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WO2024225996A1 - Nouvelle composition de comprimé pharmaceutique comprenant de l'eltrombopag olamine - Google Patents

Nouvelle composition de comprimé pharmaceutique comprenant de l'eltrombopag olamine Download PDF

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Publication number
WO2024225996A1
WO2024225996A1 PCT/TR2023/050402 TR2023050402W WO2024225996A1 WO 2024225996 A1 WO2024225996 A1 WO 2024225996A1 TR 2023050402 W TR2023050402 W TR 2023050402W WO 2024225996 A1 WO2024225996 A1 WO 2024225996A1
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WIPO (PCT)
Prior art keywords
eltrombopag olamine
pharmaceutical
tablet
composition
eltrombopag
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/TR2023/050402
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English (en)
Inventor
Hatice ONCEL
Onur Pinarbasli
Feristah BILGIN
Gizem TABANSIZ
Nurdan ATILGAN
Asuman AYBEY DOGANAY
Nagehan SARRACOGLU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ilko Ilac Sanayi ve Ticaret AS
Original Assignee
Ilko Ilac Sanayi ve Ticaret AS
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Filing date
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Application filed by Ilko Ilac Sanayi ve Ticaret AS filed Critical Ilko Ilac Sanayi ve Ticaret AS
Priority to PCT/TR2023/050402 priority Critical patent/WO2024225996A1/fr
Publication of WO2024225996A1 publication Critical patent/WO2024225996A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to an immediate release stable pharmaceutical formulation for oral administration, comprising a therapeutically effective amount of eltrombopag olamine having specific particle size distribution, and wet granulation method for the preparation of said tablet by using a combination of sodium starch glycolate and crospovidone as disintegrant.
  • Eltrombopag olamine is a non-peptide haematopoietic receptor agonist, which mimics haematopoietic growth factors, including thrombopoietin (TPO), particularly enhancing platelet production and, thus, is particularly useful in the treatment of thrombocytopenia.
  • TPO thrombopoietin
  • the chemical name is 3'- ⁇ (2Z)-2-[l(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-4H-pyrazol-4- ylidene]hydrazino ⁇ -2'-hydroxy-3biphenylcarboxylic acid-2-aminoethanol (1:2). It has the molecular formula C25H22N4O4 • 2(C 2 H 7 NO). The molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free acid.
  • the free acid is poorly soluble in water (approximately 5 micrograms per milliliter). This poor solubility adversely affects the ability of the free acid to be formulated into pharmaceutical dosage forms and reduces the bioavailability of the compound in vivo.
  • Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 1 to 7.4, and is sparingly soluble in water. Eltrombopag olamine salt form is preferred for the solubility.
  • EP1294378 Bl relates to thrombopoietin (TPO) mimetics and their use as promoters of thrombopoiesis and megakaryocytopoiesis.
  • EP2152237 Bl relates to granules and solid oral pharmaceutical dosage forms, suitably tablets, comprising eltrombopag olamine wherein the tablet is made using a diluent or diluents that are substantially free of coordinating metals and/or that are substantially free of reducing sugars.
  • EP3409272 Bl discloses a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising eltrombopag olamine as active ingredient and one or more pharmaceutically acceptable excipients including one or more reducing sugars, characterized in that the composition comprises or consists of eltrombopag olamine in a therapeutically effective amount, lactose as reducing sugar, and povidone as polymeric binder agent, with the proviso that in case the pharmaceutical tablet composition is obtained by granulation compression exhibiting an intragranular composition and an extragranular composition, the eltrombopag olamine, the reducing sugar and the polymeric binder agent are present in the same composition.
  • EP3041511 Bl relates a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising eltrombopag olamine and a disintegrant in an amount of 13% to 20% by weight based on total weight of the composition, wherein said disintegrant is sodium starch glycolate.
  • eltrombopag olamine is approved under the tradename Revolade® (Novartis) comprising eltrombopag olamine in an amount corresponding to 12.5 mg, 25 mg, 50 mg, and 75 mg eltrombopag free acid in tablet form. Accordingly, inventors of the present invention have developed compositions of eltrombopag olamine that were found to be comparable with marketed Revolade® tablets.
  • Eltrombopag olamine presents the formulator with unique concerns when attempting to formulate this compound into a suitable solid oral pharmaceutical dosage form, suitably a tablet, with a desirable pharmacokinetic profile, particularly on a commercial scale.
  • Such concerns include, but are not limited to; the tendency of the compound to form insoluble metal complexes when contacted with excipients that contain a coordinating metal, slow dissolution of the compound from solid dosage forms and the tendency of the compound to undergo a Maillard reaction when contacted with excipients that contain reducing sugars.
  • Significant realization of these concerns will have an adverse effect on the in vivo administration of eltrombopag olamine.
  • eltrombopag olamine undergoes a Maillard reaction with respective pharmaceutically acceptable excipients, such as reducing sugars, e.g. lactose. It is known that eltrombopag olamine is degraded in presence of lactose and forms impurities, which can be measured in the pharmaceutical tablet composition. Mr.
  • Kapsi one of the inventors of WO 2008/136843 Al provided in the corresponding US examination of US 2010/0040684 Al a declaration (in the context of the present application called "Kapsi declaration") disclosing experimental stability data for the use of the lactose containing eltrombopag tablet composition of example 6 in WO 03/098992 A2 in comparison to a tablet formulation, which is free of reducing sugars using mannitol instead.
  • the eltrombopag olamine tablet formulation comprising lactose shows an "increase in degradation products when compared to the mannitol based formulation (4 fold difference in degradation products at 3 months".
  • Mr. Kapsi followed that the "experimental data described herein demonstrates that the formulation described as Example 6 in publication WO 03/098992 A2 leads to a tablet formulation with a four-fold higher level of degradation products at 3 months and in my experience leads to an unacceptable tablet formulation".
  • WO 2008/136843 Al teaches to use diluents substantially free of reducing sugars, in particular using mannitol.
  • the avoidance of reducing sugars as pharmaceutical excipient in an eltrombopag olamine pharmaceutical tablet is continued in WO 2012/121957 Al and WO 2015/0121957 A2.
  • the present invention addresses the problems of solubility and stability problems and provides a solution thereto.
  • the present inventors have developed a tablet formulation having specific particle size distribution of eltrombopag olamine and a combination of sodium starch glycolate and crospovidone as disintegrant.
  • the present invention relates to solid oral pharmaceutical dosage forms comprising a therapeutically effective amount of eltrombopag olamine.
  • the invention also relates to a process for making granules and solid oral pharmaceutical dosage forms comprising eltrombopag olamine.
  • the invention discloses a pharmaceutical tablet formulation comprising eltrombopag olamine in an amount of 12.5 mg, 25 mg, 50 mg and 75 mg.
  • the storage stable pharmaceutical tablet composition comprises therapeutically effective amount of eltrombopag olamine and mannitol as filler/diluent and a combination of sodium starch glycolate and crospovidone as disintegrant, wherein the said tablet composition comprises 90% of eltrombopag olamine drug particles have a particle size distribution between 10 pm to 20 pm (measured by the method of low angle laser light scattering in a wet method with Malvern Mastersizer, dispersion unit Hydro 2000S, general purpose mode, refractive index: 1.66, refraction index of dispersant
  • the storage stable pharmaceutical tablet composition comprises therapeutically effective amount of eltrombopag olamine and mannitol as filler/diluent having particle size distribution (d50) 100 pm and a combination of sodium starch glycolate and crospovidone as disintegrant in an amount of totally between 13% to 15% by weight based on total weight of the composition, wherein the said tablet composition comprises 90% of eltrombopag olamine drug particles have a particle size distribution between 10 pm to 20 pm (measured by the method of low angle laser light scattering in a wet method with Malvern Mastersizer, dispersion unit Hydro 2000S, general purpose mode, refractive index: 1.66, refraction index of dispersant 1.33).
  • the storage stable pharmaceutical tablet composition comprises therapeutically effective amount of eltrombopag olamine, mannitol and microcrystalline cellulose as filler/diluent, povidone as binder, sodium starch glycolate and crospovidone as disintegrant and magnesium stearate as lubricant.
  • tablets are coated with a film coat formed from an aqueous film coat composition.
  • Aqueous film coat compositions suitable for use in the present invention comprise a film-forming polymer, water as a vehicle, and optionally one or more adjuvants such as are known in the film-coating art.
  • the pharmaceutical composition comprising a therapeutically effective amount of eltrombopag olamine is used for the treatment of thrombocytopenia in a patient in need thereof.
  • the formulation of a solid oral pharmaceutical dosage form acceptable on a commercial scale is not always easy to develop.
  • the formulation and manufacturing process should be such as to provide a solid dosage form that maintains its integrity from manufacture to patient use.
  • the solid dosage form should also have acceptable dissolution and dispersion properties to provide the desired profile in use.
  • Pharmaceutically active compounds that have low solubility and/or can react with commonly used excipients can present particular challenges in the preparation of high quality solid dosage forms, as the physical properties of the drug affect the properties of the solid dosage form.
  • the formulator must balance the unique properties of the drug with the properties of each excipient to create a solid dosage form that is safe, effective and easy to use.
  • the most important and critical point of developing a pharmaceutical composition is to select and quantify the pharmaceutical excipients to obtain the appropriate dissolution profile and stability for the specified finished product dosage form, and to produce them with the appropriate production method.
  • the selection of the optimal composition and method of preparation of pharmaceutical auxiliary excipients is an important object to obtain the content uniform tablets having appropriate stability for the finished dosage form.
  • the developed inventive formulation fulfills the regulatory stability requirements for commercializing the pharmaceutical eltrombopag olamine tablet with having enhanced stability properties.
  • active ingredient or “active pharmaceutical ingredient” means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
  • the active ingredient is eltrombopag olamine.
  • terapéuticaally effective amount refers to the amount of eltrombopag or its pharmaceutically acceptable salts, esters, and solvates thereof, that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.
  • stable refers to a composition that substantially maintains its physical and chemical properties when stored.
  • a pharmaceutical composition comprising an active ingredient is considered to be “stable” if said ingredient degrades less or more slowly than it does on its own and/or in known pharmaceutical compositions and maintain the in-vitro dissolution profile upon the stability process.
  • improved properties encompasses the advantages of the finished product obtained from the formulation obtained with the present invention. These advantages include, in particular, the improvement of in-vitro release and obtaining a more stable product, especially under accelerated stability conditions in long term.
  • formulation refers to granules and/or solid oral pharmaceutical dosage forms of the invention that contain eltrombopag olamine.
  • intragranular phase refers to tablet ingredients which are wet granulated and thus forming granules, which then form the intragranular phase in the inventive pharmaceutical tablet composition.
  • intragranular tablet constituents comprise a therapeutically effective amount of eltrombopag olamine and other excipients.
  • extragranular phase comprises one or more tablet ingredients, which are admixed with the granules of the intragranular phase. This mixture is subsequently compressed to form the inventive pharmaceutical tablet composition (tablet core).
  • tablets may contain a number of inert materials known as excipients.
  • the pharmaceutical compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients.
  • excipient herein means any substance, not itself a therapeutic agent, which may be used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition.
  • Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralizing agents, if necessary), penetration enhancers, solubilizing agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition. Any such excipients can be used in any dosage forms according to the present disclosure.
  • excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types and combinations of excipients could be used to achieve the desired goals for release and stability of eltrombopag olamine tablet composition.
  • the excipients may be classified according to the role they play in the final tablet.
  • the primary composition includes a filler/ diluent, binder, lubricant, and disintegrant.
  • excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps, such as wet granulation, spray drying spheronization, or crystallization etc.
  • Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration.
  • disintegrants are selected from the group of starches, celluloses, gums, crosslinked polymers, and effervescent agents, such as corn starch, potato starch, pregelatinized starch, modified corn starch, croscarmellose sodium, crospovidone, sodium starch glycolate, Veegum HV, methyl cellulose, microcrystalline cellulose, cellulose, modified cellulose gum, agar, bentonite, montmorillonite clay, natural sponge, cation exchange resins, ion exchange resins (e.g., polyacrin potassium), alginic acid and alginates, guar gum, citrus pulp, carboxymethylcellulose and salts thereof such as sodium lauryl sulfate, magnesium aluminum silicate, hydrous aluminum silicate, sodium bicarbonate in admixture with an acidulant such as tartaric acid or citric acid.
  • the disintegrants are selected from the group of starches,
  • Binders are agents, which impart cohesive qualities to the powdered material.
  • binders are selected from the group of starch (e.g., paste, pregelatinized, mucilage), gelatin, sugars (e.g., sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol), polymethacrylates, natural and synthetic gums (e.g., acacia, alginic acids and salts thereof such as sodium alginate, gum tragacanth, Irish moss extract, panwar gum, ghatti gum, guar gum, zein), cellulose derivatives [such as carboxymethyl cellulose and salts thereof, methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (EC)], polyvinylpyrrolidone,
  • Filler/ diluents are added to increase the bulk weight of the blend resulting in a practical size for compression.
  • filler/ diluents are selected from the group of erythritol, isomalt, maltitol, xylitol, microcrystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol, maltodextrin.
  • the filler/ diluents are the combination of microcrystalline cellulose and mannitol.
  • Mannitol is widely used in pharmaceutical formulations and food products. In pharmaceutical preparations it is primarily used as a diluent (10-90% w/w) in tablet formulations, where it is of particular value since it is not hygroscopic and may thus be used with moisture-sensitive active ingredients. Granulations containing mannitol have the advantage of being dried easily.
  • Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight.
  • lubricants are selected from the group of talc, stearates (e.g., magnesium stearate, calcium stearate, zinc stearate, palmitostearate), stearic acid, hydrogenated vegetable oils, glyceryl behanate, polyethylene glycol, ethylene oxide polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and silica derivatives (e.g., colloidal silicon dioxide, colloidal silica, pyrogenic silica, and hydrated sodium silicoaluminate).
  • silica derivatives e.g
  • Solvents used for granulation and coating can be either aqueous or non-aqueous solvents.
  • Suitable non-aqueous solvents include, but are not limited to isopropyl alcohol, ethanol, dichloromethane, acetone and the like.
  • Aqueous solvent include water.
  • the compressed tablets are further film coated by non-aqueous coating or aqueous coating or by hydroalcoholic coating.
  • This coating composition contains film-forming substances such as hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol; solvents, colloidal silicon dioxide, optionally other excipients such as plasticizers, lubricants and colourants.
  • the wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tabletting.
  • the procedure consists of mixing the powders in a suitable blender to form feedstock followed by adding the granulating solution under shear to the mixed powders to obtain a granulation.
  • the damp mass is dried by tray drying or fluidized bed drying.
  • the dried granules are milled and screened through a suitable screen.
  • the overall process includes: weighing, dry powder blending, wet granulating, drying, milling, screening, blending lubrication and compression.
  • Comparative dissolution tests were conducted based on the general dissolution test method. The analysis was performed according to FDA Dissolution Methods - Eltrombopag olamine Tablet. The progress of dissolution is monitored for 60 minutes (recommended sampling times: 10, 15, 20, 30, 45 and 60 minutes). Dissolution test was performed at USP Apparatus II (paddle), speed 50 rpm, 900 mL volume with 0.5% polysorbate 80 in phosphate buffer pH 6.8 (FDA medium), 0.5% polysorbate 80 in acetate buffer pH 4.5 and 0.5% polysorbate 80 in 0.01 N HCI buffer. Dissolution testing measures the portion (%) of eltrombopag that has been released from tablet and has dissolved in the dissolution medium. Dissolved eltrombopag content was determined spectrophotometrically by a validated HPLC method at 230 nm.
  • Comparative dissolution tests were conducted with test formulation products (F-01 to 08) and reference product of Revolade® Tablet.
  • the conditional release profiles of the test products and reference product were plotted as the cumulative percent of drug dissolved vs. time.
  • the dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (f 2 ) (Helmy & Bedaiwy, 2013). An /2 value between 50 and 100 suggests that the two dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010).
  • the similarity factor (f 2 ) values of test formulation products (F-01 to 08) and reference product (R - Revolade ® Tablet) for the different pH media are found between 50 and 100.
  • the coated tablets were tested against stress conditions according to the method described in ICH guidelines.
  • the ICH guideline also indicates that stress testing is designed to help "determine the intrinsic stability of the molecule by establishing degradation pathways in order to identify the likely degradation products and to validate the stability indicating power of the analytical procedures used". Elevated thermal conditions are often used to accelerate chemical degradation processes that will occur at room temperature upon storage.
  • the coated tablets produced in the present invention (F-03 to F-07) were subjected to the stress conditions, the results are given below (Table 2).
  • the stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product.
  • the rules in force e.g. "Note for Guidance on Impurities in New Drug Products” CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.
  • the stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment.
  • Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions.
  • the accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/Q.WP/122/02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ⁇ 2°C and 75% ⁇ 5 %RH (Relative Humidity) for six months.
  • Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”
  • the fixed-dose capsules produced with the present invention have been found to be bioequivalent to reference product Revolade® with the bioequivalence study conducted in normal, healthy, adult subjects under fasting condition.

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Abstract

La présente invention concerne une composition de comprimé pharmaceutique ayant une stabilité au stockage améliorée comprenant de l'eltrombopag olamine, une combinaison de glycolate d'amidon sodique et de crospovidone en tant que délitant et au moins un autre excipient pharmaceutiquement acceptable qui ne contient pas de lactose et un procédé de préparation dudit comprimé à l'aide d'une distribution granulométrique spécifique des particules de médicament d'eltrombopag olamine.
PCT/TR2023/050402 2023-04-28 2023-04-28 Nouvelle composition de comprimé pharmaceutique comprenant de l'eltrombopag olamine Pending WO2024225996A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/050402 WO2024225996A1 (fr) 2023-04-28 2023-04-28 Nouvelle composition de comprimé pharmaceutique comprenant de l'eltrombopag olamine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2023/050402 WO2024225996A1 (fr) 2023-04-28 2023-04-28 Nouvelle composition de comprimé pharmaceutique comprenant de l'eltrombopag olamine

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018078644A1 (fr) * 2016-10-24 2018-05-03 Hetero Labs Limited Comprimés d'eltrombopag à désintégration orale
WO2021110959A1 (fr) * 2019-12-06 2021-06-10 Synthon B.V. Composition pharmaceutique comprenant de l'eltrombopag bis(monoéthanolamine)
CN115919789A (zh) * 2022-12-08 2023-04-07 山东新时代药业有限公司 一种艾曲泊帕乙醇胺片及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018078644A1 (fr) * 2016-10-24 2018-05-03 Hetero Labs Limited Comprimés d'eltrombopag à désintégration orale
WO2021110959A1 (fr) * 2019-12-06 2021-06-10 Synthon B.V. Composition pharmaceutique comprenant de l'eltrombopag bis(monoéthanolamine)
CN115919789A (zh) * 2022-12-08 2023-04-07 山东新时代药业有限公司 一种艾曲泊帕乙醇胺片及其制备方法

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