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WO2019138346A1 - Pharmaceutical composition of osimertinib - Google Patents

Pharmaceutical composition of osimertinib Download PDF

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Publication number
WO2019138346A1
WO2019138346A1 PCT/IB2019/050176 IB2019050176W WO2019138346A1 WO 2019138346 A1 WO2019138346 A1 WO 2019138346A1 IB 2019050176 W IB2019050176 W IB 2019050176W WO 2019138346 A1 WO2019138346 A1 WO 2019138346A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutical
osimertinib
diluent
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2019/050176
Other languages
French (fr)
Inventor
Dr. Pankaj Kumar KHAPRA
Dr. Rahul DABRE
Soumik Ghosh
Sartaj ALI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alembic Pharmaceuticals Ltd
Original Assignee
Alembic Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alembic Pharmaceuticals Ltd filed Critical Alembic Pharmaceuticals Ltd
Publication of WO2019138346A1 publication Critical patent/WO2019138346A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising osimertinib or a pharmaceutically acceptable salt thereof and at least one diluent.
  • the process to prepare such a pharmaceutical composition is also disclosed.
  • Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is developed by AstraZeneca for mutated EGFR cancers.
  • Osimertinib mesylate is also known by the chemical name: N-(2- ⁇ 2-dimethylaminoethyl-methylamino ⁇ -4-methoxy-5- ⁇ [4-(l- methylindol-3-yl) pyrimidin-2-yl] amino ⁇ phenyl) prop-2-enamide mesylate salt and is reported to have the following chemical structure:
  • Osimertinib mesylate in the form of 40 mg and 80 mg film coated tablet is approved in US under the brand name Tagrisso ® .
  • Tagrisso ® is administered orally, once daily, with or without food for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.
  • EGFR epidermal growth factor receptor
  • NSCLC non-small cell lung cancer
  • Osimertinib mesylate exhibits high solubility and higher than moderate permeability. It is highly soluble in stomach and upper gastrointestinal tract; moreover it has high solubility over a wide pH range.
  • United States Patent No 8,946,235 discloses osimertinib and its mesylate salt. It further discloses pharmaceutical composition of osimertinib or its pharmaceutically acceptable salt thereof with pharmaceutically acceptable carrier. It also discloses method of treating non-small cell lung cancer in a warm blooded animal by administering to osimertinib mesylate. It further discloses polymorphic form A and form B of osimertinib mesylate.
  • US20160324854 discloses an oral pharmaceutical composition of osimertinib mesylate, wherein, osimertinib mesylate is present in an amount from 2 to 70 parts by weight, two or more pharmaceutical diluents in an amount from 5 to 96 parts by weight, wherein one of the two diluent is microcrystalline cellulose (MCC) in an amount from 7 to 30 weight% of the two diluents.
  • MMC microcrystalline cellulose
  • US’ 854 publication discloses pharmaceutical compositions containing at least two diluents including microcrystalline cellulose as one of the diluent. There is a need in the art for alternative pharmaceutical compositions.
  • the present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least one diluent.
  • the composition may further comprise other pharmaceutically acceptable excipients.
  • the present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least two diluents, wherein in none of the two diluent is microcrystalline cellulose or wherein one of the two diluent is microcrystalline cellulose in an amount greater than 30 % by weight of two or more diluents.
  • the present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least two diluents, wherein one of the two diluent is microcrystalline cellulose in an amount greater than 30% by weight of two or more diluents.
  • the object of the present invention is to provide a pharmaceutical composition comprising osimertinib or a pharmaceutically acceptable thereof and at least one diluent.
  • An aspect of the present invention provides a pharmaceutical composition comprising,
  • An aspect of the present invention provides a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • composition comprising
  • the present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient, at least one diluent, and other pharmaceutically acceptable excipients.
  • present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and one diluent, wherein the one diluent is microcrystalline cellulose or one diluent is other than microcrystalline cellulose, which can be selected from, but not limited to, mannitol, lactose, dicalcium phosphate and pregelatinized starch.
  • present invention relates to a solid oral pharmaceutical composition
  • a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least two diluent, wherein optionally one diluent is microcrystalline cellulose in an amount greater than 30% by weight of two or more diluents, or none of the two diluents is microcrystalline cellulose and the diluents can be selected from, but not limited to, mannitol, lactose, dicalcium phosphate and pregelatinized starch.
  • pharmaceutical composition may comprise osimertinib in the‘free base form’ or as a pharmaceutically acceptable salt, or as any mixture thereof.
  • osimertinib present in pharmaceutical composition is in free base form.
  • osimertinib present in pharmaceutical composition is in the form of acceptable salt of osimertinib.
  • osimertinib present in pharmaceutical composition is in the form of mesylate salt of osimertinib.
  • osimertinib mesylate is in crystalline form.
  • the osimertinib mesylate crystalline form is polymorphic Form B (wherein polymorphic Form B of the mesylate salt of osimertinib may be defined in any of the ways described in international patent application number PCT/GB2012/05 l783/publication number WO2013/014448).
  • the osimertinib mesylate crystalline form is Form A of the mesylate salt of osimertinib (wherein polymorphic Form A of the mesylate salt of osimertinib may be defined in any of the ways described in international patent application number PCT/GB20l2/05l783/publication number WO2013/014448).
  • D90 of osimertinib mesylate is from about 5 mih to about 25 mih or from about 25 mih to about 45 mih or from about 45 mih to about 100 mih.
  • An aspect of the present invention provides a pharmaceutical composition comprising,
  • An aspect of the present invention provides a pharmaceutical composition comprising,
  • Suitable diluent can be selected form the group of, but not limited to sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride and microcrystalline cellulose.
  • sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • the only one diluent which is other than microcrystalline cellulose can be selected from sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride.
  • sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, treha
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • the two diluents can be selected from sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride; more preferably mannitol and lactose.
  • sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose
  • Another aspect of the present invention provides a pharmaceutical composition comprising (a) Osimertinib mesylate,
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • the two diluents can be selected from sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride and microcrystalline cellulose; wherein the microcrystalline cellulose is in an amount greater than 30 % by weight of two or more diluents.
  • sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythrito
  • the pharmaceutical composition as defined herein may have from 5 to 70 % of the amount of the Osimertinib mesylate (a).
  • the pharmaceutical composition of the present invention comprises Osimertinib mesylate and (ii) one or more of the following excipients:
  • composition of the present invention comprises Osimertinib mesylate and (ii) one or more of the following excipients:
  • An aspect of the present invention provides a pharmaceutical composition comprising,
  • the two pharmaceutically acceptable diluents are selected from mannitol, lactose, dicalcium phosphate and pregelatinized starch, wherein microcrystalline cellulose in not a preferred diluent.
  • Suitable disintegrants according to the present invention can be selected form but not limited to croscarmellose sodium, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium carboxymethylcellulose, sodium starch glycolate and starch.
  • the one or more disintegrant comprise croscarmellose sodium, crospovidone, or a mixture thereof.
  • the one or more disintegrant comprises croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone.
  • Suitable pharmaceutical lubricant can be selected form but not limited to magnesium stearate, aluminium stearate , zinc stearate, calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine (e.g. a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), myristic acid, palmitic acid, stearic acid, talc, tribehenin.
  • the one or more pharmaceutical lubricants comprise magnesium stearate, stearic acid or a mixture thereof.
  • the one or more pharmaceutical lubricants comprises magnesium stearate and sodium stearyl fumarate.
  • glidant and“glidants” are intended to be interpreted in the context of pharmaceutical formulation science.
  • Suitable glidants according to the present invention can be selected from but not limited to magnesium oxide, colloidal silicon dioxide, pyrogenic silica, hydrated sodium silioaluminate, magnesium stearate, stearic acid, calcium phosphate, magnesium carbonate, starch, corn starch and talc.
  • the one or more pharmaceutical glidants comprise colloidal silicon dioxide, talc and starch.
  • a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.
  • a pharmaceutical tablet comprising a tablet core wherein the tablet core comprises the pharmaceutical composition as defined herein and wherein the tablet core has a coating.
  • the coating is a film coating.
  • the film coating may be applied using conventional methods.
  • a coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation, or to modify or control the release of the osimertinib mesylate from the formulation.
  • the pharmaceutical composition is a pharmaceutical tablet composition (for oral administration).
  • the pharmaceutical composition of the present invention is a pharmaceutical tablet composition suitable for oral administration to a human.
  • the pharmaceutical composition of the present invention is a pharmaceutical tablet composition suitable for oral administration to a human who has cancer [particularly lung cancer, more particularly non-small cell lung cancer (NSCLC), for example EGFRM+NSCLC] .
  • cancer particularly lung cancer, more particularly non-small cell lung cancer (NSCLC), for example EGFRM+NSCLC.
  • NSCLC non-small cell lung cancer
  • the pharmaceutical composition of the present invention is a pharmaceutical tablet composition suitable for oral administration to a human who has EGFRM+ and T790M+ non-small cell lung cancer.
  • the pharmaceutical tablet comprising 40 mg and 80 mg osimertinib free base, equivalent to 47.7 mg and 95.4 mg of osimertinib mesylate respectively.
  • a pharmaceutical composition as defined herein, for the manufacture of a medicament for the treatment of cancer.
  • composition for use as a medicament.
  • a pharmaceutical tablet as defined herein, for use as a medicament.
  • composition for use in the treatment of cancer.
  • a pharmaceutical tablet as defined herein, for use in the treatment of cancer.
  • a method of treating cancer in a patient in need thereof comprises the oral administration of an effective amount of the pharmaceutical composition, as defined herein, to the patient.
  • the patient is an adult human patient.
  • a method of treating cancer in a patient in need thereof comprises the oral administration of an effective number of the pharmaceutical tablet(s), as defined herein, to the patient.
  • cancer in any aspect, embodiment or claim where “cancer” is mentioned in this specification, the cancer may be further defined according to the embodiments listed below, unless such a definition would be inappropriate in a particular context.
  • the cancer is non-small cell lung cancer.
  • the cancer is EGFR-mutation positive non-small cell lung cancer.
  • the cancer is T790M+ non-small cell lung cancer.
  • the process for preparation of osimertinib mesylate tablet can be selected form, but not limited to wet granulation process, dry granulation process and direct compression process.
  • the Osimertinib mesylate tablets were prepared using dry granulation method. Osimertinib mesylate with all intragranular excipients were sifted through the suitable mesh. Then the material was loaded in blender and after blending, compacted using roll compactor. The compacts were milled using suitable mill and screen. The milled granules were passed through suitable mesh. The extragranular excipients and lubricants were sifted through suitable mesh and were blended with milled granules. The blend was then compressed into tablets using suitable punches and then coated to a target build-up.
  • the dissolution described herein were performed according to the general procedure of the United States Pharmacopoeia using Apparatus II (Paddle), at 50 rpm with 900 ml of OGD media (0.2% Nacl solution in water, adjust to pH 1.3) at a temperature of 37° C. The samples were withdrawn at 5, 10, 15, 20, 30 and 45 minutes.

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Abstract

The present invention relates to pharmaceutical composition comprising osimertinib or a pharmaceutically acceptable salt thereof and at least one diluent. The process to prepare such a pharmaceutical composition is also disclosed.

Description

PHARMACEUTICAL COMPOSITION OF OSIMERTINIB
TECHNICAL FIELD:
The present invention relates to a pharmaceutical composition comprising osimertinib or a pharmaceutically acceptable salt thereof and at least one diluent. The process to prepare such a pharmaceutical composition is also disclosed.
BACK GROUND:
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is developed by AstraZeneca for mutated EGFR cancers. Osimertinib mesylate is also known by the chemical name: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{ [4-(l- methylindol-3-yl) pyrimidin-2-yl] amino} phenyl) prop-2-enamide mesylate salt and is reported to have the following chemical structure:
Figure imgf000002_0001
Osimertinib mesylate in the form of 40 mg and 80 mg film coated tablet is approved in US under the brand name Tagrisso®. Tagrisso® is administered orally, once daily, with or without food for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy. Osimertinib mesylate exhibits high solubility and higher than moderate permeability. It is highly soluble in stomach and upper gastrointestinal tract; moreover it has high solubility over a wide pH range.
United States Patent No 8,946,235 discloses osimertinib and its mesylate salt. It further discloses pharmaceutical composition of osimertinib or its pharmaceutically acceptable salt thereof with pharmaceutically acceptable carrier. It also discloses method of treating non-small cell lung cancer in a warm blooded animal by administering to osimertinib mesylate. It further discloses polymorphic form A and form B of osimertinib mesylate.
United States Patent Application Publication US20160324854 (US’854 publication) discloses an oral pharmaceutical composition of osimertinib mesylate, wherein, osimertinib mesylate is present in an amount from 2 to 70 parts by weight, two or more pharmaceutical diluents in an amount from 5 to 96 parts by weight, wherein one of the two diluent is microcrystalline cellulose (MCC) in an amount from 7 to 30 weight% of the two diluents.
Further US’854 publication discloses osimertinib mesylate compositions with at least two diluents including MCC as one of the diluent. The publication provides that such compositions result in improved dissolution and higher overall release of osimertinib mesylate, achieving a faster initial dissolution rate and reducing the risk of inter-dose and inter-patient variability.
US’ 854 publication discloses pharmaceutical compositions containing at least two diluents including microcrystalline cellulose as one of the diluent. There is a need in the art for alternative pharmaceutical compositions.
In an embodiment, the present invention relates to a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least one diluent. The composition may further comprise other pharmaceutically acceptable excipients.
In an embodiment, the present invention relates to a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least two diluents, wherein in none of the two diluent is microcrystalline cellulose or wherein one of the two diluent is microcrystalline cellulose in an amount greater than 30 % by weight of two or more diluents.
In another embodiment, the present invention relates to a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least two diluents, wherein one of the two diluent is microcrystalline cellulose in an amount greater than 30% by weight of two or more diluents.
SUMMARY OF THE INVENTION:
The object of the present invention is to provide a pharmaceutical composition comprising osimertinib or a pharmaceutically acceptable thereof and at least one diluent.
An aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least one pharmaceutically acceptable diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
An aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least one pharmaceutically acceptable diluent, (c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants.
Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) Microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) Microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants.
Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) A diluent other than microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants
Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) A diluent other than microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants, (d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants.
Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluent, wherein none of the two diluents is microcrystalline cellulose,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
Another aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluent, wherein none of the two diluents is microcrystalline cellulose,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluents, wherein one of the two diluents is microcrystalline cellulose in an amount greater than 30 % by weight of two or more diluents,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants. Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluents, wherein one of the two diluents is microcrystalline cellulose in an amount greater than 30 % by weight of two or more diluents,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants.
DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention relates to a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient, at least one diluent, and other pharmaceutically acceptable excipients.
In one embodiment, present invention relates to a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and one diluent, wherein the one diluent is microcrystalline cellulose or one diluent is other than microcrystalline cellulose, which can be selected from, but not limited to, mannitol, lactose, dicalcium phosphate and pregelatinized starch.
In one embodiment, present invention relates to a solid oral pharmaceutical composition comprising osimertinib mesylate as an active ingredient and at least two diluent, wherein optionally one diluent is microcrystalline cellulose in an amount greater than 30% by weight of two or more diluents, or none of the two diluents is microcrystalline cellulose and the diluents can be selected from, but not limited to, mannitol, lactose, dicalcium phosphate and pregelatinized starch. For the purpose of the present invention, pharmaceutical composition may comprise osimertinib in the‘free base form’ or as a pharmaceutically acceptable salt, or as any mixture thereof.
In one embodiment, osimertinib present in pharmaceutical composition is in free base form.
In one embodiment, osimertinib present in pharmaceutical composition is in the form of acceptable salt of osimertinib.
In one embodiment, osimertinib present in pharmaceutical composition is in the form of mesylate salt of osimertinib.
In one embodiment, osimertinib mesylate is in crystalline form.
In one embodiment the osimertinib mesylate crystalline form is polymorphic Form B (wherein polymorphic Form B of the mesylate salt of osimertinib may be defined in any of the ways described in international patent application number PCT/GB2012/05 l783/publication number WO2013/014448).
In one embodiment, crystalline osimertinib mesylate salt exhibits an x-ray powder diffraction pattern with specific peaks at 2-theta=7.2, 8.6, 15.3, 10.4, 25.7, 26.1, 16.4, 9.5, 22.1 and 18.8° 2-theta, wherein said values may be plus or minus 0.2° 2-theta, measured using CuKa radiation.
In one embodiment, the osimertinib mesylate crystalline form is Form A of the mesylate salt of osimertinib (wherein polymorphic Form A of the mesylate salt of osimertinib may be defined in any of the ways described in international patent application number PCT/GB20l2/05l783/publication number WO2013/014448). In one embodiment, D90 of osimertinib mesylate is from about 5 mih to about 25 mih or from about 25 mih to about 45 mih or from about 45 mih to about 100 mih.
An aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least one pharmaceutically acceptable diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
An aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least one pharmaceutically acceptable diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants.
In this specification the terms “diluent” and “diluents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluent according to the present invention can be selected form the group of, but not limited to sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride and microcrystalline cellulose.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate, (b) Microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) Microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidant.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) A diluent other than microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) A diluent other than microcrystalline cellulose as the only diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidant.
According to an aspect of the invention (b) the only one diluent which is other than microcrystalline cellulose can be selected from sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluents, wherein none of the two diluent is microcrystalline cellulose,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluents, wherein none of the two diluent is microcrystalline cellulose,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidant.
Another aspect of the invention, wherein (b) the two diluents can be selected from sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride; more preferably mannitol and lactose.
Another aspect of the present invention provides a pharmaceutical composition comprising (a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluents, wherein one of the two diluent is microcrystalline cellulose in an amount greater than 30 % by weight of two or more diluents,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants.
Another aspect of the present invention provides a pharmaceutical composition comprising
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluents, wherein one of the two diluent is microcrystalline cellulose in an amount greater than 30 % by weight of two or more diluents,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidant.
Another aspect of the invention the wherein the two diluents can be selected from sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride and microcrystalline cellulose; wherein the microcrystalline cellulose is in an amount greater than 30 % by weight of two or more diluents.
In further embodiments of the invention the pharmaceutical composition as defined herein may have from 5 to 70 % of the amount of the Osimertinib mesylate (a). In one embodiment the pharmaceutical composition of the present invention comprises Osimertinib mesylate and (ii) one or more of the following excipients:
(a) 5 % to 70 % w/w Osimertinib mesylate,
(b) 30 % to 95 % w/w at least one Diluent,
(c) 1 % to 15 % w/w at least one Disintegrant,
(d) 1 % to 5 % at least one Lubricant.
In one embodiment the pharmaceutical composition of the present invention comprises Osimertinib mesylate and (ii) one or more of the following excipients:
(a) 5 % to 70 % w/w Osimertinib mesylate,
(b) 30 % to 95 % w/w at least one Diluent,
(c) 1 % to 15 % w/w at least one Disintegrant,
(d) 1 % to 5 % at least one Lubricant,
(e) optionally up to 10% w/w at least one Glidant.
An aspect of the present invention provides a pharmaceutical composition comprising,
(a) Osimertinib mesylate,
(b) at least two pharmaceutically acceptable diluent,
(c) one or more pharmaceutical disintegrants,
(d) one or more pharmaceutical lubricants,
(e) optionally one or more pharmaceutical glidants,
wherein the two pharmaceutically acceptable diluents are selected from mannitol, lactose, dicalcium phosphate and pregelatinized starch, wherein microcrystalline cellulose in not a preferred diluent.
In this specification the terms“disintegrant” and“disintegrants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present invention can be selected form but not limited to croscarmellose sodium, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium carboxymethylcellulose, sodium starch glycolate and starch.
According to this aspect of the invention, in one embodiment the one or more disintegrant comprise croscarmellose sodium, crospovidone, or a mixture thereof.
In another embodiment the one or more disintegrant comprises croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospovidone.
In this specification the terms“lubricant” and“lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant according to the present invention can be selected form but not limited to magnesium stearate, aluminium stearate , zinc stearate, calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine (e.g. a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), myristic acid, palmitic acid, stearic acid, talc, tribehenin.
According to this aspect of the invention, in one embodiment the one or more pharmaceutical lubricants comprise magnesium stearate, stearic acid or a mixture thereof.
In another embodiment the one or more pharmaceutical lubricants comprises magnesium stearate and sodium stearyl fumarate.
Glidants are frequently used in tablet formulations to improve flow. In this specification the terms“glidant” and“glidants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable glidants according to the present invention can be selected from but not limited to magnesium oxide, colloidal silicon dioxide, pyrogenic silica, hydrated sodium silioaluminate, magnesium stearate, stearic acid, calcium phosphate, magnesium carbonate, starch, corn starch and talc.
According to this aspect of the invention, in one embodiment the one or more pharmaceutical glidants comprise colloidal silicon dioxide, talc and starch.
In this specification, the word“comprise” or“comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.
In one aspect there is provided a pharmaceutical tablet comprising the pharmaceutical composition as defined herein.
In one embodiment there is provided a pharmaceutical tablet comprising a tablet core wherein the tablet core comprises the pharmaceutical composition as defined herein and wherein the tablet core has a coating. In one embodiment the coating is a film coating.
When the tablet has a film coating, the film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to colour the formulation, or to modify or control the release of the osimertinib mesylate from the formulation.
In one embodiment the pharmaceutical composition is a pharmaceutical tablet composition (for oral administration).
In one embodiment the pharmaceutical composition of the present invention is a pharmaceutical tablet composition suitable for oral administration to a human.
In one embodiment the pharmaceutical composition of the present invention is a pharmaceutical tablet composition suitable for oral administration to a human who has cancer [particularly lung cancer, more particularly non-small cell lung cancer (NSCLC), for example EGFRM+NSCLC] .
In one embodiment the pharmaceutical composition of the present invention is a pharmaceutical tablet composition suitable for oral administration to a human who has EGFRM+ and T790M+ non-small cell lung cancer.
In one embodiment the pharmaceutical tablet comprising 40 mg and 80 mg osimertinib free base, equivalent to 47.7 mg and 95.4 mg of osimertinib mesylate respectively.
In a further aspect of the invention there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament.
In one embodiment there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament for the treatment of cancer.
In one aspect of the invention there is provided a pharmaceutical composition, as defined herein, for use as a medicament.
In one embodiment there is provided a pharmaceutical tablet, as defined herein, for use as a medicament.
In one embodiment there is provided a pharmaceutical composition, as defined herein, for use in the treatment of cancer.
In one embodiment there is provided a pharmaceutical tablet, as defined herein, for use in the treatment of cancer.
In one aspect of the invention there is provided a method of treating cancer in a patient in need thereof, which method comprises the oral administration of an effective amount of the pharmaceutical composition, as defined herein, to the patient.
In another embodiment the patient is an adult human patient.
In one embodiment there is provided a method of treating cancer in a patient in need thereof, which method comprises the oral administration of an effective number of the pharmaceutical tablet(s), as defined herein, to the patient.
In any aspect, embodiment or claim where “cancer” is mentioned in this specification, the cancer may be further defined according to the embodiments listed below, unless such a definition would be inappropriate in a particular context.
In one embodiment the cancer is non-small cell lung cancer.
In one embodiment the cancer is EGFR-mutation positive non-small cell lung cancer.
In one embodiment the cancer is T790M+ non-small cell lung cancer.
According to one embodiment, the process for preparation of osimertinib mesylate tablet can be selected form, but not limited to wet granulation process, dry granulation process and direct compression process.
Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical compositions and dosage forms provided herein, but are not in any way limiting.
Example 1 Table 1
Figure imgf000018_0001
Example 2 Table 2
Figure imgf000018_0002
Example 3
Table 3
Figure imgf000019_0001
Example 4
Table 4
Figure imgf000019_0002
Example 5 Table 5
Figure imgf000020_0001
Example 6
Table 6
Figure imgf000020_0002
Example 7
The Osimertinib mesylate tablets were prepared using dry granulation method. Osimertinib mesylate with all intragranular excipients were sifted through the suitable mesh. Then the material was loaded in blender and after blending, compacted using roll compactor. The compacts were milled using suitable mill and screen. The milled granules were passed through suitable mesh. The extragranular excipients and lubricants were sifted through suitable mesh and were blended with milled granules. The blend was then compressed into tablets using suitable punches and then coated to a target build-up.
Table 7
Figure imgf000021_0001
Example 8
Dissolution Study
The dissolution described herein were performed according to the general procedure of the United States Pharmacopoeia using Apparatus II (Paddle), at 50 rpm with 900 ml of OGD media (0.2% Nacl solution in water, adjust to pH 1.3) at a temperature of 37° C. The samples were withdrawn at 5, 10, 15, 20, 30 and 45 minutes.
The dissolution profile of the 7A, 7B and 7C (Example 7) formulations are presented in Table 8. Table 8
Figure imgf000022_0001

Claims

We claim:
1. A pharmaceutical composition comprising a therapeutically effective amount of Osimertinib or a pharmaceutically acceptable salt thereof, at least one pharmaceutical diluent and one or more pharmaceutical acceptable excipients.
2. The pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises 30 to 95 % w/w of the at least one pharmaceutical diluent based on the total weight of the composition.
3. The pharmaceutical composition as claimed in claim 1 or 2, wherein at least one pharmaceutical diluent is selected from microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, mannitol and lactose.
4. The pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutical acceptable excipients are selected from disintegrants, lubricants and glidants.
5. The pharmaceutical composition as claimed in claim 4, wherein the pharmaceutical composition comprises 1 to 15 % w/w of the disintegrant based on the total weight of composition.
6. The pharmaceutical composition as claimed in claim 5, wherein the disintegrant is selected from crospovidone, croscarmellose sodium, sodium starch glycolate, alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminium silicate, methylcellulose, povidone, sodium carboxymethylcellulose and L-substituted hydroxy propyl cellulose.
7. The pharmaceutical composition as claimed in claim 4, wherein the pharmaceutical composition comprises 1 to 5 % w/w of the lubricant based on the total weight of composition.
8. The pharmaceutical composition as claimed in claim 7, wherein the lubricant is selected from magnesium stearate, stearic acid, myristic acid, tribehenin, palmitic acid, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate and sodium stearyl fumarate.
9. The pharmaceutical composition as claimed in claim 4, wherein the pharmaceutical composition comprises 0 to 10 % w/w of the glidant based on the total weight of composition.
10. The pharmaceutical composition as claimed in claim 9, wherein the glidant is selected from magnesium oxide, pyrogenic silica, corn starch, calcium phosphate, colloidal silicon dioxide, talc and starch.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2015101791A1 (en) * 2014-01-02 2015-07-09 Astrazeneca Ab Pharmaceutical compositions comprising azd9291

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015101791A1 (en) * 2014-01-02 2015-07-09 Astrazeneca Ab Pharmaceutical compositions comprising azd9291

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