WO2018078644A1 - Orally disintegrating tablets of eltrombopag - Google Patents

Orally disintegrating tablets of eltrombopag Download PDF

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Publication number
WO2018078644A1
WO2018078644A1 PCT/IN2017/050457 IN2017050457W WO2018078644A1 WO 2018078644 A1 WO2018078644 A1 WO 2018078644A1 IN 2017050457 W IN2017050457 W IN 2017050457W WO 2018078644 A1 WO2018078644 A1 WO 2018078644A1
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WIPO (PCT)
Prior art keywords
dosage form
eltrombopag olamine
pharmaceutical dosage
orally disintegrating
tablet
Prior art date
Application number
PCT/IN2017/050457
Other languages
French (fr)
Inventor
Parthasarathi Reddy BANDI
Khadgapathi Podile
Sunil Deviprasad Tiwari
Ramarao NELLURI
Original Assignee
Hetero Labs Limited
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Publication of WO2018078644A1 publication Critical patent/WO2018078644A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to orally disintegrating pharmaceutical dosage forms of eltrombopag olamine and process for preparation thereof.
  • Eltrombopag olamine is a small molecule thrombopoietin (TPO) receptor agonist disclosed in U.S. Patent Nos. 7,160,870, 7,452,874, 7,473,686 and 7,547,719.
  • TPO thrombopoietin
  • Eltrombopag olamine is chemically described as 3'- ⁇ (2Z)-2-[l-(3,4- dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-4H-pyrazol-4ylidene]hydrazino ⁇ -2'-hydroxy- 3-biphenylcarboxylic acid - 2-aminoethanol (1 :2), indicated for the treatment of thrombocytopenia.
  • U.S. Patent No. 8,052,994 discloses conventional tablet composition of eltrombopag olamine.
  • Oral administration in the form of a conventional tablet, pill or capsule constitutes a generally preferred route for administration of pharmaceuticals, since this route is generally convenient and acceptable to patients.
  • Such compositions may be associated with certain disadvantages, particularly in the treatment of pediatric or geriatric patients, who have difficulty in swallowing or may dislike such compositions, or where administration of a conventional tablet, pill or capsule is not feasible.
  • Preparations for oral administration normally come in the form of a tablet, capsule, granule, powder or solution.
  • dosage forms such as a liquid preparation or a rapidly disintegrating tablet which easily disintegrates by the action of saliva.
  • liquid dosage forms may be suitable for the elders, infants or patients who have difficulty in swallowing, they have shortcomings such as difficulty in handling, especially in measuring an accurate dosage, and in that they are not suitable for drugs which are unstable in a moist environment.
  • Orally disintegrating solid dosage forms have significant advantages over other dosage forms, particularly for patients who cannot, or will not swallow a tablet or capsule. Moreover, solid dosage forms are far more convenient than liquids.
  • inventors of the present invention have developed orally disintegrating solid dosage forms comprising eltrombopag formulations for oral administration with good patient convenience and acceptance, especially for children or the elders.
  • the present invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients.
  • One embodiment of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine as an active ingredient and one or more pharmaceutically acceptable excipients.
  • Another embodiment of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1 ⁇ to 70 ⁇ and one or more pharmaceutically acceptable excipients.
  • Another embodiment of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
  • Another embodiment of this invention relates to pharmaceutical dosage form, in the form of orally disintegrating tablet which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1 ⁇ to 70 ⁇ and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein the tablet disintegrates within 180 seconds.
  • Another embodiment of the present invention relates to pharmaceutical dosage form of eltrombopag olamine which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent, a super disintegrant, a sweetener and optionally a diluent, a binder, a surfactant, a glidant, a lubricant and a flavoring agent.
  • an orally disintegrating tablet composition comprising: (a) 5 wt% to 25 wt % of eltrombopag olamine as an active agent, having a particle size distribution d90 from 1 ⁇ to 70 ⁇ , and (b) one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein said tablet is prepared either by direct compression or wet granulation.
  • the orally disintegrating tablet according to the present invention has hardness of not less than 35 Newtons.
  • the orally disintegrating tablet according to the present invention has friability of less than 1%.
  • the orally disintegrating tablet according to present invention shows disintegration time of not more than 180 seconds and shows dissolution of not less than 85% within 15 minutes.
  • the method of treating thrombocytopenia in a patient in need thereof, comprising administering to the patient, the dosage form of the present invention.
  • the present invention relates to pharmaceutical solid dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent.
  • active ingredient or “active agent” used interchangeably, is defined to mean active drug (e.g. eltrombopag olamine), that induce a desired pharmacological or physiological effect.
  • pharmaceutically acceptable as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
  • excipients as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
  • solid dosage form or “dosage form” or “composition” as used herein refers to a solid dosage form suitable for administration, such as a tablet, capsule, spheroids, mini-tablets, pellets, granules, pills and the like; preferably, orally disintegrating tablet.
  • a solid dosage form suitable for administration, such as a tablet, capsule, spheroids, mini-tablets, pellets, granules, pills and the like; preferably, orally disintegrating tablet.
  • the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
  • Orally Disintegrating Tablet as used herein means "A solid dosage form containing medicinal substances which disintegrates within 180 seconds”.
  • the present invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients.
  • One aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine as an active ingredient and one or more pharmaceutically acceptable excipients.
  • Another aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1 ⁇ to 70 ⁇ and one or more pharmaceutically acceptable excipients.
  • Another aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
  • Another aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1 ⁇ to 70 ⁇ and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
  • Another aspect of this invention relates to pharmaceutical dosage form, in the form of orally disintegrating tablet which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1 ⁇ to 70 ⁇ and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein the tablet disintegrates within 180 seconds.
  • Another aspect of the present invention relates to pharmaceutical dosage form of eltrombopag olamine which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent, a super disintegrant, a sweetener and optionally a diluent, a binder, a surfactant, a glidant, a lubricant and a flavoring agent.
  • an orally disintegrating tablet composition comprising: (a) 5 wt% to 25 wt % of eltrombopag olamine as an active agent, having a particle size distribution d90 from 1 ⁇ to 70 ⁇ , preferably, from 5 ⁇ to 40 ⁇ , and (b) one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein said tablet is prepared either by direct compression or wet granulation.
  • the orally disintegrating tablet according to the present invention has hardness of not less than 35 Newtons.
  • the orally disintegrating tablet according to the present invention has friability of less than 1%.
  • the orally disintegrating tablet according to present invention shows disintegration time in the oral cavity is within 180 seconds and shows dissolution of not less than 85% within 15 minutes.
  • Pharmaceutically acceptable excipients of the present invention comprise diluents, binders, disintegrants, surfactants, glidants, lubricants, sweeteners, flavoring agents and combinations thereof.
  • Diluents include but are not limited to microcrystalline cellulose, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, calcium silicate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, talc, lactose, sugar, starches, sorbitol, inorganic salts, cellulose derivatives, calcium sulfate, xylitol, lactitol, kaolin, sucrose, sorbitol, dextrates, dextrin, maltodextrin, dextrose and the like, and combinations thereof.
  • Binders according to the present invention include but are not limited to polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, powdered acacia, gelatin, guar gum, carbomers and the like and combinations thereof.
  • Disintegrants according to the present invention include but are not limited to polacrilin potassium, croscarmellose sodium, crospovidone, sodium starch glycolate, carboxymethyl cellulose calcium, starches such as corn starch, potato starch, pre-gelatinized and modified starches, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and the like and combinations thereof.
  • Surfactants according to the present invention include but are not limited to sodium lauryl sulfate, poloxamer, polyethylene glycol, docusate sodium, d-a-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) and the like and combinations thereof.
  • Glidants according to the present invention include but are not limited to colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica and the like and combinations thereof.
  • Lubricants according to the present invention include but are not limited to magnesium stearate, aluminium stearate, sucrose stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, glyceryl monostearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like and combinations thereof.
  • Sweeteners according to the present invention include but are not limited to aspartame, acesulfame potassium, sodium saccharin, sorbitol, mannitol, maltitol solution, xylitol, erythritol, sucrose, fructose, maltose, sugars derivatives and the like and combinations thereof.
  • Flavoring agents according to the present invention include but are not limited to strawberry, cherry, almond, lemon, lime, citrus fruit, chocolate and the like and combinations thereof.
  • Orally disintegrating tablets of the present invention are prepared by either conventional techniques or proprietary techniques.
  • Conventional techniques include dry or wet formulation techniques, whereas dry formulation technique is direct compression and wet formulation technique is wet granulation process.
  • Proprietary techniques include Zydis Technology, Durasolv Technology, Orasolv Technology, Wowtab Technology, Flash Dose Technology, Flash Tab Technology, Oraquick Technology and Nanocrystal Technology.
  • One aspect of the present invention relates to process for preparing orally disintegrating tablet composition of eltrombopag comprises:
  • step (b) lubricating the blend of step (a) with a suitable lubricant
  • step (c) compressing the lubricated blend of step (b) into tablets with sufficient hardness of not less than 35 Newtons.
  • step (b) wet granulating the blend of step (a), using a suitable solvent, followed by milling and sifting to get desired size granules, (c) lubricating the granules of step (b) with a suitable lubricant, and finally,
  • step (d) compressing the lubricated blend of step (c) into tablets with sufficient hardness of not less than 35 Newtons.
  • the method of treating thrombocytopenia in a patient in need thereof comprising administering to the patient, the dosage form of the present invention.
  • Step (iii) sifted materials of Step (i) were blended for about 15 minutes, (iv) the blend of Step (iii) was lubricated with sifted magnesium stearate of Step (ii) in a suitable blender for about 5 minutes and finally,
  • Step (v) the lubricated blend of Step (iv) was compressed into tablets with sufficient hardness of not less than 35 Newtons.
  • Example 1 Disintegration & Dissolution study: The tablets obtained in Example 1 were shown disintegration within 60 seconds and dissolution of not less than 85% within 15 minutes.
  • Step (iv) the blend of Step (iii) was lubricated with sifted magnesium stearate of Step (ii) in a suitable blender for about 5 minutes and finally,
  • Step (v) the lubricated blend of Step (iv) was compressed into tablets with sufficient hardness of not less than 35 Newtons.
  • Disintegration & Dissolution study The tablets obtained in Example 2 were shown disintegration within 60 seconds and dissolution of not less than 85% within 15 minutes.
  • Step (iv) sifted materials of Step (i) and Step (ii) were blended for about 15 minutes
  • Step (v) the blend of Step (iv) was lubricated with sifted magnesium stearate of Step (iii) in a suitable blender for about 5 minutes and finally,
  • binder solution was prepared by dispersing the povidone in purified water
  • Step (iv) the combined blend of Step (i) and (ii) was granulated with solution of Step (iii) followed by, drying and milling,
  • Step (viii) the blend of Step (viii) was lubricated with sifted magnesium stearate of Step (vii) in a suitable blender for about 5 minutes and finally,
  • Step (iv) sifted materials of Step (i) and Step (ii) were blended for about 15 minutes
  • Step (iv) the blend of Step (iv) was lubricated with sifted magnesium stearate of Step (iii) in a suitable blender for about 5 minutes and finally,
  • Step (v) the lubricated blend of Step (v) was compressed into tablets.

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Abstract

The present invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine and one or more pharmaceutically acceptable excipients.

Description

TITLE OF THE INVENTION
"ORALLY DISINTEGRATING TABLETS OF ELTROMBOPAG"
PRIORITY
This patent application claims priority to Indian patent application number IN201641036370, filed on October 24, 2016, the contents of which are incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
The present invention relates to orally disintegrating pharmaceutical dosage forms of eltrombopag olamine and process for preparation thereof.
BACKGROUND OF THE INVENTION
Eltrombopag olamine is a small molecule thrombopoietin (TPO) receptor agonist disclosed in U.S. Patent Nos. 7,160,870, 7,452,874, 7,473,686 and 7,547,719.
Eltrombopag olamine is chemically described as 3'-{(2Z)-2-[l-(3,4- dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-4H-pyrazol-4ylidene]hydrazino}-2'-hydroxy- 3-biphenylcarboxylic acid - 2-aminoethanol (1 :2), indicated for the treatment of thrombocytopenia.
U.S. Patent No. 8,052,994 discloses conventional tablet composition of eltrombopag olamine.
Oral administration in the form of a conventional tablet, pill or capsule constitutes a generally preferred route for administration of pharmaceuticals, since this route is generally convenient and acceptable to patients. Unfortunately, such compositions may be associated with certain disadvantages, particularly in the treatment of pediatric or geriatric patients, who have difficulty in swallowing or may dislike such compositions, or where administration of a conventional tablet, pill or capsule is not feasible. It is highly desirable, particularly in the treatment of acute conditions, that pharmaceutical compositions have a rapid and consistent onset of action combined with sustained activity and good bioavailability. Rapid absorption can be achieved by parenteral injection but this is unacceptable to many patients, particularly if the drug is to be self-administered without direct medical supervision.
Preparations for oral administration normally come in the form of a tablet, capsule, granule, powder or solution. However, since a solid preparation need to be swallowed with some water, the elders, infants and patients who have difficulty in swallowing, prefer dosage forms such as a liquid preparation or a rapidly disintegrating tablet which easily disintegrates by the action of saliva.
Although certain liquid dosage forms may be suitable for the elders, infants or patients who have difficulty in swallowing, they have shortcomings such as difficulty in handling, especially in measuring an accurate dosage, and in that they are not suitable for drugs which are unstable in a moist environment.
Orally disintegrating solid dosage forms have significant advantages over other dosage forms, particularly for patients who cannot, or will not swallow a tablet or capsule. Moreover, solid dosage forms are far more convenient than liquids.
Accordingly, inventors of the present invention have developed orally disintegrating solid dosage forms comprising eltrombopag formulations for oral administration with good patient convenience and acceptance, especially for children or the elders. SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients. One embodiment of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine as an active ingredient and one or more pharmaceutically acceptable excipients. Another embodiment of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1μ to 70μ and one or more pharmaceutically acceptable excipients.
Another embodiment of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
Another embodiment of this invention relates to pharmaceutical dosage form, in the form of orally disintegrating tablet which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1μ to 70μ and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein the tablet disintegrates within 180 seconds.
Another embodiment of the present invention relates to pharmaceutical dosage form of eltrombopag olamine which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent, a super disintegrant, a sweetener and optionally a diluent, a binder, a surfactant, a glidant, a lubricant and a flavoring agent.
Another embodiment of this invention relates to an orally disintegrating tablet composition comprising: (a) 5 wt% to 25 wt % of eltrombopag olamine as an active agent, having a particle size distribution d90 from 1μ to 70μ, and (b) one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein said tablet is prepared either by direct compression or wet granulation. In another embodiment, the orally disintegrating tablet according to the present invention has hardness of not less than 35 Newtons.
In another embodiment, the orally disintegrating tablet according to the present invention has friability of less than 1%.
In another embodiment, the orally disintegrating tablet according to present invention shows disintegration time of not more than 180 seconds and shows dissolution of not less than 85% within 15 minutes. In yet another embodiment, the method of treating thrombocytopenia in a patient in need thereof, comprising administering to the patient, the dosage form of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical solid dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent.
The term "active ingredient" or "active agent" used interchangeably, is defined to mean active drug (e.g. eltrombopag olamine), that induce a desired pharmacological or physiological effect. The term "pharmaceutically acceptable" as used herein means that which is useful in preparing a pharmaceutical composition that is generally safe and non-toxic.
The term "excipients" as used herein means a component of a pharmaceutical product that is not an active ingredient such as, for example, fillers, diluents, carriers and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
By the term "solid dosage form" or "dosage form" or "composition" as used herein refers to a solid dosage form suitable for administration, such as a tablet, capsule, spheroids, mini-tablets, pellets, granules, pills and the like; preferably, orally disintegrating tablet. As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure so forth.
The term "Orally Disintegrating Tablet" as used herein means "A solid dosage form containing medicinal substances which disintegrates within 180 seconds".
The present invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients.
One aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine as an active ingredient and one or more pharmaceutically acceptable excipients.
Another aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1μ to 70μ and one or more pharmaceutically acceptable excipients.
Another aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
Another aspect of this invention relates to pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1μ to 70μ and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
Another aspect of this invention relates to pharmaceutical dosage form, in the form of orally disintegrating tablet which disintegrates rapidly in the mouth, comprising 5wt% to 25wt% of eltrombopag olamine having a particle size distribution d90 from 1μ to 70μ and one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein the tablet disintegrates within 180 seconds.
Another aspect of the present invention relates to pharmaceutical dosage form of eltrombopag olamine which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent, a super disintegrant, a sweetener and optionally a diluent, a binder, a surfactant, a glidant, a lubricant and a flavoring agent.
Another aspect of this invention relates to an orally disintegrating tablet composition comprising: (a) 5 wt% to 25 wt % of eltrombopag olamine as an active agent, having a particle size distribution d90 from 1μ to 70μ, preferably, from 5μ to 40μ, and (b) one or more pharmaceutically acceptable excipients selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof, wherein said tablet is prepared either by direct compression or wet granulation.
In another aspect, the orally disintegrating tablet according to the present invention has hardness of not less than 35 Newtons.
In another aspect, the orally disintegrating tablet according to the present invention has friability of less than 1%.
In another aspect, the orally disintegrating tablet according to present invention shows disintegration time in the oral cavity is within 180 seconds and shows dissolution of not less than 85% within 15 minutes. Pharmaceutically acceptable excipients of the present invention comprise diluents, binders, disintegrants, surfactants, glidants, lubricants, sweeteners, flavoring agents and combinations thereof. Diluents according to the present invention include but are not limited to microcrystalline cellulose, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, calcium silicate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, talc, lactose, sugar, starches, sorbitol, inorganic salts, cellulose derivatives, calcium sulfate, xylitol, lactitol, kaolin, sucrose, sorbitol, dextrates, dextrin, maltodextrin, dextrose and the like, and combinations thereof.
Binders according to the present invention include but are not limited to polyvinyl pyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, powdered acacia, gelatin, guar gum, carbomers and the like and combinations thereof. Disintegrants according to the present invention include but are not limited to polacrilin potassium, croscarmellose sodium, crospovidone, sodium starch glycolate, carboxymethyl cellulose calcium, starches such as corn starch, potato starch, pre-gelatinized and modified starches, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and the like and combinations thereof. Surfactants according to the present invention include but are not limited to sodium lauryl sulfate, poloxamer, polyethylene glycol, docusate sodium, d-a-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) and the like and combinations thereof.
Glidants according to the present invention include but are not limited to colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica and the like and combinations thereof. Lubricants according to the present invention include but are not limited to magnesium stearate, aluminium stearate, sucrose stearate, stearic acid, talc, fumaric acid, palmitic acid, sodium stearyl fumarate, glyceryl monostearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like and combinations thereof.
Sweeteners according to the present invention include but are not limited to aspartame, acesulfame potassium, sodium saccharin, sorbitol, mannitol, maltitol solution, xylitol, erythritol, sucrose, fructose, maltose, sugars derivatives and the like and combinations thereof.
Flavoring agents according to the present invention include but are not limited to strawberry, cherry, almond, lemon, lime, citrus fruit, chocolate and the like and combinations thereof.
Orally disintegrating tablets of the present invention are prepared by either conventional techniques or proprietary techniques. Conventional techniques include dry or wet formulation techniques, whereas dry formulation technique is direct compression and wet formulation technique is wet granulation process. Proprietary techniques include Zydis Technology, Durasolv Technology, Orasolv Technology, Wowtab Technology, Flash Dose Technology, Flash Tab Technology, Oraquick Technology and Nanocrystal Technology.
One aspect of the present invention relates to process for preparing orally disintegrating tablet composition of eltrombopag comprises:
(a) sifting and blending eltrombopag olamine with one or more excipients,
(b) lubricating the blend of step (a) with a suitable lubricant, and finally,
(c) compressing the lubricated blend of step (b) into tablets with sufficient hardness of not less than 35 Newtons.
Another aspect of the present invention relates to process for preparing orally disintegrating tablet composition of eltrombopag comprises:
(a) sifting and blending eltrombopag olamine with one or more excipients,
(b) wet granulating the blend of step (a), using a suitable solvent, followed by milling and sifting to get desired size granules, (c) lubricating the granules of step (b) with a suitable lubricant, and finally,
(d) compressing the lubricated blend of step (c) into tablets with sufficient hardness of not less than 35 Newtons. In yet another aspect, the method of treating thrombocytopenia in a patient in need thereof, comprising administering to the patient, the dosage form of the present invention.
The following examples further describe and demonstrate particular embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the invention.
Example 1
Orally disintegrating tablet compositions of Eltrombopag olamine:
Figure imgf000010_0001
Preparation Method:
(i) Eltrombopag olamine, mannitol, microcrystalline cellulose, sodium starch glycolate, crocarmellose sodium, sodium saccharin, strawberry flavour and colloidal silicon dioxide were sifted through #40,
(ii) magnesium stearate was sifted through mesh #60,
(iii) sifted materials of Step (i) were blended for about 15 minutes, (iv) the blend of Step (iii) was lubricated with sifted magnesium stearate of Step (ii) in a suitable blender for about 5 minutes and finally,
(v) the lubricated blend of Step (iv) was compressed into tablets with sufficient hardness of not less than 35 Newtons.
Disintegration & Dissolution study: The tablets obtained in Example 1 were shown disintegration within 60 seconds and dissolution of not less than 85% within 15 minutes.
Example 2
Orally disintegrating tablet compositions of Eltrombopag olamine:
Figure imgf000011_0001
Preparation Method:
(i) Eltrombopag olamine, mannitol, microcrystalline cellulose, sodium starch glycolate, crocarmellose sodium, sodium saccharin, strawberry flavour and colloidal silicon dioxide were sifted through #40,
(ii) magnesium stearate was sifted through mesh #60,
(iii) sifted materials of Step (i) were blended for about 15 minutes,
(iv) the blend of Step (iii) was lubricated with sifted magnesium stearate of Step (ii) in a suitable blender for about 5 minutes and finally,
(v) the lubricated blend of Step (iv) was compressed into tablets with sufficient hardness of not less than 35 Newtons. Disintegration & Dissolution study: The tablets obtained in Example 2 were shown disintegration within 60 seconds and dissolution of not less than 85% within 15 minutes.
Example 3-5
Orally disintegrating tablet compositions of Eltrombopag olamine:
Figure imgf000012_0001
Preparation Method:
(i) Eltrombopag olamine, mannitol, microcrystalline cellulose, sodium saccharin, Strawberry flavour and colloidal silicon dioxide were sifted through #40,
(ii) Sodium starch glycolate, croscarmellose sodium, polacrilin potassium and/or crospovidone were sifted through #40,
(iii) magnesium stearate was sifted through mesh #60,
(iv) sifted materials of Step (i) and Step (ii) were blended for about 15 minutes,
(v) the blend of Step (iv) was lubricated with sifted magnesium stearate of Step (iii) in a suitable blender for about 5 minutes and finally,
(vi) the lubricated blend of Step (v) was compressed into tablets. Example 6-10
Orally disintegrating tablet compositions of Eltrombopag olamine:
Figure imgf000013_0001
5
Preparation Method:
(i) Eltrombopag olamine, mannitol and microcrystalline cellulose and povidone were sifted and blended,
(ii) crocarmellose sodium and/or crospovidone were sifted and blended,
(iii) binder solution was prepared by dispersing the povidone in purified water,
(iv) the combined blend of Step (i) and (ii) was granulated with solution of Step (iii) followed by, drying and milling,
(v) extragranular crocarmellose sodium, crospovidone and/ or sodium starch glycolate were sifted and blended,
(vi) acesulfame potassium, cherry flavour and colloidal silicon dioxide were sifted together through mesh #40,
(vii) magnesium stearate was sifted through mesh #60, (viii) granules of Step (iv) were blended with the materials of Step (v) and (vi) in a suitable blender for about 15 minutes.
(ix) the blend of Step (viii) was lubricated with sifted magnesium stearate of Step (vii) in a suitable blender for about 5 minutes and finally,
5 (x) the lubricated blend of Step (ix) was compressed into tablets with sufficient hardness of not less than 35 Newtons.
Example 11-14
Figure imgf000014_0001
10
Preparation Method:
(i) Eltrombopag olamine, mannitol and/or xylitol, microcrystalline cellulose, sodium lauryl sulfate, sodium saccharin, Strawberry flavour and colloidal silicon dioxide were sifted through
15 #40,
(ii) Sodium starch glycolate, croscarmellose sodium and/or crospovidone were sifted through #40,
(iii) magnesium stearate was sifted through mesh #60,
(iv) sifted materials of Step (i) and Step (ii) were blended for about 15 minutes,
20 (v) the blend of Step (iv) was lubricated with sifted magnesium stearate of Step (iii) in a suitable blender for about 5 minutes and finally,
(vi) the lubricated blend of Step (v) was compressed into tablets.

Claims

WE CLAIM:
1. A pharmaceutical dosage form which disintegrates rapidly in the mouth, comprising eltrombopag olamine as an active agent and one or more pharmaceutically acceptable excipients.
2. The pharmaceutical dosage form according to claim 1, wherein the eltrombopag olamine is present in an amount of from 5wt% to 25wt% based on total weight of the dosage form.
3. The pharmaceutical dosage form according to claim 1, wherein the eltrombopag olamine is having a particle size distribution d90 from 1μ to 70μ.
4. The pharmaceutical dosage form according to claim 1, wherein said excipient is selected from a diluent, a binder, a disintegrant, a surfactant, a glidant, a lubricant, a sweetener, a flavoring agent and combinations thereof.
5. The pharmaceutical dosage form according to claim 1, is in the form orally disintegrating tablet.
6. The pharmaceutical dosage form according to claim 1, is a tablet which disintegrates within 180 seconds.
7. An orally disintegrating tablet composition comprising:
(a) 5 wt% to 25 wt % of eltrombopag olamine as an active agent, having a particle size distribution d90 from 1μ to 70μ,
(b) disintegrant,
(c) sweetener, and
(d) one or more pharmaceutically acceptable excipients.
8. The orally disintegrated tablet according to claim 7, is prepared by either direct compression or wet granulation.
9. The orally disintegrated tablet according to claim 8, wherein said the tablet is having a hardness of not less than 35 Newtons and friability of less than 1%.
10. The method of treating thrombocytopenia in a patient in need thereof, comprising administering to the patient, the dosage form of claim 1.
PCT/IN2017/050457 2016-10-24 2017-10-07 Orally disintegrating tablets of eltrombopag WO2018078644A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021055820A1 (en) * 2019-09-20 2021-03-25 Novartis Ag 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid and its salts formulation
WO2021091510A1 (en) * 2019-11-07 2021-05-14 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A capsule comprising eltrombopag olamine
WO2021110959A1 (en) * 2019-12-06 2021-06-10 Synthon B.V. Pharmaceutical composition comprising eltrombopag bis(monoethanolamine)
EP3970700A1 (en) * 2020-09-16 2022-03-23 Sanovel Ilac Sanayi ve Ticaret A.S. A solid oral pharmaceutical formulation comprising eltrombopag olamine
EP4014970A1 (en) * 2020-12-21 2022-06-22 Genepharm S.A. A solid oral composition of eltrombopag olamine
CN115919789A (en) * 2022-12-08 2023-04-07 山东新时代药业有限公司 Esprop-pasolamine tablet and preparation method thereof

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WO2008136843A1 (en) * 2007-05-03 2008-11-13 Smithkline Beecham Corporation Novel pharmaceutical composition

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021055820A1 (en) * 2019-09-20 2021-03-25 Novartis Ag 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid and its salts formulation
WO2021091510A1 (en) * 2019-11-07 2021-05-14 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A capsule comprising eltrombopag olamine
WO2021110959A1 (en) * 2019-12-06 2021-06-10 Synthon B.V. Pharmaceutical composition comprising eltrombopag bis(monoethanolamine)
EP3970700A1 (en) * 2020-09-16 2022-03-23 Sanovel Ilac Sanayi ve Ticaret A.S. A solid oral pharmaceutical formulation comprising eltrombopag olamine
EP4014970A1 (en) * 2020-12-21 2022-06-22 Genepharm S.A. A solid oral composition of eltrombopag olamine
CN115919789A (en) * 2022-12-08 2023-04-07 山东新时代药业有限公司 Esprop-pasolamine tablet and preparation method thereof

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