WO2014198342A1 - Pharmaceutical composition comprising amorphous sunitinib - Google Patents

Pharmaceutical composition comprising amorphous sunitinib Download PDF

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Publication number
WO2014198342A1
WO2014198342A1 PCT/EP2013/062422 EP2013062422W WO2014198342A1 WO 2014198342 A1 WO2014198342 A1 WO 2014198342A1 EP 2013062422 W EP2013062422 W EP 2013062422W WO 2014198342 A1 WO2014198342 A1 WO 2014198342A1
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Prior art keywords
sunitinib
pharmaceutically acceptable
composition according
polymer
solid composite
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PCT/EP2013/062422
Other languages
French (fr)
Inventor
Rolf Keltjens
Jacobus Theodorus Henricus EUPEN VAN
Marco Peter Johannes Michiel HENDRIKX
Original Assignee
Synthon B.V.
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Publication date
Application filed by Synthon B.V. filed Critical Synthon B.V.
Priority to EP13728425.3A priority Critical patent/EP3007678A1/en
Priority to PCT/EP2013/062422 priority patent/WO2014198342A1/en
Publication of WO2014198342A1 publication Critical patent/WO2014198342A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • GIST gastrointestinal stromal tumors
  • MRCC metastatic renal cell carcinoma
  • pancreatic pancreatic
  • sunitinib L-malate which is the active ingredient in the medicinal product sold under the brand name SUTENT® by Pfizer.
  • Sunitinib L-malate exhibits polymorphism.
  • WO03016305 discloses form I and II of sunitinib L-malate, processes for their preparation and compositions comprising these forms. Form I is the most stable form and is present in the marketed capsules.
  • Other polymorphic forms of sunitinib L-malate are disclosed in WO2009067686, WO2009104021, WO2010010454, WO2010055082, WO2010076805 and WO2011092664.
  • Sunitinib L-malate is considered to be a low permeability compound. Furthermore, its solubility rapidly decreases at pH greater than 6.8. For this reason, sunitinib is classified as a low solubility compound according to the biopharmaceutical classification. To improve its dissolution behavior and bioavailability, it would be desirable to have sunitinib L-malate in amorphous form, since the solubility of amorphous forms is higher compared to the solubility of crystalline forms.
  • WO2009156837 discloses amorphous sunitinib L-malate. Amorphous compositions comprising sunitinib and its acid addition salt are disclosed in WO2009100929 and
  • WO2010039798 Paragraph [0045] of WO2010039798 reads: "Attempts to prepare amorphous sunitinib malate or an amorphous composition of sunitinib base and L-malic acid without excipients (see Ex. 7 and 28) or even with an excipient (see Ex. 8-27 and 29) were unsuccessful, i.e., the sunitinib base-L-malic acid composition was not amorphous. In the obtained product, peaks of crystalline composition of sunitinib base and L-malic acid are evident.” In our laboratory, these findings were confirmed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients.
  • the invention provides a process for preparing said pharmaceutical composition comprising mixing or granulating said solid composite with one or more excipients and filling into hard shell capsules.
  • Said pharmaceutical composition may be used as a medicament, particularly in the treatment of a tyrosine kinase-related disorder.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients.
  • sunitinib, or a pharmaceutically acceptable salt thereof, and the (co)polymer are preferably intimately associated, meaning that there is attractive interaction between the active pharmaceutical ingredient and the (co)polymer.
  • the weight ratio of sunitinib, or a pharmaceutically acceptable salt thereof, to (co)polymer in the solid composite typically ranges from 1: 1 to 1:6, preferably from 1: 1.5 to 1:3.
  • a carboxylic acid group bearing (co)polymer, a hydroxyl group bearing (co)polymer, as well as a mixture of a carboxylic acid bearing (co)polymer and a hydroxyl group bearing (co)polymer can be used.
  • a carboxylic acid group bearing (co)polymer, a hydroxyl group bearing (co)polymer, as well as a mixture of a carboxylic acid bearing (co)polymer and a hydroxyl group bearing (co)polymer can be used.
  • a carboxylic acid group bearing (co)polymer, a hydroxyl group bearing (co)polymer, as well as a mixture of a carboxylic acid bearing (co)polymer and a hydroxyl group bearing (co)polymer can be used.
  • (co)polymer bearing both carboxylic acid and hydroxyl groups can be used.
  • a carboxylic acid group bearing (co)polymer or a hydroxyl group bearing (co)polymer is used.
  • the (co)polymer is preferably a carboxylic acid group bearing copolymer, preferably selected from the group consisting of acrylate (co)polymers, celluloses and phthalate
  • the carboxylic acid group bearing copolymer is an acrylate copolymer of methacrylic acid and divinylbenzene, and is known under the international non- proprietary name (INN) polyacrilex resin.
  • the carboxylic acid groups are in the H+ form.
  • Typical examples of commercially available resins include Amberlite IRP 64 and Indion 214.
  • the (co)polymer of the solid composite may also be a hydroxyl group bearing
  • polyvinyl alcohol preferably polyvinyl alcohol.
  • PVA polyvinyl alcohol
  • Kollicoat IR polyvinyl alcohol- polyethylene glycol graft copolymer
  • the (co)polymer of the solid composite may also bear both carboxylic acid and hydroxyl groups.
  • Typical examples of such commercially available resins include
  • HPMCP hypromellose phthalate
  • the solid composite of the present invention containing sunitinib, or a pharmaceutically acceptable salt thereof, is present in a stabilized amorphous form, which means that during stability studies no conversion into any crystalline form was observed.
  • the solid composite in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties.
  • the solid composite is very suitable to be used for the preparation of pharmaceutical compositions.
  • compositions of the present invention comprise the solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients.
  • excipients to be used in accordance with the present invention are well- known to and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants or lubricants.
  • one or more excipients from the group of stabilizers, surface active agents or pH-adjusting agents may be added.
  • compositions of the present invention display dissolution behavior typical for immediate-release formulations.
  • compositions of the present invention the solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer remains in the amorphous form.
  • the present invention further provides a process to prepare a solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer, comprising combining the (co)polymer with sunitinib, or a pharmaceutically acceptable salt thereof, in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), using equipment and methods well-known in the art.
  • the solvent or solvent mixture is a polar solvent or a mixture of water and a polar organic solvent.
  • sunitinib, or a pharmaceutically acceptable salt thereof is dissolved in a polar solvent or a mixture of water and a polar organic solvent and the solution is added to a suspension of the copolymer in water.
  • Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone and acetonitrile.
  • a mixture of an alcohol and water is used.
  • the present invention still further provides a process to prepare pharmaceutical compositions comprising a solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer, and one or more pharmaceutically acceptable excipients.
  • the process comprises mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients and filling into hard shell capsules, using equipment and methods well-known to the skilled artisan.
  • the hard shell capsules may be filled with just the solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer, in the absence of any excipient.
  • the pharmaceutical composition in accordance with the present invention may be used as a medicament.
  • the pharmaceutical composition typically may be used in the treatment of a tyrosine kinase-related disorder, preferably for the treatment of gastrointestinal stromal tumors (GIST), metastatic renal cell carcinoma (MRCC) and pancreatic neuroendocrine tumors (pNET).
  • GIST gastrointestinal stromal tumors
  • MRCC metastatic renal cell carcinoma
  • pNET pancreatic neuroendocrine tumors
  • the present invention is illustrated by the following Examples.
  • XRPD data showed that the isolated solid composite was fully amorphous.
  • XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C /90% RH and 3 months at 40°C/75 RH showed that the composite was still fully amorphous.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a pharmaceutical composition comprising an amorphous solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients. The invention further relates to the use of said composition as a medicament, particularly in the treatment of a tyrosine kinase-related disorder.

Description

PHARMACEUTICAL COMPOSITION COMPRISING AMORPHOUS
SUNITINIB BACKGROUND OF THE PRESENT INVENTION
Sunitinib, chemically (Z)-N-[2-(diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro- lH-indol-3-ylidenemethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide of formula (I),
Figure imgf000002_0001
is a pharmaceutically active compound used for the treatment of gastrointestinal stromal tumors (GIST), metastatic renal cell carcinoma (MRCC) and pancreatic
neuroendocrine tumors (pNET). The compound was discovered by Sugen and is disclosed in WO0160814. The compound may form acid addition salts, for instance sunitinib L-malate, which is the active ingredient in the medicinal product sold under the brand name SUTENT® by Pfizer. Sunitinib L-malate exhibits polymorphism. WO03016305 discloses form I and II of sunitinib L-malate, processes for their preparation and compositions comprising these forms. Form I is the most stable form and is present in the marketed capsules. Other polymorphic forms of sunitinib L-malate are disclosed in WO2009067686, WO2009104021, WO2010010454, WO2010055082, WO2010076805 and WO2011092664.
Sunitinib L-malate is considered to be a low permeability compound. Furthermore, its solubility rapidly decreases at pH greater than 6.8. For this reason, sunitinib is classified as a low solubility compound according to the biopharmaceutical classification. To improve its dissolution behavior and bioavailability, it would be desirable to have sunitinib L-malate in amorphous form, since the solubility of amorphous forms is higher compared to the solubility of crystalline forms.
WO2009156837 discloses amorphous sunitinib L-malate. Amorphous compositions comprising sunitinib and its acid addition salt are disclosed in WO2009100929 and
WO2010039798. Paragraph [0045] of WO2010039798 reads: "Attempts to prepare amorphous sunitinib malate or an amorphous composition of sunitinib base and L-malic acid without excipients (see Ex. 7 and 28) or even with an excipient (see Ex. 8-27 and 29) were unsuccessful, i.e., the sunitinib base-L-malic acid composition was not amorphous. In the obtained product, peaks of crystalline composition of sunitinib base and L-malic acid are evident." In our laboratory, these findings were confirmed. Attempts were made to prepare stable amorphous sunitinib L-malate preparations, amongst others by repeating Example 2 of WO2009156837. However, all these attempts failed, since sunitinib L-malate crystallizes very easily.
Thus in view of the prior art cited above, there is still a need for stable, amorphous compositions comprising sunitinib, or a pharmaceutically acceptable salt thereof, having improved solubility.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention provides a pharmaceutical composition comprising an amorphous solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients.
It also provides a process for preparing said solid composite by combining sunitinib, or a pharmaceutically acceptable salt thereof, with a carboxylic acid and/or hydroxyl group bearing (co)polymer in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s).
Additionally, the invention provides a process for preparing said pharmaceutical composition comprising mixing or granulating said solid composite with one or more excipients and filling into hard shell capsules.
Said pharmaceutical composition may be used as a medicament, particularly in the treatment of a tyrosine kinase-related disorder.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a pharmaceutical composition comprising an amorphous solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients.
In the solid composite, sunitinib, or a pharmaceutically acceptable salt thereof, and the (co)polymer are preferably intimately associated, meaning that there is attractive interaction between the active pharmaceutical ingredient and the (co)polymer. The weight ratio of sunitinib, or a pharmaceutically acceptable salt thereof, to (co)polymer in the solid composite typically ranges from 1: 1 to 1:6, preferably from 1: 1.5 to 1:3.
In accordance with the present invention a carboxylic acid group bearing (co)polymer, a hydroxyl group bearing (co)polymer, as well as a mixture of a carboxylic acid bearing (co)polymer and a hydroxyl group bearing (co)polymer can be used. Moreover, a
(co)polymer bearing both carboxylic acid and hydroxyl groups can be used. Preferably, either a carboxylic acid group bearing (co)polymer or a hydroxyl group bearing (co)polymer is used. The (co)polymer is preferably a carboxylic acid group bearing copolymer, preferably selected from the group consisting of acrylate (co)polymers, celluloses and phthalate
(co)polymers. More preferably the carboxylic acid group bearing copolymer is an acrylate copolymer of methacrylic acid and divinylbenzene, and is known under the international non- proprietary name (INN) polyacrilex resin. Typically, the carboxylic acid groups are in the H+ form. Typical examples of commercially available resins include Amberlite IRP 64 and Indion 214.
The (co)polymer of the solid composite may also be a hydroxyl group bearing
(co)polymer, preferably a polyvinyl alcohol. Typical examples of commercially available polyvinyl alcohols are polyvinyl alcohol (PVA) and Kollicoat IR (polyvinyl alcohol- polyethylene glycol graft copolymer).
The (co)polymer of the solid composite may also bear both carboxylic acid and hydroxyl groups. Typical examples of such commercially available resins include
hypromellose phthalate (HPMCP).
The solid composite of the present invention containing sunitinib, or a pharmaceutically acceptable salt thereof, is present in a stabilized amorphous form, which means that during stability studies no conversion into any crystalline form was observed. The solid composite in accordance with the present invention advantageously is in the form of a free-flowing powder, with excellent handling properties. The solid composite is very suitable to be used for the preparation of pharmaceutical compositions.
The pharmaceutical compositions of the present invention comprise the solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well- known to and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients.
Preferably, the pharmaceutically acceptable excipients are chosen from one or more binders, diluents, disintegrants, glidants or lubricants. In addition, one or more excipients from the group of stabilizers, surface active agents or pH-adjusting agents may be added.
The pharmaceutical compositions of the present invention display dissolution behavior typical for immediate-release formulations. During preparation and storage of the
pharmaceutical compositions of the present invention, the solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer remains in the amorphous form.
The present invention further provides a process to prepare a solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer, comprising combining the (co)polymer with sunitinib, or a pharmaceutically acceptable salt thereof, in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s), using equipment and methods well-known in the art.
Preferably, the solvent or solvent mixture is a polar solvent or a mixture of water and a polar organic solvent. In an advantageous variant of the process of the present invention, sunitinib, or a pharmaceutically acceptable salt thereof, is dissolved in a polar solvent or a mixture of water and a polar organic solvent and the solution is added to a suspension of the copolymer in water. Preferred polar organic solvents are alcohols, particularly ethanol or methanol, ethers, particularly tetrahydrofuran, ketones, particularly acetone and acetonitrile. Preferably, a mixture of an alcohol and water is used.
The present invention still further provides a process to prepare pharmaceutical compositions comprising a solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer, and one or more pharmaceutically acceptable excipients. The process comprises mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients and filling into hard shell capsules, using equipment and methods well-known to the skilled artisan. Alternatively, the hard shell capsules may be filled with just the solid composite of sunitinib, or a pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer, in the absence of any excipient.
The pharmaceutical composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition typically may be used in the treatment of a tyrosine kinase-related disorder, preferably for the treatment of gastrointestinal stromal tumors (GIST), metastatic renal cell carcinoma (MRCC) and pancreatic neuroendocrine tumors (pNET).
The present invention is illustrated by the following Examples.
EXAMPLES
Example 1, sunitinib L-malate:Amberlite IRP 64 (weight ratio 1:4)
To 8 g of Amberlite IRP 64, 32 ml of water was added and the resulting mixture was stirred for 60 minutes at 60°C. 2 g of Sunitinib L-malate was dissolved in 50 ml of a mixture of water and ethanol (1: 1) while heating. The clear solution was added to the Amberlite mixture and the resulting suspension was stirred for 3 hours at 60°C. The suspension was concentrated in vacuo. Due to foaming, 20 ml of ethanol was added and the concentration in vacuo was continued. The residue was dried over night at 40°C under vacuum.
XRPD data showed that the isolated solid composite was fully amorphous. XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C/90 RH and 3 months at 40°C Π5% RH showed that the composite was still fully amorphous. Example 2, sunitinib free base: Amberlite IRP 64 (weight ratio 1:4)
To 8 g of Amberlite IRP 64, 32 ml of water was added and the resulting mixture was stirred for 60 minutes at 60°C. 2 g of Sunitinib free base was dissolved in 70 ml of ethanol while heating. The clear solution was added to the Amberlite mixture and the resulting suspension was stirred for 2 hours at 60°C. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
Isolated solid: 8.6 g
XRPD data showed that the isolated solid composite was fully amorphous. XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C /90% RH and 3 months at 40°C/75 RH showed that the composite was still fully amorphous.
Example 3, sunitinib L-malate: Amberlite IRP 64 (weight ratio 1:3)
To 1 g of Amberlite IRP 64, 4 ml of water was added and the resulting mixture was stirred for 60 minutes at 60°C. 0.33 g of Sunitinib L-malate was dissolved in 8 ml of a mixture of water and ethanol (1: 1) while heating. The clear solution was added to the
Amberlite mixture and the resulting suspension was stirred for 2 hours at 60°C. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
XRPD data showed that the isolated solid composite was fully amorphous.
Example 4, sunitinib besylate: Amberlite IRP 64 (weight ratio 1:4)
To 1 g of Amberlite IRP 64, 4 ml of water was added and the resulting mixture was stirred for 60 minutes at 60°C. 0.25 g of Sunitinib besylate was dissolved in 8 ml of a mixture of water and ethanol (1: 1) while heating. The clear solution was added to the Amberlite mixture and the resulting suspension was stirred for 2 hours at 60°C. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
XRPD data showed that the isolated solid composite was fully amorphous. XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C/90 RH showed that the composite was still fully amorphous.
Example 5, sunitinib succinate: Amberlite IRP 64 (weight ratio 1:4)
To 1 g of Amberlite IRP 64, 4 ml of water was added and the resulting mixture was stirred for 60 minutes at 60°C. 0.25 g of Sunitinib succinate was dissolved in 8 ml of a mixture of water and ethanol (1: 1) while heating. The clear solution was added to the
Amberlite mixture and the resulting suspension was stirred for 2 hours at 60°C. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
XRPD data showed that the isolated solid composite was fully amorphous. XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C/90 RH showed that the composition was still fully amorphous.
Example 6, sunitinib hydrochloride: Amberlite IRP 64 (weight ratio 1:4)
To 0.64 g of Amberlite IRP 64, 2.6 ml of water was added and the resulting mixture was stirred for 60 minutes at 60°C. 0.16 g of Sunitinib hydrochloride was dissolved in 5.1 ml of a mixture of water and ethanol (1: 1) while heating. The clear solution was added to the Amberlite mixture and the resulting suspension was stirred for 2 hours at 60°C. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum. XRPD data showed that the isolated solid composite was fully amorphous. XRPD analysis performed 4 weeks after subjecting the powder in open dish to 55°C/90 RH showed that the composition was still fully amorphous.
Example 7, sunitinib L-malate:HPMCP (weight ratio 1:4)
To 1 g of HPMCP, 5 ml of water was added and the resulting suspension was stirred for 60 minutes at 60°C. 0.25 g of Sunitinib L-malate was dissolved in 6.5 ml of a mixture water and ethanol (1: 1). The clear solution was added to the HPMCP mixture and the resulting suspension was stirred for 2 hours at 60°C. The suspension was concentrated in vacuo. The residue was dried over night at 40°C under vacuum.
XRPD data showed that the isolated solid composite was fully amorphous.

Claims

1. A pharmaceutical composition comprising a solid composite of sunitinib, or a
pharmaceutically acceptable salt thereof, and a carboxylic acid and/or hydroxyl group bearing (co)polymer and optionally one or more pharmaceutically acceptable excipients.
2. The composition according to claim 1, wherein the carboxylic acid group bearing
(co)polymer is selected from the group consisting of acrylate (co)polymers, celluloses, and phthalate (co)polymers.
3. The composition according to claim 2, wherein the acrylate copolymer is a polacrilex resin.
4. The composition according to claim 1, wherein the hydroxyl group bearing
(co)polymer is a polyvinyl alcohol.
5. The composition according to any one of claims 1 to 4, wherein the weight ratio of sunitinib, or a pharmaceutically acceptable salt thereof, to (co)polymer ranges from 1: 1 to 1:6.
6. The composition according to any one of claims 1 to 5 comprising the L-malic acid salt of sunitinib.
7. The composition according to any one of claims 1 to 6, wherein sunitinib [in the solid composite] is in an amorphous form.
8. The composition according to any one of claims 1 to 7, wherein the pharmaceutically acceptable excipients are one or more binders, diluents, disintegrants, glidants, lubricants, stabilizers, surface active agents or pH-adjusting agents.
9. A process for preparing the composition according to any one of claims 1 to 7
comprising combining sunitinib, or a pharmaceutically acceptable salt thereof, with a carboxylic acid and/or hydroxyl group bearing (co)polymer in a suitable solvent or solvent mixture, followed by evaporation of the solvent(s).
10. The process according to claim 9, wherein the solvent is a polar solvent selected from the group consisting of alcohols, ethers, ketones, acetonitrile and water or a mixture thereof.
11. The process according to claim 9 or 10 further comprising mixing or granulating the solid composite with one or more pharmaceutically acceptable excipients and filling into hard shell capsules.
12. The composition according to any one of claims 1 to 8, for use as a medicament.
13. The composition according to claim 12 for use in the treatment of a tyrosine kinase- related disorder.
PCT/EP2013/062422 2013-06-14 2013-06-14 Pharmaceutical composition comprising amorphous sunitinib WO2014198342A1 (en)

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Cited By (3)

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WO2020091439A1 (en) * 2018-10-31 2020-05-07 주식회사 삼양바이오팜 Oral formulation comprising sunitinib and preparation method therefor
KR20200050399A (en) * 2018-10-31 2020-05-11 주식회사 삼양바이오팜 Oral tablet composition containing sunitinib
US10758623B2 (en) 2013-12-09 2020-09-01 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same

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Publication number Priority date Publication date Assignee Title
WO2009100929A1 (en) * 2008-02-13 2009-08-20 Ratiopharm Gmbh Pharmaceutical compositions comprising n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2- dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide

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US11529420B2 (en) 2013-12-09 2022-12-20 Durect Corporation Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same
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KR20200050399A (en) * 2018-10-31 2020-05-11 주식회사 삼양바이오팜 Oral tablet composition containing sunitinib
KR102308227B1 (en) 2018-10-31 2021-10-05 주식회사 삼양홀딩스 Oral tablet composition containing sunitinib

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