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

AVATROMBOPAG MALEATE-CONTAINING PHARMACEUTICAL COMPOSITION Field of Invention The present invention describes avatrombopag maleate in amorphous or crystalline form and at least one filler. It relates to a pharmaceutical composition containing the substance d(0.9), where the filler is d(0.9) It is lactose monohydrate with a particle size of less than 250 µm. The present invention also describes, It also involves a simple and cost-effective process for preparing pharmaceutical compounds. Background of the Invention Avatrombopag, sold under the brand name Doptelet, is a planned medical or dental treatment. Thrombocytopenia due to chronic liver disease in adults undergoing the procedure used for certain conditions that lead to thrombocytopenia, such as (low platelet count) It is a medicine. 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). Its molecular formula is C29H34Cl2N6O3S2·C4H4O4. Molecular Its weight is 765.73 and its structural formula (I) is as follows: Formula I Avatrombopag is a white to off-white powder with a non-chiral structure, and It is not hygroscopic. The compound exhibits very low water solubility and is practically insoluble in water. It is insoluble. The pharmaceutically acceptable salt form, avatrombopag maleate, is also included. It exhibits very low water solubility and is almost 2% soluble in water and 0.1 M hydrochloric acid. It is insoluble. Solubility measurements also show that avatrombopag maleate has a wide pH range. It remains practically insoluble in the range, especially between pH 1 and pH 11. It shows. Avatrombopag maleate can mimic the biological effect of TPO, increasing platelet production. oral, small, clinical emergency drugs that can stimulate and increase platelet count. It is a 2-molecule thrombopoietin (TPO) receptor (c-Mpl) agonist. Patent number CN112022825A covers avatrombopag maleate tablets and their preparation. This patent describes the method. In this patent, the crystalline form of avatrombopag maleate is C. It is the form. Patent number CN118453530A describes an avatrombopag maleate tablet and avatrombopag This describes a preparation method for maleate tablets. Avatrombopag maleate tablets, It consists of a tablet core and a film coating layer; the tablet core part of the drug. It contains avatrombopag maleate (D90 particle size less than or equal to 85.6 µm); The filler material is anhydrous lactose and lactose, and their ratio is (4.6:1)-(3:1), There are two modes of application for decomposition agents and lubricants: internal and external addition. Internal and external addition ratio of the decomposition agent (2:1)-(4:1) and internal and external of the lubricant agent The addition ratio is (1:1)-(1:2.4). In this patent, the crystalline form of avatrombopag maleate is described. It is form C. Avatrombopag maleate presents certain technical challenges in formulation development. It is an active ingredient. Its low solubility in water has led to the development of oral solid dosage forms. This is a significant disadvantage that makes it difficult and potentially leads to limited dissolution rates and Therefore, it may lead to decreased bioavailability. Also, avatrombopag maleate Formulations usually contain a low dose of the active ingredient, in powder mixtures. This makes it difficult to ensure a homogeneous distribution, which in turn affects content uniformity. This can lead to problems. There were several patent applications related to avatrombopag maleate in the previous period. However, none of these applications resulted from the low solubility of the active ingredient. problems and content uniformity issues resulting from low dose usage It does not offer a solution at the same time. Therefore, in pharmaceutical formulations containing avatrombopag maleate, the active ingredient ensuring homogeneous distribution within the mixture and overcoming the limitations associated with low solubility. An improved formulation is needed that helps overcome this. We By selecting lactose monohydrate with particle size less than 250 µm (d(0.9)), these problems can be avoided. We overcame it. Detailed Description of the Invention The main objective of the present invention is to achieve the desired dissolution profile, content uniformity and fluidity. The aim is to provide a pharmaceutical compound containing avatrombopag maleate. Another aim of the present invention is to provide a simple and effective method for preparing pharmaceutical compounds. The goal is to provide a cost-effective process. The low water solubility of avatrombopag maleate makes oral solid dosage forms difficult. Low water levels constitute a significant disadvantage that makes development difficult. Due to its solubility, the rate of dissolution of the active substance may be limited, and this can This can lead to decreased bioavailability. Additionally, avatrombopag maleate is usually included in the formulation in a low dose. Therefore, ensuring homogeneous distribution within the powder mixture is also an important technique. This is a challenge. With active ingredients present in low doses, particles may appear during mixing. Disintegration can occur, leading to serious problems in terms of content uniformity. This can open the mold during tableting due to poor flow properties. Furthermore, the poor flow characteristics of the mixture can cause mold filling issues. This can lead to irregularities and consequently increase the risk of weight fluctuations. Within the scope of this invention, the disadvantages described above can be overcome. for the purpose of using lactose monohydrate as a filler with specific particle properties. It is used, in particular, for lactose with a particle size smaller than 250 µm. The use of monohydrate improves the flow properties of the powder mixture and production. This ensures a more homogeneous filling of the mold during the process. Furthermore, the particle size and surface properties of lactose monohydrate, at low doses Avatrombopag facilitates the adsorption of maleate particles onto the lactose surface. This contributes to a more homogeneous distribution of the active substance within the mixture, and It reduces the risk of decomposition. In this way, substances with low solubility and low dosages can be treated. For avatrombopag maleate, an improved pharmaceutical in terms of manufacturability and content uniformity. The following composition is obtained. 4 As used here, “particle size” refers to the laser diffraction method (i.e., Malvern). as tested by any traditionally accepted method (such as analysis) The term d(0.9) expresses the cumulative volume size distribution of the particles. It refers to the size where 90% of it is thinner. According to an application of the present invention, avatrombopag in amorphous or crystalline form. a pharmaceutical compound containing maleate and at least one filler, where the filler is... The material has a volumetric dimension distribution determined by laser diffraction method, d(0.9) It is lactose monohydrate with a particle size less than 250 µm. In the present invention, the term "core composition" refers to a compressed or molded material that is free from any outer film coating, capsule shell (e.g., gelatin or HPMC) or any other It refers to a pharmaceutical compound that does not contain an outer layer. According to an application of the present invention, the amount of avatrombopag maleate in the nucleus Its composition ranges from 1.0% to 25.0% by weight. Preferably, avatrombopag maleate. The amount is between 5.0% and 22.0% by weight in the kernel composition, more preferably. It is between 10.0% and 20.0% by weight in the core composition. According to one application of this invention, avatrombopag maleate is crystalline form B. Crystalline form Form B is better compared to other crystalline forms of avatrombopag maleate, such as forms A and C. It has been found that it provides improved resolution. Accordingly, the use of crystal form B offers improved resolution. This contributes to obtaining a formulation that exhibits a dissolution profile. According to an application of the present invention, the particle size of lactose monohydrate d(0.9) is 1 Between µm and 200 µm, preferably between 50 µm and 150 µm, and even more preferably 75 µm It is between 95 µm. According to an application of the present invention, the amount of lactose monohydrate in the nucleus Its composition ranges from 55.0% to 90.0% by weight. Preferably, lactose monohydrate. The amount is between 60.0% and 85.0% by weight in the kernel composition, more preferably. The core composition is between 70.0% and 80.0% by weight. According to an application of the present invention, avatrombopag maleate and lactose monohydrate The weighting ratio between them is less than 1:5, preferably between 1:20 and 1:5, and even more preferably... It is between 1:10 and 1:5. Due to the relatively low dose of avatrombopag maleate used in the formulation The proportion of the filler is consequently high. Lactose 5% relative to the active ingredient. The amount of monohydrate affects the homogeneity and flow of the mixture during the direct compression process. This can affect its properties and compressibility. Therefore, with lactose monohydrate The ratio between avatrombopag and maleate for tablet production via direct compression. The mixture is selected to ensure appropriate homogeneity and compressibility. Otherwise, Excessively high filler ratios can lead to segregation in the mixture and poor flow properties. This can lead to a decrease in tablet hardness or variability in dissolution profiles. Therefore, the ratio between avatrombopag maleate and lactose monohydrate is within these ranges. Selection within it affects the fluidity, content uniformity and compressibility of the mixture. while improving, it also contributes to achieving the desired dissolution profile. It is found. According to one application of the present invention, the pharmaceutical composition also includes binders, the best selected from the group containing dispersers, sliders, glidants or a combination thereof It contains a small number of pharmaceutically acceptable excipients. Suitable binders include microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl... methylcellulose, polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose, calcium carboxymethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethyl methylcellulose, It is selected from the group containing hydroxypropyl starch or a mixture thereof. According to one application of the present invention, the binder is microcrystalline cellulose. According to an application of the present invention, the amount of binder is determined by the core composition. It ranges from 1.0% to 25.0% by weight. Preferably, the amount of binder depends on the core. It contains between 5.0% and 15.0% by weight in its composition. Suitable dispensers: crospovidon (Kollidon® CL), croscarmellose sodium, sodium starch. glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, It is selected from the group containing carboxymethyl cellulose, glycine, or a mixture thereof. According to one application of the present invention, the dispersant is crospovidon. According to an application of the present invention, the amount of dispersant is determined by the core composition. It is between 0.1% and 10.0% by weight. Preferably, the amount of dispersant, the kernel It contains between 1.0% and 5.0% by weight in its composition. According to an application of the present invention, the distributor's avatrombopag maleata weight The ratio is less than 3:5, preferably between 1:10 and 1:2, and even more preferably 1:5. 6 The dispenser being within the specified range according to avatrombopag maleate means the tablet is sufficient. It allows for dispersion and dissolution, while preventing excessive disintegration and crumbling. This The situation concerns the manufacturability and printability of tablets produced using the direct printing method. It contributes to its increase and provides a consistent dissolution profile. Suitable lubricants include magnesium stearate, sodium stearyl fumarate, talc, and calcium stearate. from the group containing zinc stearate, stearic acid, glyceryl behenate or a mixture thereof. is selected. According to one application of the present invention, the lubricant is magnesium stearate. According to one application of the present invention, the amount of the slider is in the core composition. It ranges from 0.01% to 10.0% by weight. Preferably, the amount of lubricant is in the core composition. It is between 0.5% and 5.0% by weight. Suitable glidants include colloidal silicon dioxide, magnesium oxide, magnesium silicate, or It is selected from a group that contains a mixture of these. According to one application of the present invention, the glidant is colloidal silicon dioxide. According to an application of the present invention, the amount of glidant is determined by weight in the core composition. It ranges from 0.01% to 8.0%. Preferably, the amount of glidant should be within the kernel composition by weight. It is between 0.1% and 3.0%. According to one application of this invention, the pharmaceutical compound is in the form of capsules or tablets. According to one application of this invention, the pharmaceutical compound can be packaged in compressed tablets, coated tablets. or uncoated tablets, multi-layer tablets, mini tablets, dual-layer tablets, buccal tablets, sublingual tablets, effervescent tablets, film-coated tablets, orally disintegrating tablets including tablets, chewable tablets, disintegrating tablets, lozenges or lozenges They are formulated as tablets. According to one application of this invention, the pharmaceutical compound is formulated as a film-coated tablet. It has been done. According to an application of the present invention, the pharmaceutical composition may also include one or more It contains a film coating agent. Suitable film coating agents include polyvinyl alcohol (PVA), macrogol (PEG 3350), and yellow iron. oxide, talc, titanium dioxide, indigo carmine, aluminum lake, carnauba wax, 7 hydroxypropyl methylcellulose, polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers, lecithin, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), pigments, It is selected from the group containing paints or mixtures thereof. According to this application of the present invention, the film coating agent is polyvinyl alcohol or It is macrogol, or yellow iron oxide, or talc, or a mixture of these. According to this application of the present invention, the amount of film coating material is the total It is between 1.0% and 8.0% by weight in the tablet. Preferably, the film coating agent. The amount is between 2.0% and 5.0% by weight of the total tablet. According to an application of the present invention, avatrombopag in amorphous or crystalline form A pharmaceutical compound containing maleate is obtained by a direct compression process. Direct During compression, the pharmaceutical compound components are not exposed to moisture, solvents, or heat. Thus, this invention involves processing avatrombopagi that is sensitive to moisture, solvents and / or heat. Direct compression is used for this. According to one application of the present invention, the tablet's hardness is between 150 N and 180 N. preferably between 165 N and 175 N. According to one application of the present invention, the tablet's rigidity is 170 N. Tablet hardness can affect the tablet's disintegration behavior. Approximately 4-5 minutes... To obtain the dispersion time, the compressive force determines the resulting tablet hardness. It is selected to fit within the range. Thus, the tablet maintains sufficient mechanical strength, It also allows for sufficient dispersion. A process for preparing a pharmaceutical compound containing avatrombopag maleate. The process involves the following steps: a) Weighing of avatrombopag maleate and all excipients, b) Avatrombopag maleate, a mixture of a binder and a dispersant, c) Next, a filler and a glidant are added to the mixture obtained in step (b). Addition and mixing; d) Sieving the mixture in step (c), e) Finally, add a slider to the mixture in step (d) and mix, f) Compressing the mixture into tablets. 8 Example 1; Components (by weight %) (by weight %) Avatrombopag Maleat Form B (20 mg 14.3 1.0-25.0 Avatrombopag equivalent) Lactose Monohydrate 73.2 55.0-90.0 Microcrystalline cellulose 7.9 1.0-25.0 Crospovidon 3.1 0.1-10.0 Colloidal Silicon Dioxide 0.5 0.01-8.0 Magnesium Stearate 1.0 0.01-10.0 Tablet core weight 100.0 92.0-99.0 Film Coating: Polyvinyl alcohol (PVA) Talk 3.0 1-8 Macrogol Yellow iron oxide TOTAL - - A process for Example 1; a) Avatrombopag maleate, lactose monohydrate, crospovidone, microcrystalline cellulose, Weighing of magnesium stearate and colloidal silicon dioxide, b) Mixing of avatrombopag maleate, microcrystalline cellulose and crospovidon, c) Then, the addition of lactose monohydrate and colloidal silicon dioxide and mixing, d) Sifting the mixture through a 0.6 mm sieve, e) Finally, add and mix in magnesium stearate. f) Forming the mixture into tablets at a pressure of 170 N.

Claims

1. Avatrombopag maleate in amorphous or crystalline form and at least one filler. It is a pharmaceutical compound containing a filler, characterized by its laser diffraction properties. According to the volume size distribution determined by the method, the particle size d(0.9) is 250 It means that the amount of lactose monohydrate is less than µm.

2. It is a pharmaceutical compound according to claim 1, and its characteristic is; lactose monohydrate d(0.9) Particle size between 1 µm and 200 µm, preferably between 50 µm and 150 µm The mesh size should be between 75 µm and 95 µm, and more preferably between 95 µm and 75 µm.

3. A pharmaceutical compound according to claim 1, characterized by the presence of avatrombopag maleate. The amount should be between 1.0% and 30.0% by weight in the core composition.

4. A pharmaceutical compound according to claim 1, characterized by being the crystalline form of avatrombopag maleate. It is form B.

5. A pharmaceutical compound according to Claim 1, characterized by the amount of lactose monohydrate; The core composition should be between 55.0% and 90.0% by weight.

6. It is a pharmaceutical compound according to Claim 1, and its characteristic is that the pharmaceutical compound also binders, dispersants, sliders, glidants, or a mixture thereof at least one pharmaceutically acceptable excipient selected from the group containing It contains substances.

7. A pharmaceutical composition according to claim 6, characterized by its microcrystalline binders. cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose, calcium carboxymethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl starch or selection from a group containing a mixture of these.

8. A pharmaceutical compound according to claim 6 or 7, characterized by the binder. It is microcrystalline cellulose.

9. A pharmaceutical compound according to claim 6, characterized by its distributors being crospovidon. (Kollidon® CL), croscarmellose sodium, sodium starch glycolate, low substitution. hydroxypropyl cellulose, calcium carboxymethyl cellulose, carboxymethyl It is the selection of a group containing cellulose, glycine, or a mixture thereof.

10. A pharmaceutical compound according to claim 9, characterized by the fact that the distributor is crospovidon. that is. 10 11. A pharmaceutical compound according to claim 6, characterized by its magnesium content as a lubricant. stearate, sodium stearyl fumarate, talc, calcium stearate, zinc stearate, stearic acid, It is chosen from the group containing glyceryl behenate or a mixture thereof.

12. A pharmaceutical composition according to claim 11, characterized by its magnesium content as a lubricant. It is stearate.

13. A pharmaceutical compound according to claim 6, characterized by its glidants being colloidal silicon. containing dioxide, magnesium oxide, magnesium silicate, or a mixture thereof. It is the selection from the group.

14. A pharmaceutical compound according to claim 13, characterized by its colloidal silicon content (glidant). It is dioxide.

15. A preparation of a pharmaceutical compound containing avatrombopag maleate. It is a process, and its characteristic feature is that the process includes the following steps: a) Weighing of avatrombopag maleate and all excipients, b) Avatrombopag maleate, a mixture of a binder and a dispersant, c) Next, a filler and a Adding and mixing the glidant; d) Sieving the mixture in step (c), e) Finally, add a slider to the mixture in step (d) and mixing, f) Compressing the mixture into tablets.