WO2010081443A2 - Dosage forms of tyrosine kinase inhibitors - Google Patents

Dosage forms of tyrosine kinase inhibitors Download PDF

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Publication number
WO2010081443A2
WO2010081443A2 PCT/CZ2010/000002 CZ2010000002W WO2010081443A2 WO 2010081443 A2 WO2010081443 A2 WO 2010081443A2 CZ 2010000002 W CZ2010000002 W CZ 2010000002W WO 2010081443 A2 WO2010081443 A2 WO 2010081443A2
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WIPO (PCT)
Prior art keywords
complexes
crystals
complexes according
tyrosine kinase
imatinib
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PCT/CZ2010/000002
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English (en)
French (fr)
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WO2010081443A3 (en
Inventor
Vladimir Kral
Josef Jampilek
Jaroslav Havlicek
Hana Brusova
Tomas Pekarek
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Zentiva, K.S.
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Publication of WO2010081443A2 publication Critical patent/WO2010081443A2/en
Publication of WO2010081443A3 publication Critical patent/WO2010081443A3/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
    • A61K9/145—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 compounds
    • 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
    • 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 application relates to the use of co-crystals of API and solid dispersions of active pharmaceutical substances (API) for modern dosage forms.
  • API active pharmaceutical substances
  • Solid dosage forms may contain the API in the form of a crystal, anhydrate, hydrate, an amorphous form, a salt or a co-crystal. A number of these forms may manifest polymorphism.
  • the selection of the optimal API for a chosen dosage formulation is determined by pharmacokinetic, biological, chemical, physical and technological aspects and, in the case of generics, also by patent aspects in a remarkable extent. A great attention is paid to salts, which represent about 1/2 of all formulations today. Research of co-crystals exhibits the fastest development among all solid forms.
  • polymorphous systems are complex, which is mainly caused by a lot of possible hydrates and solvates that the molecule may create in the solid state.
  • the pharmaceutical development is mainly focused on the anhydrate (ansolvate), i.e. the pure polymorph, which is produced either by means of direct crystallization or by drying (dehydration, desolvation) of hydrated (solvated) phases. If the anhydrate cannot be used for some reasons, e.g. patent reasons, the hydrate can also be used for the preparation of a dosage form.
  • Solvates are usually not used for the formulation, but they are important precursors the desolvation of which provides meta-stable but kinetically stable phases that cannot be crystallized from a solution.
  • the shape of crystals can be influenced with crystallization additives, which are preferentially adsorbed on certain surfaces, thus blocking their growth rate.
  • the principle of action of the additives is that every crystal surface has a differently oriented building molecule in the surface layer and the additive is only bonded to certain orientations.
  • the additives can include, e.g., urea, ionic salts.
  • the very common phenomenon of polymorphism of pharmaceutical substances and especially uncontrollable polymorphous transitions make manufacturers put the crystallization of the desired polymorph from the solution under thorough kinetic and thermodynamic control.
  • the meta-stable polymorph is typically the first to crystallize, and then it passes over to a more stable form more or less quickly, so that often a polymorphous mixture is produced.
  • Controlled crystallization of active substances in the pharmaceutical production is achieved by seeding of the solution with crystals of the product. This way, reproducibility of production batches as well as the product quality is guaranteed.
  • the inoculation technique requires deep knowledge of the system (polymorphous behaviour, solubility curves, widths of meta-stable areas) to enable determination of the exact moment when the seeds should be added to the solution and in what quantity.
  • Other important factors of targeted crystallization include the type of the used crystallizer, its hydrodynamic properties, the used solvent or mixture of solvents and the crystallization additives.
  • the monitored parameters of the resulting product include: yield, chemical and physical (polymorphous) purity of crystals, distribution of their size, the shape of crystals and content of residual solvents.
  • simplification or circumvention of the polymorphism problem may consist in transition to a suitable salt if the substance can be transformed to an acidic or alkaline form.
  • co-crystal can be crystallized.
  • a co-crystal is a general compound of the host-guest type where the original host structure of the substance is synthetically complemented with a guest, which is not a solvent. The guest does not easily volatilize from the co-crystal structure (does not get desolvated), which makes the co-crystals different from the solvates. This is because firm H-bridges are often created between the components.
  • a number of co-crystals have been described, most with a simple proportion between the guest and host (1 :1, 1 :2 or 2:1).
  • Co-crystals may also be defined in another way, e.g. as general multi-component compounds, to which belong salts, hydrates and solvates as well.
  • a crystal of an organic substance organized by non-covalent intermolecular interactions should be considered as a supramolecular formation.
  • mutual recognitions occurs between individual molecules and subsequently they are arranged in accordance with the requirements of intermolecular interactions. This process is spontaneous and therefore it is referred to as "self-assembly”.
  • Exploration of intermolecular forces in general is the object of supramolecular chemistry.
  • Study of relations of non-bonding interactions with the inner structure of crystals is the field of crystal engineering.
  • crystal engineering does not have a firmly defined content yet and is used in various contexts; more frequently it is understood as the field of basic research while the application outputs are part of material chemistry.
  • crystal engineering is defined as designing crystalline structures from molecular components; it is referred to as a synonym to supramolecular synthesis of new solid phase forms with pre-envisaged stoichiometry and architecture.
  • These definitions already contain the principal subject of crystal engineering - preparation of crystalline material with desired characteristics. The effort to achieve such targeted supramolecular composition can be compared to the already successfully managed construction of molecules in organic synthesis, in which knowledge of organic chemistry and of mechanisms of chemical reactions are used to prepare new substances.
  • the purpose of the analytic phase is to collect, evaluate and sort all available information about non-bonding interaction.
  • the most important source of information is X-ray structural analysis. This is of extraordinary significance for crystal engineering because in the determined crystalline structures there is reflected the action of non-bonding interactions in the solid phase.
  • Information obtained by means of X-ray structural analysis is also used for the evaluation of interactions e.g. in solutions, even though it is a different environment. In spite of this, most particular considerations about the spatial arrangement of the guest and host molecules in a solution are based on the structure of the crystalline complex if it was possible to obtain it by the X-ray structural analysis.
  • a specific feature of the crystalline phase is that also the types of weaker non-bonding interactions are involved, especially dispersion forces, which cannot be manifested in solutions due to the dynamic effect of molecules of the solvent.
  • the evaluation and sorting of information about non- bonding interactions consists in finding characteristic interactions for certain structural types of compounds, or more specifically, for functional groups, and in understanding their influence on crystalline structure geometry. Designing building blocks
  • the findings of the analytic phase serve for designing suitable molecular construction blocks to achieve a certain crystalline structure as the basis for the synthetic phase.
  • the simplest form of designing is a design of one building molecule for mono-component self-assembly.
  • the target structure of the crystal can be achieved through planned arrangement of more suitably selected molecular components.
  • Each of the components may participate in the formation of the structure in a different way.
  • the involvement of the components may continuously change from the guest-host relationship, where the framework of the structure is made of one type of molecules (host) and is filled with guest molecules, up to structurally equal molecular components.
  • a suitably designed tecton should have a sufficiently rigid structure to be able to truly transfer the geometrical information from the shape of its molecule to the structure of the crystal. It should also contain such functional groups or structural elements that participate in intermolecular contacts with predictable parameters. These interactions should be directed in order to form the expected structural pattern and sufficiently strong to be able to assert themselves in the self-assembly process with their energy contribution.
  • composition of such ideal tectons can be compared to a brick-box construction.
  • Individual bricks represent perfectly rigid molecules of the tecton (or more tectons respectively) and the connection protrusion/cavities of the bricks illustrate intermolecular contacts defined by the direction and type.
  • This illustration of crystal composition is considerably different from the actual condition. When working with bricks you must select each of the bricks, turn it in a suitable way and put it in the right place to get the desired formation as various constructions can be made of the same bricks.
  • Molecular building units also exhibit such composition variability and the resulting isomerism on the supramolecular level of crystalline structures is called polymorphism (this phenomenon with important significance for crystal engineering will be described in a more detailed way below).
  • a targeted crystal structure may be designed as an arrangement of molecules of one type (mono-component self-assembly) or the structure may be constructed of more building blocks (multi-component self-assembly).
  • these molecules must be self-complementary from the point of view of non-bonding interactions and the shape of the molecule and the layout of groups for the planned non- bonding interactions must define the geometry of the crystalline structure.
  • multi- component self-assembly the individual structural molecules generally differ in their chemical character as well as in directionality of the functional groups.
  • one of the factors of development of crystal engineering includes requirements for new materials with specific characteristics.
  • a task of crystal engineering is - if not to directly bring such materials - to look for and verify the ways of their formation through crystal self-assembly.
  • An overview of non-bonding interactions indicates that the requirements of strength and directionality that are necessary for the crystal design are best fulfilled by hydrogen bonds.
  • Some examples will be mentioned for various geometrical types of structures.
  • Other types of non-bonding interactions often significantly contribute to the resulting design of the crystal structure.
  • their use in the field of crystal engineering is limited.
  • CML chronic myelogenous leukaemia
  • Chronic myelogenous leukaemia is a myeloproliferative disease characterized by the presence of abnormal fusion gene BCR-ABL, which codes the constitutively active Bcr-Abl tyrosine kinase.
  • BCR-ABL abnormal fusion gene
  • Bcr-Abl tyrosine kinase The activity of this kinase is necessary and sufficient for cell transformation, and therefore it is an ideal target of pharmacotherapy.
  • Imatinib mesylate (Glivec(R)) a specific inhibitor of Bcr-Abl kinase, has become the medicament of choice in patients with newly diagnosed chronic myelogenous leukaemia for its high efficiency and low toxicity.
  • Imatinib therapy is the development of resistance.
  • Mechanisms of the development of resistance to Imatinib can be divided into two basic groups - dependent and independent of Bcr-Abl kinase.
  • Imatinib does not inhibit Bcr-Abl kinase at all or inhibits it in an insufficient manner.
  • the most frequent causes of this type of resistance are amplification of the BCR-ABL gene, increased expression of the Bcr-Abl protein or mutation in the AbI kinase domain.
  • Imatinib (it is contained in the mesylate form - EVI - in the product) is a derivative of phenylaminopyrimidine. It acts as a selective competitive inhibitor of tyrosine kinases ABL, BCR/ ABL, c-Kit, PDGFR-a, PDGFR-b and Arg.
  • Imatinib is indicated for treatment of patients with Philadelphia chromosome - Ph (or bcr/abl) positive chronic myelogenous leukaemia (CML) in the first line, with Ph+ acute lymphoblastic leukaemia (ALL), gastrointestinal stromal tumour, chronic eosinophilic leukaemia, or hypereosinophilic syndrome, and systemic mastocytosis with FIPlLl/PDGFR-a or ETV6/PDGFR-b positivity.
  • CML chronic myelogenous leukaemia
  • ALL Ph+ acute lymphoblastic leukaemia
  • gastrointestinal stromal tumour chronic eosinophilic leukaemia
  • hypereosinophilic syndrome or systemic mastocytosis with FIPlLl/PDGFR-a or ETV6/PDGFR-b positivity.
  • Glivec Novartis
  • IM interacts with the Bcr/Abl ( ⁇ 210) protein in a nucleotide binding site such that it prevents the ATP from binding, thus stabilizing the Bcr/Abl protein in the inactive conformation. Thanks to this the active phosphate is not transferred to tyrosine of the proteins that belong to the substrates of the Bcr/Abl protein.
  • the blocking of phosphorylation of the tyrosine residues of proteins stops the activation of a number of signal pathways that participate in the formation of the leukaemic phenotype of the cell.
  • IM does not prevent production of the BCR/ ABL leukaemic gene, which plays the key role in the development of CML, but prevents its effect from being applied on the protein level. According to present findings the effect of IM onto leukaemic cells leads to their apoptosis and causes proliferation of the pathological clone to stop. It is true that IM also reacts with other tyrosine kinases that have an important position in a number of physiological processes (AbI, c-Kit, PDGFR); however, the growth of normal cells is not significantly affected, probably due to compensation mechanisms and the existence of alternative signal pathways.
  • EVI is absorbed quickly and achieves the maximum concentration in plasma approx. 1 to 3 hours after administration, independently of simultaneous food intake. Bioavailability of the substance exceeds 97%.
  • the biological half-time of Imatinib elimination varies in the range of 15 to 20 hours, which allows administration in one daily dose.
  • the pharmacokinetic parameters do not change after repeated administration and the balanced condition is achieved at plasmatic concentrations of 1.5 to 3 times higher than those achieved after a single administration.
  • the state of equilibrium is achieved approximately after one- month administration.
  • Imatinib is bio-transformed in the liver with the cytochrome P-450 system, especially with the CYP3A4 isoenzyme.
  • the degradation results in a number of substances that are excreted from the organism predominantly in faeces (about 70%); a smaller part in urine (10%). About 20% of the administered dose is excreted in faeces in the initial form. About 80% of the drug is excreted within a week, the terminal half-time of elimination after one dose amounts to three weeks.
  • the performed studies did not confirm any significant influence of age or sex on the pharmacokinetic characteristics of Imatinib. Therefore, in children EVI can be applied in the doses of 260-340 mg/m 2 , which correspond to the dose of 400 to 600 mg in adults. Similarly, there are no limitations in elderly persons.
  • the reported drug interactions are related to the bio-transformation of the drug in the liver.
  • Inductors e.g. dexamethasone, phenytoin, carbamazepine, rifampicine or phenobarbital
  • inhibitors of CYP3A4 e.g. ketoconazole, itraconazole, erythromycin, ciclosporin or clarithromycin
  • administration of EVI together with simvastatin increases the maximum concentration of this drug to twice the value and reduces its clearance by 70%.
  • EvI is usually administered in a dose of 400 to 800 mg once a day during a meal with a sufficient quantity of liquid. From the point of view of occurrence of undesired gastrointestinal effects it is recommended to use EVI during the largest meal of the day. In hitherto studies the maximum tolerated dose has not been described, but doses exceeding 1,000 mg do not cause a significant increase of efficiency. Conversely, with doses below 300 mg the efficient plasmatic concentration cannot be achieved and this is why they are not recommended.
  • a 400 mg dose is used in most of the indications as the starting dose, 600 to 800 mg doses are indicated in more advanced stages of CML and a gastrointestinal stromal tumour and they can also be tested with the aim to overcome resistance. Crystalline forms of Imatinib
  • Cipla - Imatinib mesylate Preparation of form alpha, form alpha; Stable crystal form; Stable crystal form of needle crystals
  • WO04106326A1 HeteroDrugs - Crystalline form Hl; Imatinib mesylate hydrate
  • CML chronic myelogenous leukaemia
  • Imatinib is able to induce a complete cytogenetic response and molecular genetic response in 6-12 months in a great part of patients in the early stage of CML. All the patients who after 12 months of Imatinib treatment manifested a complete cytogenetic response and at the same time reduction of BCR/ ABL > 3 log transcripts have been alive for 54 months without progression into the accelerated phase or blastic reversal (1).
  • the primary goal of CML treatment in the era of Imatinib has become the achievement of the best possible cytogenetic and molecularly genetic response within the shortest possible time and maintaining of this response as long as possible.
  • a novelty that will be mainly appreciated by patients is a change of the dosage form of Glivec®, which is available in the form of 400mg film-coated tablets from this year.
  • Glivec® which is available in the form of 400mg film-coated tablets from this year.
  • the interest of research institutes as well as clinicians is focused on the issue of resistance to Imatinib, which appears in the early chronic stage of CML in less than 5% of patients a year, but in more advanced stages of the disease it has been observed much more frequently.
  • In the blastic reversal primary resistance was found in 66% of patients, relapse of progression in more than 80% of patients treated with Imatinib and it generally appears within 3-6 months of treatment.
  • Primary resistance to Imatinib is rare and its causes have not been thoroughly investigated.
  • the most frequent cause of acquired resistance to Imatinib is point mutations in the site of the kinase domain of the BCR-ABL fusion gene. So far, more than 40 various mutations related to resistance to Imatinib have been described; they differ in the site of formation, frequency of occurrence and clinical significance.
  • the mutation caused by the exchange of amino acids in position 315 (T315I), which prevents binding of Imatinib to kinase, is considered the most frequent and most serious cause of resistance to Imatinib at present.
  • Imatinib Less frequent causes of resistance to Imatinib are overproduction (amplification) of the BCR-ABL gene, gene instability, development of a new clone, independent of BCR-ABL and pharmacological factors (alpha- 1 glycoprotein, cell transport mechanisms).
  • Prevention of development of resistance to Imatinib consists in the initial standard dosing of Imatinib and permanent uninterrupted treatment. Serious toxicity should be the only reason to reduce doses of Imatinib. In some cases resistance can be overcome by increasing of the Imatinib dose. Patients that have acquired resistance to Imatinib are indicated for transplantation of haematopoietic cells, or may be included in clinical studies with inhibitors of kinases of the next generation (Dasatinib, Nilotinib).
  • Dasatinib (BMS-354825, thiazo carboxamide) differs from Imatinib in its structure and binding in the active sphere of AbI kinase. Its efficiency is 300 times higher in comparison to Imatinib, it also inhibits SRC kinases. It is administered orally and is effective in most mutations of the BCR-ABL gene. At present, Dasatinib is available in the Czech Republic in the frame of clinical studies.
  • Nilotinib (AMNl 07, aminopyrimidine) is similar to Imatinib in its structure, it binds in the inactive area of AbI kinase and is 25 times more efficient than Imatinib. 32 out of 33 cell lines with mutations of the BCR-ABL gene were sensitive to Nilotinib; only cells with mutation of T315I exhibited resistance.
  • controlled release of the drug has been used in the international terminology since 1970's. However, the terminology is not unified and besides the term controlled release, also modified release, protracted release or gradual release of drug are used. In our country the term controlled release is first mentioned as standard by the Czech Pharmacopoeia issued in 2002. It distinguishes several types of controlled release: protracted, retarded and pulse.
  • protracted drug release means ensuring the therapeutic level of the pharmaceutical substance in the blood plasma for the required time interval, i.e. for a longer time than would occur after application of a single dose of the drug resulting from its pharmacokinetic characteristics (binding to proteins, metabolism, elimination).
  • the delayed and pulse drug release is associated with the findings about the influence of circadian biorhythms onto physiological functions and the development of some diseases (chronopharmacology) published by numerous experts in late 1990's.
  • Release of drug after a pre-determined time following the administration finds its use e.g. when night application of the medicament is necessary, i.e. in case of asthmatic attacks, manifestations of early waking up, in the prevention of unpleasant morning feelings related to, e.g., arthritis or Parkinson's disease, or if it is necessary to deliver the drug to a certain effective place in the gastrointestinal tract (GIT), e.g. in the duodenum or colon.
  • Pulse dosing can be used e.g. if physiological repeated daily application of a drug (insulin) is necessary or if tolerance to the administered pharmaceutical substance develops.
  • Dosage forms of the 2 nd generation control releasing of the drug.
  • Solid oral medicament forms of the 2nd generation are divided into dosage forms with protracted, retarded and pulse release of the drug.
  • Solid oral dosage forms with protracted release of the drug can be divided into retardets and oral therapeutic systems. Preparations with protracted release are not only distinguished by their indication (SR, CR, RET, MR), but also by the fact for how long they are able to release the drug in the protracted way and by the release kinetics. Based on these two parameters the physician can select from individual preparations. For the patient zero order kinetics is the most convenient as a constant amount of the drug per time unit is released into the organism; the dependence of the total amount of released substance in time has the shape of a straight line.
  • Solid oral dosage forms of the 2 nd generation with protracted release of the drug include preparations with and acid-resistant coating, preparations releasing the drug in the colon only, coated tables with protracted release of the substance, the Pulsincap® system and others, characterized by the fact that they release the whole amount of the drug in a retarded manner based on a change of the environment (pH changes in different parts of GIT, presence of bacterial microflora in the colon), or based on a technological intention.
  • API's represent extremely valuable "core" materials for the pharmaceutical industry.
  • BCS II and IV i.e. newly developed molecules exhibit poor solubility in physiological conditions or are difficult to absorb, or possibly they manifest both these principal problems for dosage form development.
  • These problems are traditionally solved by the formation of salts, as well as of polymorphs, hydrates, solvates, or nanoparticles, of the API.
  • Pharmaceutically useful co-crystals have been profiled as one of the modern approaches to obtaining API's with the desired physical and chemical parameters. In comparison to the other groups of solid forms of API's, co-crystals offer a number of benefits both in the sense of modulation of API characteristics (a unique structure and the profile of physical and chemical characteristics associated therewith) and in the sense of IP.
  • co-crystals as crystalline molecular complexes provide an alternative solid modification of API's to salts and polymorphs, although this domain has not reached their status yet.
  • the definition of molecules with which API's can form a co-crystal is very wide from the point of view of regulatory authorities, e.g. according to the definition of FDA this is any component that may be part of food in the U.S. At present, more than 3000 such components have been defined in the U.S.
  • prospective candidates can be selected on the basis of a reasonable design with regard to the formation of hydrogen bonds and modulation of characteristics of the studied API in the sense of solubility, stability (both chemical and morphological), dissolution profile and biological availability.
  • Co-crystallization (design, preparation and use of co-crystals) is a dynamically developing field with great application possibilities in the sphere of pharmaceutical industry. Benefits are evaluated on the case to case basis, which also holds good for the strategy of formation of co- crystals, where a general prediction theory allowing determining suitable co-crystallization partners without an experiment is very remote for the time being. Since this field often permits bigger modifications of physical-chemical characteristics with the aim to achieve bioavailability than simple polymorphism together with IP protection of the product, it is obvious that dynamic development in this field will continue.
  • the improved characteristics concern hygroscopicity, solubility, dissolution kinetics, chemical morphological stability and, last but not least, transport characteristics of API's.
  • inhibitors of tyrosine kinases are polyaromatic substances, insoluble in water in the base form, production of co-crystals with highly hydrophilic excipients represents a possibility how to formulate these highly hydrophobic substances, strongly aggregating in the physiological environment.
  • co-crystals can be used for purification of API's, namely in the sense of both chemical, morphological (e.g. stabilization of the usually instable amorphous form), and optical purity.
  • the method of preparation of co-crystals of kinase inhibitors according to the present invention represents a very simple, industrially applicable procedure, the principle of which consists in a designed and controlled crystallization of the API with selected excipients and with easy isolation of the product by filtration or centrifugation.
  • the method of preparation is illustrated in the examples below.
  • the invention relates to new complexes of inhibitors of tyrosine kinases containing one or several carriers - tectons, soluble in water, able to form strongly directed intermolecular contacts with the active substance, the molar proportion of the active substance and the monomelic tecton or the number of monomeric units of the polymeric tecton being 1 : 1 to 0.1 : 99.9.
  • the invention also includes preparation procedures of these complexes and their use.
  • the invention relates to new complexes of inhibitors of tyrosine kinases, containing one or several carriers - tectons, soluble in water, able to form strongly directed intermolecular contacts with the active substance, the molar proportion of the active substance (API) and the monomeric tecton or the number of monomeric units of the polymeric tecton being 1 : 1 to 0.1 : 99.9.
  • the invention also includes preparation procedures of these complexes and their use.
  • the components are not bound by covalent bonds, but supramolecular, non-covalent interactions are involved, which are based, in a combined way or individually, on hydrogen bonds, hydrophobic interaction, use of van der Waals forces, ⁇ - ⁇ interactions, interaction of halogens, as well as on coordination and dipole-dipole interactions.
  • the kinase inhibitor for the formation of the complex is selected from the group comprising: Axitinib, Bosutinib, Cediranib, Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sunitinib, Vandetanib, Sorefenib, Tipifarnib. Imatinib appears to be especially preferable.
  • the kinase inhibitor used may be in the form of a base or salt and in a crystalline or amphoteric form.
  • the kinase inhibitor may be in the form of a salt with an alkyl or aryl sulfonic acid, hydrochloric, sulfuric, phosphoric, formic, acetic, oxalic, tartaric, citric and fumaric acids, preferably with methane sulfonic acid.
  • the tectons either low-molecular substances or substances of the polymeric character are used. If a low-molecular compound is used as the tecton, the resulting complex may have a crystalline character; if a polymeric tecton is used, the resulting complex has the form of a solid solution.
  • substances selected from the group including mono- and oligosaccharides with 1 to 9 monomeric units, ascorbic acid, vitamins A and E, amino acids, guanidine and its derivatives, urea, thiourea, aminosaccharides, amides of aliphatic and aromatic acids, sulfoamides, surfactants-excipients, such as tween 80, are used.
  • the complex can also be composed of two or more complementary tectons, which are complementary to the surface of the active substance at the same time.
  • the composition of the complexes can be controlled by the molar proportion of the active substance and excipient.
  • the proportion of the active substance (API) and the excipient (tecton) can be also used to influence solubility and bio-availability of the resulting complex.
  • Complexes of kinase inhibitors are prepared by crystallization, where water or a mixture of water and an organic solvent, preferably ethanol, is used as the solvent, optionally with the addition of a buffer for optimal pH for the formation of the active substance-excipient complex.
  • the organic solvent alone may be used, preferably an alcohol ROH with 1 to 8 carbon atoms, a bipolar aprotic solvent, a mixed organic solvent, preferably EtOH and DMSO, supercritical liquids (liquid carbon dioxide with 1 to 10 % of EtOH).
  • Crystallization is carried out in the temperature range of -80 °C to +120 0 C.
  • kinase inhibitors in the form of complexes appears very convenient for the preparation of a pharmaceutical composition.
  • a medicament prepared using these complexes has considerably better characteristics than a medicament prepared using a non-complex ed active substance, it has better solubility, biological availability and is also considerably more stable.
  • Complexes of kinase inhibitors enable preparation of pharmaceutical compositions for treatment of chronic myelogenous leukaemia (CML), acute lymphoblastic leukaemia (ALL), gastrointestinal stromal tumour, chronic eosinophilic leukaemia, or hypereosinophilic syndrome, and systemic mastocytosis. They also enable preparation of a composition with controlled release of the active substance.
  • CML chronic myelogenous leukaemia
  • ALL acute lymphoblastic leukaemia
  • gastrointestinal stromal tumour chronic eosinophilic leukaemia
  • hypereosinophilic syndrome and systemic mastocytosis.
  • the invention relates to the formation of complexes (either in the form of co-crystals or in the form of solid dispersions) of both the crystalline and amorphous form of the active substance (API), which makes it possible to influence both the dissolution kinetics and chemical and morphological stabilization for the family of substances of tyrosine inhibitors in the desired way.
  • API active substance
  • non-covalent complexes itself, based on mixing of the API and excipient in a suitable proportion and in a suitable solvent, or by mixing in the solid phase or by melting;
  • API-excipient proportion can be varied in a wide range from 1 to 99% of API in the selected excipient.
  • Preferred is a method of production of a precisely defined complex in the molar proportion of 1:1, 1:2, 1:1.5, 1:3, 1 :4, or 1:10 for low-molecular excipients.
  • the proportion is defined by the initial molar proportion API- excipient, which can be also expressed as the proportion of the number of monomers to the API. After crystallization the API is in a crystalline form, or after precipitation or evaporation it is in the amorphous form, stabilized with a high-molecular excipient, typical for the use of functionalized polysaccharides.
  • Solvent evaporation is performed by lyophilization, evaporation in vacuum, removal by distillation, fluidization drying.
  • Characterization is performed, besides the above mentioned spectroscopic techniques, also by thermal techniques.
  • the entire process is based on: - Production of the defined complex in a solution;
  • a dosage form for oral administration such as capsules, tablets, granules or powder.
  • the co-crystals or solid dispersion are mixed with excipients for the production of the final dosage form, both in the solid and liquid form, both the co-crystals and the solid dispersion being subsequently soluble in water and allow to adjust the API characteristics to the desired values, be it both the dissolution and stability and absorption characteristic.
  • composition of the dosage form can then be both solid and liquid, or possibly semi-solid for oral and subcutaneous administration, and the forms can be prepared in the sterile form.
  • Pharmaceutically applicable excipients can principally include all commonly used excipients.
  • FT-Raman spectra were measured on a FT-Raman spectrometer, RFS 100/S (Bruker, Germany) by accumulation of 256 scans with the spectral resolution of 2 cm “1 and laser power of 25O mW.
  • NMR spectra were measured on a Bruker AVANCE 500 MHz NMR spectrometer using a 4 mm CP/MAS probe; rotation speed 13 kHz, contact time 2 ms, number of scans 500.
  • NIR spectroscopy The records presented were obtained using a Smart Near-IR UpDriftTM NicoletTM 6700 FT-IR/NIR spectrometer, Thermo Scientifis, U.S.A. By comparison with the spectra of individual starting substances significant changes or interactions were observed in the spectra of all the presented samples.
  • Fig. 1 FT-Raman spectra of Imatinib mesylate-guanidine HCl in aqueous suspensions (repeatedly prepared samples) in comparison with the Imatinib molecule alone (at the top).
  • Fig. 2 FT-Raman spectra of Imatinib mesylate-guanidine HCl (repeatedly prepared samples) in comparison with the Imatinib molecule alone (at the top).
  • Fig. 3 FT-Raman spectra of Imatinib mesylate-N-methylglucamine HCl (in the middle) in comparison with the alone molecules of Imatinib (at the top) and N-methylglucamine (at the bottom).
  • Fig. 4 FT-Raman spectra of Imatinib mesylate-lactose in the middle in comparison with the input substances Imatinib (at the top) and lactose (at the bottom).
  • Fig. 5 FT-Raman spectra of Imatinib mesylate-L-arginine (two spectra in the middle) in comparison with the input substances Imatinib (at the top) and L-arginine (at the bottom).
  • Fig. 6 FT-Raman spectra of Imatinib mesylate-L-histidine (in the middle) in comparison with the input substances Imatinib (at the top) and an L-histidine (at the bottom).
  • Fig. 7 FT-Raman spectrum of co-crystals of Imatinib mesylate-glucose (at the bottom) in comparison with the used Imatinib mesylate.
  • Fig. 8 Comparison of 13 C CP/MAS spectra of polymorphs of Imatinib mesylate (alpha - in the middle, beta - at the top) and their mixture 1 : 1 (at the bottom).
  • Fig. 9 Comparison of 13 C CP/MAS spectra of Imatinib base (at the bottom) and Imatinib mesylate-guanidine HCl (at the top). The spectra indicate a complete change of the form of Imatinib. The signal of guanidine HCl indicates interactions of both the components.
  • Fig. 10 X-ray diffraction record of Imatinib mesylate-L-arginine; the sharp peaks are caused by the covering foil.
  • Fig. 11 X-ray diffraction record of Imatinib mesylate-guanidine HCl; characteristic peaks: 3.95; 15.63; 17.93; 22.25° 2theta ⁇ 0.2° 2theta.
  • Fig. 12 X-ray diffraction record of Imatinib mesylate-alginic acid; the sharp peaks are caused by the covering foil.
  • Fig. 13 X-ray diffraction record of Imatinib mesylate-guanidine HCl; characteristic peaks: 5.13; 7.30; 10.55; 15.10; 16.69 ° 2theta ⁇ 0.2° 2theta.
  • Fig. 14 X-ray diffraction record of Imatinib mesylate-pectin 3; the sharp peaks are caused by the covering foil.
  • Fig. 15 X-ray diffraction record of the complex (solid dispersion of the amorphous form of the API for Imatinib mesylate-alginic acid); characteristic peaks: 3.1; 7.3; 9.0; 10.9; 17.1° 2theta ⁇ 0.2° 2theta.
  • Fig. 16 X-ray diffraction record of the Imatinib mesylate-pectin 4 complex; characteristic peaks: 3.1; 7.3; 9.0; 10.9; 12.2° 2theta ⁇ 0,2° 2theta.
  • Fig. 17 X-ray diffraction record of the co-crystal of Imatinib mesylate- fructose; characteristic peaks: 5.06; 10.1; 16.85; 19.59, 24.41; 28.41° 2theta ⁇ 0.2° 2theta.
  • Fig. 18 NIR spectrum of Imatinib mesylate+glucose.
  • Fig. 19 NIR spectrum of Imatinib mesylate+L-arginine.
  • Fig. 20 NIR spectrum of Imatinib mesylate+N-methylglucamine.
  • Fig. 21 NIR spectrum of Imatinib mesylate+pectin 3.
  • Fig. 22 NIR spectrum of Imatinib mesylate+pectin 4.
  • Fig. 23 NIR spectrum of Imatinib mesylate+alginic acid (proportion 1 :1).
  • Fig. 24 NIR spectrum of Imatinib mesylate+alginic acid (proportion 1 :5).
  • Fig. 25 NIR spectrum of a solution of Imatinib mesylate+guanidine hydrochloride (proportion 1 :1).
  • Fig. 26 NIR spectrum of Imatinib mesylate+guanidine hydrochloride (proportion 1 :1).
  • Fig. 27 NIR spectrum of Imatinib mesylate+guanidine hydrochloride (proportion 1:5).
  • Fig. 27 NIR spectrum of Imatinib mesylate+guanidine hydrochloride (proportion 1 :5).
  • Example 1 1 mmole of Imatinib mesylate was dissolved in water (10-50 ml), then a solution of 1-50 molar equivalents of guanidine hydrochloride (in 3-150 ml of water) was added at the temperature of 25 0 C and this mixture was left to crystallize for 1-24 hours.
  • the product co- crystals of Imatinib mesylate with guanidine hydrochloride was aspirated and dried in vacuo at a temperature of 20-30°C and characterized by means of elementary analysis (C,H,N,S) and a series of spectroscopic and thermal methods; DSC, ssNMR, Raman, FTIR, NIR and XRPD X-ray structural analysis.
  • Imatinib mesylate 500 mg were dissolved in MeOH (10-50 ml), then a solution of 50 mg of guanidine hydrochloride (in 3-15 ml of water) was added at the temperature of 25°C and this mixture was left to crystallize for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate with guanidine hydrochloride) was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 150 mg of L-arginine hydrochloride (in 3-15 ml of water) was added at the temperature of 25°C and this mixture was left to crystallize for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate) was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 100 mg of N-methylglucamine hydrochloride (in 3-15 ml of water) was added at the temperature of 25 0 C and this mixture was left to crystallize for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate) was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 100 mg of N-methylglucamine hydrochloride (in 3-15 ml of water) was added at the temperature of 25 0 C and this mixture was left to crystallize at 5°C for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate) was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Example 7 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then a solution of 100 mg of fructose (in 3-15 ml of water) was added at the temperature of 25 0 C, then 20-50 ml of EtOH were added and this mixture was left to crystallize at 0-20°C for 1-24 hours.
  • the product co- crystals of Imatinib mesylate with fructose was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 100 mg of glucose (in 3-15 ml of water) was added at the temperature of 25°C, then 20-50 ml of EtOH and 3 ml of a IM solution of KCl were added; this mixture was left to crystallize at -5 to 25 0 C for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate with glucose) was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 500 mg of lactose (in 3-15 ml of water) was added at the temperature of 25°C, then 20-50 ml of EtOH and 3 ml of a IM solution of KCl were added; this mixture was left to crystallize at 0-20°C for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate) was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in MeOH (10-50 ml) and placed in an autoclave together with 200 mg of polylactide-polyglycolide, then solid CO 2 (10-100 g) was added, possibly modified with a polar solvent, e.g. EtOH, heated to 80°C, crystallization in the temperature range of 60-0°C. This mixture was left to crystallize for 1-24 hours.
  • the product (co-crystals of Imatinib mesylate) was aspirated and dried in vacuo at a temperature of 20- 30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 100 mg of alginic acid (in 3-15 ml of water) was added at the temperature of 25 0 C; this mixture was left to crystallize at 25°C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a solution of 100 mg of a pectin (list of pectins - see the attached table, they differ in the carboxylate-ester proportion) (in 3-15 ml of water) was added at the temperature of 25°C; this mixture was left to crystallize at 25 0 C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20- 30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a 1% solution of beta glucan (in 3-15 ml) was added at the temperature of 25 0 C; this mixture was left to crystallize at 25°C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20- 30 0 C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a 1% solution of beta glucan (in 3-15 ml) was added at the temperature of 25°C, 3-15 ml of methanol were added; this mixture was left to crystallize at 25°C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then a 1% solution of dextran (in 3-15 ml) was added at the temperature of 25°C, 3-15 ml of MeOH were added; this mixture was left to crystallize at 25°C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Example 19 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then an aqueous solution of 50 mg of guanidine hydrochloride was added at the temperature of 25 0 C, followed by a solution of 50 mg of dextran (in 3-15 ml); this mixture was left to crystallize at 25°C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Example 20 500 mg of Dasatinib were dissolved in MeOH (10-50 ml), then an aqueous solution of 500 mg of fructose was added at the temperature of 25 0 C, followed by a solution of 500 mg of alginic acid (in 3-15 ml); this mixture was left to crystallize at 25°C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of lactose was added at the temperature of 25°C, followed by a solution of 50 mg of alginic acid (in 3-15 ml) and then 3-15 ml of ethanol were added; this mixture was left to crystallize at 25 0 C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of fructose was added at the temperature of 25°C, followed by a solution of 150 mg of sucrose (in 3-15 ml) and then 3-15 ml of ethanol were added; this mixture was left to crystallize at -15 0 C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Example 23 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of fructose was added at the temperature of 25°C, followed by a solution of PEG 1500 (in 3-15 ml) and then 3-15 ml of ethanol were added; this mixture was left to crystallize at 20 0 C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20- 30 0 C and characterized.
  • Example 25 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of Pluronic F 68 was added at the temperature of 25°C, followed by a solution of dextran (in 3-15 ml of water); this mixture was left to precipitate at 25 0 C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then an aqueous solution of 250 mg of Pluronic F 68 was added at the temperature of 25°C, followed by a solution of 250 mg of PEG chitosan (in 3-15 ml of water); this mixture was left to precipitate at 25°C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.
  • Imatinib mesylate 500 mg were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of L-histidine was added at the temperature of 25°C, followed by a solution of PEG 1500 (in 3-15 ml), then 3-15 ml of ethanol were added; this mixture was left to crystallize at 20 0 C for 1-24 hours.
  • the product was aspirated and dried in vacuo at a temperature of 20- 3O 0 C and characterized.
  • Example 28 500 mg of Imatinib mesylate, or possibly other kinase inhibitors, were dissolved in water (10- 50 ml), then an aqueous solution of 150 mg of nicotinamide was added at the temperature of 25°C, followed by a solution of 100 mg of PVP (in 3-15 ml); this mixture was left to crystallize at 20 0 C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized. Stability of the co-crystals was evaluated in stress tests by means of HPLC with the result that the co-crystals show significant chemical stability as compared to the non-modified API.
  • Example 29 500 mg of Imatinib mesylate, or possibly other kinase inhibitors, were dissolved in water (10- 50 ml), then an aqueous solution of 150 mg of nicotinamide was added at the temperature of 25°C, followed by a solution of 100 mg of PVP (in
  • Example 30 500 mg of Lapatinib were dissolved in MeOH (10-20 ml), then an aqueous solution of 250 mg of galactose was added at the temperature of 25 0 C. This mixture was left to crystallize at 2O 0 C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0 C and characterized.

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WO2011023146A1 (en) * 2009-08-26 2011-03-03 Zentiva, K.S. Imatinib mesylate polymorphs generated by crystallization in aqueous inorganic salt solutions
WO2011063776A2 (en) 2009-11-25 2011-06-03 Zentiva, K.S. Soluble beta-glucan-api complexes for pharmaceutical use
CN102188365A (zh) * 2011-05-11 2011-09-21 中山大学 一种难溶性药物共晶固体分散体及其制备方法
JP2021073228A (ja) * 2012-01-13 2021-05-13 エックススプレイ ファーマ パブリーク・アクチエボラグＸＳｐｒａｙ Ｐｈａｒｍａ ＡＢ（ｐｕｂｌ） 少なくとも１種のプロテインキナーゼ阻害剤及び少なくとも１種のポリマー性安定化マトリックス形成性成分を含む安定な非晶質のハイブリッドナノ粒子を製造する方法
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