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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent. Manufacturing processes of such formulations are also described.
• Eltrombopag olamine, 3’-(N’-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1 ,5-dihydropyrazol -4-ylidene]hydrazino ⁇ -2’-hydroxy-biphenyl- 3-carboxylic acid - 2-aminoethanol is a nonpeptide 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 (see e.g. WO 03/098992 A2 and WO 2008/136843 A1).
• TPO thrombopoietin
• the process for the synthesis of eltrombopag acid is described in WO 01/89457 A2.
• Revolade® is in tablet form and comprises eltrombopag olamine in an amount corresponding to 12.5 mg, 25 mg, 50 mg, and 75 mg of eltrombopag free acid.
• the tablet composition of the different strength is not dose proportional.
• eltrombopag olamine undergoes a Maillard reaction with respective pharmaceutically acceptable excipients, such as reducing sugars, e.g. lactose, maltose, glucose, arabinose and fructose.
• reducing sugars e.g. lactose, maltose, glucose, arabinose and fructose.
• eltrombopag olamine is degraded and forms impurities, which can be measured in the pharmaceutical tablet composition.
• WO 2008/136843 A1 teaches to use diluents substantially free of reducing sugars and coordinating metals.
• mannitol is used as an excellent diluent.
• mannitol is a widely used pharmaceutical diluent where its particular value lies in the fact that it is not hygroscopic and may be used with moisture-sensitive active ingredients such as eltrombopag. Further, granulations containing mannitol have the advantage of being easily dried (Handbook of pharmaceutical excipients, 2016, 8th ed by Pharmaceutical Press, Sheskey).
• a tablet composition comprising eltrombopag that exhibits excellent stability and be suitable for production on a commercial scale.
• the composition should also exhibit adequate dissolution and disintegration resulting in a good bioavailability.
• the first aspect of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a nonreducing disaccharide as a diluent.
• a second aspect of the present invention deals with a process for the preparation of the said pharmaceutical composition.
• a third aspect of the present invention provides said pharmaceutical composition for use as a medicament, preferably for use in thrombocytopenia.
• Good dissolution according to the invention is understood as achieving at least a 90% dissolution rate after 60 minutes, since it has been observed that when at least 90% is dissolved after 60 minutes, eltrombopag plasma levels are adequate to achieve a therapeutic effect.
• Good stability according to the invention is understood so that the physical-chemical characteristics of the product remain stable throughout time.
• the inventors have found that using one or more non-reducing disaccharides as diluents, optionally in combination with other diluents, allows the obtaining of such pharmaceutical compositions which can be manufactured on a commercial scale with desirable pharmacokinetic profile and stability. In addition, the different strengths are dose proportional.
• the inventors have also found out that when non-reducing disaccharides such as trehalose are used in combination with other diluents such as lactose, the dissolution rates of the resulting compositions are improved.
• compositions of the present invention may comprise eltrombopag free base or any acceptable pharmaceutically salts and can include further active ingredients in the same or in a separate composition.
• the active ingredient refers to eltrombopag olamine (bis-monoethanolamine) salt.
• Eltrombopag or pharmaceutically acceptable salts thereof can be in a crystalline or non-crystalline solid form.
• diotin refers to pharmaceutically acceptable excipients which are added to the bulk volume of the active ingredient making up the solid composition. As a result, the size of the solid composition increases, which makes its size suitable for handling.
• diotin and filler are considered equivalent.
• disintegrant means a substance or a mixture of substances added to a tablet to facilitate its breakup or disintegration after administration.
• lubricant means a substance that reduces friction between the composition of the present invention and the surfaces of the apparatus used to compact the composition into a compressed form.
• binder means a substance that imparts cohesive properties to a formulation. Binders ensure that tablets, powders, granules and others can be formed by the required mechanical strength
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a nonreducing disaccharide as diluent.
• the non-reducing disaccharide is selected from sucrose or trehalose or mixtures thereof. More preferably, the diluent is selected from trehalose.
• the pharmaceutical composition of the present invention can further include other diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, fructose, kaolin, mannitol, lactitol, maltose, isomaltose, xylitol, inositol, starch, calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, sodium alginate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.
• lactose monohydrate, spray-dried monohydrate, anhydrous and
• microcrystalline cellulose may be suitable for use in the formulations described herein.
• microcrystalline cellulose include Avicel® types: PH101 , PH102, PH103, PH105, PH 112, PH113, PH200, PH301 , and other types of microcrystalline cellulose, such as silicified microcrystalline cellulose (SMCC).
• SMCC silicified microcrystalline cellulose
• the other diluents are selected from calcium phosphate dibasic, calcium phosphate tribasic, microcrystalline cellulose, lactose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, magnesium carbonate, maltose, isomaltose, xylitol, starch and mixtures thereof.
• the other diluents are selected from microcrystalline cellulose, lactose, lactose monohydrate, anhydrous lactose, mannitol, sorbitol, xylitol, magnesium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, or mixtures thereof. Even more preferably the other diluents are selected from lactose, lactose monohydrate, anhydrous lactose, calcium phosphate, microcrystalline cellulose or mixtures thereof.
• Diluents are frequently used in an amount ranging from 15 wt% to 75 wt% weight of the formulation.
• the pharmaceutical composition comprises eltrombopag, trehalose and lactose.
• the composition further comprises calcium phosphate.
• the pharmaceutical composition comprises: eltrombopag olamine, trehalose and lactose.
• the lactose content with respect to the total weight of the tablet is at least 1 %.
• the said pharmaceutical composition further comprises at least one disintegrant.
• disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, starch and sodium alginate.
• the at least one disintegrant is selected from croscarmellose, sodium croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, starch, sodium starch glycolate, carmellose and mixtures thereof. More preferably, the disintegrant is selected from sodium starch glycolate, sodium croscarmellose or mixtures thereof.
• Disintegrants are frequently used in an amount ranging from 1 wt% to 25 wt% by weight of the formulation, preferably from 5 wt% to 20 wt%.
• the pharmaceutical composition comprises at least one lubricant.
• lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, talc, stearic acid, waxes, glycerides, light mineral oil, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycols, alkyl sulfates, or sodium benzoate and mixtures thereof .
• the at least one lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, talc, stearic acid and sodium stearyl fumarate. More preferably, the lubricant is selected from magnesium stearate.
• Lubricants are frequently used from 0.25 wt% to 10 wt% by weight of the formulation.
• the pharmaceutical composition optionally comprises at least one binder.
• binders suitable for use in the present invention include: cellulose derivatives (such as carboxymethyl cellulose and salts thereof, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose), polyvinylpyrrolidone, povidone, polyethylene glycol, waxes, water, alcohol, magnesium aluminum silicate, and bentonites or mixtures thereof.
• Binders are frequently used from 0 wt% to 15 wt% by weight of the formulation.
• the pharmaceutical composition of the invention is free from a binder.
• eltrombopag or any pharmaceutical acceptable salts thereof is micronized.
• eltrombopag or any pharmaceutical acceptable salts thereof has a particle size volume distribution with a D90 less than 200 pm, preferably less than 150 pm, more preferably from less than 100 pm. The particle size volume distribution is analysed by laser diffraction spectroscopy using a Malvern Mastersizer 3000 particle size analyzer.
• the pharmaceutical composition is a tablet or a capsule, preferably a tablet.
• the tablet composition is 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.
• Such coating agents may optionally further comprise one or more additional adjuvants such as a detackifier, flow aid, surfactant, and secondary film-forming polymer.
• additional adjuvants such as a detackifier, flow aid, surfactant, and secondary film-forming polymer.
• detackifiers include lecithin, stearic acid, mineral oil, modified derivatized starch, tapioca dextrin, and polyethylene glycol.
• optional secondary film-forming polymers include sodium alginate, propylene glycol alginate, and polyvinylpyrrolidone.
• optional surfactants include dioctyl sodium sulfosuccinate and polysorbate 80.
• optional flow aids include talc, fumed silica, bentonite, hydrogenated vegetable oils, stearines, and waxes.
• the coating agent comprises is selected from hypromellose, macrogol 400, polysorbate 80 and titanium dioxide (commercially available as Opadry® White), or hypromellose, macrogol 400, titanium dioxide, iron oxide yellow and iron oxide red (commercially available as Opadry® Brown), or hypromellose, macrogol 400, titanium dioxide, iron oxide red and iron oxide black (commercially available as Opadry® Brown).
• the present invention relates to a process for the manufacture of a pharmaceutical composition of the first aspect.
• compositions of the present invention may be manufactured in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing the active compounds into preparations which can be used pharmaceutically.
• physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing the active compounds into preparations which can be used pharmaceutically.
• auxiliaries which facilitate processing the active compounds into preparations which can be used pharmaceutically.
• Such conventional manufacturing techniques are, for instance, mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.
• One conventional manufacturing techniques for the preparation of the formulation of the present invention is compression.
• Another conventional manufacturing techniques for the preparation of the formulation of the present invention is granulation.
• the term “granulation” includes dry and wet granulation techniques.
• the term “wet granulation” refers to any process comprising the steps of addition of a liquid to the powder starting materials, preferably kneading, and drying to yield a solid dosage form.
• the term “dry granulation” refers to any process that comprises compacting the powder, usually either by slugging or with a roller compactor, and preferably milling the compacted powder to obtain the granules. No liquid is employed for the dry granulation.
• the granules can be compressed, optionally with other pharmaceutical excipients such as lubricants, into tablets. Alternatively, the granules can be filled into capsules.
• the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent, comprising the following steps:
• step (ii) compressing the mixture obtained in step (i) to form a tablet
• step (iii) optionally, coating the resulting tablet of step (ii).
• the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent, comprising the following steps:
• step (ii) optionally, granulating the mixture obtained in step (i)
• step (iii) encapsulating the mixture obtained in step (i) or the granules obtained in step (ii)
• step (ii) optionally, granulating the mixture obtained in step (i)
• step (iii) encapsulating the mixture obtained in step (i) or the granules obtained in step
• the present invention relates to a process for the manufacture of a pharmaceutical composition
• a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a mixture of a non-reducing disaccharide and lactose as diluents, comprising the following steps:
• step (ii) optionally, granulating the mixture obtained in step (i)
• step (iii) encapsulating the mixture obtained in step (i) or the granules obtained in step (ii)
• the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent, comprising the following steps:
• step (ii) optionally, compacting the mixture obtained in step (i),
• step (iii) granulating the mixture obtained in step (i) or the compacted mixture obtained in step (ii),
• step (iv) optionally, mixing the granules obtained in step (iii) with at least one pharmaceutically acceptable excipient, and
• step (v) compressing the granules obtained in step (iii) or the mixture obtained in step
• step (vi) optionally coating the resulting tablet of step (v)
• the present invention relates to a process for the manufacture of a pharmaceutical composition
• a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a mixture of lactose and a non-reducing disaccharide as diluents, comprising the following steps:
• step (ii) optionally, compacting the mixture obtained in step (i),
• step (iii) granulating the mixture obtained in step (i) or the compacted mixture obtained in step (ii),
• step (iv) optionally, mixing the granules obtained in step (iii) with at least one pharmaceutically acceptable excipient, and
• step (v) compressing the granules obtained in step (iii) or the mixture obtained in step
• step (vi) optionally coating the resulting tablet of step (v)
• the present invention relates to a process for the manufacture of a pharmaceutical composition
• a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof, and a mixture of lactose and a non-reducing disaccharide as diluents, comprising the following steps:
• step (iii) granulating the mixture obtained in step (i) or the compacted mixture obtained in step (ii),
• step (iv) mixing the granules obtained in step (iii) with lactose and at least one pharmaceutically acceptable excipient, and
• step (v) compressing the granules obtained in step (iii) or the mixture obtained in step (iv) to form a tablet
• step (vi) optionally coating the resulting tablet of step (v)
• the present invention relates to a process for the manufacture of a pharmaceutical composition comprising eltrombopag or any acceptable pharmaceutical salt thereof and a non-reducing disaccharide as diluent, comprising the following steps:
• step (ii) granulating the mixture obtained in step (i) (iii) optionally, mixing the granules obtained in step (iii) with at least one pharmaceutically acceptable excipient, and
• step (iv) compressing the granules obtained in step (ii) or the mixture obtained in step (iii) to form a tablet
• step (v) optionally coating the resulting tablet of step (iv)
• the present invention relates to the use of the pharmaceutical composition of the first aspect as a medicament.
• thrombocytopenia for use in treating thrombocytopenia, for use in enhancing platelet production, for use in treating adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) splenectomised patients who are refractory to other treatments (e.g.
• corticosteroids for use in adult non-splenectomised patients where surgery is contraindicated, for use 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 and for use in 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.
• HCV chronic hepatitis C virus
• Example 1 All examples of the invention have been carried out by using a particle size volume distribution D90 of 15 microns and a particle size volume distribution D90 of 60 microns. The different tested particle sizes did not impact the stability or the dissolution profile results.
• Example 1
• Table 1 As a general procedure, the ingredients trehalose, microcrystalline cellulose and povidone were blended with eltrombopag olamine and then wet-granulated (in a high- shear wet-granulator) with purified water. The wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled. Then extragranular ingredients (microcrystalline cellulose and sodium starch glycolate) were separately weighed, screened and blended with the granules. Magnesium stearate was added and blended with the mixture. The blend was compressed.
• This composition showed good stability and dissolution rate.
• the ingredients sodium croscarmellose, trehalose and anhydrous lactose were blended with eltrombopag olamine and then wet-granulated (in a high-shear wet-granulator) with purified water.
• the wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled.
• extragranular ingredients anhydrous lactose, calcium phosphate, microcrystalline cellulose and sodium starch glycolate
• extragranular ingredients anhydrous lactose, calcium phosphate, microcrystalline cellulose and sodium starch glycolate
• magnesium stearate was added and blended with the mixture. The blend was compressed.
• This composition showed good stability and dissolution rate.
• Example 3 Wet granulated tablets comprising eltrombopag olamine and the ingredients in
• the ingredients sodium croscarmellose, trehalose and anhydrous lactose were blended with eltrombopag olamine and then wet-granulated (in a high-shear wet-granulator) with purified water.
• the wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled.
• extragranular ingredients anhydrous lactose, microcrystalline cellulose and sodium starch glycolate
• extragranular ingredients anhydrous lactose, microcrystalline cellulose and sodium starch glycolate
• This composition showed good stability and dissolution rate.
• the ingredients sodium croscarmellose, mannitol and microcrystalline cellulose were blended with eltrombopag olamine and then wet- granulated (in a high-shear wet-granulator) with purified water.
• the wet-granule mass was wet-milled, then dried in a fluid-bed dryer and the dried granules were milled.
• extragranular ingredients microcrystalline cellulose and sodium starch glycolate
• extragranular ingredients microcrystalline cellulose and sodium starch glycolate
• Magnesium stearate was added and blended with the mixture. The blend was compressed.
• Figure 1 shows dissolution profiles of compositions from Example 3 and Example
• Composition from Example 3 comprising trehalose and lactose, shows a faster dissolution profile at 5, 10 and 15 minutes, which is therapeutically beneficial for the patients under treatment.
• Compositions from Example 3 and 4 were manufactured and placed under temperature stress conditions at 50°C for 15 and 30 days.
• FIG. 26 shows dissolution profiles of compositions from Example 3 and Example 4 which have been carried out at pH 6.8 (phosphate buffer) using a USP Type II apparatus, 50 rpm, 37°C in a 900 mL medium. Assay analyzed by HPLC.
• Composition from Example 3 shows a greater stability under temperature stress conditions. After 15 and 30 days, the dissolution rate at 15 minutes remains at approximately 80%, whereas example 4 composition drops to approximately 60% after 15 days and approximately 50% after 30 days.
• Composition from Example 1 was manufactured and placed under temperature stress conditions at 50°C for 15 and 30 days.
• Figure 3 shows dissolution profiles of composition from Example 1 which have been carried out at pH 6.8 (phosphate buffer) using a USP Type II apparatus, 50 rpm, 37°C in a 900 mL medium. Assay analyzed by HPLC.
• Example 6 the dissolution rate remains the same after temperature stress conditions. This shows an improvement in stability over composition from Example 4 (comprising mannitol) placed under stress conditions and analyzed in Example 6.
• Impurities were analysed by HPLC. The area corresponding to the eltrombopag olamine and of the major peaks, if any, was determined. The percentage of impurities was calculated by comparing the areas of the measured peaks with those obtained from the standard.

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• 2022
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