Classifications

• • 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
  • 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
  • A61K9/2022—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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• composition comprising Eltrombopag Olamine, Reducing Sugar, and Polymeric Binder
• the present invention relates to a pharmaceutical tablet composition comprising eltrombopag olamine, one or more reducing sugars, and one or more polymeric binder agents, a production process therefore, a pharmaceutical tablet composition comprising eltrombopag olamine, one or more reducing sugars, and one or more polymeric binder agents obtainable by the production process, a use / method of use of the pharmaceutical tablet compositions in the treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA).
• IDP immune idiopathic thrombocytopenic purpura
• SAA acquired severe aplastic anaemia
• eltrombopag olamine is approved under the tradename Revolade ® comprising eltrombopag olamine in an amount corresponding to 12.5 mg, 25 mg, 50 mg, and 75 mg eltrombopag free acid in tablet form.
• eltrombopag olamine is approved under the tradename Promacta ® comprising eltrombopag olamine in an amount corresponding to 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg eltrombopag free acid in tablet form.
• Revolade ® tablets are packed in Alu-Alu blisters, whereas Promacta ® tablets are packed in HDPE bottles.
• Revolade ® is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins). Revolade ® may be considered as second line treatment for adult non- splenectomised patients where surgery is contraindicated.
• ITP thrombocytopenic purpura
• Revolade ® is also indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.
• HCV chronic hepatitis C virus
• Revolade ® is furthermore indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.
• SAA severe aplastic anaemia
• an eltrombopag tablet composition is disclosed in example 6 which comprises in addition to 8.45 mg eltrombopag olamine, furthermore 112 mg microcrystalline cellulose, 70 mg lactose, 8 mg sodium starch glycolate and 2 mg magnesium stearate.
• 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 A1 provided in the corresponding US examination of US 2010/0040684 A1 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" (see section Results on page 1 ).
• 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 A1 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 A1 and WO 2015/0121957 A2.
• a first aspect of the present invention relates to 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
• the composition comprises or consists of a) eltrombopag olamine in a therapeutically effective amount, b) one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and c) one or more semisynthetic and/or synthetic polymeric binder agents, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydrox- ypropyl methyl cellulose
• a second aspect of the present invention relates to an inventive pharmaceutical tablet composition for use in the treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA).
• IDP immune thrombocytopenic purpura
• SAA acquired severe aplastic anaemia
• a third aspect of the present invention relates to a process of production of an inventive pharmaceutical tablet comprising or consisting of a) eltrombopag olamine in a therapeutically effective amount, b) one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and c) one or more semisynthetic and/or synthetic polymeric binder agents, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl starch, and d) optionally one or more further pharmaceutically acceptable excipients, characterized in that the pharmaceutical tablet composition is either
• a fourth aspect of the present invention relates to 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 comprising or consisting of a) eltrombopag olamine in a therapeutically effective amount, b) one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and c) one or more semisynthetic and/or synthetic polymeric binder agents, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxy propyl cellulose, hydroxypropyl methyl cellulose
• a fifth aspect of the present invention relates to a use of an inventive pharmaceutical tablet composition, wherein the pharmaceutical tablet composition is used in the manufacture of a medicament for the treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA).
• IDP immune thrombocytopenic purpura
• SAA acquired severe aplastic anaemia
• a sixth aspect of the present invention relates to a method of treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA), comprising administering to a patient in need an inventive pharmaceutical tablet composition.
• IDP immune thrombocytopenic purpura
• SAA acquired severe aplastic anaemia
• inventive aspects of the present invention as disclosed hereinbefore can comprise - in case it is reasonable for a person skilled in the art - any possible combination of the preferred inventive embodiments as set out in the dependent claims or disclosed in the following detailed description.
• inventive pharmaceutical tablet composition containing a polymeric binder agent is not subjected to a substantial degradation of the active ingredient eltrombopag olamine in view of Maillard reactions with the reducing sugar and, thus, fulfills the regulatory stability requirements for commercializing the pharmaceutical eltrombopag olamine tablet (cf. Part E, table 1 of the Example section below).
• binder is defined as an agent used to increase the cohesion of the powdery particles or granules during the compression, in order to obtain pharmaceutical forms with a defined hardness, or to act as processing aid during the granulation process.
• the binder may be present in the pharmaceutical composition in the form of a single constituent / ingredient or in the form of a mixture of constituents / ingredients.
• the binder agents are classified into 3 classes: 1 ) “natural binder", 2) “semisynthetic polymeric binder", and 3) “synthetic polymeric binder”.
• the natural binder agents Due to their natural source the natural binder agents generally exhibit an inherent variability relating to the natural polymers of different batches, which sometimes gives rise to problems in production. To reduce potential processing problems, (natural) binder agents may also be further characterized, e.g., by their viscous properties. In comparison to the natural binder agents, the variability between batches of the semisynthetic and/or synthetic binder agents from the same supplier is reduced due to the adjustment by chemical derivatization or a total chemical synthesis. For almost each polymeric binder agent type, several viscosity grades are generally available.
• ..natural binder refers to a natural polymer binder or a salt thereof, preferably selected from the group consisting of starch, processed starch or starch salt, e.g., corn starch, potato starch, pregelatinized starch, sodium starch; alginic acid or salts thereof, e.g. sodium alginate; gelatin; Guar gum; gum Arabic; Candelilla wax; Car- nauba wax.
• the expression “semisynthetic polymeric binder” refers to a chemically modified natural polymer binder, usually a derivative of cellulose or starch, preferably selected from the group consisting of hydroxypropyl cellulose (HPC, hyprollose), hydroxy- propyl methyl cellulose (HPMC, hypromellose), sodium carboxymethyl cellulose, and hydroxy- propyl starch.
• HPC hydroxypropyl cellulose
• HPMC hypromellose
• sodium carboxymethyl cellulose sodium carboxymethyl cellulose
• hydroxy- propyl starch preferably selected from the group consisting of hydroxypropyl cellulose (HPC, hyprollose), hydroxy- propyl methyl cellulose (HPMC, hypromellose), sodium carboxymethyl cellulose, and hydroxy- propyl starch.
• the expression locallysynthetic polymeric binder refers to a fully chemically synthesized, non-natural polymer or co-polymer binder agent, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol (PEG), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and polyethylene glycol-polyvinyl alcohol graft copolymer (PEG-PVA).
• polymeric binder / "polymer binder” refers to a group of polymeric binder agents consisting of "semisynthetic polymeric binders” and/or “synthetic polymeric binders”, as defined above.
• the expression "the eltrombopag olamine, the one or more reducing sugars and the one or more polymeric binder agents are present in the same composition” means that i) in case the inventive pharmaceutical tablet is obtained by direct compression the ingredients a) to c) are respectively present in the mixture of ingredients to be compressed to tablet cores and ii) in case the inventive pharmaceutical tablet composition is obtained by granulation compression exhibiting a granular composition (forming the intragranular composition in the tablet core) and a non-granular composition (forming the extragranular composition in the tablet core), the ingredients a) to c) are present either in the intragranular composition or in the extragranular composition or the ingredients a) to c) are present in both the intragranular and the extragranular composition respectively.
• ingredient(s) b i.e. one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and/or ingredient(s) c), i.e.
• one or more semisynthetic and/or synthetic polymeric binder agents preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolac- tam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl starch, may additionally be present in the intragranular or extragranular composition, which does not comprise eltrombopag olamine.
• the experimental data provided in table 2 in Part E) of the Example section shows that 75 wt.% or more, preferably more than 80 wt.%, more preferably more than 90 wt.% of eltrombopag olamine in the inventive pharmaceutical tablet composition is dissolved within 45 minutes in accordance with the regulatory standard test.
• a comparative tablet composition not comprising the polymeric binder in the same composition does not fulfil the dissolution requirements of at least 75 wt.% dissolution of the active ingredient after 45 minutes.
• inventive pharmaceutical composition is produced by granulation compression technique (cf. Parts A and B of the Example section below), the inventive composition exhibits an intragranular composition as well as an extragranular composition.
• intragranular composition / "intragranular phase” refers to tablet constituents / ingredients which are wet granulated and thus forming granules, which then form the intragranular composition / phase in the inventive pharmaceutical tablet composition.
• the intragranular tablet constituents comprise a therapeutically effective amount of eltrombopag olamine
• the intragranular composition must also comprise ingredient b), i.e. one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and ingredient c), i.e.
• one or more semisynthetic and/or synthetic polymeric binder agents preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl starch.
• extragranular composition / "extragranular phase” comprises one or more tablet constituents / ingredients, which are admixed with the granules of the intragranular composition. This mixture is subsequently compressed to form the inventive pharmaceutical tablet composition (tablet core).
• the extragranular composition comprises or consists of a therapeutically effective amount of eltrombopag olamine
• the extragranular composition must also comprise one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose and one or more semisynthetic and/or synthetic polymeric binder agents, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl starch.
• one or more reducing sugars preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose
• the inventive pharmaceutical tablet composition may be obtained by direct (dry) compression.
• Direct compression provides less complex and shorter production process for producing tablets.
• Eltrombopag olamine as a moisture sensitive active ingredient is particularly suitable for direct compression production processes, as the risk of a Maillard reaction between eltrombopag olamine and the one or more reducing sugars is furthermore reduced.
• the inventive pharmaceutical tablet composition comprises eltrombopag olamine as the active ingredient in a therapeutically effective amount and optionally one or more further active ingredients.
• eltrombopag olamine refers to an amorphous form or one or more polymorphic crystalline forms of eltrombopag olamine, wherein eltrombopag olamine has been defined hereinbefore as eltrombopag biseth- anolamine.
• the amorphous as well as polymorphic forms I, II, and III of eltrombopag olamine have been disclosed, e.g., in WO 2010/114943 A1. More preferably, eltrombopag olamine in particular polymorphic form I of eltrombopag olamine (cf.
• FIG 28 of WO 2010/1 14943 A1 shows polymorphic form I of eltrombopag bisethanolamine) is used in accordance with all aspects and preferred embodiments of the present invention.
• the eltrombopag olamine is generally used exhibiting suitable particle sizes for formulating the inventive pharmaceutical tablet composition, wherein preferably the particle size distribution by volume (PSD) is 30 ⁇ or less for 90 Vol. % of the particles (D 0.9), 8 ⁇ or less for 50 Vol. % of the particles (D 0.5), and/or 2 ⁇ or less for 10 Vol. % of the particles (D 0.1 ).
• PSD particle size distribution by volume
• the particle size distribution by volume may be determined by use of the Malvern technique (by volume).
• the active ingredient eltrombopag olamine is used per tablet unit in an amount of 16.05 mg, 32.1 mg, 64.2 mg, 96.3 mg or 128.4 mg eltrombopag olamine (respectively corresponding to 12.5 mg, 25 mg, 50 mg, 75 mg or 100 mg eltrombopag free acid).
• the inventive pharmaceutical tablet composition is effective for use in the treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA).
• IDP immune thrombocytopenic purpura
• SAA acquired severe aplastic anaemia
• the inventive pharmaceutical tablet composition is indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) in splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).
• ITP thrombocytopenic purpura
• the inventive pharmaceutical tablet composition may also be considered as second line treatment for adult non-splenectomised patients where surgery is contraindicated.
• the inventive pharmaceutical tablet composition is preferably furthermore indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.
• HCV chronic hepatitis C virus
• the inventive pharmaceutical tablet composition is preferably furthermore indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immu- nosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.
• SAA severe aplastic anaemia
• suitable reducing sugars i.e. sugar constituents which generally may form a Maillard reaction with the active ingredient eltrombopag olamine, are used as the one or more reducing sugars acting as diluents in the extragranular composition of the inventive pharmaceutical tablet composition.
• the one or more reducing sugars are selected from the group consisting of lactose, maltose, glucose, arabinose and fructose, more preferably the one or more reducing sugar comprises or consists of lactose selected from the group consisting of lactose monohydrate, anhydrous lactose, spray dried lactose and co-processed lactose.
• lactose examples include Ludipress ® (lactose monohydrate 93 wt.%, 3.5 wt.% povidone (Kol- lidon ® 30) and 3.5 wt.% crospovidone (Kollidon ® CL); Cellactose ® (75% lactose and 25% micro- crystalline cellulose MCC); Starlac ® (85% lactose and 15% starch) and Combilac ® (70% lactose, 20% MCC and 10% corn starch).
• Ludipress ® lactose monohydrate 93 wt.%, 3.5 wt.% povidone (Kol- lidon ® 30) and 3.5 wt.% crospovidone (Kollidon ® CL)
• Cellactose ® (75% lactose and 25% micro- crystalline cellulose MCC
• Starlac ® 85% lactose and 15% starch
• Combilac ® 70% lactose, 20% MCC and 10% corn
• lactose as diluent in the tablet composition is advantageous, as lactose is in particular cheaper than other excipients and thus allows a more economic production of pharmaceutical eltrombopag olamine tablet compositions.
• lactose is advantageous, as a variety of commercially available grades (lactose monohydrate, anhydrous lactose and spray- dried lactose) exists, which enables the skilled person to choose the best fitting grade for the present situation. Accordingly, the skilled person is enabled with respect to all aspects of the present invention to select the best fitting lactose excipient based on the required characteristics for tablet compression.
• lactose excipient shall also facilitate non- sticking at the compression facilities
• lactose comprising a comparatively large particle size will be selected.
• fine grades are usually used for the granulation compression process, as they permit better mixing with other excipients.
• the reducing sugar content in the inventive pharmaceutical tablet composition is preferably greater than 5 wt.%, preferably at least 9 wt.%, more preferably in the range of 15 to 75 wt.% alternatively 30 to 70 wt.% respectively based on the total weight of the pharmaceutical tablet composition
• the inventive pharmaceutical eltrombopag olamine tablet is made using at least 31 to 40 wt. % or 53 to 62 wt. % lactose, e.g. lactose monohydrate, respectively based on the total weight of the tablet.
• lactose e.g. lactose monohydrate
• the relative content of lactose in comparison to the total weight of the tablet increases with reducing the relative content of the active ingredient eltrombopag olamine.
• the composition also comprises or consists of one or more semisynthetic and/or synthetic polymeric binder agents selected from the group consisting of povidone (non-crosslinked polyvinyl pyrrolidone, also called PVP, e.g. commercially available as Plasdone K29/32 or Kollidon ® 30), copovidone (vinylpyrrolidone-vinyl acetate copolymer in a ratio of 3:2 by mass, also called PVP/VA, e.g. commercially available as Kollidon ® VA64), polyvinyl alcohol (e.g. commercially available as PVA Emprove ® 4-88), polyethylene glycol (also called PEG or Macrogol, e.g.
• povidone non-crosslinked polyvinyl pyrrolidone
• PVP non-crosslinked polyvinyl pyrrolidone
• copovidone vinylpyrrolidone-vinyl acetate copolymer in a ratio of 3:2 by mass
• CarbowaxTM PEG polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer
• Soluplus ® polyethylene glycol-polyvinyl alcohol graft copolymer
• PEG- PVA polyethylene glycol-polyvinyl alcohol graft copolymer
• HPC hydroxypropyl cellulose
• hyprollose e.g. commercially available as KlucelTM ELF
• HPMC hydroxypropyl methyl cellulose
• MethocelTM K3 Premium LV sodium carboxymethyl cellulose
• Na-CMC sodium carboxymethyl cellulose
• HPS hydroxypropyl starch
• one or two polymeric binder agents are selected from povidone and copovidone.
• co-processed lactose comprising one or more polymeric binder agents are used in the composition, then a separate amount of polymeric binder agent in the composition may be reduced (see also below paragraph).
• the additional use of one or more polymeric binder agents in the intragranular composition and optionally also in the extragranular composition is preferred, as the respective inventive tablet composition shows an additionally reduced degradation of eltrombopag olamine.
• co-processed lactose is preferred, as it already comprises a mixture of lactose and one or more further excipients.
• the one or more further excipients in the co-processed lactose are preferable selected from microcrystalline cellulose (MCC), starch, povidone, and crospovidone (crosslinked polyvinyl pyrrolidone, so called PVPP or polyvinyl polypyrrolidone, e.g. commercially available as Polyplasdone XL or Kollidon ® CL).
• co-processed lactose is available as, e.g., Ludipress ® which comprises of lactose, povidone (Kollidon ® 30) and crospovidone (Kollidon ® CL), Cellactose ® (lactose with MCC); Starlac ® (lactose with starch) and Combilac ® (lactose with MCC and starch).
• Ludipress ® which comprises of lactose, povidone (Kollidon ® 30) and crospovidone (Kollidon ® CL), Cellactose ® (lactose with MCC); Starlac ® (lactose with starch) and Combilac ® (lactose with MCC and starch).
• the inventive pharmaceutical tablet composition may further comprise suitable natural binder agents, preferably selected from the group consisting of starch processed starch or starch salts, e.g., corn starch, potato starch, pregelatinized starch, sodium starch; alginic acid or salts thereof, e.g. sodium alginate; gelatin, Guar gum; gum Arabic; Candelilla wax; and Carnauba wax.
• suitable natural binder agents preferably selected from the group consisting of starch processed starch or starch salts, e.g., corn starch, potato starch, pregelatinized starch, sodium starch; alginic acid or salts thereof, e.g. sodium alginate; gelatin, Guar gum; gum Arabic; Candelilla wax; and Carnauba wax.
• Starch and pregelatinized starch are multifunctional excipients. They can be considered as natural binder agents, but they can be used also as natural diluent agents, and furthermore also have disintegrant-like properties.
• a disintegrant is typically an agent used in the preparation of solid pharmaceutical formulations which causes them to disintegrate and release their medicinal substances on contact with moisture. However, the disintegrant may also be considered as a diluent and/or binder, depending on the properties of the particular excipient employed as a disintegrant.
• a binder is typically a substance used to create a desired consistency in a formulation, whereby a diluent is typically considered as a bulking agent to increase the mass of the formulation.
• the disintegrant exhibits properties of disintegration upon contact with aqueous environments, and is preferably a non-soluble disintegrant, but may also show properties associated with a diluent or binder.
• PGS is a starch that has been chemically and/or mechanically processed to rupture all or part of the starch granules. This typically renders the starch flowable and directly compressible (Handbook of Pharmaceutical Excipients (Ed: Rowe)).
• Partially pregelatinized starch is commercially available.
• pregelatinized starch contains 5% of free amylose, 15% of free amylopectin, and 80% unmodified starch.
• Pregelatinized starch is typically obtained from maize (corn), potato, or rice starch.
• the inventive pharmaceutical tablet composition may further comprise suitable further diluent agents (in addition to the one or more reducing sugars), preferably one or more further diluent agents are selected from the group consisting of erythritol, isomalt, maltitol, xylitol, micro- crystalline cellulose, powdered cellulose, pregelatinized starch, starch, lactitol, mannitol, sorbitol, maltodextrin more preferably one, two or more further diluent agents are selected from erythritol, isomalt, maltitol, xylitol, and microcrystalline cellulose, even more preferably the further diluent agents are selected from microcrystalline cellulose and one, two or more selected from erythritol, isomalt, maltitol and xylitol, preferably xylitol.
• suitable further diluent agents are selected from the group consisting of ery
• the composition comprising the eltrombopag olamine and the reducing sugar(s) comprises at least one further diluent agent as set out above, preferably comprising microcrystalline cellulose.
• the composition comprising the eltrombopag olamine and the reducing sugar(s) comprises at least one further diluent agent as set out above, preferably comprising microcrystalline cellulose.
• microcrystalline cellulose as insoluble diluent agent acts as counterpart of the reducing sugar representing a soluble diluent, thereby facilitating the tuning of the disintegration time of the inventive pharmaceutical tablet composition.
• the inventive pharmaceutical tablet composition - in case of granulation compression preferably the extragranular composition - may further comprise suitable one or more suitable disintegrant agents, preferably one or more disintegrant agents are selected from the group consisting of low-substituted hydroxypropyl cellulose (L-HPC), sodium starch glycolate, crospovidone, and croscarmellose sodium, more preferably one or two selected from sodium starch glycolate and crospovidone.
• L-HPC low-substituted hydroxypropyl cellulose
• crospovidone sodium starch glycolate
• crospovidone crospovidone
• croscarmellose sodium more preferably one or two selected from sodium starch glycolate and crospovidone.
• the inventive tablet composition is obtained by granular compression
• the composition comprises one or more disintegrant agents in both the intragranular and extragranular composition, in particular in case a higher amount of eltrom- bopag olamine is used in the intragranular phase and/or an insoluble diluent can be used in the intragranular phase in addition to eltrombopag olamine and the reducing sugar.
• the same or different disintegrant agent may be used both in the intragranular and extragranular composition, wherein the weight ratios of disintegrant in intra- and extragranular phase is preferably in the range of 1 : 1 to 1 :5, in particular 1 :3 or 1 :4 or 1 :4.6.
• the intragranular phase may comprise no disintegrant agent and the extragranular phase may comprise low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone or croscarmellose sodium or a combination of sodium starch glycolate and crospovidone or sodium starch glycolate and croscarmellose sodium or crospovidone and croscarmellose sodium, more preferably sodium starch glycolate as disintegrant agent(s), wherein the disintegrant agent in total in the extragranular phase is in particular present in a range of 5 to 10 wt.%, preferably 8 wt.% based on the total weight of the inventive tablet composition.
• the intragranular phase may comprise low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone or croscarmellose sodium or a combination of sodium starch glycolate and crospovidone or sodium starch glycolate and croscarmellose sodium or crospovidone and croscarmellose sodium, more preferably sodium starch glycolate as disintegrant agent(s), wherein the disintegrant agent in total in the intragranular phase is in particular present in a weight range of 1 to 5 wt.%, preferably 2 wt.% based on the total weight of the inventive tablet composition, while the extragranular phase may comprise low-substituted hydroxypropyl cellulose, sodium starch glycolate, crospovidone or croscarmellose sodium, or a combination of sodium starch glycolate and crospovidone or sodium starch glycolate and croscarmellose sodium or crospovidone and croscarmellose sodium, wherein the disintegrant
• the inventive pharmaceutical composition - in case of granulation compression preferably the extragranular composition - may further comprise one or more suitable lubricant agents, preferably selected from the group consisting of magnesium stearate, stearic acid, and sodium stearyl fumarate, more preferably magnesium stearate.
• suitable lubricant agents preferably selected from the group consisting of magnesium stearate, stearic acid, and sodium stearyl fumarate, more preferably magnesium stearate.
• the pharmaceutical tablet composition may further be film coated with a coating agent, preferably comprising one or more pharmaceutically acceptable polymers, optionally one or more pharmaceutically acceptable plasticizers, and optionally one or more pharmaceutically acceptable pigments.
• a coating agent preferably comprising one or more pharmaceutically acceptable polymers, optionally one or more pharmaceutically acceptable plasticizers, and optionally one or more pharmaceutically acceptable pigments.
• the one or more polymer agents of the pharmaceutically acceptable coating agent are preferably selected from one or more of the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene glycol-polyvinyl alcohol graft copolymer, and polysorbate.
• the one or more pigments are preferably selected from the group of titanium dioxide, aluminium lakes, and iron oxides, preferably iron oxide yellow, iron oxide red, and iron oxide black.
• inventive pharmaceutical tablet compositions comprising 16.05 mg or 32.1 mg eltrombopag olamine, or
• the total content of binder agent(s) is at least 0.5 wt.% or more, more preferably is in the range of 1 to 7 wt.%, more preferably 2 to 5 wt.% and/or ii.
• the total content of diluent agent(s) including the reducing sugar amount is at least 5 wt.% or more, preferably is present in the range of 10 to 86 wt.%, alternatively in the range of 40 to 57 wt.%, alternatively in the range of 58 to 86 wt.%, alternatively in the range of 58 wt.% to 61 wt.%, alternatively in the range of 79 wt.% to 82 wt.% and/or iii.
• the total content of the disintegrant agent(s) is at least 3 wt.% or more, preferably is in the range of 4 to 15 wt.%, alternatively is in the range of 6 to 10 wt.% or alternatively is in the range of 3 to 5 wt.% and/or iv.
• the total content of the lubricant agent(s) is at least 0.5 wt.% or more, preferably is present in the range of 0.5 to 5 wt.%, preferably 0.8 to 3 wt.%, more preferably 0.9 to 1.5 wt.% and more preferably is 1 wt.% and/or v.
• the total content of the coating agent(s) is at least 2 wt.%, preferably in the range of 3 to 7 wt.%, more preferably 4 to 5 wt.%, respectively based on the total weight of the pharmaceutical tablet composition.
• the intragranular composition comprises in addition to eltrombopag olamine at least one reducing sugar, preferably lactose monohydrate in the range of 38 to 55 wt.%, at least one polymeric binder agent, preferably povidone, preferably in the range of 2 to 3 wt.%, and optionally one further diluent agent, preferably insoluble diluent agent, e.g.
• the extragranular composition may comprise one or more further diluent agents, preferably microcrystalline cellulose, preferably in the range of 1 to 15 wt.%, more preferably 2 to 10 wt.% and one or more disintegrant agents, preferably in an amount of at least at least 3 wt.% or more, preferably 6 to 12 wt.%, more preferably the disintegrant agent is sodium starch glycolate or croscarmellose sodium or a mixture of sodium starch glycolate and croscarmellose sodium.
• the extra- granular phase may additionally comprise one or more polymeric binder agents, preferably in an amount of at least 0.5 wt.% or more, preferably 2 to 4 wt.%, more preferably 1 to 2 wt.%, more preferably povidone.
• the extragranular composition may comprise at least one lubricant, preferably in an amount of at least 0.5 wt.% or more, preferably 0.9 to 1.2 wt.%, more preferably the lubricant is magnesium stearate.
• the inventive tablet composition may be film coated comprising suitable coating agents, preferably in an amount of least 2 wt.%, preferably 3 to 5 wt.%. The respective weight amounts as set out before respectively are based on the total weight of the inventive tablet composition. According to a furthermore preferred embodiment, the total weight of the inventive tablet composition is 348 mg relating to an uncoated tablet core unit and 363 mg per film coated tablet unit.
• the inventive pharmaceutical tablet composition is obtained by direct compression and comprises 15.951 mg eltrom- bopag olamine per tablet unit (equivalent to 12.5 mg eltrombopag free base)
• the tablet composition may comprise or consist of one or more reducing sugars, preferably lactose monohydrate, in the range of 31 to 62 wt.%; one or more polymeric binder agents, preferably one polymeric binder agent, e.g.
• the inventive tablet composition may be film-coated comprising suitable agents, wherein the weight of the film coating is in the range of 3 to 5 wt.%.
• the respective weight amounts as set out before respectively are based on the total weight of the inventive tablet composition.
• the total weight of the inventive tablet composition is 174 mg relating to an uncoated tablet core unit and 181.5 mg per film coated tablet unit.
• the inventive pharmaceutical tablet composition may additionally comprise or consist of a therapeutically effective amount of one or more additional active ingredients.
• the one or more additional active ingredients may be comprised in the intra- granular composition or - in case of prevention of interaction between the active ingredients and eltrombopag olamine - in the opposite composition than the one comprising eltrombopag olamine.
• the one or more additional active ingredients are simultaneously or sequentially co-administered in a separate pharmaceutical formulation.
• the one or more additional active ingredients are selected from constituents which are effective in the treatment of prophylaxis of thrombocytopenia, preferably adult chronic immune (idiopathic) thrombocytopenic purpura (ITP), acquired severe aplastic anaemia (SAA) and/or chronic hepatitis C virus (HCV) infection.
• IDP adult chronic immune
• SAA acquired severe aplastic anaemia
• HCV chronic hepatitis C virus
• one or more additional active ingredients are selected from the group of corticosteroids, lithium carbonate, folate, rituximab, and immunoglobuline, in particular anti-Rh (D) immunoglobuline generally used to treat thrombocytopenia, in particular chronic immune (idiopathic) thrombocytopenic purpura (ITP).
• D anti-Rh
• ITP chronic immune thrombocytopenic purpura
• one or more additional active ingredients are selected from the group of anti-infective agents, such as antibiotics and antifungal agents, immunosuppressive agents, such as anti-thymocyte globulin (ATG) and cyclosporine-A (CSA) and cytokine agents, such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), generally used to treat acquired severe aplastic anaemia (SAA).
• anti-infective agents such as antibiotics and antifungal agents
• immunosuppressive agents such as anti-thymocyte globulin (ATG) and cyclosporine-A (CSA)
• cytokine agents such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), generally used to treat acquired severe aplastic anaemia (SAA).
• SAA severe aplastic anaemia
• one or more additional active ingredients are selected from the group of antiviral agents, such as daclatasvir, elbasvir, grazoprevir, ledipasvir, sofosbuvir, ombitasvir, paritaprevir, ritonavir, dasabuvir, simeprevir, sofosbuvir, velpatasvir, ribavirin, peginterferon alfa-2a or pegin- terferon alfa-2b generally used to treat chronic hepatitis C virus (HCV) infection.
• antiviral agents such as daclatasvir, elbasvir, grazoprevir, ledipasvir, sofosbuvir, ombitasvir, paritaprevir, ritonavir, dasabuvir, simeprevir, sofosbuvir, velpatasvir, ribavirin, peginterferon alfa-2a or pegin- terferon alfa-2b
• the properties or the physical and chemical stability of the inventive pharmaceutical tablet composition may be tested in conventional manner, e.g. by measurement of appearance, hardness (or resistance to crushing), disintegration time, dissolution, friability, water content, assay for eltrombopag olamine and/or its degradation products (related substances), and/or uniformity of dosage units or mass after storage at controlled storage conditions; e.g. at intermediate and/or accelerated conditions according to ICH guideline Q1 A(R2) (i.e. at 25 °C / 60 % relative humidity (RH) and/or at 40 °C / 75 % RH).
• ICH guideline Q1 A(R2) i.e. at 25 °C / 60 % relative humidity (RH) and/or at 40 °C / 75 % RH.
• the dissolution (profile) of the inventive pharmaceutical tablet composition according to the present invention e.g. a tablet or film-coated tablet, is stable over at least 6 months when stored preferably in Alu-Alu blisters at intermediate or long-term storage conditions, i.e. 25 °C / 60 % RH or 40 °C / 75 % RH.
• dissolution and further additional attributes such as, e.g., assay, related substances or uniformity of dosage units or mass are also stable after storage over at least 6 months when stored at intermediate or long-term storage conditions.
• stable in the context of the present invention means that a measured value falls within range of specified values determined in accordance with a respective applicable regulatory guideline, e.g. the European Pharmacopeia.
• the inventive pharmaceutical tablet composition may vary in shape and be, e.g., round, oval, oblong, cylindrical, caplet shaped or any other suitable shape, preferably it is round or caplet shaped. Furthermore, the inventive pharmaceutical tablet composition comprises means for dividing the tablet, such as scores or engravings.
• the inventive pharmaceutical tablet composition, preferably film-coated tablet has a diameter ranging between 3.5 and 15 mm and most preferably between 5.5 and 7.0 mm for round tablets and the dimension of a caplet is between 9.0 x 3.0 mm and 17.0 x 7.5 mm, preferably it is 12.7 x 5.9 mm. Thickness is ranging from 2.0 to 5.0 mm, preferably between 2.5 and 4.6 mm.
• the inventive pharmaceutical tablet composition has a suitable hardness (or resistance to crushing), preferably the film-coated tablets may have a hardness (or resistance to crushing) of at least 40 N, preferably from 50 N to 130 N, more preferably 85 N to 1 10 N.
• the inventive pharmaceutical tablet composition according to all aspects has a suitable disintegration time, preferably the film-coated tablets may have a disintegration time of at least 2 minutes, preferably in the range of 2 to 6 minutes.
• inventive pharmaceutical tablet composition preferably film-coated tablet
• inventive pharmaceutical tablet composition may be colored and/or marked so as to impart an individual appearance and to make them instantly recognizable.
• the use of dyes can serve to enhance the appearance as well as to identify the inventive pharmaceutical composition.
• Dyes suitable for use in pharmacy typically include carot- enoids, iron oxides or chlorophyll.
• the inventive pharmaceutical tablet composition, preferably a film-coated tablet may be marked using an imprint code.
• the inventive pharmaceutical composition may be packed in any conventional packaging known in the art, for example blisters, polypropylene or polyethylene (e.g. HDPE, high density polyethylene) containers or glass bottles.
• the inventive tablet composition is preferably packed in a blister known in the art, e.g. sealed aluminum blister (Alu-Alu), Aluminum / Aluminum peel-push blisters or PVC/PE/PVDC/aluminum-blisters.
• the inventive process of production of a pharmaceutical tablet comprising or consisting of a) eltrombopag olamine in a therapeutically effective amount, b) one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and c) one or more semisynthetic and/or synthetic polymeric binder agents, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl starch, and d) optionally one or more further pharmaceutically acceptable excipients, characterized in that the pharmaceutical tablet composition is either obtained by
• the provided constituents such as eltrombopag olamine, reducing sugars, disinte- grants, (polymeric) binders, diluents, disintegrants and coating agents are sifted prior to use, preferably they are sifted through a # 35 mesh (Tyler Equivalent) screen, which corresponds to a screen with an opening of 0.420 mm in diameter.
• the sifted materials excluding the lubricant agent(s) and coating agent(s) are loaded into a suitable blender and mixed until homogeneous distribution, e.g., for 10 minutes. Subsequently, the lubricant agent is added to the mixture and further mixed until homogeneous distribution, e.g. for further 5 minutes. Subsequently, the mixture is compressed with suitable tablet compression machines using suitable tooling and parameters into inventive tablet cores as inventive pharmaceutical tablet compositions. Preferably a rotary tablet compression machine is used.
• the inventive tablet cores are furthermore film-coated with suitable coating agents in a suitable coating means, preferably a coating pan.
• the suitable coating agent comprises one or more polymers, optionally one or more plasticizers, and optionally one or more pigments.
• the preferred coating agents as disclosed with respect to the inventive pharmaceutical tablet composition can also be used with respect to the second aspect of the present invention.
• the inventive pharmaceutical tablet composition is obtained by granulation compression, suitable processing means are used.
• suitable processing means are used.
• the provided constituents such as eltrombopag olamine, reducing sugars, disintegrate, (polymeric) binders, diluents, disintegrants and coating agents are sifted prior to use, preferably they are sifted through a # 35 mesh (Tyler Equivalent) screen, which corresponds to a screen with an opening of 0.420 mm in diameter.
• the provided constituents forming the intragranular composition e.g., eltrombopag olamine, reducing sugar, e.g. lactose monohydrate, further diluent agent, e.g. microcrystalline cellulose and optionally the polymeric binder agent, e.g. povidone are loaded into a high shear mixer granulator or an equivalent granulator and preferably mixed for 10, more preferably 5 minutes with impeller at preferably slow speed.
• the suitable granulation fluid preferably water or an aqueous solution of the polymeric binder agent, is added to the mixture in the high shear mixer granulator and the impeller is preferably used at low speed.
• the obtained granules after wet granulation are subsequently dried at suitable conditions.
• the obtained preferably dried granules are subsequently milled, preferably using a Quadro ® Comil equipped with a suitable screen.
• the (milled, dried) granules forming the intragranular phase and the sifted and admixed extragranular constituents i.e. further diluent agent, e.g. microcrystalline cellulose, disintegrant agent, e.g., sodium starch glycolate are loaded into a blender and mixed until homogeneous distribution, preferably for 10 minutes.
• a lubricant such as magnesium stearate
• this constituent is preferably subsequently added to the blender and mixed preferably until homogeneous distribution, preferably for further 5 minutes.
• the preferably lubricated blended mixture is compressed into the inventive pharmaceutical tablet composition (tablet cores) using a suitable tablet compression machine, preferably on a rotary tablet compression machine using suitable tooling and parameters.
• the resulting inventive pharmaceutical tablet composition may furthermore be film coated in a subsequent step using one or more pharmaceutically acceptable excipients as suitable coating agent.
• suitable coating agent comprises one or more polymers, optionally one or more plasticizers, and optionally one or more pigments.
• the preferred coating agents as disclosed with respect to the inventive pharmaceutical tablet composition can also be used with respect to the second aspect of the present invention. As set out in the Example Section of the present application (see Part E, table 1 ), the amount of impurities measured for the inventive pharmaceutical tablet compositions of the first and third aspect initially after production is below detection limit (BLD) or at 0.05 % total impurities.
• BLD detection limit
• the inventive pharmaceutical tablet compositions of the first and third aspect show a decreased degradation of eltrombopag olamine as active ingredient in comparison to the lactose composition of the prior art (see Kapsi declaration), where the composition already initially after production comprises 1.5 % total impurities.
• the reduced degradation of eltrombopag olamine may be due to the use of the inventive combination of the lactose with polyvinyl pyrrolidone.
• the inventive 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 comprising or consisting of a) eltrombopag olamine in a therapeutically effective amount, b) one or more reducing sugars, preferably selected from the group consisting of lactose, maltose, glucose, arabinose, and fructose, and c) one or more semisynthetic and/or synthetic polymeric binder agents, preferably selected from the group consisting of povidone, copovidone, polyvinyl alcohol, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol-polyvinyl alcohol graft copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose,
• the use the inventive pharmaceutical tablet composition is claimed, wherein the pharmaceutical tablet composition is used in the manufacture of a medicament for the treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA).
• the method of treatment or prophylaxis of immune (idiopathic) thrombocytopenic purpura (ITP), thrombocytopenia and/or acquired severe aplastic anaemia (SAA) comprises administering to a patient in need an inventive pharmaceutical tablet composition.
• the eltrombopag olamine constituent used in the following example formulations F1 tom F5 and C1 exhibits polymorphic form I.
• Part A General Procedure for the wet granulation compression (eltrombopag olamine and lactose intra ranular)
• Stage A (Dry Mix / Granulation)
• step-1 Sifted materials of step-1 loaded into high shear mixer granulator and mixed for 5 minutes with impeller at slow speed.
• Step-2 material was granulated with a suitable binder solution, e.g., water or an aqueous solution such as aqueous povidone solution, at impeller slow speed.
• a suitable binder solution e.g., water or an aqueous solution such as aqueous povidone solution
• step-3 material The granules of step-3 material were dried in a suitable equipment to get required loss on drying.
• step-4 The dried granules of step-4 were milled using Quadro ® Comil equipped with suitable screen.
• step 7 Milled granules of step 5 and sifted extragranular materials of step 6 were loaded into the blender and mixed for 10 min.
• Lubrication agents e.g., magnesium stearate sifted through #35 mesh and added to blend mixture of step 7 and lubricated for 5 minutes.
• step 8 The blend mixture of step 8 was compressed into tablets on rotary tablet compression machine using suitable tooling and parameters.
• inventive pharmaceutical tablet compositions F1 and F2 are produced in accordance with the general procedure as set out in Part A above:
• Stage-A (Dry Mix / Wet Granulation)
• Film-coated tablet weight (mg) 363.000 363.000 The following inventive pharmaceutical tablet compositions F3 to F8 can be produced in accordance with the general procedure as set out in Part A above:
• Examples F3 and F4 inventive pharmaceutical film-coated tablet compositions comprising microcrystalline cellulose, sodium starch glycolate and magnesium stearate in extragranular phase and eltrombopag olamine, lactose monohydrate, microcrystalline cellulose and polyvinyl alcohol or macrogol as synthetic polymeric binder in intragranular phase
• Stage-A (Dry Mix / Wet Granulation)
• Examples F5 and F6 inventive pharmaceutical film-coated tablet compositions comprising microcrystalline cellulose, sodium starch glycolate and magnesium stearate in extragranular phase and eltrombopag olamine, lactose monohydrate, microcrystalline cellulose and hydroxy- propyl methylcellulose or hydroxypropyl cellulose as semisynthetic polymeric binder in intra- granular phase
• Stage-A (Dry Mix / Wet Granulation)
• Film-coated tablet weight (mg) 363.000 363.000
• Examples F7 and F8 inventive pharmaceutical film-coated tablet compositions comprising microcrystalline cellulose, sodium starch glycolate and magnesium stearate in extragranular phase and eltrombopag olamine, lactose monohydrate, microcrystalline cellulose and hydroxy- propyl starch as semisynthetic polymeric binder or polyethylene glycol-polyvinyl alcohol graft copolymer (PEG-PVA) as synthetic polymeric binder in intragranular phase
• PEG-PVA polyethylene glycol-polyvinyl alcohol graft copolymer
• Stage-A (Dry Mix / Wet Granulation)
• Part C General Procedure for the direct compression (eltrombopag olamine and lactose in one composition)
• Stage-A materials were sifted through #35 mesh and collected separately. 2. The sifted materials of step-1 were loaded in to the blender and mixed for 10 min. Stage B: (Lubrication / Direct compression of core tablets)
• Stage-B lubrication agent sifted through #35 mesh and added to step-2 blend and lubricated for 5 minutes.
• step-3 Compressed the step-3 blend into tablet cores on rotary tablet compression machine using suitable tooling and parameters.
• step-4 Core tablets of step-4 were coated in coating pan using Opadry ® White suspension.
• Part D Process of production of inventive and comparative pharmaceutical tablet compositions (direct compression of eltrombopag olamine and lactose)
• inventive pharmaceutical tablet compositions F9 to F1 1 are produced in accordance with the general procedure as set out in Part C above.
• Examples F9 to F1 1 inventive pharmaceutical film-coated tablet compositions comprising eltrombopag olamine, Ludipress ® (93 wt.% lactose monohydrate, 3.5 wt.% polyvinyl pyrrolidone (Kollidon ® 30) and 3.5 wt.% crospovidone (Kollidon ® CL)) or lactose monohydrate and povidone, microcrystalline cellulose, sodium starch glycolate and magnesium stearate
• Film-coated tablet weight (mg) 181.500 181.500 181.500 The following inventive pharmaceutical tablet compositions F12 to F11 can be produced in accordance with the general procedure as set out in Part C above.
• Examples F12 to F14 inventive pharmaceutical film-coated tablet compositions comprising eltrombopag olamine, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, copovidone or polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer as synthetic polymeric binder or carmellose sodium (Na-CMC) as semisynthetic polymeric binder and magnesium stearate
• Comparative Example C1 comparative pharmaceutical film-coated tablet composition comprising eltrombopag olamine, lactose monohydrate, microcrystalline cellulose, sodium starch glyco- late, and magnesium stearate
• An Accelerated Stability Assessment Program for up to 2-3 weeks under open exposure, according to Waterman 2011 (Waterman KC, The application of the Accelerated Stability Assessment Program (ASAP) to quality by design (QbD) for drug product stability, AAPS PharmSciTech, Vol. 12, No. 3, September 2011) is usually applied for a quick estimation of chemical stability (cf. Table 1 ).
• the storage was conducted at 50 °C, 75 % relative humidity for 14 days at open exposure (ASAP data).
• the amount of impurities measured for the inventive pharmaceutical tablet compositions F1 , F2, and F9 to F11 initially after production is respectively below detection limit or at 0.05 % unspecified / total impurities.
• Dissolution testing according to table 2 was performed using USP Apparatus II, 50 rpm, 900 ml of phosphate buffer pH 6.8 containing 0.5% Tween 80 as recommended for Eltrombopag Olamine in the FDA Dissolution Methods Database on the FDA webpage. Based on the Ph. Eur. (5.17.1 ) recommendation for immediate-release dosage forms, the specification is set as at least 75% of the active substance is dissolved within 45 minutes.
• the experimental data of table 2 shows that 75 wt.% or more, preferably more than 80 wt.%, more preferably more than 90 wt.% of eltrombopag olamine of the inventive pharmaceutical tablet compositions F1 , F2, and F9 to F11 is dissolved within 45 minutes in accordance with the regulatory standard test.
• the comparative composition C1 does not fulfil the regulatory standard test for dissolution, as only 72 wt.% of eltrombopag olamine is dissolved within 45 minutes.

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