WO2020101596A2 - Composition de capsule comprenant du sunitinib - Google Patents

Composition de capsule comprenant du sunitinib Download PDF

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Publication number
WO2020101596A2
WO2020101596A2 PCT/TR2019/050579 TR2019050579W WO2020101596A2 WO 2020101596 A2 WO2020101596 A2 WO 2020101596A2 TR 2019050579 W TR2019050579 W TR 2019050579W WO 2020101596 A2 WO2020101596 A2 WO 2020101596A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition according
sunitinib
capsule composition
weight
capsule
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/TR2019/050579
Other languages
English (en)
Other versions
WO2020101596A3 (fr
Inventor
Ali Turkyilmaz
Yuksel TOPALOGLU
Ali Ihsan SECKIN
Irem Yenice
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.)
Arven Ilac Sanayi ve Ticaret AS
Original Assignee
Arven Ilac Sanayi ve Ticaret AS
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 Arven Ilac Sanayi ve Ticaret AS filed Critical Arven Ilac Sanayi ve Ticaret AS
Publication of WO2020101596A2 publication Critical patent/WO2020101596A2/fr
Publication of WO2020101596A3 publication Critical patent/WO2020101596A3/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention relates to a capsule comprising sunitinib and at least one binder. Further, the present invention provides a method for the preparation of the said composition.
  • Sunitinib is an indolinone derivative and tyrosine kinase inhibitor with potential antineoplastic activity. Sunitinib blocks the tyrosine kinase activities of vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor b, and c-kit, thereby inhibiting angiogenesis and cell proliferation. This agent also inhibits the phosphorylation of fms- related tyrosine kinase 3 (FLT3), another receptor tyrosine kinase expressed by some leukemic cells.
  • FLT3 fms- related tyrosine kinase 3
  • Sunitinib is known by the chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-l ,2- dihydro-2-oxo-3FI-indol-3-ylidene)methyl]-2,4-dimethyl-l FI-pyrrole-3-carboxamide and its chemical structure is shown in the Formula I.
  • Sunitinib was disclosed in International application publication no. WO 01/60814 and U.S. Patent No. 6,573,293.
  • sunitinib is administered in a dose of 50 mg once daily, which has to be varied according to individual tolerance and safety.
  • individual dosage forms generally contain 12.5, 25 and 50 mg sunitinib.
  • Capsules comprising the malate salt of sunitinib are sold under the brand name Sutent® by Pfizer.
  • W001/60814(A2) discloses a composition comprising sunitinib or a pharmaceutically acceptable salt thereof which is used in a high proportion in the composition. Furthermore, the composition is a capsule which comprises povidone as a binder, mannitol, croscarmellose sodium and magnesium stearate.
  • WO 2004/024127(A2) discloses a composition comprising sunitinib or a pharmaceutically acceptable salt thereof and povidone as binder.
  • the formulation of the present invention can easily be processed during the filling step into capsule dosage forms and has high chemical and mechanical stability during the shelf-life.
  • the main object of the present invention is to provide a capsule composition which has a desired dissolution rate and high chemical and mechanical stability with the help of selection of excipients in a certain ratio.
  • Another object of the present invention is to provide a capsule composition which can disperse easily and fast in body and have high absorption, and bioavailability during oral use.
  • sunitinib refers to not only sunitinib, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
  • sunitinib is present in the form of its free base form or sunitinib malate salt. The forms are more stable, reproducible, and suitable for conversion to pharmaceutically acceptable salt preparations.
  • the capsule composition comprises sunitinib and the amount of sunitinib in the capsule is less than 40.0% by weight, preferably between 1 1 .0% and 35.0% by weight, preferably between 1 1 .0% and 18.0% or preferably between 18.0% and 30.0% or preferably between 30.0% and 35.0% by weight.
  • the composition comprises pharmaceutically acceptable excipients which are selected from the group comprising binders, fillers, disintegrants, lubricants or mixtures thereof.
  • Binders are one of the most essential elements in the pharmaceutical composition, because they promote cohesiveness.
  • the binders also called adhesives, help the other ingredients in a capsule to mix together.
  • suitable binders are selected from group comprising hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, pregelatinized starch, gelatins, pullulan, agar, alginate, sodium alginates, glycyrrhizin, polymethacrylates, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, cetostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose, polyethylene oxide, xylitol, sucrose stearate or mixtures thereof.
  • the binder is hydroxypropyl cellulose or hydroxypropyl methyl cellulose or mixtures thereof.
  • povidone is used as a binder.
  • Povidone may contain peroxides as trace contaminants. These can lead to degradation of sunitinib that is sensitive to oxidation so it affects stability adversely.
  • hydroxypropyl cellulose and/or hydroxypropyl methyl cellulose is selected as a suitable binder. Due to hydrophilic property of hydroxypropyl cellulose and/or hydroxypropyl methyl cellulose, the composition does not have the disadvantages of povidone in respect of stability and dissolution.
  • the amount of the binders in the composition is between 3.0% and 10.0%, preferably between 4.0% and 7.0% by weight. This provides good fluidity and convenience during capsule filling.
  • the weight ratio of sunitinib to binders is between 0.1 and 13.0, preferably between 1.6 and 9.0, preferably between 3.0 and 7.0. This certain ratio helps to provide the desired chemical and mechanical stability.
  • Suitable fillers are selected from the group comprising mannitol, pregelatinized starch, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, dextrates, dextrin, erythritol, ethylcellulose, fructose, glyceryl palmitostearate, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, microcrystalline cellulose, polydextrose, polymethacrylates, polyvinylpyrrolidone, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sucrose or mixtures thereof.
  • the filler is mannitol.
  • the amount of the fillers in the composition is between 50.0% and 80.0%, preferably between 50.0% and 77.0% by weight, preferably between 50.0% and 55.0% by weight, preferably between 70.0% and 77.0% by weight.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, polyacrylate potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • the disintegrant is croscarmellose sodium.
  • the amount of the disintegrants in the composition is between 5.0% and 10.0%. According to one embodiment of the present invention, 60% by weight of the total amount of croscarmellose sodium by weight is intragranular phase, and the other parts of the amount is extra granular phase.
  • Suitable lubricants are selected from the group comprising magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide, calcium stearate, zinc stearate, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyceryl palmito sulphate, sodium lauryl sulphate or mixtures thereof.
  • the lubricant is magnesium stearate.
  • the amount of the lubricants in the composition is between 0.1 % and 4.0%.
  • the preferred dosage forms are capsules filled with pellets, granules or minitablets as these are more convenient and easier to administer.
  • Suitable capsule shell ingredients are selected from the group comprising gelatin, titanium dioxide, iron oxides (yellow, red, black), polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), ethylcellulose dispersions (Surelease), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and all kinds of Opadry®, pigments, dyes, polymethylmethacrylate copolymers (Eudragit) or mixtures thereof.
  • the capsule composition of the present invention may be prepared by using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.
  • the stable composition is obtained by using a wet granulation method and therefore a simple and low-cost production method was employed.
  • a good dissolution of the capsule composition is obtained and a good content uniformity and a simple preparation process are in favor of industrial production.
  • Wet granulation is a widely used method for the production of capsules. The steps required in the preparation of capsules by this method may be separated as follows: weighing and blending the ingredients, preparing the wet granulation, screening the damp mass into pellets or granules, drying, dry screening, lubrication and blending and encapsulating.
  • Example 1 The capsule composition comprising sunitinib
  • Example 2 The capsule composition comprising sunitinib
  • Example 3 The capsule composition comprising sunitinib
  • Example 4 The capsule composition comprising sunitinib
  • the process for preparation of the capsule composition comprises the following steps:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une capsule comprenant du sunitinib et au moins un liant. La présente invention concerne en outre un procédé de préparation de ladite composition.
PCT/TR2019/050579 2018-08-10 2019-07-16 Composition de capsule comprenant du sunitinib Ceased WO2020101596A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2018/11687 2018-08-10
TR201811687 2018-08-10

Publications (2)

Publication Number Publication Date
WO2020101596A2 true WO2020101596A2 (fr) 2020-05-22
WO2020101596A3 WO2020101596A3 (fr) 2020-07-09

Family

ID=70730567

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2019/050579 Ceased WO2020101596A2 (fr) 2018-08-10 2019-07-16 Composition de capsule comprenant du sunitinib

Country Status (1)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440495A (zh) * 2021-07-14 2021-09-28 北京鑫开元医药科技有限公司 苹果酸舒尼替尼胶囊及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013160916A1 (fr) * 2012-04-25 2013-10-31 Hetero Research Foundation Dispersion solide de malate de sunitinib
CN104069076A (zh) * 2013-03-29 2014-10-01 浙江九洲药业股份有限公司 一种无定型的舒尼替尼与pvp的组合物
CN105434399B (zh) * 2015-12-24 2018-03-06 湖南尔康制药股份有限公司 一种肾细胞癌治疗药物舒尼替尼‑PLGA/Fe3O4复合微球及其制备方法
EP3442531A1 (fr) * 2016-04-15 2019-02-20 Exelixis, Inc. Procédé de traitement du cancer à cellules rénales à l'aide de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophény)cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate
EP3539536A1 (fr) * 2018-03-15 2019-09-18 MH10 Spolka z ograniczona odpowiedzialnoscia Composition pharmaceutique de sunitinib ou de son sel dans sa forme polymorphe i

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440495A (zh) * 2021-07-14 2021-09-28 北京鑫开元医药科技有限公司 苹果酸舒尼替尼胶囊及其制备方法
CN113440495B (zh) * 2021-07-14 2022-07-12 北京鑫开元医药科技有限公司 苹果酸舒尼替尼胶囊及其制备方法

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Publication number Publication date
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