WO2010039798A2 - Compositions amorphes d’une base de sunitinib et d’acide l-malique - Google Patents

Compositions amorphes d’une base de sunitinib et d’acide l-malique Download PDF

Info

Publication number
WO2010039798A2
WO2010039798A2 PCT/US2009/058975 US2009058975W WO2010039798A2 WO 2010039798 A2 WO2010039798 A2 WO 2010039798A2 US 2009058975 W US2009058975 W US 2009058975W WO 2010039798 A2 WO2010039798 A2 WO 2010039798A2
Authority
WO
WIPO (PCT)
Prior art keywords
combination
malic acid
composition
amorphous
sunitinib
Prior art date
Application number
PCT/US2009/058975
Other languages
English (en)
Other versions
WO2010039798A3 (fr
Inventor
Alexandr Jegorov
Ales Gavenda
Pavel Vraspir
Judith Aronhime
Original Assignee
Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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 Teva Pharmaceutical Industries Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Teva Pharmaceutical Industries Ltd.
Priority to CA2704448A priority Critical patent/CA2704448A1/fr
Publication of WO2010039798A2 publication Critical patent/WO2010039798A2/fr
Publication of WO2010039798A3 publication Critical patent/WO2010039798A3/fr

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
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/30—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
    • 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
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2

Definitions

  • the invention encompasses a combination of a pharmaceutically acceptable excipient and a composition of sunitinib base and L-malic acid, and processes for the preparation thereof.
  • sunitinib salts such as sunitinib malate of the following formula:
  • Sunitinib malate is a multi-kinase inhibitor marketed in the United States under the trade name SUTENT ® by Pfizer, Inc.
  • SUTENT ® is approved by the FDA for the treatment of gastrointestinal stromal tumor after disease progression or intolerance to imatinib mesylate and for the treatment of advanced renal cell carcinoma.
  • SUTENT ® is available as hard-shell capsules containing an amount of sunitinib malate that is equivalent to 12.5 mg, 25 mg, or 50 mg of sunitinib.
  • the capsules contain sunitinib malate together with the inactive ingredients mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate.
  • U.S. Patent No. 6,573,293 refers to the preparation of sunitinib base and salts thereof, as well as the use of these salts.
  • the '293 patent refers to the synthesis of sunitinib base by condensing 5-formyl-2,4-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide with 5-fluoro-l,3-dihydro-indol-2-one in ethanol in the presence of pyrrolidine. See '293 patent, col. 204, 11. 33-50 (example 80, alternative synthesis).
  • the sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with ethanol, slurried in ethanol, isolated from the slurry by filtration, washed with ethanol, and dried under vacuum to give an orange solid. See id.
  • U.S. Patent No. 7,119,209 also refers to the preparation of sunitinib base.
  • the '209 patent refers to the preparation of sunitinib base by reacting 4-(1H- imidazol-l-ylcarbonyl)-3, 5 -dimethyl- lH-pyrrole-2-carbaldehyde, N, N- diethylethylenediamine, 5-fluorooxindole in acetonitrile in the presence of triethylamine. See '209 patent, col. 15, 11. 1-36.
  • the sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with acetonitrile, and dried under vacuum.
  • the invention encompasses a combination of a pharmaceutically acceptable excipient selected from a group consisting of microcrystallinecellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and an amorphous composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi- crystalline, when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w); when the pharmaceutically acceptable excipient is polyvinylpyrrolidone, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w); when the pharmaceutically acceptable excipient is microcrystalline cellulose, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
  • a pharmaceutically acceptable excipient selected from a group consisting of microcrystallinecellulose,
  • Figure 1 illustrates a powder X-ray diffraction pattern of a semi-crystalline combination of microcrystalline cellulose and an amorphous composition of sunitinib base and L-malic acid combined with microcrystalline cellulose in a ratio of 10:1 w/w, respectively obtained by drying.
  • Figure 2 illustrates a powder X-ray diffraction pattern of microcrystalline cellulose.
  • Figure 3 illustrates a powder X-ray diffraction pattern of an amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L- malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 4 illustrates a powder X-ray diffraction pattern of an amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1.4 w/w, respectively obtained by lyophilization.
  • Figure 5 illustrates a powder X-ray diffraction pattern of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 6 illustrates a powder X-ray diffraction pattern of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid, in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 7 illustrates a powder X-ray diffraction pattern of an amorphous combination of polyvinylpyrrolidone and an amorphous composition of sunitinib base and L- malic acid combined in a ratio of 2:1 w/w, respectively obtained by lyophilization.
  • Figure 8 illustrates a powder X-ray diffraction pattern of crystalline composition G containing Sunitinib base and L-malic acid obtained by lyophilization
  • Figure 9 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer (Poloxamer 407) and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
  • Figure 10 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer (Poloxamer 407) and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
  • Figure 11 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxy ethylene -polyoxypropylene block polymer (Poloxamer 188) and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
  • Figure 12 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of Polyoxy ethylene -polyoxypropylene block polymer (Poloxamer 188) and a composition of sunitinib base and L-malic acid in a ratio of 1.7:1 w/w, respectively obtained by lyophilization.
  • Figure 13 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of hypromellose and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
  • Figure 14 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyethyleneglycol and a composition of sunitinib base and L-malic acid in a ratio of 1 :7 w/w, respectively obtained by lyophilization.
  • Figure 15 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 16 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 17 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of fructose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 18 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyoxyl 40 hydrogenated castor oil and a composition of sunitinib base and
  • Figure 19 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of sucrose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 20 illustrates a powder X-ray diffraction pattern of a crystalline combination of mannit and a composition of sunitinib base and L-malic acid in a ratio of 1 :1 w/w, respectively obtained by lyophilization.
  • Figure 21 illustrates a powder X-ray diffraction pattern of a crystalline combination of mannit and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 22 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of galactose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 23 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of 2-hydroxyethyl octadecanoate and a composition of sunitinib base and L- malic acid in a ratio of 1 : 1 w/w, respectively obtained by lyophilization.
  • Figure 24 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of trehalose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 25 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of polyvinylpyrrolidone and a composition of sunitinib base and L-malic acid in a ratio of 1 :2.8 w/w, respectively obtained by lyophilization.
  • Figure 26 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 27 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of maltose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 28 illustrates a powder X-ray diffraction pattern of a semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid in a ratio of
  • Figure 29 illustrates a powder X-ray diffraction pattern of crystalline composition G containing Sunitinib base and L-malic acid prepared by spray drying.
  • Figure 30 illustrates a powder X-ray diffraction pattern of a semi-crystalline combination of lactose and a composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, respectively, prepared by spray drying.
  • Figure 31 illustrates a powder X-ray diffraction pattern of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, respectively, prepared by spray drying.
  • w/w refers to g/g.
  • crystalline sunitinib malate form I refers to a crystalline form characterized by diffraction peaks at about 13.2 and 24.2 degrees two-theta ⁇ 0.2 degrees 2-theta, and more preferably, at about 13.2, 19.4, 24.2 and 25.5 degrees two- theta ⁇ 0.2 degrees 2-theta.
  • composition G of Sunitinib base and L-malic acid refers to a composition containing Sunitinib base and L-malic acid characterized by a PXRD pattern having any 5 peaks at positions selected from the group consisting of: 6.2, 7.7, 9.3, 12.4, 14.5, 23.2 and 27.4 ⁇ 0.2 degrees 2-theta.
  • the present invention offers a new combination of an amorphous composition of sunitinib base and L-malic acid that is combined with a pharmaceutically acceptable excipient, wherein the entire combination is either semi-crystalline (see figure 1) or amorphous (see figures 3-6).
  • the composition of sunitinib base and L-malic acid is amorphous. See figures 1, and 3-7 where no peaks of sunitinib base and L-malic acid are evident; in figure 1 the evident peaks are of the excipient (see comparison between figure 1 and 2).
  • Amorphous is herein defined as a composition having PXRD pattern with one broad bump with at most one peak that can be assigned to a crystalline composition of sunitinib base and L-malic acid superimposed on the broad bump.
  • Silicon-crystalline is herein defined as a composition having PXRD pattern that contains peaks that can be detected and assigned to a composition of sunitinib base and
  • the invention encompasses a combination of a pharmaceutically acceptable excipient selected from a group consisting of microcrystalline cellulose, polyvinylpyrrolidone, cyclodextrin, and disaccharide or derivatives thereof and an amorphous composition of sunitinib base and L-malic acid; wherein the combination is either amorphous or semi-crystalline; when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide, the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 : 1 (w/w), the pharmaceutically acceptable excipient is polyvinylpyrrolidone and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :2 (w/w), the pharmaceutically acceptable excipient is microcrystalline cellulose and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10 (w/w).
  • a pharmaceutically acceptable excipient selected from a group consisting of microcrystalline cellulose, poly
  • the amorphous composition of sunitinib base and L-malic acid is polymorphically pure.
  • polymorphically pure amorphous refers to a composition of sunitinib base and L-malic acid that has a PXRD pattern without all the following list of peaks at 6.2, 7.7, 9.3, 12.4, 14.6, 23.2 and 27.2 ⁇ 0.5 degrees 2-theta that can be detected and/or assigned to a composition of sunitinib base and L-malic acid.
  • the cellulose derivative is microcrystalline cellulose.
  • the cyclodextrin derivative is beta-cyclodextrin.
  • the disaccharide derivative is either trehalose, lactose or maltose.
  • the ratio between sunitinib base and L-malic acid is 1 : 1 mole/mole.
  • the semi-crystalline combination of microcrystalline cellulose and the amorphous composition of sunitinib base and L-malic acid in a ratio of 10:1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 1.
  • the amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 :1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 3.
  • the amorphous combination trehalose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1.4 (w/w), respectively, can be characterized by
  • the amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 (w/w), respectively, can be characterized by
  • the amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 (w/w), respectively, can be characterized by
  • the amorphous combination of polyvinylpyrrolidone and an amorphous composition of sunitinib base and L-malic acid in a ratio of 2:1 (w/w), respectively, can be characterized by PXRD pattern as depicted in figure 7.
  • the amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid in a ratio of 1 : 1 w/w, can be characterized by PXRD pattern as depicted in figure 31.
  • the above combination can be prepared by a process comprising removing water from a mixture comprising Sunitinib base, L-malic acid and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from a group consisting of cellulose, polyvinylpyrrolidone, cyclodextrin, disaccharide or derivatives thereof, when the pharmaceutically acceptable excipient is cyclodextrin or disaccharide and the ratio between the amorphous composition and the pharmaceutical acceptable excipient is about 1 : 1 (w/w), the pharmaceutically acceptable excipient is polyvinylpyrrolidone and the ratio between the amorphous composition and the pharmaceutical acceptable excipient is about 1 :2 (w/w), the pharmaceutically acceptable excipient is cellulose and the ratio between the amorphous composition and the pharmaceutically acceptable excipient is about 1 :10
  • the mixture consists essentially of water, Sunitinib base, L-malic acid and a pharmaceutically acceptable excipient, as mentioned above.
  • the said mixture is a suspension or solution.
  • the mixture is a suspension that is provided by dissolving Sunitinib malate in water and combining the obtained solution with the said pharmaceutically acceptable excipient to obtain the said suspension.
  • the mixture is a solution that is provided by dissolving
  • the dissolution is done by heating to a temperature of about 50 0 C to about 100 0 C. More preferably, the dissolution is done by heating to a temperature of about
  • water is removed by drying, lyophilizing or spray-drying the said mixture.
  • the drying is done by heating the mixture to a temperature of about
  • the drying is done at a temperature of about 90 0 C.
  • water is removed under reduced pressure, for example 0.05 to about 300 mBar, preferably at a pressure of about 1 to about 20 mBar, more preferably the drying is done at a pressure of about 10 mBar.
  • the drying is done for a period of about 2 hours.
  • Lyophilization is also known as freeze drying.
  • the mixture is frozen.
  • the frozen mass is then subjected to a pressure of less than about one atmosphere, to remove the solvent.
  • the lyophilization is done at a temperature of about -30 0 C to about
  • the lyophilization is done at a pressure of about 0.1 to about 1 mBar.
  • Sunitinib base (6 g) was dissolved in dioxane (160 ml) at 100 0 C and the hot solution was filtered and the filter was cleaned with additional dioxane (40 ml).
  • L-malic acid (2.02 g in 10 ml of water) was added. The solution was heated for 15 min to 100 0 C, allowed to cool to 20 0 C within 30 min, and allowed to crystallize overnight (12 hrs). Crystals were recovered by filtration, washed with t-BME (20 ml) and allowed to dry for 5 hrs on air.
  • Example 1 Preparation of a semi-crystalline combination of microcrystalline cellulose and an amorphous composition of sunitinib base and L-malic acid
  • Sunitinib L-malate (form I, 400 mg) was dissolved in water at 80 0 C (8 ml) and microcrystalline cellulose (4 g) was added. The suspension thus formed was dried at 10 mBar at 90 0 C for 1 hour providing a semi-crystalline combination of cellulose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 2 Preparation of an amorphous combination of beta-cyclodextrin and an amorphous composition of sunitinib base and L-malic acid.
  • Beta-Cyclodextrin 150 mg was added, boiled for 3 min, allowed to cool, frozen -30 C, lyophilized, 1 mBar. An amorphous combination of Beta-Cyclodextrin and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 3 Preparation of an amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate 140 mg, Form I
  • trehalose 100 mg
  • An amorphous combination of trehalose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 4 Preparation of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate (150 mg, Form I) and lactose (150 mg) were dissolved in water (10 ml) by heating to 100 0 C for 5 min, allowed to cool, frozen by liquid N 2 to about - 50 0 C, lyophilised, 10 Pa, 24 h. An amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 4a Preparation of an amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate 150 mg, Form I
  • lactose 250 mg
  • water 10 ml
  • An amorphous combination of lactose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 5 Preparation of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid.
  • Sunitinib malate (150 mg, Form I) and maltose (150 mg) were dissolved in water (10 ml) by heating to 100 0 C for 5 min, allowed to cool, frozen by liquid N 2 to about - 50 0 C, lyophilised, 10 Pa, 24 h. An amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid was obtained.
  • Example 6 Preparation of an amorphous combination of polyvinylpyrrolidone (Polyvidone 25) and an amorphous composition of sunitinib base and L-malic acid [0077] Sunitinib malate (150 mg, Form I) and Polyvinylpyrrolidone (Polyvidone 25)
  • Sunitinib malate 140 mg, Form II
  • Polyoxyethylene-polyoxypropylene block polymer 50 mg
  • a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and Polyoxyethylene-polyoxypropylene block polymer (150 mg) were dissolved in water (10 ml) b heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h
  • a semi crystalline combination of Polyoxyethylene-polyoxypropylene block polymer and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • Lutrol F68 150 mg
  • a semi crystalline combination of Lutrol F68 and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • Lutrol F68 250 mg
  • a semi crystalline combination of Lutrol F68 and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 140 mg, Form II
  • polyethyleneglycole 20 mg
  • a semi crystalline combination of polyethyleneglycole and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • dulcite 100 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • dulcite 250 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of dulcite and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • fructose 100 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of fructose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and mannit (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a crystalline combination of mannit and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • mannit 250 mg
  • water 10 ml
  • mannit 250 mg
  • a crystalline combination of mannit and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and galactose (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of galactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate (150 mg, Form I) and 2-hydroxy ethyl octadecanoate (150 mg) were dissolved in water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about -50 C, lyophilised, 10 Pa, 24 h.
  • a semi crystalline combination of 2- hydroxyethyl octadecanoate and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 140 mg, Form I
  • trehalose 50 mg
  • water (10 ml) by heating to 100 C for 5 min, allowed to cool, frozen by liquid N2 to about - 100 C, lyophilised, 1 mBar.
  • a semi crystalline combination of trehalose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Sunitinib malate 150 mg, Form I
  • lactose 100 mg
  • a semi crystalline combination of lactose and a composition of sunitinib base and L-malic acid was obtained as determined by XRPD.
  • Example 30 Preparation of an amorphous combination of maltose and an amorphous composition of sunitinib base and L-malic acid by spray drying

Landscapes

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

Abstract

L’invention concerne la préparation de combinaisons d’un excipient pharmaceutiquement acceptable choisi parmi le groupe constitué de la cellulose microcristalline, de la polyvinylpyrrolidone, de la cyclodextrine et d’un disaccharide ou de dérivés de ceux-ci, et d’une composition d’une base de sunitinib et d’acide L-malique.
PCT/US2009/058975 2008-09-30 2009-09-30 Compositions amorphes d’une base de sunitinib et d’acide l-malique WO2010039798A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA2704448A CA2704448A1 (fr) 2008-09-30 2009-09-30 Compositions amorphes d'une base de sunitinib et d'acide l-malique

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US10152708P 2008-09-30 2008-09-30
US61/101,527 2008-09-30
US11741308P 2008-11-24 2008-11-24
US61/117,413 2008-11-24
US14347709P 2009-01-09 2009-01-09
US61/143,477 2009-01-09
US15964409P 2009-03-12 2009-03-12
US61/159,644 2009-03-12

Publications (2)

Publication Number Publication Date
WO2010039798A2 true WO2010039798A2 (fr) 2010-04-08
WO2010039798A3 WO2010039798A3 (fr) 2010-08-19

Family

ID=41815067

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/058975 WO2010039798A2 (fr) 2008-09-30 2009-09-30 Compositions amorphes d’une base de sunitinib et d’acide l-malique

Country Status (3)

Country Link
KR (1) KR20100051769A (fr)
CA (1) CA2704448A1 (fr)
WO (1) WO2010039798A2 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2015031604A1 (fr) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Signatures d'expression génique permettant de prédire la réponse d'un sujet à un inhibiteur multikinase et leurs procédés d'utilisation
WO2020216450A1 (fr) 2019-04-25 2020-10-29 Synthon B.V. Composition pharmaceutique comprenant du sunitinib amorphe
CN114025800A (zh) * 2019-06-26 2022-02-08 株式会社理光 药物组合物

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020091439A1 (fr) * 2018-10-31 2020-05-07 주식회사 삼양바이오팜 Formulation orale comprenant du sunitinib et procédé de préparation de celle-ci
KR102308227B1 (ko) * 2018-10-31 2021-10-05 주식회사 삼양홀딩스 수니티닙을 함유하는 경구용 정제 조성물
KR20240025990A (ko) * 2022-08-19 2024-02-27 주식회사 스카이테라퓨틱스 무정형 수니티닙, 그 제조방법 및 이를 포함한 의약 조성물

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024127A2 (fr) * 2002-09-10 2004-03-25 Pharmacia Italia S.P.A. Formulations contenant un compose indolinone
EP2090306A1 (fr) * 2008-02-13 2009-08-19 Ratiopharm GmbH Compositions pharmaceutiques comportant du N-[2-(diethylamino)ethyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004024127A2 (fr) * 2002-09-10 2004-03-25 Pharmacia Italia S.P.A. Formulations contenant un compose indolinone
EP2090306A1 (fr) * 2008-02-13 2009-08-19 Ratiopharm GmbH Compositions pharmaceutiques comportant du N-[2-(diethylamino)ethyl]-5-[5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PETIT S ET AL: "The Amorphous State" 1 January 2006 (2006-01-01), 20060101, PAGE(S) 259 - 285 , XP002481458 ISBN: 9783527311460 page 261, last paragraph *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2015031604A1 (fr) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Signatures d'expression génique permettant de prédire la réponse d'un sujet à un inhibiteur multikinase et leurs procédés d'utilisation
WO2020216450A1 (fr) 2019-04-25 2020-10-29 Synthon B.V. Composition pharmaceutique comprenant du sunitinib amorphe
CN114025800A (zh) * 2019-06-26 2022-02-08 株式会社理光 药物组合物
EP3991750A4 (fr) * 2019-06-26 2022-08-03 Ricoh Company, Ltd. Composition pharmaceutique

Also Published As

Publication number Publication date
CA2704448A1 (fr) 2010-04-08
WO2010039798A3 (fr) 2010-08-19
KR20100051769A (ko) 2010-05-18

Similar Documents

Publication Publication Date Title
WO2010039798A2 (fr) Compositions amorphes d’une base de sunitinib et d’acide l-malique
JP5486012B2 (ja) ニロチニブＨＣｌ結晶形
US11292793B2 (en) Solid dispersions of amorphous Lumateperone p-Tosylate
EP2253629A1 (fr) Polymorphes de malate de sunitinib racémique, compositions les contenant et leur préparation
CN109563096A (zh) 固体形式的维奈托克和用于制备维奈托克的方法
JP2016153404A (ja) 医薬活性物質の固体形態
US20110112164A1 (en) Novel polymorphs and processes for their preparation
US20220220123A1 (en) Amorphous and crystalline forms of relugolix
KR20080089659A (ko) 아프레피탄트의 비정질 및 결정 형태 및 그것의 제조 방법
US10513526B2 (en) Solid state forms of spiro-oxindole compounds
US20190300483A1 (en) POLYMORPHS OF BETRlXABAN & ITS MALEATE SALT
EP2315764A2 (fr) Nouvelle forme cristalline et ses procédés de préparation
WO2014016842A1 (fr) Coprécipités amorphes du rivaroxaban
US20110071169A1 (en) Preparation of polymorphic form of lapatinib ditosylate
EP3784676A1 (fr) Formes polymorphes de bictégravir et son sel de sodium
WO2018134843A1 (fr) Formes polymorphes de (e)-n-{4-[3-chloro-4-((pyridin-2-yl-méthoxy)-anilino]-3-cyano-7-éthoxyquinolin-6-yl)-4-(diméthylamino)-but-2-énamide, son sel de maléate et un procédé de préparation correspondant
US20110263670A1 (en) Novel polymorphs of sunitinib and processes for their preparation
WO2011100325A2 (fr) Polymorphes de sels de sunitinib
US20100310870A1 (en) Amorphous bazedoxifene acetate and preparation thereof
US20070299123A1 (en) Amorphous frovatriptan succinate and process for the preparation thereof
US20070105927A1 (en) Amorphous rizatriptan benzoate
WO2010133590A1 (fr) Compositions pharmaceutiques pour n-[2-(diéthylamino)éthyl]-5-[(fluoro-1,2-dihydro-2-oxo-3h-indole-3-ylidene)méthyl]-2,4-diméthyl-1h-pyrrole-3-carboxamide
SPECIFICATION CRYSTALLINE FORMS OF MIRABEGRON AND PROCESS FOR THEIR PREPARATION

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 20097024709

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2704448

Country of ref document: CA

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

Ref document number: 09736525

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09736525

Country of ref document: EP

Kind code of ref document: A2