume of the particles are finer.

[0022] According to one embodiment of the present invention, a pharmaceutical composition comprising avatrombopag maleate in amorphous or crystalline form, and at least one filler, wherein the filler is lactose monohydrate having a d(0.9) particle size based on volume size distribution of less than 250 pm which is determined by laser diffraction method.

[0023] In the present invention, the term “core composition” refers to a pharmaceutical composition that is compressed or molded and does not include any external film coating, capsule shell (e.g., gelatin or HPMC), or any other outer layer.

[0024] According to one embodiment of the present invention, the amount of avatrombopag maleate is between 1.0% and 25.0% by weight of the core composition. Preferably, the amount of avatrombopag maleate is between 5.0% and 22.0% by weight of the core composition, more preferably between 10.0% and 20.0% by weight of the core composition.

[0025] According to one embodiment of this invention, avatrombopag maleate is in crystalline form B. Crystalline form B has been found to provide improved solubility compared to other crystalline forms of avatrombopag maleate, such as forms A and C. Accordingly, the use of crystalline form B contributes to obtaining a formulation exhibiting an improved dissolution profile.According to one embodiment of the present invention, lactose monohydrate has a d(0.9) particle size between 1 pm and 200 pm, preferably between 50 pm and 150 pm, and more preferably between 75 pm and 95 pm.<

[0026] According to one embodiment of the present invention, the amount of lactose monohydrate is between 55.0% and 90.0% by weight of the core composition. Preferably, the amount of lactose monohydrate is between 60.0% and 85.0% by weight of the core composition, more preferably between 70.0% and 80.0% by weight of the core composition.

[0027] According to one embodiment of the present invention, the weight ratio of avatrombopag maleate to lactose monohydrate is less than 1:5, preferably from 1:20 to 1:5, and more preferably from 1:10 to 1:5.

[0028] Due to the relatively low dose of avatrombopag maleate, the proportion of filler used in the formulation is correspondingly high. The amount of lactose monohydrate relative to the active ingredient may influence the blend uniformity, flow properties, and compressibility during the direct compression process. Therefore, the ratio of lactose monohydrate to avatrombopag maleate is selected to provide suitable blend uniformity and compressibility for tablet manufacturing by direct compression. Otherwise, excessively high filler ratios may lead to segregation in the blend, poor flow properties, reduced tablet hardness, or variability in dissolution profiles.

[0029] Therefore, selecting the ratio of avatrombopag maleate to lactose monohydrate within these ranges improves the flowability, content uniformity of the mixture, and compressibility, while also contributing to achieving the desired dissolution profile. According to one embodiment of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising binders, disintegrants, lubricants, glidants or a mixture thereof.

[0030] Suitable binders are selected from the group comprising microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (PVP), carboxymethylcellulose sodium, carboxymethylcellulose calcium, glyceryl behenate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, or a mixture thereof.According to one embodiment of the present invention, the binder is microcrystalline cellulose.

[0031] According to one embodiment of the present invention, the amount of binder is between 1.0% and 25.0% by weight of the core composition. Preferably, the amount of binder is between 5.0% and 15.0% by weight of the core composition.

[0032] Suitable disintegrants are selected from the group comprising crospovidone (Kollidon® CL), croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, glycine or a mixture thereof.

[0033] According to one embodiment of the present invention, the disintegrant is crospovidone.

[0034] According to one embodiment of the present invention, the amount of disintegrant is between 0.1% and 10.0% by weight of the core composition. Preferably, the amount of disintegrant is between 1.0% and 5.0% by weight of the core composition.

[0035] According to one embodiment of the present invention, the weight ratio of the disintegrant to avatrombopag maleate is less than 3:5, preferably from 1 : 10 to 1 :2, and more preferably 1 :5.

[0036] The fact that the disintegrant is within the specified range relative to avatrombopag maleate ensures adequate disintegration and dissolution of the tablet, while preventing excessively rapid disintegration and crumbling. This contributes to increased manufacturability and compressibility in directly pressed tablets and provides a consistent dissolution profile.

[0037] Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, talc, calcium stearate, zinc stearate, stearic acid, glyceryl behenate or a mixture thereof.

[0038] According to one embodiment of the present invention, the lubricant is magnesium stearate.

[0039] According to one embodiment of the present invention, the amount of lubricant is between 0.01% and 10.0% by weight of the core composition. Preferably, the amount of lubricant is between 0.5% and 5.0% by weight of the core composition.Suitable glidants are selected from the group comprising colloidal silicon dioxide, magnesium oxide, magnesium silicate, or a mixture thereof.

[0040] According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.

[0041] According to one embodiment of the present invention, the amount of glidant is between 0.01% and 8.0% by weight of the core composition. Preferably, the amount of glidant is between 0.1% and 3.0% by weight of the core composition.

[0042] According to one embodiment of this invention, the pharmaceutical composition is in the form of capsule or tablet.

[0043] According to one embodiment of this invention, the pharmaceutical composition is formulated as tablets including compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, film-coated tablets, orally disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles.

[0044] According to one embodiment of this invention, the pharmaceutical composition is formulated as film coated tablet.

[0045] According to one embodiment of the present invention, the pharmaceutical composition further comprises one or more film-coating agents.

[0046] Suitable film coating agents are selected from the group comprising polyvinyl alcohol (PVA), macrogol (PEG 3350), iron oxide yellow, talc, titanium dioxide, Indigo carmine aluminum lake, carnauba wax, hydroxypropyl methylcellulose, polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers, lecithin, polyvinylpyrrolidonevinyl acetate copolymer (PVP-VA), pigments, dyes or a mixture thereof.

[0047] According to this embodiment of the present invention, film coating agent is polyvinyl alcohol or macrogol or iron oxide yellow or talc or a mixture thereof.

[0048] According to this embodiment of the present invention, the amount of film coating agent is between 1.0% and 8.0% by weight of the total tablet. Preferably, the amount of film coating agent is between 2.0% and 5.0% by weight of total tablet.According to one embodiment of the present invention, a pharmaceutical composition comprising avatrombopag maleate in amorphous or crystalline form thereof is obtained by direct compression process. In direct compression, the pharmaceutical composition ingredients are not exposed to moisture, solvents and heat. Thus, in this invention, direct compression is used to process moisture, solvent and / or heat sensitive avatrombopag.

[0049] According to one embodiment of the present invention, the tablet has a hardness between 150 N and 180 N, preferably between 165 N and 175 N.

[0050] According to one embodiment of the present invention, the tablet has a hardness of 170 N.

[0051] Tablet hardness may influence the disintegration behavior of the tablet. In order to obtain a disintegration time of approximately 4-5 minutes, the compression force is selected such that the resulting tablet hardness falls within this range. Thus, the tablet maintains sufficient mechanical strength while still allowing adequate disintegration. A process for preparing a pharmaceutical composition comprising avatrombopag maleate, the process comprising the steps of:

[0052] a) Weighing avatrombopag maleate and all excipients,

[0053] b) Mixing avatrombopag maleate, a binder and a disintegrant,

[0054] c) Subsequently adding a filler and a glidant to the mixture obtained in step (b), and mixing;

[0055] d) Sieving the mixture in step (c),

[0056] e) Finally adding a lubricant to the mixture in step (d) and mixing,

[0057] f) Compressing the mixture into tablets.Example 1 ;

[0058]

[0059] A process for Example 1 ;

[0060] a) Weighing avatrombopag maleate, lactose monohydrate, crospovidone, microcrystalline cellulose, magnesium stearate, and colloidal silicon dioxide, b) Mixing avatrombopag maleate, microcrystalline cellulose, and crospovidone, c) Subsequently adding lactose monohydrate and colloidal silicon dioxide and mixing,

[0061] d) Sieving the mixture through a 0.6 mm sieve,

[0062] e) Finally adding magnesium stearate and mixing,

[0063] f) Compressing the mixture into tablets at 170 N.

Claims

CLAIMS1. A pharmaceutical composition comprising avatrombopag maleate in amorphous or crystalline form, and at least one filler, wherein the filler is lactose monohydrate having a d(0.9) particle size based on volume size distribution of less than 250 pm which is determined by laser diffraction method.

2. The pharmaceutical composition according to claim 1, wherein lactose monohydrate has a d(0.9) particle size between 1 pm and 200 pm, preferably between 50 pm and 150 pm, and more preferably between 75 pm and 95 pm.

3. The pharmaceutical composition according to claim 1, wherein the amount of avatrombopag maleate is between 1.0% and 30.0% by weight of the core composition.

4. The pharmaceutical composition according to claim 1, wherein avatrombopag maleate is in crystalline form B.

5. The pharmaceutical composition according to claim 1, wherein the amount of lactose monohydrate is between 55.0% and 90.0% by weight of the core composition.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising binders, disintegrants, lubricants, glidants or a mixture thereof.

7. The pharmaceutical composition according to claim 6, wherein binders are selected from the group comprising microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (PVP), carboxymethylcellulose sodium, carboxymethylcellulose calcium, glyceryl behenate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch, or a mixture thereof.

8. The pharmaceutical composition according to claim 6 or 7, wherein the binder is microcrystalline cellulose.

9. The pharmaceutical composition according to claim 6, wherein disintegrants are selected from the group comprising crospovidone (Kollidon® CL), croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, glycine or a mixture thereof.

10. The pharmaceutical composition according to claim 9, wherein the disintegrant is crospovidone.

11. The pharmaceutical composition according to claim 6, wherein lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, talc, calcium stearate, zinc stearate, stearic acid, glyceryl behenate or a mixture thereof.

12. The pharmaceutical composition according to claim 11, wherein the lubricant is magnesium stearate.

13. The pharmaceutical composition according to claim 6, wherein glidants are selected from the group comprising colloidal silicon dioxide, magnesium oxide, magnesium silicate, or a mixture thereof.

14. The pharmaceutical composition according to claim 13, wherein the glidant is colloidal silicon dioxide.

15. A process for preparing a pharmaceutical composition comprising avatrombopag maleate, the process comprising the steps of:a) Weighing avatrombopag maleate and all excipients,b) Mixing avatrombopag maleate, a binder and a disintegrant,c) Subsequently adding a filler and a glidant to the mixture obtained in step (b), and mixing;d) Sieving the mixture in step (c),e) Finally adding a lubricant to the mixture in step (d) and mixing, f) Compressing the mixture into tablets.

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