WO2022039701A1 - A solid oral composition comprising eltrombopag choline - Google Patents

A solid oral composition comprising eltrombopag choline Download PDF

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Publication number
WO2022039701A1
WO2022039701A1 PCT/TR2021/050799 TR2021050799W WO2022039701A1 WO 2022039701 A1 WO2022039701 A1 WO 2022039701A1 TR 2021050799 W TR2021050799 W TR 2021050799W WO 2022039701 A1 WO2022039701 A1 WO 2022039701A1
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Prior art keywords
solid oral
oral composition
less
composition according
sodium
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Ceased
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PCT/TR2021/050799
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French (fr)
Inventor
Fatih Sunel
Gulcin TOK
Bulent DEMIR
Selin KOKSAL UZUN
Salih Sermet BASARAN
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Sanovel Ilac Sanayi ve Ticaret AS
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Sanovel Ilac Sanayi ve Ticaret AS
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Priority to EP21858732.7A priority Critical patent/EP4199921A4/en
Publication of WO2022039701A1 publication Critical patent/WO2022039701A1/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a solid oral composition comprising eltrombopag choline and at least one pharmaceutically acceptable excipient.
  • the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
  • THPO Thrombopoietin
  • MGDF megakaryocyte growth and development factor
  • thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts.
  • Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches for activating the thrombopoietin receptor were sought.
  • thrombopoietin receptor agonists Two thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for other thrombocytopenic conditions.
  • Eltrombopag is an orally active thrombopoietin receptor agonist with megakaryopoiesis stimulating activity. Eltrombopag binds to and stimulates the platelet thrombopoietin receptor (TPO-R or CD110), a member of the hematopoietin receptor superfamily. Activation of TPO- R leads to the proliferation and differentiation of megakaryocytes, thereby increasing the production of blood platelets.
  • TPO-R platelet thrombopoietin receptor
  • eltrombopag 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1 H- pyrazol-4-yl]diazenyl]-2-hydroxyphenyl] benzoic acid and its chemical structure is shown in the Formula 1 .
  • Eltrombopag is marketed under the trade name Promacta® by GlaxoSmithKline and Ligand Pharmaceuticals as eltrombopag olamine for the treatment of conditions leading to thrombocytopenia.
  • Eltrombopag has been disclosed in U.S. Patent Nos. 7,332,481 and 7,160,870, as well as WO 01/89457; and in EP Patent No. 1 ,294,378.
  • Eltrombopag bisethanolamine salt and eltrombopag olamine salt has been disclosed in WO 03/098992 and U.S. Patent No. 8,052,994, respectively.
  • Some of the concerns is that slow dissolution of the compound from solid dosage forms, the tendency of the compound to form insoluble metal complexes when contacted with excipients that contain a coordinating metal, and the tendency of the compound to under-go a Maillard reaction when contacted with excipients that contain reducing sugars.
  • compositions comprising the new eltrombog salt are needed.
  • WO 19/071111A1 discloses eltrombopag choline.
  • the solid state form of eltrombopag choline disclosure have advantageous properties chemical or polymorphic purity, dissolution profile, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents.
  • a solid oral composition comprising eltrombopag choline is improved for the treatment of conditions leading to thrombocytopenia. It is used to overcome the disadvantages and side effects of the active agent’s other salts meanwhile increasing the dissolution rate and stability in the desired manner.
  • the main object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art.
  • the more clearly main object of the present invention is to provides a solid oral composition comprising eltrombopag choline having desired dissolution profile, stability (chemical stability or towards dehydration and/or storage stability) for the treatment of conditions leading to thrombocytopenia.
  • Another object of the present invention is to provides a process for a solid oral composition comprising eltrombopag choline.
  • the process is a simple, rapid, cost effective, time-saving and industrially convenient method.
  • a solid oral composition comprising eltrombopag choline and at least one pharmaceutically acceptable excipient.
  • the solid state form of eltrombopag choline has advantageous properties chemical or polymorphic purity, dissolution profile, bioavailability, stability. While creating the formulation for the treatment of conditions leading to thrombocytopenia, using eltrombopag choline was achieved effective treatment by making a low cost and easy production.
  • the amount of eltrombopag choline is between 3.0% and 40.0% by weight in the total formulation. This amount provides an effective treatment for the treatment of conditions leading to thrombocytopenia.
  • the amount of eltrombopag choline is between 5.0% and 35.0%, between 6.0% and 30.0%, between 7.0% and 27.0%, by weight in the total formulation.
  • excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
  • the formulations should have no physicochemical incompatibility between the active agents and the excipients. In the present invention, all excipients selected are compatible with eltrombopag choline.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, starch, pregelatinize starch, powdered cellulose, mannitol, spray-dried mannitol, dextrose, sucrose, sorbitol, xylitol, inorganic salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate or mixtures thereof.
  • the amount of diluents is between 45.0% and 90.0% by weight in the total formulation.
  • the amount of diluents is between 50.0% and 85.0% by weight in the total formulation.
  • the diluent is microcrystalline cellulose or mannitol or mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, natural gums, sucrose, sodium alginate, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • the amount of binders is between 0.05% and 10.0% by weight in the total formulation. Preferably, it is between 0.1% and 5.0% by weight in the total formulation.
  • used binder’s rate is very important in the solid oral composition. Thanks to the rate, dissolution problems are solved and surprisingly better dissolution profile is gained.
  • the binder is polyvinylpyrrolidone.
  • the active ingredient did not interact at polyvinylpyrrolidone, and polyvinylpyrrolidone also ensured that the composition had the desired dissolution profile.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, ion-exchange resins, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
  • the amount of disintegrants is between 1.0% and 25.0% by weight in the total formulation. Preferably, it is between 1.0% and 20.0%, between 1 .0% and 15.0% by weight in the total formulation.
  • the disintegrant is croscarmellose sodium or sodium starch glycolate or mixtures thereof.
  • Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol or mixtures thereof.
  • the amount of the lubricants is 0.1% to 5.0% or 0.1% to 4.0% by weight of the total composition.
  • the lubricant is sodium stearyl fumarate.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof.
  • the amount of the glidants is 0.05% to 5.0% or 0.05% to 3.0% by weight of the total composition.
  • the glidant is colloidal silicon dioxide.
  • particle size distribution means the cumulative volume size distrubition as tested by any conventionally accepted method such as the laser diffraction method (i.e. malvern analysis) .
  • d(0.9) means, the size at which 90% by volume of the particles are finer.
  • eltrombopag choline has a particle size of d(0.9) less than 150 pm or less than 140 pm or less than 130 pm or less than 120 pm or less than 110 pm or less than 100 pm or less than 90 pm or less than 80 pm or less than 70 pm or less than 60 pm or less than 50 pm or less than 40 pm or less than 30 pm or less than 20 pm. This property provides improved flow properties, also it helps to provide the desired dissolution profile. According to one embodiment of the invention, eltrombopag choline has a particle size of d(0.9) less than 10 pm.
  • the solid oral composition is in the form of tablets, capsules, strips, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films.
  • the solid oral composition is in the form of tablets or capsules.
  • the solid oral composition is in the form of tablet and the tablet are coated film-coating comprising coating agents.
  • Suitable coating agents are selected from the group comprising copovidone, polymethacrylates, polydextrose, polyethoxylated sorbitan, oleic acid, polyalkylacrylates copolymers, triacetin, hydroxyl propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.
  • the solid oral composition can be prepared as tablet form.
  • Tablet comprises at least one type of particle, for example; mini-tablets, pellets, core, agglomerates, granules, powders, liposomes, sphericals or mixtures thereof.
  • the solid oral composition is formulated as capsule form.
  • Capsule comprises at least one type of particle, for example; mini-capsules, mini-tablets, pellets, core, agglomerates, granules, powders, liposomes, sphericals or mixtures thereof.
  • the solid form composition of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • the solid oral composition is obtained by using a wet granulation method therefore, a simple and low-cost production method was employed.
  • the solid oral composition comprises;
  • the solid oral composition comprises;
  • Example 1 The solid oral composition comprising eltrombopag choline
  • Example 2 The tablet formulation comprising eltrombopag
  • Example 3 The tablet formulation comprising eltrombopag
  • Process for example 2 or 3 a) Mixing eltrombopag choline, microcrystalline cellulose, mannitol, polyvinylpyrrolidone, b) Granulating the mixture with water in a high-shear wet granulator, c) Wet milling the granule and drying in fluid bed dryer, d) Sieving the mixture and obtained homogeneous powder, e) Adding microcrystalline cellulose, disintegrant (croscarmellose sodium or sodium starch glycolate), colloidal silicon dioxide and mixing, f) Adding sodium stearyl fumarate and mixing, g) Compressing the mixture to form of a tablet, h) Coating tablets.
  • a) Mixing eltrombopag choline, microcrystalline cellulose, mannitol, polyvinylpyrrolidone b) Granulating the mixture with water in a high-shear wet granulator, c) Wet milling the granule and drying in

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Abstract

The present invention relates to a solid oral composition comprising eltrombopag choline and at least one pharmaceutically acceptable excipient. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.

Description

DESCRIPTION
A SOLID ORAL COMPOSITION COMPRISING ELTROMBOPAG CHOLINE
Field of the Invention
The present invention relates to a solid oral composition comprising eltrombopag choline and at least one pharmaceutically acceptable excipient. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process.
Background of the Invention
Thrombopoietin (THPO), also known as megakaryocyte growth and development factor (MGDF), is a protein that in humans is encoded by the THPO gene.
The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches for activating the thrombopoietin receptor were sought.
Two thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for other thrombocytopenic conditions.
Eltrombopag is an orally active thrombopoietin receptor agonist with megakaryopoiesis stimulating activity. Eltrombopag binds to and stimulates the platelet thrombopoietin receptor (TPO-R or CD110), a member of the hematopoietin receptor superfamily. Activation of TPO- R leads to the proliferation and differentiation of megakaryocytes, thereby increasing the production of blood platelets.
The chemical name of eltrombopag is 3-[3-[[2-(3,4-dimethylphenyl)-5-methyl-3-oxo-1 H- pyrazol-4-yl]diazenyl]-2-hydroxyphenyl] benzoic acid and its chemical structure is shown in the Formula 1 .
Figure imgf000003_0001
Formula 1 : Eltrombopag
Eltrombopag is marketed under the trade name Promacta® by GlaxoSmithKline and Ligand Pharmaceuticals as eltrombopag olamine for the treatment of conditions leading to thrombocytopenia.
Eltrombopag has been disclosed in U.S. Patent Nos. 7,332,481 and 7,160,870, as well as WO 01/89457; and in EP Patent No. 1 ,294,378. Eltrombopag bisethanolamine salt and eltrombopag olamine salt has been disclosed in WO 03/098992 and U.S. Patent No. 8,052,994, respectively.
Some salts of eltrombopag, especially olamine, presents the formulator with unique concerns when attempting to formulate this compound into a suitable solid oral pharmaceutical dosage form with a desirable pharmacokinetic profile. Some of the concerns is that slow dissolution of the compound from solid dosage forms, the tendency of the compound to form insoluble metal complexes when contacted with excipients that contain a coordinating metal, and the tendency of the compound to under-go a Maillard reaction when contacted with excipients that contain reducing sugars.
Due to the problems of eltrombopag described above, compositions comprising the new eltrombog salt are needed.
WO 19/071111A1 discloses eltrombopag choline. The solid state form of eltrombopag choline disclosure have advantageous properties chemical or polymorphic purity, dissolution profile, bioavailability, morphology or crystal habit, stability - such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, a lower degree of hygroscopicity, low content of residual solvents.
In this present invention, a solid oral composition comprising eltrombopag choline is improved for the treatment of conditions leading to thrombocytopenia. It is used to overcome the disadvantages and side effects of the active agent’s other salts meanwhile increasing the dissolution rate and stability in the desired manner. Detailed Description of the Invention
The main object of the present invention is to eliminate problems and bringing additional advantages to the relevant prior art.
The more clearly main object of the present invention is to provides a solid oral composition comprising eltrombopag choline having desired dissolution profile, stability (chemical stability or towards dehydration and/or storage stability) for the treatment of conditions leading to thrombocytopenia.
Another object of the present invention is to provides a process for a solid oral composition comprising eltrombopag choline. The process is a simple, rapid, cost effective, time-saving and industrially convenient method.
According to one embodiment of the present invention, a solid oral composition comprising eltrombopag choline and at least one pharmaceutically acceptable excipient. The solid state form of eltrombopag choline has advantageous properties chemical or polymorphic purity, dissolution profile, bioavailability, stability. While creating the formulation for the treatment of conditions leading to thrombocytopenia, using eltrombopag choline was achieved effective treatment by making a low cost and easy production.
According to one embodiment of the present invention, the amount of eltrombopag choline is between 3.0% and 40.0% by weight in the total formulation. This amount provides an effective treatment for the treatment of conditions leading to thrombocytopenia.
According to one embodiment of the present invention, the amount of eltrombopag choline is between 5.0% and 35.0%, between 6.0% and 30.0%, between 7.0% and 27.0%, by weight in the total formulation.
According to one embodiment of the present invention, at least one pharmaceutically acceptable excipient is selected from the group comprising diluents, binders, disintegrants, lubricants, glidants or mixtures thereof.
In general terms, excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed. The formulations should have no physicochemical incompatibility between the active agents and the excipients. In the present invention, all excipients selected are compatible with eltrombopag choline. Suitable diluents are selected from the group comprising microcrystalline cellulose, starch, pregelatinize starch, powdered cellulose, mannitol, spray-dried mannitol, dextrose, sucrose, sorbitol, xylitol, inorganic salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate or mixtures thereof.
According to one embodiment of the present invention, the amount of diluents is between 45.0% and 90.0% by weight in the total formulation.
According to one embodiment of the present invention, the amount of diluents is between 50.0% and 85.0% by weight in the total formulation.
According to one embodiment of the present invention, the diluent is microcrystalline cellulose or mannitol or mixtures thereof.
It has now surprisingly been found that using binders help to provide the desired dissolution profile.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, natural gums, sucrose, sodium alginate, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
According to one embodiment of the present invention, the amount of binders is between 0.05% and 10.0% by weight in the total formulation. Preferably, it is between 0.1% and 5.0% by weight in the total formulation. In the present invention, used binder’s rate is very important in the solid oral composition. Thanks to the rate, dissolution problems are solved and surprisingly better dissolution profile is gained.
According to one embodiment of the present invention, the binder is polyvinylpyrrolidone. The active ingredient did not interact at polyvinylpyrrolidone, and polyvinylpyrrolidone also ensured that the composition had the desired dissolution profile.
Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, ion-exchange resins, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
According to one embodiment of the present invention, the amount of disintegrants is between 1.0% and 25.0% by weight in the total formulation. Preferably, it is between 1.0% and 20.0%, between 1 .0% and 15.0% by weight in the total formulation.
According to one embodiment of the present invention, the disintegrant is croscarmellose sodium or sodium starch glycolate or mixtures thereof.
Suitable lubricants are selected from the group comprising sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol or mixtures thereof.
According to one embodiment of the invention, the amount of the lubricants is 0.1% to 5.0% or 0.1% to 4.0% by weight of the total composition.
According to one embodiment of the invention, the lubricant is sodium stearyl fumarate.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof.
According to one embodiment of the invention, the amount of the glidants is 0.05% to 5.0% or 0.05% to 3.0% by weight of the total composition.
According to one embodiment of the invention, the glidant is colloidal silicon dioxide.
As used here in, ‘particle size distribution’ means the cumulative volume size distrubition 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.
According to one embodiment of the invention, eltrombopag choline has a particle size of d(0.9) less than 150 pm or less than 140 pm or less than 130 pm or less than 120 pm or less than 110 pm or less than 100 pm or less than 90 pm or less than 80 pm or less than 70 pm or less than 60 pm or less than 50 pm or less than 40 pm or less than 30 pm or less than 20 pm. This property provides improved flow properties, also it helps to provide the desired dissolution profile. According to one embodiment of the invention, eltrombopag choline has a particle size of d(0.9) less than 10 pm.
According to one embodiment of the present invention, the solid oral composition is in the form of tablets, capsules, strips, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films. Preferably, the solid oral composition is in the form of tablets or capsules.
According to an embodiment of this present invention, the solid oral composition is formulated as tablet comprising film-coated tablets, bilayer tablets, inlay tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, modified release tablets, gastric disintegrating tablets, chewable tablets, dispersing tablets or lozenges.
According to one embodiment of the invention, preferably the solid oral composition is in the form of tablet and the tablet are coated film-coating comprising coating agents.
Suitable coating agents are selected from the group comprising copovidone, polymethacrylates, polydextrose, polyethoxylated sorbitan, oleic acid, polyalkylacrylates copolymers, triacetin, hydroxyl propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.
According to one embodiment of the present invention, the amount of coating comprising coating agents is between 0.1% and 5.0% by weight in the total formulation. Preferably, it is between 1 .5% and 3.5% by weight in the total formulation.
In this present invention, the solid oral composition can be prepared as tablet form. Tablet comprises at least one type of particle, for example; mini-tablets, pellets, core, agglomerates, granules, powders, liposomes, sphericals or mixtures thereof.
According to another embodiment of the present invention, the solid oral composition is formulated as capsule form. Capsule comprises at least one type of particle, for example; mini-capsules, mini-tablets, pellets, core, agglomerates, granules, powders, liposomes, sphericals or mixtures thereof. The solid form composition of the present invention may be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
Furthermore, the solid oral composition is obtained by using a wet granulation method therefore, a simple and low-cost production method was employed.
According to another embodiment of the present invention, the solid oral composition comprises;
• 5.0 - 30.0 % by weight of eltrombopag choline
• 45.0 - 85.0 % by weight of diluents
• 0.05 - 10.0 % by weight of binders
• 1.0 - 25.0 % by weight of disintegrants of the total composition.
According to another embodiment of the present invention, the solid oral composition comprises;
• 5.0 - 35.0 % by weight of eltrombopag choline
• 45.0 - 90.0 % by weight of diluents
• 0.05 - 10.0 % by weight of binders
• 1.0 - 25.0 % by weight of disintegrants
• 0.1 - 5.0 % by weight of lubricants
• 0.05 - 5.0 % by weight of glidants of the total composition.
Example 1 : The solid oral composition comprising eltrombopag choline
Figure imgf000009_0001
Example 2: The tablet formulation comprising eltrombopag
Figure imgf000009_0002
Example 3: The tablet formulation comprising eltrombopag
Figure imgf000010_0001
Process for example 2 or 3; a) Mixing eltrombopag choline, microcrystalline cellulose, mannitol, polyvinylpyrrolidone, b) Granulating the mixture with water in a high-shear wet granulator, c) Wet milling the granule and drying in fluid bed dryer, d) Sieving the mixture and obtained homogeneous powder, e) Adding microcrystalline cellulose, disintegrant (croscarmellose sodium or sodium starch glycolate), colloidal silicon dioxide and mixing, f) Adding sodium stearyl fumarate and mixing, g) Compressing the mixture to form of a tablet, h) Coating tablets.

Claims

CLAIMS A solid oral composition comprising eltrombopag choline and at least one pharmaceutically excipient. The solid oral composition according to claim 1 , wherein amount of eltrombopag choline is between 3.0% and 40.0% by weight in the total formulation. The solid oral composition according to claim 1 , wherein at least one pharmaceutically acceptable excipient is selected from the group comprising diluents, binders, disintegrants, lubricants, glidants or mixtures thereof. The solid oral composition according to claim 3, wherein diluents are selected from the group comprising microcrystalline cellulose, starch, pregelatinize starch, powdered cellulose, mannitol, spray-dried mannitol, dextrose, sucrose, sorbitol, xylitol, inorganic salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate or mixtures thereof. The solid oral composition according to claim 4, wherein the amount of diluents is between 45.0% and 90.0% by weight in the total formulation. The solid oral composition according to claim 3, wherein binders are selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, natural gums, sucrose, sodium alginate, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. The solid oral composition according to claim 6, wherein the amount of binders is between 0.05% and 10.0% by weight in the total formulation. The solid oral composition according to claim 3, wherein disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, alginic acid, alginates, ion-exchange resins, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof. The solid oral composition according to claim 8, wherein the amount of disintegrants is between 1 .0% and 25.0% by weight in the total formulation. The solid oral composition according to claim 1 , wherein eltrombopag choline has a particle size of d(0.9) less than 150 pm or less than 140 pm or less than 130 pm or less than 120 pm or less than 110 pm or less than 100 pm or less than 90 pm or less than 80 pm or less than 70 pm or less than 60 pm or less than 50 pm or less than 40 pm or less than 30 pm or less than 20 pm. The solid oral composition according to claim 1 , wherein the solid oral composition is in the form of tablets, capsules, strips, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films. The solid oral composition according to claim 11 , wherein the solid oral composition is in the form of tablets or capsules. The solid oral composition according to claim 3, wherein the solid oral composition comprises;
• 5.0 - 35.0 % by weight of eltrombopag choline
• 45.0 - 90.0 % by weight of diluents
• 0.05 - 10.0 % by weight of binders
• 1.0 - 25.0 % by weight of disintegrants
• 0.1 - 5.0 % by weight of lubricants
• 0.05 - 5.0 % by weight of glidants of the total composition. The solid oral composition according to any preceding claims, wherein the solid oral composition is obtained by using a wet granulation method. The solid oral composition according to any preceding claims, for use in preventing or treating conditions leading to thrombocytopenia.
PCT/TR2021/050799 2020-08-21 2021-08-13 A solid oral composition comprising eltrombopag choline Ceased WO2022039701A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117281780A (en) * 2023-11-24 2023-12-26 山东则正医药技术有限公司 Eltrombopag ethanolamine dry suspension and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017042839A1 (en) * 2015-09-08 2017-03-16 Actavis Group Ptc Ehf. Novel eltrombopag salt and preparation thereof
EP3409272A1 (en) * 2018-03-07 2018-12-05 Alfred E. Tiefenbacher (GmbH & Co. KG) Pharmaceutical composition comprising eltrombopag olamine, reducing sugar, and polymeric binder
WO2019071111A1 (en) * 2017-10-06 2019-04-11 Teva Pharmaceuticals Usa, Inc. Solid state forms of eltrombopag choline

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018078644A1 (en) * 2016-10-24 2018-05-03 Hetero Labs Limited Orally disintegrating tablets of eltrombopag
WO2020055364A2 (en) * 2018-08-02 2020-03-19 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A pharmaceutical composition comprising eltrombopag olamine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017042839A1 (en) * 2015-09-08 2017-03-16 Actavis Group Ptc Ehf. Novel eltrombopag salt and preparation thereof
WO2019071111A1 (en) * 2017-10-06 2019-04-11 Teva Pharmaceuticals Usa, Inc. Solid state forms of eltrombopag choline
EP3409272A1 (en) * 2018-03-07 2018-12-05 Alfred E. Tiefenbacher (GmbH & Co. KG) Pharmaceutical composition comprising eltrombopag olamine, reducing sugar, and polymeric binder

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4199921A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117281780A (en) * 2023-11-24 2023-12-26 山东则正医药技术有限公司 Eltrombopag ethanolamine dry suspension and preparation method thereof
CN117281780B (en) * 2023-11-24 2024-02-02 山东则正医药技术有限公司 Eltrombopag ethanolamine dry suspension and preparation method thereof

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