WO2011049474A1 - Salts of imatinib with tartaric acids - Google Patents
Salts of imatinib with tartaric acids Download PDFInfo
- Publication number
- WO2011049474A1 WO2011049474A1 PCT/PL2010/000105 PL2010000105W WO2011049474A1 WO 2011049474 A1 WO2011049474 A1 WO 2011049474A1 PL 2010000105 W PL2010000105 W PL 2010000105W WO 2011049474 A1 WO2011049474 A1 WO 2011049474A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- imatinib
- tartaric
- salts
- salt
- formula
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Definitions
- the present invention relates to the new salts of imatinib with tartaric acids, their preparation and the pharmaceutical compositions thereof.
- Imatinib is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and with Kit- positive gastrointestinal stromal tumours (GIST) including unresectable and/ or metastatic malignant disease and resected disease post-surgery, for use in adult patients with newly diagnosed Ph+ acute lymphoblastic leukemia (ALL) in combination with chemotherapy, and as a single agent for patients with relapsed or refractory Ph+ALL.
- Ph+ Philadelphia chromosome positive
- CML chronic myeloid leukemia
- GIST Kit- positive gastrointestinal stromal tumours
- ALL Ph+ acute lymphoblastic leukemia
- the new salts exhibiting the same pharmaceutical activity as imabinib, may be used as anticancer active substances.
- the active ingredient of imatinib tablets marketed as Gleevec® or Glivec® is imatinib acid addition salt with methanesulfonic acid, imatinib mesylate.
- Therapeutic daily dose of imatinib in leukemia treatment in humans varies from 100 mg to 800 mg of imatinib active ingredient.
- the administration of tablets comprising from 100 mg to 400 mg of imatinib (119,5 and 478 mg of imatinib mesylate, respectively) is required.
- formation of tablets with high active substance content is necessary.
- the European Patent EP 1501485 Bl the 'compact' tablet with the content of imatinib mesylate varying from 30 to 80 % by weight calculated on the total tablet weight, was disclosed. Tablets were manufactured in wet granulation process using active substance and excipients forming the inner phase, followed by mixing the obtained granulate with the excipients forming the outer phase, then compressing the mixture and coating the cores.
- imatinib mesylate may crystallize in at least two polymorphic forms, a and ⁇ , disclosed in the publication of international patent application WO 99/03854.
- ⁇ -Crystal form is thermodynamically stable and it has relatively good processing parameters, while a-crystal form, crystallizing as elongated, fragile needle-like crystals, is highly hygroscopic.
- wet granulation process is not useful in case of hygroscopic a- crystal form of imatinib mesylate.
- the coated tablets having the desired technological properties ie. characterized by appropriate hardness and abrasion resistance, may be obtained when dry granulation step is performed prior to compression of granulate.
- the active substance content in a tablet core or a granule varies from 25% to 80% of the total tablet weight, and the particle size of at least 80 % by weight of the active substance ranges from 0,01 to 1,0 nm.
- imatinib mesylate This diversity of crystalline forms of imatinib mesylate may be disadvantageous to keep uniformity of different manufacturing batches and, as a consequence, to preserve uniformity of tablets content.
- imatinib salt with methanesulfonic acid when used in therapy seriously threatens patients health.
- Preclinical studies showed the activity towards DNA alkylation of methanesulfonic acid alkyl esters, therefore their presence even as trace impurities ( ⁇ 5 ppm) may cause mutagenic, cancerogenic and teratogenic changes in a living organism.
- Potential genotoxic effects of these esters were the topics of considerations by European Medicines Agency, which advised the pharmaceutical manufacturers to take particular precautions to produce pharmaceuticals free of alkyl sulfonates impurities.
- imatinib salt composed of the acid other than methanesulfonic acid, that would not generate the risk of formation of DNA alkylating agent.
- imatinib salts such as tartrates, hydrochloride, citrate, malates, fumarate, succinate, benzoate, malonate, salicilate, lactates, mandelates, hemiglutarate, vanilate, ascorbate and sulfate salts, were revealed.
- imatinib salts due to their physico-chemical properties are not useful in solid pharmaceutical dosage form production. Water content above 0,5%, detected in a majority of the crystalline salts, is the evidence of hygroscopic properties of these compounds.
- the described salts are also hardly soluble in water, it is proved over 10 fold lower in comparison with mesylate solubility, therefore the described salts cannot be used as the direct mesylate equivalents.
- a number of new salts obtained are characterized by low melting points, for example melting point measured for imatinib maleates is below 50°C.
- the present invention relates to imatinib acid addition salts
- R represents O-acyl group of L- or D-tartaric acid
- n represents any number in the range from 1 to 2.
- the present invention encompasses also all solvates and hydrates of imatinib acid addition salts represented by general formula (1).
- the preferred salts according to the present invention are the salts selected from the group consisting, of imatinib salts with dibenzoyl-L- tartaric, dibenzoyl-D-tartaric, di-p-anizoyl-L-tartaric, di-p-anizoyl-D- tartaric, di-p-tolyl-L-tartaric, di-pivaloyl-L-tartaric and diacetyl-L-tartaric acids.
- New salts of the present invention may consist of 0.5 to 1 mole of dicarboxylic acid per 1 mole of imatinib.
- the salts consist of dicarboxylic acid and imatinib at the molar ratio 1 : 2 or 1 : 1.
- imatinib diacetyl-L-tartrate (1 :2), which consists of one molecule of diacetyl-L-tartaric acid and two molecules of imatinib.
- XRPD pattern of imatinib diacetyl-L-tartrate (1:2) is depicted on Fig. 1, and the IR spectrum on Fig. 2.
- Another preferred salt according to the present invention is imatinib di-p-anizoyl-D -tartrate (1: 1), which consists of one molecule of di-p-anizoyl- D-tartaric acid and one molecule of imatinib base.
- the other preferred salt according to the present invention is imatinib di-benzoyl-L- tartrate (1: 1), which consists of one molecule of di-benzoyl-L- tartaric acid and one molecule of imatinib base.
- step (a) from 0,5 to 1 equivalents of dicarboxylic acid is reacted with 1 mol of imatinib, its salt or solvate, in respect to free base.
- Organic solvent in step (a) is selected from a group comprising aliphatic alcohols, such as methanol or ethanol; aliphatic ketones, such as acetone; esters of carboxylic acids, such as ethyl acetate; ethers, such as tetrahydrofuran; nitriles, such as acetonitrile, or their mixtures.
- aliphatic alcohols such as methanol or ethanol
- aliphatic ketones such as acetone
- esters of carboxylic acids such as ethyl acetate
- ethers such as tetrahydrofuran
- nitriles such as acetonitrile, or their mixtures.
- the solvent of choice is methyl alcohol or ethyl alcohol.
- Crystalline imatinib salt is isolated from the crystallizing mixture in the manner known per se, and depending on the used solvent. It comprises filtration or decantation of the formed crystalline product or its precipitation out of the post-reaction mixture due to co-solvent addition.
- Imatinib salt may be isolated from the post-reaction mixture either free of solvent or in the form of solvate. The isolated salt may be purified by crystallization, maceration and/ or recrystallization, and subsequently dried.
- Imatinib salts obtained according to the present invention are isolated as the homogenous crystals, characterized by regular crystalline shape, which is suitable for pharmaceutical applications. Unlike imatinib mesylate, in particular its a-crystal form, new tartrate salts absorb trace amounts of water and have ' comparatively good solubility (above 5000 mg/ml of water).
- the new salts exhibit good stability under accelerated and long-term storage conditions; the increase of by-products resulting from degradation is not observed. Unexpectedly, due to advantageous physico-chemical properties and processability, the new salts are suitable for direct use in solid pharmaceutical dosage forms manufacture.
- the salts obtained according to the present invention will have the same pharmacological activity as imatinib mesylate.
- the new imatinib salts can be used in a treatment and prevention of myeloid leukemia, acute lymphoblastic leukemia, gastrointestinal stromal tumor and other diseases mediated by tyrosine kinases.
- Imatinnib salts according to the invention may be administered to the patient per se or they may be formulated as the pharmaceutical compositions including therapeutic amount of active substance together with at least one pharmaceutically accepted carrier and/ or excipient.
- composition of the invention may be administered in suitable pharmaceutical dosage form, by any convenient route, eg. orally or parenterally, depending on the pharmaceutical dosage form used.
- therapeutic daily dose of imatinib salt as well as the dosage scheme is connected with the nature and severity of condition being treated, age and body mass of the patient, and may be defined by the skilled person according to the standard treatment procedures and prophylactics in that kind of diseases.
- Therapeutic daily dose of the derivative of the present invention may vary from 100 mg to 800 mg, calculated on imatinib free base. Daily dose can be administered on once-a-day basis or it can be divided into small portion doses, in monotherapy or in a combined treatment with other active substance.
- the combined active substances may be administered as a fixed unit dosage form, concomitantly as two different drugs or within a certain period of time, in accordance with the prescription.
- composition according to the present invention may be formulated into any suitable pharmaceutical form, by any method known in the art, such as the one described, eg., in Remington's Pharmaceutical Sciences, ed. XVI, Mack Publ. Co., 1980.
- composition according to the invention may be formulated in any convenient pharmaceutical form, by any method known in the art, such as the one described, eg., in Remington's Pharmaceutical Sciences, ed. XVI, Mack Publ. Co., 1980.
- Pharmaceutical dosage forms for oral administration include solid pharmaceutical dosage forms, such as tablets, dragees, powders, granules, pellets and capsules.
- the liquid dosage form embrace, for example, suspensions and syrups.
- pharmaceutically accepted diluents and/ or excipients are also present.
- Pharmaceutically accepted diluents and excipients are any pharmacologically inert substances or their mixtures known in pharmaceutical practice.
- Suitable diluents for conventional release solid dosage forms include corn starch, lactose, macrocrystalline cellulose, saccharose, sorbitol, talc, mannitol, mono- or dibasic calcium phosphate, pregelatinized starch, glycine and other.
- Solid pharmaceutical compositions which are compacted into solid dosage form, such as tablet, may include other excipients to facilitate manufacturing process and to obtain drug of desired physico-chemical properties.
- Disintegrants increasing dissolution rate of a compacted solid pharmaceutical composition in patient's gastrointestinal tract, comprise for example, starch and its derivatives, croscarmellose sodium, microcrystalline cellulose, crosslinked polyvinylpyrolidon, sodium starch glycolate or other ingredients based on crosslinked polymers.
- Binders for solid form compositions include polyvinylpyrolidon, gelatin, guar gum, cellulose derivatives, hydroxypropylmethylcellulose (HPMC), hydroxycellulose, hydroxypropylcellulose, for instance.
- Lubricants contain, for example, sodium lauryl sulfate, magnesium stearate, talc, fumaric acid and others.
- the tablets may be protected with a coating as it is described, for example, in Pharmaceutical Dosage Forms and Drug Delivery Systems, H.C.Ansel, L.V.Allen, N.G.Popovich, ed. VII (1999), Lippincott Williams & Wilkins.
- a coating as it is described, for example, in Pharmaceutical Dosage Forms and Drug Delivery Systems, H.C.Ansel, L.V.Allen, N.G.Popovich, ed. VII (1999), Lippincott Williams & Wilkins.
- different substances of high molecular weight and film-forming properties are used, to enable dissolution of solid composition in appropriate part of gastro -intestinal tract. These substances are carefully selected and used together with excipients, such as plasticizers, diluents, colorants, dispersing and opacifying agents.
- liquid pharmaceutical composition of the new imatinib salts may comprise compositions for intravenous, subcutaneous or intramuscular injections, for instance.
- liquid pharmaceutical compositions comprise sterile aqueous, hydro- organic and anhydrous solutions, suspensions, dry substances as well as tablets for making solutions.
- suspensions some excipients are used to disperse active substance uniformly through the composition in the liquid carrier.
- Such emulsifying agents include, for example, polysorbates, lecitin, polyoxyethylene and polyoxypropylene copolymers, peptizers, such as phosphates, polyphosphates and citrates, water soluble polymers, such as carboxymethylcellulose, methylcellulose, polyvinylpyrolidon, gums and gelatin.
- Injection compositions contain, for example, pharmaceutically accepted excipients, such as pH-regulators, buffers, preservatives. Dry substances are designed for the preparation of solutions or suspensions ex tempore, due to dilution of the substance with suitable solvent.
- the present invention provides new imatinib salts, characterized by advantageous physico-chemical properties, such as low hygroscopicity and uniform crystalline form. These properties make new imatinib salts suitable for solid dosage forms preparation of homogenous composition.
- the invention is illustrated by the following examples, which should not be constructed to limit its scope in any way.
- Nuclear magnetic resonance spectra were recorded on Bruker Avance spectrometer type DRX 500 MHz. IR spectra were recorded on Perkin Elmer Spectrum BC spectrometer.
- composition of obtained salts was determined by nuclear magnetic resonance method ( ⁇ -NMR).
- ⁇ -NMR nuclear magnetic resonance method
- the molar ratio of acid and imatinib base was determined on the basis of signals integrations of the corresponding protons assigned to base and acid moieties, respectively.
- Imatinib base 5,0 g (0,010 mol) and diacetyl-L-tartrate anhydride 1,1 g (0,0051 mol) were dissolved in 50 ml of 96% ethanol. After 18 h, to the dense solution 50 ml portion of 96% ethanol was added and stirring was continued for 2 h. The solid was filtered off, washed with small amount of ethanol and dried under vacuum at 60°C for 24. Imatinib diacetyl-L-tartrate (1:2) of > 99,9% purity was obtained in 5,6 yield. M.p. 150-151 °C (uncorrected). The identity of the product was confirmed by spectroscopic data analysis.
- IR KBr cm- i 3264, 2829, 1735, 1650, 1577, 1538, 1480, 1453, 1421, 1373, 1324, 1291, 1247, 1225, 1182, 1130, 1054, 1026, 984, 915, 879, 851, 800, 710, 647, 585, 549, 454.
- Imatinib base 5,0 g (0,010 mol) and di-p-anizoyl-D-tartaric acid 4,24 g (0,0101 mol) were dissolved in 100 ml of methanol. After 18 h the solid was filtered off, washed with small amount of methanol and dried under vacuum at 60°C for 24 h. Imatinib di-p-anizoyl-D-tartrate (1: 1) of > 99,9% purity was obtained in 6,9 g yield. M.p. 150-152°C (uncorrected). The identity of the product was confirmed by spectroscopic data analysis.
- IR KBr cm-i 3268, 2839, 1715, 1654, 1605, 1577, 1533, 1511, 1479, 1450, 1418, 1255, 1169, 1102, 1025, 986, 850, 798, 770, 704, 646, 612.
- Imatinib base 5,0 g (0,010 mol) and di-benzoyl-L-tartaric acid 3,80 g (0,0101 mol) were dissolved in 100 ml of methanol. After 18 h the solid was filtered off, washed with small amount of methanol and dried under vacuum at 60°C for 24 h. Imatinib di-benzoyl-L-tartrate (1: 1) of > 99,9% purity was obtained in 6,3 g yield. M.p. 187-191°C (uncorrected) . The identity of the product was confirmed by spectroscopic data analysis.
- IR KBr cm-i 3251, 2837, 1714, 1643, 1599, 1579, 1544, 1507, 1482, 1454, 1424, 1334, 1308, 1293, 1265, 1209, 1172, 1106, 1068, 1038, 1023, 1005, 988, 909, 846, 796, 748, 723, 691, 671, 647, 623, 587, 546, 450.
- Microcrystalline cellulose (Vivapur) 4 5 b) Components of the outer phase of granulate:
- Imatinib mesylate granulate was dried for 20 min., sieved through # 1,0 mm mash screen (mesh gluing was observed), dried for 5 min., and sieved through # 0,8 mm mash screen.
- Granulate was blended with the components of the outer phase, compressed into tablets in a tabletting machine, using 7 mm concave punches. Tablets were obtained of average weight 145 mg.
- Active substance imatinib di-acetyl-L-tartrate was more suitable for technological process in comparison to imatinib mesylate; obtained tablets were characterized by satisfactory hardness, disintegration time and composition homogeneity.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP10784881A EP2491027A1 (en) | 2009-10-22 | 2010-10-21 | Salts of imatinib with tartaric acids |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL389357A PL389357A1 (pl) | 2009-10-22 | 2009-10-22 | Sole imatinibu z pochodnymi kwasów winowych i sposób ich wytwarzania |
PLP.389357 | 2009-10-22 |
Publications (1)
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WO2011049474A1 true WO2011049474A1 (en) | 2011-04-28 |
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PCT/PL2010/000105 WO2011049474A1 (en) | 2009-10-22 | 2010-10-21 | Salts of imatinib with tartaric acids |
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EP (1) | EP2491027A1 (pl) |
PL (1) | PL389357A1 (pl) |
WO (1) | WO2011049474A1 (pl) |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0564409A1 (de) | 1992-04-03 | 1993-10-06 | Ciba-Geigy Ag | Pyrimidinderivate und Verfahren zu ihrer Herstellung |
WO1999003854A1 (en) | 1997-07-18 | 1999-01-28 | Novartis Ag | Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
WO2004106326A1 (en) | 2003-06-02 | 2004-12-09 | Hetero Drugs Limited | Novel polymorphs of imatinib mesylate |
WO2005075454A2 (en) | 2004-02-04 | 2005-08-18 | Novartis Ag | SALT FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE |
WO2005095379A2 (en) | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
WO2006048890A1 (en) | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
WO2006054314A1 (en) | 2004-11-17 | 2006-05-26 | Natco Pharma Limited | Polymorphic forms of imatinib mesylate |
WO2007023182A1 (en) | 2005-08-26 | 2007-03-01 | Novartis Ag | Delta and epsilon crystal forms of imatinib mesylate |
EP1762230A1 (de) | 2005-08-15 | 2007-03-14 | Siegfried Generics International AG | Filmtablette oder Granulat enthaltend ein Pyridylpyrimidin |
WO2007059963A1 (en) | 2005-11-25 | 2007-05-31 | Novartis Ag | F,g,h,i and k crystal forms of imatinib mesylate |
EP1501485B1 (en) | 2002-04-23 | 2007-09-26 | Novartis AG | High drug load tablet |
-
2009
- 2009-10-22 PL PL389357A patent/PL389357A1/pl not_active Application Discontinuation
-
2010
- 2010-10-21 EP EP10784881A patent/EP2491027A1/en not_active Withdrawn
- 2010-10-21 WO PCT/PL2010/000105 patent/WO2011049474A1/en active Application Filing
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0564409A1 (de) | 1992-04-03 | 1993-10-06 | Ciba-Geigy Ag | Pyrimidinderivate und Verfahren zu ihrer Herstellung |
WO1999003854A1 (en) | 1997-07-18 | 1999-01-28 | Novartis Ag | Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
EP1501485B1 (en) | 2002-04-23 | 2007-09-26 | Novartis AG | High drug load tablet |
WO2004106326A1 (en) | 2003-06-02 | 2004-12-09 | Hetero Drugs Limited | Novel polymorphs of imatinib mesylate |
WO2005075454A2 (en) | 2004-02-04 | 2005-08-18 | Novartis Ag | SALT FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE |
WO2005095379A2 (en) | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
WO2006048890A1 (en) | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
WO2006054314A1 (en) | 2004-11-17 | 2006-05-26 | Natco Pharma Limited | Polymorphic forms of imatinib mesylate |
EP1762230A1 (de) | 2005-08-15 | 2007-03-14 | Siegfried Generics International AG | Filmtablette oder Granulat enthaltend ein Pyridylpyrimidin |
WO2007023182A1 (en) | 2005-08-26 | 2007-03-01 | Novartis Ag | Delta and epsilon crystal forms of imatinib mesylate |
WO2007059963A1 (en) | 2005-11-25 | 2007-05-31 | Novartis Ag | F,g,h,i and k crystal forms of imatinib mesylate |
Non-Patent Citations (2)
Title |
---|
"Remington's Pharmaceutical Sciences", 1980, MACK PUBL. CO. |
H.C.ANSEL; L.V.ALLEN; N.G.POPOVICH: "Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS |
Also Published As
Publication number | Publication date |
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PL389357A1 (pl) | 2011-04-26 |
EP2491027A1 (en) | 2012-08-29 |
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