WO2020101596A2 - A capsule composition comprising sunitinib - Google Patents

A capsule composition comprising 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
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Prior art keywords
composition according
sunitinib
capsule composition
weight
capsule
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PCT/TR2019/050579
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French (fr)
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WO2020101596A3 (en
Inventor
Ali Turkyilmaz
Yuksel TOPALOGLU
Ali Ihsan SECKIN
Irem Yenice
Original Assignee
Arven Ilac Sanayi Ve Ticaret Anonim Sirketi
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Publication of WO2020101596A2 publication Critical patent/WO2020101596A2/en
Publication of WO2020101596A3 publication Critical patent/WO2020101596A3/en

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    • 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:

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  • 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

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.

Description

A CAPSULE COMPOSITION COMPRISING SUNITINIB
Field of the invention
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.
Background of the invention
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.
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.
Figure imgf000002_0001
Formula I
Sunitinib was disclosed in International application publication no. WO 01/60814 and U.S. Patent No. 6,573,293.
Typically, sunitinib is administered in a dose of 50 mg once daily, which has to be varied according to individual tolerance and safety. Thus, in order to obtain sufficiently flexible dosing, 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.
However, in the prior art, there is a stability problem due to incompatibility of active substance with binder.
Therefore, there is still a need for new approaches in order to develop sunitinib formulations produced in capsule form which can disperse easily and fast in the body and have high absorption and bioavailability during oral use. Furthermore, 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.
Detailed description of the Invention
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.
The term "sunitinib" as used throughout the specification 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. According to this embodiment of the present invention, 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.
According to one embodiment of the present invention, 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.
According to one embodiment of the present invention, 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.
It is an object of the present invention to provide a binder that overcomes the problems associated with the prior art.
According to one embodiment of the present invention, 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.
According to one embodiment of the present invention, the binder is hydroxypropyl cellulose or hydroxypropyl methyl cellulose or mixtures thereof.
In the prior art, generally, 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. In this present invention, 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. According to one embodiment of the present invention, 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.
According to one embodiment of the present invention, 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.
According to one embodiment of the present invention, the filler is mannitol.
According to one embodiment of the present invention, 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.
According to one embodiment of the present invention, the disintegrant is croscarmellose sodium.
According to one embodiment of the present invention, 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.
According to one embodiment of the present invention, the lubricant is magnesium stearate.
According to one embodiment of the present invention, 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.
Furthermore, the stable composition is obtained by using a wet granulation method and therefore a simple and low-cost production method was employed.
In this present invention, 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
Figure imgf000007_0001
Example 2: The capsule composition comprising sunitinib
Figure imgf000007_0002
Example 3: The capsule composition comprising sunitinib
Figure imgf000007_0003
Example 4: The capsule composition comprising sunitinib
Figure imgf000008_0001
Process for example 1 or 2 or 3 or 4:
The process for preparation of the capsule composition comprises the following steps:
a) Adding sunitinib mannitol and a part of croscarmellose sodium, at least one binder and mixing,
b) Granulating step (a) mixture with pure water,
c) drying the mixture, then sieving the mixture,
d) Adding other parts of croscarmellose sodium and mixing,
e) Adding magnesium stearate and then mixing,
f) Then, filling the mixture into hard shell capsules.
60% by weight of the total amount of croscarmellose sodium by weight is added in intragranular phase, and the other parts of the amount is in extra granular phase.

Claims

1 . A capsule composition comprising sunitinib and the amount of sunitinib in the formulation is less than 40.0% by weight.
2. The capsule composition according to claim 1 , wherein the amount of sunitinib in the formulation is between 1 1 .0% and 35.0% by weight.
3. The capsule composition according to claim 2, wherein sunitinib is present in the form of its free base form or sunitinib malate salt.
4. The capsule composition according to claim 3, further comprising pharmaceutically acceptable excipients which are selected from the group comprising binders, fillers, disintegrants, lubricants or mixtures thereof.
5. The capsule composition according to claim 4, wherein the 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.
6. The capsule composition according to claim 5, wherein the binder is hydroxypropyl cellulose or hydroxypropyl methyl cellulose or mixtures thereof.
7. The capsule composition according to claim 6, wherein the amount of the binders in the composition is between 3.0% and 10.0%, preferably between 4.0% and 7.0% by weight.
8. The capsule composition according to claim 7, wherein 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.
9. The capsule composition according to claim 4, wherein the filler is mannitol.
10. The capsule composition according to claim 9, wherein the amount of the filler in the composition is between 50.0% and 80.0% by weight.
1 1. The capsule composition according to claim 4, wherein the disintegrant is croscarmellose sodium.
12. The capsule composition according to claim 4, wherein the lubricant is magnesium stearate.
13. The capsule composition according to any preceding claims, comprising; a. 10.00%-38.0% by weight of sunitinib
b. 3.0% -10.0% by weight of hydroxypropyl methyl cellulose or hydroxypropyl
cellulose as binder
c. 50.0% -80.0% by weight of mannitol
d. 5.0%-10.0% by weight of croscarmellose sodium
e. 0.1 %-4.0% by weight of magnesium stearate of the total composition.
14. The process for preparing the capsule composition according to claim 13, comprising; a. Adding sunitinib, mannitol and a part of croscarmellose sodium and at least one binder and mixing them,
b. Granulation of step (a) mixture with pure water,
c. drying the mixture, then sieving the mixture,
d. Adding other parts of croscarmellose sodium and mixing,
e. Adding magnesium stearate and then mixing to obtain final mixture,
f. Then, filling the final mixture into hard shell capsules.
PCT/TR2019/050579 2018-08-10 2019-07-16 A capsule composition comprising sunitinib WO2020101596A2 (en)

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TR201811687 2018-08-10
TR2018/11687 2018-08-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440495A (en) * 2021-07-14 2021-09-28 北京鑫开元医药科技有限公司 Sunitinib malate capsule and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013160916A1 (en) * 2012-04-25 2013-10-31 Hetero Research Foundation Sunitinib malate solid dispersion
CN104069076A (en) * 2013-03-29 2014-10-01 浙江九洲药业股份有限公司 Unshaped composition of sunitinib and PVP (Polyvinyl Pyrrolidone)
CN105434399B (en) * 2015-12-24 2018-03-06 湖南尔康制药股份有限公司 A kind of renal cell carcinoma treatment medicine Sutent PLGA/Fe3O4 complex microspheres and preparation method thereof
CN109069499A (en) * 2016-04-15 2018-12-21 埃克塞里艾克西斯公司 Use N- (4- (6,7- dimethoxy-quinoline -4- base oxygroup) phenyl)-N '-(4- fluorophenyl) cyclopropane -1,1- diformamide, the method for (2S)-hydroxysuccinic acid salts for treating clear-cell carcinoma
EP3539536A1 (en) * 2018-03-15 2019-09-18 MH10 Spolka z ograniczona odpowiedzialnoscia A pharmaceutical composition of sunitinib or its salt thereof in its polymorphic form i

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113440495A (en) * 2021-07-14 2021-09-28 北京鑫开元医药科技有限公司 Sunitinib malate capsule and preparation method thereof
CN113440495B (en) * 2021-07-14 2022-07-12 北京鑫开元医药科技有限公司 Sunitinib malate capsule and preparation method thereof

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