WO2020003196A1 - Composition pharmaceutique d'axitinib - Google Patents

Composition pharmaceutique d'axitinib Download PDF

Info

Publication number
WO2020003196A1
WO2020003196A1 PCT/IB2019/055454 IB2019055454W WO2020003196A1 WO 2020003196 A1 WO2020003196 A1 WO 2020003196A1 IB 2019055454 W IB2019055454 W IB 2019055454W WO 2020003196 A1 WO2020003196 A1 WO 2020003196A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
axitinib
another embodiment
coating
crystalline
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/IB2019/055454
Other languages
English (en)
Inventor
Dr. Pankaj Kumar KHAPRA
Dr. Rahul DABRA
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 WO2020003196A1 publication Critical patent/WO2020003196A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the present subject matter relates to a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising axitinib or a salt thereof and one or more pharmaceutically acceptable excipients.
  • Axitinib is a tyrosine kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.
  • Axitinib is chemically described as N-methyl-2-[3-((E)2-pyridin-2-yl-vinyl)-1 H-indazol-6-ylsulfanyl]- benzamide and has the following chemical structural formula:
  • Axitinib is commercially available as 1 mg and 5 mg film coated tablets under the brand name INLYTA ® .
  • Axitinib and its different polymorphs are well known in the art.
  • U.S. Patent no 6,534,524 discloses axitinib, salt, prodrug & metabolites thereof.
  • U.S. Patent application publication number 20060094763 discloses crystalline polymorphic forms of axitinib viz., form I, form II, form III, form IV, form VI, form VII, and form VIII with specific powder X-ray diffraction pattern.
  • U.S. Patent no 8,791 ,140 discloses crystalline polymorphic forms of axitinib viz., form IX, XV, XXV, XVI, XLI, XII, VIII, XLI, and XV with specific powder X-ray diffraction pattern.
  • U.S. Patent number 8,791 ,140 discloses that other polymorphs such as form XLI and form XXV are more thermodynamically and photo stable, and also have better handling properties than form IV.
  • the present subject matter relates to a solid oral composition comprising axitinib and one or more pharmaceutically acceptable excipients. In addition, it also provides a process of preparation of such composition.
  • a stable pharmaceutical composition comprising crystalline axitinib form IV and one or more pharmaceutically acceptable excipients.
  • the stable pharmaceutical composition is devoid of other polymorphic forms of axitinib other than form IV.
  • the pharmaceutical composition is devoid of iron oxide.
  • a stable pharmaceutical composition in the form of a tablet comprising a core and a coating, wherein the core comprises crystalline axitinib form IV.
  • the coating part of the tablet composition is devoid of iron oxide.
  • a stable pharmaceutical composition of axitinib in the form of a tablet dosage form which is stable and bioequivalent to the commercially available axitinib tablets (INLYTA ® ).
  • the stable pharmaceutical composition comprising crystalline axitinib form IV may further comprise a diluent, a disintegrating agent, a binder, a pH-modifying agent, a glidant and a lubricant.
  • a stable pharmaceutical composition comprising crystalline axitinib form IV and a pH modifying agent.
  • the pharmaceutical composition comprises axitinib and a pH modifying agent in a ratio of from 1 : 1 to 1 : 25.
  • the pharmaceutical composition comprises crystalline axitinib form IV, a diluent and a lubricant.
  • the pharmaceutical composition of the present subject matter is used in the treatment of a patient with advanced renal cell carcinoma after failure of one prior systemic therapy.
  • composition comprising crystalline axitinib form IV and one or more pharmaceutically acceptable excipients.
  • axitinib is a base and is present in a polymorphic form known as form IV characterized by an X-ray diffraction pattern with peaks at the following diffraction angles (2Q): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21 .6, 23.2, 24.2, 24.8, 26.2, and 27.5.
  • composition or “pharmaceutical composition” or “solid oral composition” or“dosage form” as used herein synonymously include solid dosage forms such as tablets, capsules, granules, or pellets and the like meant for oral administration.
  • subject may be a human or non-human mammal (e.g., rabbit, rat, mouse, horse, monkey, other lower-order primate, etc.).
  • any two products are considered to be “bioequivalent” if they are pharmaceutical equivalents and if the 90% confidence interval (Cl) of the relative mean Cmax, AUC(O-t) and AUC(0- ) of the test to reference is within 80.00% to 125.00% under fasting and fed states.
  • the term“stable” as used herein, indicates that the composition when exposed to light or moisture should maintain the axitinib polymorphic form in the original form used i.e. form IV, on storage without getting converted to other polymorphic form/s and without substantial photo or oxidative degradation.
  • photo stable as used herein, unless otherwise indicated, specifies that the drug axitinib is not substantially degraded to photo degradants i.e. compound of formula I referred to as the 2 + 2 dimer, the compound of formula II referred to as the asymmetric dimer, and the compound of formula III be referred to as the cis-isomer throughout the prolonged storage.
  • Axitinib is also prone to oxidation and may yield oxidative degradant due to instability which include the compound of formula IV, which may be referred to as the sulfoxide derivative.
  • impurity relates to any compound having a retention time that differs from that of axitinib by at least the detection limit of the chromatography apparatus used to determine the retention time.
  • the different retention time may be measured, for example, by HPLC.
  • impurities can be defined as photo degradants of formula I, formula II (2 + 2 dimer impurity) & formula III, oxidative degradant of formula IV (formula IV impurity), unknown impurities and total impurities.
  • a stable pharmaceutical composition comprising crystalline axitinib form IV and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is devoid of any other polymorphic forms of axitinib other than form IV.
  • the pharmaceutical composition is devoid of iron oxide.
  • a composition is defined to exhibit good stability when the composition retains at least 90% w/w of the initial potency for at least 2 month, atleast 3 months, for atleast 6 months, for atleast 12 months, for atleast 24 months or for atleast 36 months when stored at 40 °C/ 75% RH.
  • a composition is defined to exhibit good stability when the composition retains at least 90% w/w of the initial potency for at least 2 month when stored at 40 °C/ 75% RH.
  • a composition of axitinib retains at least 90% w/w, at least 95% w/w, at least 99% w/w or about 100% w/w of the initial potency.
  • a composition retains about 90% w/w, about 91 % w/w, about 92% w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about 97% w/w, about 98% w/w, about 99% w/w or about 100% w/w of the initial potency.
  • a composition of axitinib retains at least 95% w/w of the initial potency when stored at 40 °C/ 75% RH for atleast 2 months.
  • a stable pharmaceutical composition in the form of a tablet comprising a core and a coating, wherein the core comprises crystalline axitinib form IV.
  • the composition comprising crystalline axitinib form IV in an amount of from about 1 %w/w to about 5%w/w based on the total weight of the composition including coating.
  • Crystalline axitinib form IV is present in an amount of about 1 %w/w, about 2%w/w, about 3%w/w, about 4%w/w, about 5%w/w based on the total weight of the composition including coating.
  • Crystalline axitinib form IV is present in an amount of about 2%w/w, about 2.1 %w/w, about 2.2%w/w, about 2.3%w/w, about 2.4%w/w, 2.5%w/w, about 2.6%w/w, about 2.7%w/w, about 2.8%w/w, 2.9%w/w and about 3%w/w based on the total weight of the composition including coating.
  • the coating part of the tablet composition is devoid of iron oxide.
  • composition of the present subject matter provides protection of axitinib from photo degradation and oxidative degradation.
  • a composition of axitinib retains at least 90% w/w, at least 95% w/w, at least 99% w/w or about 100% w/w of axitinib in crystalline form IV when stored at 40 °C/ 75% RH for atleast 2 months.
  • a composition retains about 90% w/w, about 91 % w/w, about 92% w/w, about 93% w/w, about 94% w/w, about 95% w/w, about 96% w/w, about 97% w/w, about 98% w/w, about 99% w/w or about 100% w/w of axitinib in crystalline form IV when stored at 40 °C/ 75% RH for atleast 2 months.
  • a composition of axitinib retains at least 95% w/w of axitinib in crystalline form IV when stored at 40 °C/ 75% RH for atleast 2 months.
  • a composition of axitinib contains not more than 2% w/w, 1 % w/w, 0.9%w/w, 0.8%w/w, 0.7%w/w, 0.6%w/w, 0.5%w/w, 0.4%w/w, 0.3%w/w, 0.2%w/w, 0.1 %w/w or 0.0% w/w of total impurities when stored at 40 °C / 75% RH for atleast 2 months, atleast 3months, atleast 6 months, atleast 9 months, atleast 12 months, atleast 24 months or atleast 36 months.
  • a composition of axitinib contains not more than 1 % w/w, 0.9%w/w, 0.8%w/w, 0.7%w/w, 0.6%w/w, 0.5%w/w, 0.4%w/w, 0.3%w/w,
  • a composition of axitinib contains not more than 0.5% w/w of total impurities on storage at 40 °C/ 75% RH for a period of atleast 2 months.
  • a composition of axitinib contains not more than 1 % w/w, 0.9%w/w, 0.8%w/w, 0.7%w/w, 0.6%w/w, 0.5%w/w, 0.4%w/w, 0.3%w/w, 0.2%w/w or 0.1 %w/w of formula IV impurity on storage at 40 °C/ 75% RH for a period of atleast 2 months.
  • a composition of axitinib contains not more than 0.1 % w/w of formula IV impurity on storage at 40 °C/ 75% RH for a period of atleast 2 months.
  • a composition of axitinib lacks photo degradant impurities at initial time point.
  • a composition of axitinib is substantially free of photo degradant impurities on storage at 40 °C/ 75% RH for a period of atleast 2 months, atleast 3 months, atleast 6 months, atleast 9 months, atleast 12 months, atleast 24 months, atleast 36 months.
  • a composition of axitinib is substantially free of 2 + 2 dimer impurity on storage at 40 °C/ 75% RH for a period of atleast 2 months, atleast 3 months, atleast 6 months, atleast 9 months, atleast 12 months, atleast 24 months, atleast 36 months.
  • a stable pharmaceutical composition of axitinib in the form of a tablet dosage form which is stable and bioequivalent to the commercially available axitinib tablets (INLYTA ® ).
  • the pharmaceutical composition comprising crystalline axitinib form IV and pharmaceutically acceptable excipients such as a diluent and a lubricant.
  • the pharmaceutical composition comprising crystalline axitinib form IV, a diluent, a disintegrating agent, a binder, a pH-modifying agent, a glidant and a lubricant.
  • diluent refers to chemical compounds that are used to dilute the compound of interest prior to delivery.
  • Suitable diluent according to the subject matter is selected from the group including but not limited to, lactose (monohydrate, spray- dried monohydrate, anhydrous and the like), cellulose and derivatives thereof like powdered cellulose, microcrystalline cellulose or silicified microcrystalline cellulose, cellulose acetate, starches and derivatives thereof such as corn starch, inorganic salts like calcium carbonate, calcium phosphate, dibasic calcium phosphate (dicalcium phosphate), tri calcium phosphate, calcium sulphate, magnesium carbonate, magnesium oxide, sugars and derivatives such as confectioner's sugar, fructose, sucrose, dextrates, dextrin, D-sorbitol cyclodextrins, dextrose, polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin, sorbito
  • a pharmaceutical composition comprises axitinib and a diluent.
  • a pharmaceutical composition comprises axitinib, lactose monohydrate and/ or dicalcium phosphate.
  • the amount of diluent in the composition ranges from about 75%w/w to about 98%w/w, about 80% w/w to about 97% w/w or about 85% w/w to about 96% w/w based on the total weight of the core composition.
  • Diluent may comprise in an amount of about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w, about 95%w/w or about 98%w/w based on total weight of the core composition.
  • Diluent may comprise in an amount of about 90% w/w, about 91 % w/w, about 92% w/w or about 93% w/w, about 94%w/w, about 95%w/w, about 96%w/w, about 97%w/w or about 98%w/w based on total weight of the core composition.
  • diluent is in an amount of about 96% w/w based on total weight of the core composition.
  • diluent is in an amount of about 95% w/w based on total weight of the core composition.
  • diluent is in an amount of about 93% w/w based on total weight of the core composition.
  • the amount of diluent in the composition ranges from about 75%w/w to about 95%w/w, about 80% w/w to about 95% w/w or about 85% w/w to about 95% w/w based on the total weight of the composition including coating.
  • Diluents may comprise in an amount of about 75% w/w, about 80% w/w, about 85% w/w, about 90% w/w or about 95 % w/w based on total weight of the composition including coating.
  • Diluent may comprise in an amount of about 90% w/w, about 91 % w/w, about 92% w/w or about 93% w/w, about 94%w/w or about 95%w/w based on total weight of the composition including coating.
  • diluent is in an amount of about 93% w/w based on total weight of the composition including coating.
  • diluent is in an amount of about 95% w/w based on total weight of the composition including coating.
  • lubricant refers to an excipient which is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It aids the ejection of the tablet form the dies, and can improve powder flow.
  • Suitable lubricant according to the present subject matter is selected from the group including, but not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate, or combinations thereof.
  • the lubricant is magnesium stearate.
  • the amount of lubricant in the composition of present subject matter ranges from about 0.5%w/w to about 3%w/w based on the total weight of the core composition.
  • the lubricant is present in an amount of about 0.5%w/w, about 1 %w/w, about 1 5%w/w about 2%w/w, about 2.5%w/w or about 3%w/w based on the total weight of the core composition.
  • the lubricant is present in an amount of about 1 %w/w, based on the total weight of the core composition.
  • the amount of lubricant in the composition of present subject matter ranges from about 0.5%w/w to about 3%w/w based on the total weight of the composition including coating.
  • the lubricant is present in an amount of about 0.5%w/w, about 1 %w/w, about 1 5%w/w about 2%w/w, about 2.5%w/w or about 3%w/w based on the total weight of the composition including coating.
  • the lubricant is present in an amount of about 1 %w/w, based on the total weight of the composition including coating.
  • a pharmaceutical composition comprising crystalline axitinib form IV, a diluent, a lubricant and optionally a binder.
  • binder refers to any chemical substance which can be used to bind together the active and inert components of the carrier together to maintain cohesive and discrete portions.
  • Suitable binders according to the present subject matter are selected from the group including but not limited to, hydroxypropyl methylcellulose, acacia, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, povidone, dextrin, gelatin, guar gum, maltodextrin, methylcellulose, pregelatinized starch and sodium alginate or a mixture of one or more of said binders.
  • the amount of binder in the composition of present subject matter ranges from about 0%w/w to about 15%w/w based on the total weight of the composition including coating.
  • binder is present in an amount of about 0%w/w, about 1 %w/w, about 2%w/w, about 3%w/w, about 4%w/w, about 5%w/w, about 6%w/w, about 7%w/w, about 8%w/w, about 9%w/w, about 10%w/w, about 1 1 %w/w, about 12%w/w, about 13%w/w, about 14%w/w or about 15%w/w based on the total weight of the composition including coating.
  • binder is present in an amount of about 3%w/w based on the total weight of the composition including coating.
  • the composition is devoid of any binder.
  • a stable pharmaceutical composition comprising crystalline axitinib form IV and a pH modifying agent.
  • the pharmaceutical composition comprising crystalline axitinib form IV, diluent, lubricant and a pH modifying agent.
  • pH modifying agent refers to chemical substances that could control/ modify the local environment at the site of dissolution.
  • Suitable pH modifying agents are alkalizing agents that are selected from the group including but not limited to, ammonia, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium phosphate dibasic, trolamine, meglumine, magnesium oxide, polymers & copolymers such as of acrylic acids, methacrylic acids and their esters and derivatives thereof.
  • copolymers of methacrylic acids and esters according the subject matter are selected from amino alkyl methacrylate copolymers, methacrylic acid copolymers, methacrylic ester copolymers, ammonioalkyl methacrylate copolymers or combinations thereof, commercially available under the brand name Eudragit ® .
  • Eudragit used according to the present subject matter is selected from Eudragit ® E 100, Eudragit ® E 12,5, Eudragit ® E PO, Eudragit® L 1 GO- 55, Eudragit ® L 30 D-55, Eudragit ® L 100, Eudragit ® L 12,5, Eudragit ® S 100, Eudragit ® S 12,5 or Eudragit ® FS 30 D.
  • the amount of pH-modifying agent present in the composition ranges from about 0%w/w to about 20%w/w based on the total weight of the composition.
  • the pH-modifying agent is present in an amount of about 0%w/w, about 1 %w/w, about 2%w/w, about 3%w/w, about 4%w/w, about 5%w/w, about 6%w/w, about 7%w/w, about 8%w/w, about 9%w/w, about 10%w/w, about 1 1 %w/w, about 12%w/w, about 13%w/w, about 14%w/w, about 15%w/w, about 16%w/w, about 17%w/w, about 18%w/w, about 19%w/w or about 20%w/w based on the total weight of the core composition.
  • the amount of pH-modifying agent present in the composition ranges from about 0%w/w to about 20%w/w based on the total weight of the composition.
  • the pH-modifying agent is present in an amount of about 0%w/w, about 1 %w/w, about 2%w/w, about 3%w/w, about 4%w/w, about 5%w/w, about 6%w/w, about 7%w/w, about 8%w/w, about 9%w/w, about 10%w/w, about 1 1 %w/w, about 12%w/w, about 13%w/w, about 14%w/w, about 15%w/w, about 16%w/w, about 17%w/w, about 18%w/w, about 19%w/w or about 20%w/w based on the total weight of the composition including coating.
  • axitinib and a pH modifying agent present are in a weight ratio of from about 1 :1 to about 1 :25.
  • the weight ratio of axitinib and a pH modifying agent is selected from about 1 :1 , about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 :6, about 1 :7, about 1 :8, about 1 :9, about 1 :10, about 1 :1 1 , about 1 :12, about 1 :13, about 1 :14, about 1 :15, about 1 :16, about 1 :17, about 1 :18, about 1 :19, about 1 :20, about 1 :21 , about 1 :22, about 1 :23, about 1 :24 or about 1 :25.
  • the composition is devoid of pH modifying agent.
  • composition comprising crystalline axitinib form IV, a diluent, a lubricant and optionally a disintegrating agent.
  • disintegrating agent refers to a substance which, upon addition to a solid preparation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution.
  • Suitable disintegrating agents are selected from the group including, but not limited to, sodium starch glycolate, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate, or a combination thereof.
  • the amount of disintegrating agent in the composition of present subject matter ranges from 0%w/w to 5%w/w based on the total weight of the core composition including coating.
  • the disintegrating agent is present in an amount of about 0%w/w, about 1 %w/w, about 2%w/w, about 3%w/w, about 4%w/w or about 5%w/w based on the total weight of the composition including coating.
  • the present subject matter provides a pharmaceutical composition that is devoid of disintegrating agent.
  • a pharmaceutical composition comprising crystalline axitinib form IV, a diluent, a lubricant and optionally a disintegrating agent and a binder.
  • a pharmaceutical composition comprising crystalline axitinib form IV, a diluent, a lubricant and a glidant.
  • glidant as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
  • Suitable glidants according to the present subject matter are selected from the group including but not limited to, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, stearic acid, anhydrous colloidal silica, magnesium trisilicate, magnesium silicate or a combination thereof.
  • the amount of glidant in the composition of present subject matter ranges from 0%w/w to 5%w/w based on the total weight of the composition including coating.
  • the glidant is present in an amount of 0%w/w, 1 %w/w, 2%w/w, 3%w/w, 4%w/w or 5%w/w based on the total weight of the composition including coating.
  • a pharmaceutical composition comprising crystalline axitinib form IV, a diluent, a lubricant and optionally a glidant.
  • the present subject matter provides a pharmaceutical composition that is devoid of a glidant.
  • the pharmaceutical composition according to the present subject matter is a tablet.
  • the pharmaceutical composition according to the present subject matter is a film coated tablet.
  • the tablet is coated with suitable coating material.
  • the coating is applied is an aqueous coating or a non- aqueous coating.
  • the coating is applied as aqueous coating solution or dispersion, preferably solution.
  • aqueous coating solution is prepared by dissolving the coating material in desired amount of water under continuous stirring.
  • aqueous coating dispersion is prepared by dispersing the coating material in desired amount of water under continuous stirring.
  • the tablet composition is film coated by spraying coating solution or dispersion continuously till desired coating build up is formed.
  • the coating material comprises film forming polymer, plasticizer, filler and light protecting agent.
  • Suitable film forming polymer is selected from the group including but not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, methylcellulose, and sodium carboxymethylcellulose and vinyls such as polyvinyl pyrrolidone.
  • film forming polymer is present in an amount of from about 30%w/w to 50%w/w based on total weight of the coating material.
  • film forming polymer is present in an amount of about 30%w/w, about 35%w/w or about 40%w/w, about 45%w/w or about 50%w/w based on total weight of the coating material.
  • film forming polymer is present in an amount of 35%w/w, 36%w/w, 37%w/w, 38%w/w, 39%w/w or 40%w/w based on total weight of the coating material.
  • film forming polymer is present in an amount of 39% based on total weight of the coating material.
  • the film forming polymer in the coating material is hydroxypropyl methylcellulose.
  • Suitable plasticizer is selected from the group including but not limited to, polyhydric alcohols such as glycerol and polyethylene glycols and acetate esters such as glycerol triacetate or glyceryl triacetate, which are known as triacetin, and triethyl citrate.
  • plasticizer is present in an amount of from about 5%w/w to 15%w/w based on total weight of the coating material.
  • plasticizer is present in an amount of about 5%w/w, about 6%w/w, about 7%w/w, about 8%w/w, about 9%w/w or about 10%w/w based on total weight of the coating material.
  • plasticizer is present in an amount of about 8%w/w based on total weight of the coating material.
  • the plasticizer in the coating material is triacetin.
  • Suitable filler of coating material is selected from the group including but not limited lactose monohydrate, anhydrous lactose and the like, Mannitol, polyvinyl pyrrolidone, low molecular weight hydroxypropyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, low molecular weight hydroxypropyl methylcellulose, low molecular weight carboxymethyl cellulose, ethylcellulose, dicalcium phosphate, alginates, gelatin, polyethylene oxide, acacia, magnesium aluminum silicate, and polymethacrylates, or a combination thereof.
  • filler is present in coating material in an amount of from about 20%w/w to 40%w/w based on total weight of the coating material.
  • filler is present in an amount of about 20%w/w, about 25%w/w or about 30%w/w, about 35%w/w or about 40%w/w based on total weight of the coating material.
  • filler is present in an amount of 25%w/w, 26%w/w, 27%w/w, 28%w/w, 29%w/w or 30%w/w based on total weight of the coating material.
  • filler of coating material is present in an amount of 28%w/w based on total weight of the coating material.
  • filler of coating material is lactose monohydrate.
  • the film coated pharmaceutical tablet composition wherein, the coating is free of iron oxide.
  • Suitable light protecting material is a light blocking material selected from titanium dioxide, calcium carbonate or a light absorbing material aluminium lake selected from FD&C Red No. 40 Aluminium Lake; FD&C Red No. 4 Lake; D&C Violet No. 2 Lake; D&C Yellow No. 10 Aluminium Lake; FD&C Yellow No. 6 Aluminium Lake; FD&C Yellow No. 5 Aluminium Lake; D&C Yellow No. 7 Lake; FD&C blue No. 2 Aluminium Lake and the like or a combination thereof.
  • the light protecting material is a light blocking material calcium carbonate.
  • the light protecting material is a light absorbing material aluminium lake.
  • the light protecting material is a combination of light blocking material calcium carbonate and light absorbing material aluminium lake.
  • light blocking material is present in an amount of about 15%w/w to about 30%w/w based on total weight of the coating material.
  • light blocking material is present in an amount of about 15%w/w, about 20%w/w, about 25%w/w or about 30%w/w based on total weight of the coating material.
  • light blocking material is present in an amount of about 20%w/w, about 21 %w/w, about 22%w/w, about 23%w/w, about 24%w/w or about 25%w/w based on total weight of the coating material.
  • light blocking material is present in an amount of about 21 %w/w based on total weight of the coating material.
  • light absorbing material is present in an amount of from about 2%w/w to about 10%w/w based on total weight of the coating material.
  • light absorbing material is present in an amount of about 2%w/w, about 3%w/w, about 4%w/w, about 5%w/w, about 6%w/w, about 7%w/w, about 8%w/w, about 9%w/w or about 10%w/w based on total weight of the coating material.
  • light absorbing material comprises atleast one aluminium lake in an amount of from 2%w/w to 10%w/w.
  • Atleast one aluminium lake is present in an amount of about 2%w/w, about 3%w/w, about 4%w/w, about 5%w/w, about 6%w/w, about 7%w/w, about 8%w/w, about 9%w/w or about 10%w/w based on total weight of the coating material.
  • light absorbing material is atleast one aluminium lake in an amount of about 4%w/w based on total weight of the coating material.
  • the coating is a non-functional film coating.
  • the coating material used is Opadry ® II 32K165001 (Opadry II brown) as supplied by Colorcon having below composition: Table 1 : Qpadrv ® 32K165001 composition
  • composition comprising:
  • composition comprising:
  • (a) a comprises about 2% to about 5% of crystalline axitinib form IV, about 80% to about 95% of a diluent and about 1 % to about 3% of a lubricant by weight of the composition.
  • composition comprising:
  • composition comprising:
  • a core comprising an amount of about 2%w/w to about 5%w/w of crystalline axitinib form IV, an amount of about 80%w/w to about 95%w/w of diluent which is a combination of lactose anhydrous & dicalcium phosphate and about 1 %w/w to about 3%w/w of a lubricant which is magnesium stearate, wherein the amount is based on total weight of the composition including coating; (b) a coating that is devoid of iron oxide and is comprising atleast one aluminium lake.
  • composition comprising:
  • composition comprising:
  • a core comprising an amount of about 2%w/w to about 5%w/w of crystalline axitinib form IV, about 80%w/w to about 95%w/w of diluent, about 2%w/w to 12%w/w of pH modifying agent and about 1 %w/w to about 3%w/w of a lubricant, wherein the amount is based on total weight of the composition including coating;
  • the manufacturing process to prepare a composition of the present subject matter is selected from direct compression, dry granulation and wet granulation or any other technique known in the art.
  • the subject matter provides combination of unit operations selected from sifting, blending, granulation, drying, compression and optionally film coating as the steps involved in the preparation axitinib tablets.
  • a film coated tablet composition of crystalline axitinib form IV is prepared by a process comprising the steps of: a. sifting and blending axitinib and other desired excipients,
  • step (a) b. granulating the blend of step (a),
  • step (c) compressing lubricated blend of step (c) into tablets of desired dimensions, e. film coating tablets of step (d) using desired coating solution.
  • a film coated tablet composition of crystalline axitinib form IV is prepared by a process comprising the steps of: a. sifting axitinib and other desired excipients through desired mesh followed by blending to form a blend,
  • step (a) loading blend of step (a) into a granulator and granulating it using purified water, c. drying the wet granular mass resulted from step (b) followed by milling to get desired sized granules,
  • step (c) blending milled granules of step (c) with sifted extra granular materials, e. lubricating granules of step (c) or (d) using sifted magnesium stearate, f. compressing lubricated blend of step (e) into tablets of desired dimensions, g. film coating tablets of step (f) using coating solution.
  • a film coated tablet composition of crystalline axitinib form IV is prepared by a process comprising the steps of:
  • step (a) loading blend of step (a) into a granulator and granulating it using purified water, c. drying the wet granular mass resulted from step (b) followed by milling to get desired sized granules,
  • step (c) blending milled granules of step (c) with sifted extra granular materials, e. lubricating granules of step (c) or (d) using sifted magnesium stearate, f. compressing lubricated blend of step (e) into tablets of desired dimensions, g. film coating tablets of step (f) using opadry II 3K165001 coating solution which is devoid of iron oxide.
  • a film coated tablet composition of crystalline axitinib form IV is prepared by a process comprising the steps of:
  • step (a) loading blend of step (a) into a granulator and granulating it using binder solution of step (b),
  • step (c) drying the wet granular mass resulted from step (c) followed by milling to get desired sized granules
  • step (d) e. blending milled granules of step (d) with sifted extra granular materials, f. lubricating granules of step (d) or (e) using sifted magnesium stearate, g. compressing lubricated blend of step (f) into tablets of desired dimensions, h. film coating tablets of step (g) using coating solution.
  • Another aspect of the present subject matter provides a stable pharmaceutical composition of crystalline axitinib form IV in the form of tablet dosage form which are bioequivalent to the commercially available axitinib tablets (INLYTA®).
  • Further embodiment of the present subject matter provides method of treating advanced renal cell carcinoma after failure of one prior systemic therapy in a patient by administering the patient the tablet composition according to the present subject matter.
  • step (a) Axitinib and other desired excipients are sifted through desired mesh and blended, b. binder solution is prepared by dissolving hydroxypropyl methylcellulose in purified water under slow stirring, c. blend of step (a) is loaded into a granulator and is granulated using purified water or binder solution of step (b),
  • step (c) the resultant wet granular mass of step (c) is dried and milled to get desired sized granules
  • step (d) milled granules of step (d) is blended with sifted extra granular materials
  • step (d) or (e) are lubricated using sifted magnesium stearate, g. lubricated granular blend resulted from step (f) is compressed into tablets of desired dimensions,
  • step (g) tablets of step (g) are film coated using Opadry II Brown coating solution.
  • Axitinib and other desired excipients are sifted through desired mesh and blended,
  • binder solution if it is hydroxypropyl methylcellulose solution in the purified water, is prepared by dissolving hydroxypropyl methylcellulose in purified water under slow stirring,
  • step (a) is loaded into a granulator and is granulated using binder solution of step (b) or purified water alone,
  • step (c) the resultant wet granular mass of step (c) is dried and milled to get desired granules
  • step (d) granules of step (d) are lubricated using sifted magnesium stearate, f. lubricated granular blend resulted from step (e) is compressed into tablets of desired dimensions,
  • step (f) are film coated using Opadry II Brown coating solution.
  • Dissolution test for 6 tablets each of example 1 , example 7 and INLYTA tablets 5mg (RLD) was performed using USP apparatus II, 75 rpm in 900ml of 0.01 N HCI as medium.
  • the Q point as per USP 29, for this test is set to be 60Q at 30 minutes.
  • Example 1 b and example 7 were filled in a HDPE container along with silica canister and is subjected to a stability evaluation at 40° C and 75% relative humidity.
  • the samples from stability were evaluated at different time intervals for assay, impurity levels and dissolution and results are presented as below: Table 10: Stability studies for example 1 b

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique stable comprenant de l'axitinib sous forme polymorphe cristalline IV et un ou plusieurs excipients pharmaceutiquement acceptables. En particulier, la composition est bioéquivalente aux comprimés d'axitinib disponibles dans le commerce (INLYTA®).
PCT/IB2019/055454 2018-06-28 2019-06-27 Composition pharmaceutique d'axitinib Ceased WO2020003196A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201821024134 2018-06-28
IN201821024134 2018-06-28

Publications (1)

Publication Number Publication Date
WO2020003196A1 true WO2020003196A1 (fr) 2020-01-02

Family

ID=68986083

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2019/055454 Ceased WO2020003196A1 (fr) 2018-06-28 2019-06-27 Composition pharmaceutique d'axitinib

Country Status (1)

Country Link
WO (1) WO2020003196A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4282415A1 (fr) * 2022-05-26 2023-11-29 Genepharm S.A. Composition de comprimé stable d'axitinib
JP7579091B2 (ja) 2020-09-11 2024-11-07 日本化薬株式会社 アキシチニブを有効成分とする医薬錠剤及びその製造方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094763A1 (en) * 2004-11-02 2006-05-04 Agouron Pharmaceuticals, Inc. Polymorphic forms of 6-[2-(methylcarbomoyl) phenyl sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole
US20140248347A1 (en) * 2011-09-30 2014-09-04 Pfizer Inc. Pharmaceutical compositions of n-methyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060094763A1 (en) * 2004-11-02 2006-05-04 Agouron Pharmaceuticals, Inc. Polymorphic forms of 6-[2-(methylcarbomoyl) phenyl sulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole
US20140248347A1 (en) * 2011-09-30 2014-09-04 Pfizer Inc. Pharmaceutical compositions of n-methyl-2-[3-((e)-2-pyridin-2-yl-vinyl)-1h-indazol-6-ylsulfanyl]-benzamide

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7579091B2 (ja) 2020-09-11 2024-11-07 日本化薬株式会社 アキシチニブを有効成分とする医薬錠剤及びその製造方法
EP4282415A1 (fr) * 2022-05-26 2023-11-29 Genepharm S.A. Composition de comprimé stable d'axitinib

Similar Documents

Publication Publication Date Title
MXPA05005667A (es) Dispersiones solidas que comprenden un farmaco higroscopico y/o delicuescente.
WO2009090670A2 (fr) Composition à libération prolongée stabilisée à base de chlorhydrate de bupropion et procédé de préparation de cette composition
EP3086781A1 (fr) Composition pharmaceutique d'un inhibiteur de la dpp iv en combinaison avec la metformine
WO2008064202A2 (fr) Formulations à libération modifiée de composés actifs vis-à-vis du récepteur de calcium
WO2018167589A1 (fr) Composition pharmaceutique comprenant de la dapagliflozine
US9730932B2 (en) Pharmaceutical composition containing crystalline macitentan
PT2468361E (pt) Formulações de vildagliptina
EP2468268B1 (fr) Composition de combinaison de vildagliptine et de gliclazide
WO2023195955A1 (fr) Comprimé revêtu d'un film comprenant du sélexi̇pag et son procédé de préparation
CN104254321A (zh) 稳定性提高的药物制剂
WO2020003196A1 (fr) Composition pharmaceutique d'axitinib
US10206923B2 (en) Pharmaceutical composition of alogliptin and metformin
US20090155369A1 (en) Pharmaceutical composition containing levodopa, entacapone and carbidopa
US20140343076A1 (en) Pharmaceutical compositions of lurasidone
JP2023036924A (ja) レナリドミドを含む医薬組成物
WO2012147101A2 (fr) Compositions pharmaceutiques de raltégravir, procédés de préparation et utilisation de celles-ci
WO2019180735A1 (fr) Compositions pharmaceutiques stables comprenant un complexe de sacubitril-valsartan
JP2017048174A (ja) 化学的に安定な原薬含有被覆粒子を含む口腔内崩壊錠剤
CA3089537A1 (fr) Compositions pharmaceutiques comprenant de l'ibrutinib
WO2021220295A1 (fr) Compositions pharmaceutiques à libération immédiate comprenant du palbociclib
US20120121700A1 (en) Pharmaceutical formulations comprising valganciclovir
WO2024171019A1 (fr) Composition pharmaceutique de tramétinib et son procédé de préparation
WO2022153330A1 (fr) Compositions pharmaceutiques comprenant de l'acalabrutinib
WO2023227997A1 (fr) Composition pharmaceutique contenant une combinaison d'azilsartan et de chlorthalidone et son procédé de préparation
HUP0600839A2 (en) Solid pharmaceutical composition containing polymorph i of clopidogrel hydrogensulfate and process for the preparation thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19825748

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19825748

Country of ref document: EP

Kind code of ref document: A1