WO2022106985A1 - Solid amorphous dispersions of cabozantinib-(s)-malate and processes for the preparation thereof - Google Patents
Solid amorphous dispersions of cabozantinib-(s)-malate and processes for the preparation thereof Download PDFInfo
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- HFCFMRYTXDINDK-WNQIDUERSA-N cabozantinib malate Chemical compound OC(=O)[C@@H](O)CC(O)=O.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 HFCFMRYTXDINDK-WNQIDUERSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 11
- 239000007787 solid Substances 0.000 title claims description 11
- 230000008569 process Effects 0.000 title claims description 8
- 239000006185 dispersion Substances 0.000 title claims description 6
- 229940035945 cabozantinib (s)-malate Drugs 0.000 title description 4
- 239000007962 solid dispersion Substances 0.000 claims abstract description 33
- 229920000578 graft copolymer Polymers 0.000 claims abstract description 15
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 claims description 12
- 229960001292 cabozantinib Drugs 0.000 claims description 10
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 238000002329 infrared spectrum Methods 0.000 claims description 5
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- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 2
- 229920000570 polyether Polymers 0.000 claims description 2
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 2
- 239000011118 polyvinyl acetate Substances 0.000 claims description 2
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 claims 2
- 150000003254 radicals Chemical class 0.000 claims 1
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- 229910016860 FaSSIF Inorganic materials 0.000 description 6
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- 239000004480 active ingredient Substances 0.000 description 4
- 239000013060 biological fluid Substances 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
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- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 3
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 2
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000005102 attenuated total reflection Methods 0.000 description 2
- 229940036033 cabometyx Drugs 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940034568 cometriq Drugs 0.000 description 2
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- 238000009472 formulation Methods 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
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- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
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- 229920000858 Cyclodextrin Polymers 0.000 description 1
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- 206010017952 Gastrointestinal fistulae Diseases 0.000 description 1
- 206010018001 Gastrointestinal perforation Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000807561 Homo sapiens Tyrosine-protein kinase receptor UFO Proteins 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
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- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 1
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- 238000002441 X-ray diffraction Methods 0.000 description 1
- -1 acetate-polyethylene Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
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- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
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- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
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- 150000004701 malic acid derivatives Chemical class 0.000 description 1
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- 125000001493 tyrosinyl group Chemical class [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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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
- A61K9/141—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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
Abstract
The present invention relates to a solid dispersion of Cabozantinib malate in a graft copolymer and the preparation process thereof.
Description
SOLID AMORPHOUS DISPERSIONS OF CABOZANTINIB-(S)-MALATE AND
PROCESSES FOR THE PREPARATION THEREOF
Field of invention
The present invention relates to a solid dispersion of Cabozantinib malate in a graft copolymer and the preparation process thereof.
Background to the invention
Cabozantinib, having the formula 7V-(4-((6,7-dimethoxyquinolin-4-yl)oxy) phenyl)-N' -(4-fluorophenyl)-cy cl opropran- 1,1 -dicarboxamide (hereinafter called
“Cabozantinib 1” or “Cabozantinib free base 1”)
Formula 1 is an active pharmaceutical ingredient belonging to the class of tyrosine kinase receptor inhibitors (TKRIs), which is active against a broad spectrum of target sites, such as the kinase receptor RET, the mesenchymal epithelial transition factor receptor (MET), vascular endothelial cell growth factor receptor 2 (VEGFR2), and the AXL, FLT3 and c-KIT receptors (Griillich C., Recent Results Cancer Res. 2018; 211 :67-75); said receptors are not only involved in the ordinary cell functions, but also in disease processes, such as oncogenesis, tumour angiogenesis and maintenance of the tumoral microenvironment.
Cabozantinib 1 is approved and marketed for the treatment of medullary thyroid carcinoma (MTC), renal cell carcinoma (RC) and hepatocellular carcinoma (HCC); the formulations Cometriq® and Cabometyx®, the former designed for the treatment of
MTC and the second for the treatment of RCC and HCC, contain the malate salt having formula 2 (hereinafter called “Cabozantinib-(S)-malate 2” or “Cabozantinib malate 2”), which is more water-soluble than the free base.
Cabozantinib 1, and the preparation process thereof, were described for the first time in WO 2005/030140; however, because of its low water-solubility, Cabozantinib 1 was considered unsuitable for use in solid dosage forms for oral administration.
According to the Biopharmaceutics Classification System (BCS), Cabozantinib 1 is classified as a class II medicament because of its low solubility and high permeability (Nguyen L et al.. J Clin Pharmacol. 2015; 55(11):1293-302). The low water-solubility of the medicaments belonging to said class represents one of the major critical factors in the development of oral formulations; said administration route is generally preferred because it avoids invasive practices (such as intramuscular or intravenous administration) and, in particular cases, such as cancer patients, is accompanied by increased efficacy of the treatment, thus improving patients’ agreement to and compliance with the treatments.
Initially, the problem of low solubility was overcome by preparing various Cabozantinib 1 salts, including Cabozantinib-(S)-malate 2, disclosed in WO 2010/083414. In particular, said document discloses crystalline forms N-l and N-2 and the amorphous form of Cabozantinib malate 2.
Further known crystalline forms of Cabozantinib malate 2 are as follows: forms
Ml, M2, M3 and M4 (WO 2015/177758), II (Chinese patent application no. 108341773) S, M (WO 2018/104954), CSI, CSIII (WO 2020/0507622), C2, C3, C4 and C5 (WO 2020/075196). However, no polymorphic form has proved considerably more soluble than the others.
Solid dispersions are one of the most promising approaches to increasing the oral bioavailability of class II medicaments according to the BCS, and an alternative to the traditional investigations of the various polymorphic crystalline forms of the pharmaceutical active ingredients.
WO 2020/069138 relates to a dosage form comprising an active pharmaceutical ingredient, cyclodextrins and bicarbonate, which would enable the oral bioavailability of the active ingredient to be increased by an amount ranging between 10% and 200%. Cabozantinib malate 2 is cited in a long list of active ingredients, but not indicated as the preferred active ingredient, nor is it exemplified in the experimental section.
However, there is still a need to develop further solid forms of Cabozantinib malate 2 with even greater solubility, a factor which would improve the absorption of the medicament, increase its bioavailability and produce a better therapeutic effect; moreover, increased solubility would enable the amount of medicament administered to be reduced, while ensuring equal efficacy, at the same time reducing the serious side effects such as gastrointestinal perforations and fistulae, haemorrhages, thrombotic events, osteonecrosis of the lower jaw, etc., thereby increasing the safety of the medicament.
Description of figures
Figure 1: X-ray diffractogram of the amorphous solid dispersion of Cabozantinib malate 2 according to Example 1.
Figure 2: IR spectrum of the amorphous solid dispersion of Cabozantinib malate 2 according to Example 1.
Figure 3: TG/DTA profile of the amorphous solid dispersion of Cabozantinib malate 2 according to Example 1.
Figure 4: DSC profile of the amorphous solid dispersion of Cabozantinib malate 2 according to Example 1.
Description of the invention
The present invention relates to a solid dispersion wherein Cabozantinib malate 2 is dispersed in a graft copolymer; in particular, the dispersion of Cabozantinib malate 2 in a graft copolymer of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol (hereinafter called “graft copolymer”) is an amorphous solid dispersion. In the present invention the term “solid dispersion” defines a system of two components, wherein a first component is dispersed in a second component and the resulting system is physically uniform, typically, a. hydrophobic active pharmaceutical ingredient (first component) is dispersed in a hydrophilic polymer material (second component).
The polymer material used in the present invention consists of a graft copolymer obtained by free-radical polymerisation of an N-vinyllactam, vinyl acetate and a polyether as described in US 8,158,686, which is incorporated in full herein for reference. Preferably, the copolymer is obtained by polymerisation of polyvinylcaprolactam, polyvinyl acetate and polyethylene glycol; said copolymer is commercially available from BASF under the Soluplus trademark®.
A first aspect of the invention relates to an amorphous solid dispersion of Cabozantinib malate 2 characterised as follows:
I. the X-ray (X-R.PD) diffraction lattice presents no recognisable peaks;
II. the Fourier transform infrared spectrum (FT-IR) comprises the following absorption frequencies: 2924, 1731, 1631, 1478, 1436, 1320, 1083, 973 and 837 cm'1;
III. the thermogravimetric and differential thermal analysis (TG/DTA) profile is characterised by a weight loss from the temperature of 210°C due to decomposition.
The differential scanning calorimetry (DSC) profile does not exhibit fusion events, only decomposition of the sample at 210°C.
A second aspect of the invention relates to a process (alternatively called “method’') for the preparation of the amorphous solid dispersion of Cabozantinib malate 2, which involves the use of an organic solvent.
With special reference to the first aspect of the invention, the IR spectrum referred to in point II exhibits the following absorption frequencies: 2924, 2858, 1731, 1684, 1631, 1507, 1478, 1436, 1369, 1350, 1334, 1320, 1213, 1195, 1083, 973, 944, 837 and 714 cm-1.
With special reference to the second aspect of the invention, the preparation process of an amorphous solid dispersion involves suspending Cabozantinib malate 2 and the graft copolymer in a solvent, heating the suspension until a solution is obtained, and finally, removing the solvent; in the present invention the term “solution” refers to a physically homogeneous mixture wherein one or more ingredients are present in a single phase; the term “suspension” refers to a heterogeneous mixture wherein one or more ingredients are present in two or more phases.
In further detail, the process for preparation of an amorphous solid dispersion of Cabozantinib malate 2 comprises the following steps: a) Cabozantinib malate 2 and the graft copolymer are suspended in an organic solvent to give suspension A; b) suspension A is maintained under reflux and under stirring until a solution B is obtained; c) solution B is filtered to give solution C; d) the solvent of solution C is removed until a solid D is obtained; e) solid D is ground until the amorphous solid dispersion of Cabozantinib 2 is obtained as a powdery solid.
Typically, the ratio of the amount of Cabozantinib malate 2 to graft copolymer in step a) falls into the range 0.1-10; preferably 0.1-2.5. The use of said copolymer has proved particularly advantageous; it not only prevents crystallisation of Cabozantinib malate 2 in the dispersion, but also performs the function of active solubiliser due to the
formation of micelles in contact with water.
Typically, the organic solvent used in step a) is selected from acetone, tetrahydrofuran, acetonitrile, methylene chloride, ethyl acetate, methanol and ethanol, preferably tetrahydrofuran.
Typically, suspension A is maintained under stirring for a time ranging between 30 seconds and 60 minutes; preferably for 10 minutes.
Typically, the filtration referred to in step b) is conducted through a 5-15 pm sintered filter (type G4). Typically, a technique selected from distillation, low-pressure distillation, freeze-drying and spray drying is used in step d) to remove the solvent; preferably, low-pressure distillation.
The solubility of the amorphous solid dispersion of Cabozantinib malate 2 was evaluated in water and in simulated biological fluids. In particular, comparative solubility studies were conducted between the amorphous solid dispersion of Cabozantinib malate 2 and the corresponding polymorphic cry stalling form N-2 in water and in various simulated biological fluids, such as fasted-state simulated gastric fluid at pH 1.6 (hereinafter called FaSSGF), fasted-state simulated intestinal fluid at pH 6.5 (hereinafter called FaSSIF), and fed-state simulated intestinal fluid at pH 5 (hereinafter called FeSSIF). As will be seen from the results set out in Table 1 to Example 2 in the Experimental Section, the amorphous dispersion of Cabozantinib malate 2 proved more soluble than the crystalline form, both in water and in simulated biological fluids; in particular, the solubility of the amorphous solid dispersion in FaSSIF is about 100 times greater than that of form N-2, and 28 times greater in FeSSIF, while in FaSSGF and in water, the solubility is 8 and 16 times greater respectively. The solubility data highlight two surprising aspects of the invention; firstly, in view of its ionic and hydrophilic nature, it would be expected that, as taught by Shamma R. et al., the solubility of the copolymer would not change in the gastrointestinal tract (Shamma R. N. et al., Powder Technology 2013, 237, 406-414), but surprisingly, the solubility of the solid dispersion varies significantly between FaSSGF and FaSSIF. A second advantageous aspect that emerges
from the solubility data is that the greatest solubility is observed in FaSSIF; this finding is surprisingly useful because, as the administration of both Cometriq® and Cabometyx® is indicated on an empty stomach, the increased solubility under said conditions would enable Cabozantinib malate 2 to be replaced with the solid dispersion, thus significantly reducing the amount of medicament administered.
Experimental section
Materials and methods
Soluplus®, commercially available from BASF, was used as graft copolymer.
X-ray powder diffraction (Fig. 1)
The X-ray diffraction pattern was recorded on a Bruker D2-Phaser diffractometer. The X-ray generator was set to 30 kV and 10 mA, using CuK as radiation source. The sample was prepared in a sample holder and irradiated for an irradiation length of 10 mm. The data were recorded between 2 and 50 29 degrees every 0.02 29 degrees, with a recording time of 3 seconds per 29 degree.
Fourier-transform infrared spectroscopy (FTIR) (Fig. 2)
The infrared spectrum was recorded in attenuated total reflectance (ATR) using the Perkin Elmer Spectrum One Fourier Transform spectrometer, equipped with the Specac ATR Golden Gate accessory. The spectrum results from the acquisition and transformation of 16 scans in the spectral region between 4000-500 cm'1 at a resolution of 4 cm'1.
Thermogravimetry (TG) and differential thermal analysis (DTA) (Fig. 3)
The analysis was conducted with a Seiko TG/DTA7200 simultaneous system instrument and open aluminum crucibles (volume 40 pL). The TG/DT signal was recorded between 30°C and 300°C with a linear heating gradient (10°C/min) under nitrogen flow (200 mL/min). About 10 mg of sample was used for the measurement.
Differential scanning calorimetry (DSC) (Fig. 4)
The analysis was conducted with a Mettler DSC1 System instrument. The heat flow was recorded in a range between 30° and 300°C with linear gradient (10°C/min) and
under nitrogen flow (50 mL/min). About 5 mg of sample was used for the measurement, in a sealed and then perforated aluminum crucible (volume 40 pl).
High-performance liquid chromatography (HPLC)
The analysis was conducted with an Agilent 1100 instrument, equipped with a Symmetry shield RP18 column, 150 x 4.6, 5 pm. Table 1 shows the gradient used for the eluent mixture (Eluent A: 10 Mm ammonium formate buffer, pH 6.6; Eluent B: acetonitrile).
Table 1
Examples
Example 1- Preparation of an amorphous solid dispersion of Cabozantinib malate 2
2.5 g of Cabozantinib malate 2 and 10 g of Soluplus® were suspended in 400 mL of tetrahydrofuran. The suspension was heated to reflux for 10 minutes until a solution was obtained, which was then filtered through a sintered filter typically having a pore diameter ranging between 5 and 15 pm. The solvent was removed by distillation under vacuum until a soft mass was obtained. The soft mass was dried under vacuum at 50°C for 24 hours. The resulting solid was ground until a powdery white solid was obtained.
Example 2- Solubility studies in simulated gastrointestinal fluids
The solubility studies on the solid dispersion prepared according to Example 1 were conducted in different biologically relevant media to evaluate its behaviour in the various sections of the gastrointestinal tract. The solubility studies were conducted in water, FaSSIF (pH 6.5), FeSSIF (pH 5) and FaSSGF (pH 1.6).
10-20 mL of water, FaSSIF, FeSSIF or FaSSGF were placed in 40 mL glass vials.
An amount of solid dispersion prepared according to Example 1, in excess of the
expected saturated solubility, was added to the vials; the resulting mixtures were maintained under stirring for 2 hours at room temperature. The mixtures were filtered through 0.45 pm PTFE membrane filters. The filtered solutions were analysed with HPLC instrumentation. Table 2 compares the concentrations of Cabozantinib malate 2 and the solid dispersion prepared according to Example 1 in various simulated gastrointestinal fluids.
*50 mg of solid dispersion according to Example 1 contains 10 mg of
Cabozantinib malate 2 Table 2. Concentrations of Cabozantinib malate 2 in water and in various simulated biological fluids expressed in mg/mL.
Claims
1. A solid dispersion of Cabozantinib malate 2 in a graft copolymer.
2. The solid dispersion according to claim 1, wherein the graft copolymer is obtained by free radical polymerisation of an N-vinyl lactam, vinyl acetate and a polyether.
3. The solid dispersion according to claim 2, wherein the graft copolymer is obtained by polymerisation of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol.
4. The solid dispersion according to claims 1-3 wherein the dispersion is in amorphous form.
5. The solid dispersion according to claims 1-3 with IR spectrum comprising the following absorption frequencies: 2924, 1731, 1631, 1478, 1436, 1320, 1083, 973 837 cm'1.
6. The solid dispersion according to claim 5, wherein the IR spectrum comprises the following absorption frequencies: 2924, 2858, 1731, 1684, 1631, 1507, 1478, 1436, 1369, 1350, 1334, 1320, 1213, 1195, 1083, 973, 944, 837 714 cm'1.
7. Process of preparation of the solid dispersion according to claims 1-6 which involves the use of an organic solvent.
8. The process according to claim 7 comprising the following steps: a. Cabozantinib malate 2 and the graft copolymer are suspended in an organic solvent to give suspension A; b. suspension A is kept under reflux and stirring until a solution B is obtained; c. solution B is filtered to give solution C; d. the solvent of solution C is removed until a solid D is obtained; e. solid D is ground until the amorphous solid dispersion of Cabozantinib 2 is obtained as a powdery solid.
9. The process according to claim 8 wherein in step a), the ratio of Cabozantinib malate 2 to graft copolymer is included in the range 0.1-10.
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| IT102020000027678 | 2020-11-18 | ||
| IT102020000027678A IT202000027678A1 (en) | 2020-11-18 | 2020-11-18 | CABOZANTINIB-(S)-MALATO AMORPHOUS SOLID DISPERSIONS AND PROCESSES FOR THEIR PREPARATION |
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| DE102005053066A1 (en) | 2005-11-04 | 2007-05-10 | Basf Ag | Use of copolymers as solubilizers for sparingly water-soluble compounds |
| SG173014A1 (en) | 2009-01-16 | 2011-08-29 | Exelixis Inc | Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quin0lin-4-yl] oxy}phenyl)-n' - (4 -fluorophenyl) cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer |
| EP3145913A1 (en) | 2014-05-23 | 2017-03-29 | Mylan Laboratories Ltd. | Novel polymorphs of cabozantinib (s)-malate and cabozantinib free base |
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