(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 22 July 2010 (22.07.2010) WO 2010/081443 A2

(51) International Patent Classification: Not classified (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, PCT/CZ20 10/000002 CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (22) International Filing Date: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 13 January 2010 (13.01 .2010) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (25) Filing Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (26) Publication Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (30) Priority Data: TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. PV 2009-8 13 January 2009 (13.01 .2009) CZ (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): ZENTI- kind of regional protection available): ARIPO (BW, GH, VA, K.S. [CZ/CZ]; U Kabelovny 130, 102 37 Praha GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (CZ). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, (72) Inventors; and ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (75) Inventors/Applicants (for US only): KRAL, Vladimir MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, [CZ/CZ]; Na Kozacce 8, 120 00 Praha 2 (CZ). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, JAMPILEK, Josef [CZ/CZ]; Husova 17, 293 0 1 Mlada ML, MR, NE, SN, TD, TG). Boleslav (CZ). HAVLICEK, Jaroslav [CZ/CZ]; Dono- valska 1659, 149 00 Praha 4 (CZ). BRUSOVA, Hana Declarations under Rule 4.17: [CZ/CZ]; Martinicka 3, 197 00 Praha9 (CZ). — as to applicant's entitlement to apply for and be granted PEKAREK, Tomas [CZ/CZ]; Renoirova 620, 150 00 a patent (Rule 4.1 7(H)) Praha 5 (CZ). Published: (74) Agent: JIROTKOVA, Ivana; Rott, Ruzicka & Guttmann, P.O. Box 44, 120 00 Praha 2 (CZ). — without international search report and to be republished upon receipt of that report (Rule 48.2(g))

(54) Title: DOSAGE FORMS OF TYROSINE KINASE INHIBITORS (57) Abstract: Co-crystals of inhibitors of tyrosine kinases, especially of Imatinib mesylate, have been found as a suitable form of API for dosage forms, both conventional and with controlled release for medicaments of the second generation. Complexes of ki- nase inhibitors with functionalized polysaccharides form solid dispersions suitable for pharmaceutical applications. Dosage forms of tyrosine kinase inhibitors

Technical Field:

The present application relates to the use of co-crystals of API and solid dispersions of active pharmaceutical substances (API) for modern dosage forms.

Background Art:

The present pharmaceutical industry uses a variety of solid pharmaceutical substances for the formulation of a dosage form. 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.

Identification and production of the optimal API form for the development of a dosage form is one of the principal tasks. In the pharmaceutical production empirical and theoretical approaches are combined for the optimization of crystallization conditions, just with regard to frequent polymorphous behaviour of API's and the sensitivity of the transition from the laboratory scale to the semi-production and production scales. Generic companies, e.g. for the reason of circumventing patent protection or therapeutic benefits, select an instable polymorph (hydrate). For targeted production of an instable polymorph (hydrate) inoculated crystallization is used. A problem occurs if no crystallization seed is available as there is no universal technique of how to regulate the polymorphous behaviour of a certain API in the desired direction, i.e. to produce a certain polymorph in a robust and reproducible way. This fact is related to the present absence of a fundamental theory of polymorphism. The fact which polymorph will crystallize is determined in the pre-nucleation stage, i.e. in molecular aggregates, on the basis of competition of kinetic and thermo-dynamical factors. Recently, there has been an effort to monitor and control the pre-nucleation and nucleation mechanisms directly in the molecular scale (crystal engineering). For this purpose various surfaces that initiate nucleation are used, e.g. polymers, Langmuir- Blodgett films, graphite, specifically oriented crystalline surfaces of substrates, etc. These surfaces specifically interact with pre-nucleation clusters. If a certain polymorph has similar lattice geometry as the substrate, epitaxial growth occurs. In the case of a polymorph that exhibits considerable lattice incoherence with regard to the substrate the growth is blocked. This means that the substrate surface has a polymorph selective function. 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. During spontaneous nucleation 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. However, 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. In the case of complex polymorphous systems 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.

Alternatively, a so-called 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. During the formation of crystals 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.

Definition and goals of crystal engineering

The term 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. Nowadays, 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. Analogously, for a successful result of crystal engineering it would be necessary to not only select properly designed molecular building blocks, but also to control the involvement of individual types of non-bonding interactions in crystal formation and to influence all aspects of the crystallization process itself. This is a goal that can only be approximated also for objective reasons; therefore achieving the expected structure and characteristics of crystalline material is not an objective that can be easily met. A way to its fulfilment consists in collection and evaluation of findings about the crystalline self-assembly of molecular components.

CRYSTAL ENGINEERING STRATEGY

The basic strategy of crystal engineering can be expressed as a combination of two research phases - analytic and synthetic phases.

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. For the purposes of crystal engineering 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, however, 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.

In the case of a general organic compound its conformation flexibility and the possibility of various types of intermolecular interactions must be taken into account. This is because the shape of a molecule in the crystal and the arrangement of individual molecules is the result of synergistic (in the contribution to the energy stability of the crystal) as well as antagonistic (in the sense of different requirements for the spatial layout) effects of individual interactions. In such a general case it is very difficult to correctly predict the crystalline arrangement. Therefore, in crystal engineering such compounds are selected as the building molecules that are sometimes referred to as tectons or supramolecular synthons whose conformation mobility and variability of non-bonding interactions are limited as much as possible. So 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.

The 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). However, unlike bricks individual molecules cannot be handled in an isolated way, their selection and assembly in the crystal are automatic (spontaneous) and this process can only be controlled with external influences to a limited extent. Further, virtually no building molecule is as perfectly rigid as a brick and intermolecular contacts are not as type and direction fixed as the connection elements of bricks of this brick-box. In addition, every real tecton, although designed in accordance with recommended principles, can exhibit "unwanted" interactions besides targeted interactions. They result from the fact that functional groups or structural fragments as sources of targeted interactions must be placed on a real molecular skeleton while all the parts of the whole building molecule are generally capable of intermolecular contacts. The actual crystal structure is then a result of combination of planned as well as unplanned interactions. Thus, the resulting structure may differ more or less from the presumed design.

An agreement of design considerations and experimentally found crystal structure is not as frequent as it may seem. Achieving a certain crystalline arrangement is often the matter of lucky coincidence, especially when the problem of polymorphism is usually completely disregarded.

The compounds that are commercially available are seldom sufficient for the intentions of both mono-component and multi-component self-assembly. Therefore, the phases of designing and the entire preparation of molecular building blocks require synthetic experience of an organic chemist so that the intentions can be realized with the use of "tailor-made" components. A necessary, but not sufficient, precondition of fulfilment of the crystal design intentions is a proper selection of building blocks (tectons). They must have the characteristics that have been generally discussed and that comprise both the rigidity of tectons and their ability to form predictable, strong and directed intermolecular contacts.

In a simpler case 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). In the case of one type of building molecules 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. In the case of multi- component self-assembly the individual structural molecules generally differ in their chemical character as well as in directionality of the functional groups. As mentioned at the beginning, 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. Out of the great quantity of crystalline structures formed by hydrogen bridging 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. However, with regard to low predictability of their effects their use in the field of crystal engineering is limited.

Crystal structures based on hydrogen bonds

With regard to the general requirement of strength and directionality of the interaction, mainly "traditional" hydrogen bonds are used, in which the acceptors are atoms of oxygen or nitrogen and donors are hydrogen atoms bound to said hetero-atoms. Such donor and acceptor centres are strongly polarized and this is a basis for the desired strength of these hydrogen bonds. Functional groups containing the above mentioned centres can be additionally ionized, which further increases the energy of the hydrogen bonds. Based on the amount of analyzed crystal structures it is possible to make a good prediction of preferences of certain interactions (Etter's Rules) even in case of building molecules containing more types of acceptor or donor sites.

References:

B. Kratochvil: Chem. Listy 101, 3-12 (2007)

Dunitz J. D.: Pure Appl. Chem. 1991, 63, 177-185. Kuduva S. S., Craig D. C , Nangia A., Desiraju G. R.: J. Am. Chem. Soc. 1999, 121, 1936- 1944.

Moulton B., Zaworotko M. J.: Chem. Rev. 2001, 101, 1629-1658.

Braga D., Grepioni F., Desiraju G. R.: Chem. Rev. 1998, 98, 1375-1405.

Etter M. C : Ace. Chem. Res. 1990, 23, 120-126. Pharmaceutical application of co-crystals:

This area has been attracting a lot of interest as it opens possibilities of modifying, generally improving physical and chemical characteristics of API's, such as solubility in the regime of physiological pH, hygroscopicity, morphology, size and shape of particles, surface of particles and, last but not least, it makes it possible to solve the serious problem of stability of API's in the dosage form. Recently, this topic has been summarized in review articles. Thus, the pharmaceutical crystalline form can be used for optimization of characteristics of API's and the co-crystals represent a fast-growing, new alternative to polymorphous applications in this context. The field of co-crystals also represents an interesting area from the point of view of intellectual property.

Expert Opinion on Drue Discovery

January 2007, Vol. 2, No. 1, Pages 145-154 New solid-state chemistry technologies to bring better drugs to market: knowledge-based decision making Aeri Park 1, Leonard J Chyall 1, Jeanette Dunlap 1 2, Christine Schertz 1, David Jonaitis 1, Barbara C Stahly' , Simon Bates', Rex Shipplett' & Scott Childs' 1SSCI, Inc., 3065 Kent Avenue West Lafayette, IN 47906, USA. apark(α),ssci-inc.com 2LiIIy Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA

Cocrystals: Design, Properties and Formation Mechanisms

Nair Rodriguez-Hornedo ; Sarah J. Nehm ; Adivaraha Jayasankar Encyclopedia of Pharmaceutical Technology October 2006, DOI: 10.1081/E-EPT-120041485

Mol.Pharmaceutics, 4 (3), 360-372, 2007. Mechanisms by Which Moisture Generates Cocrystals : Adivaraha Jayasankar, David J. Good, and Nair Rodriguez-Hornedo

Form and Function Ann M. Thayer: C&EN: June 18, 2007, Volume 85, Number 25, pp. 17-30

MoI. Pharmaceutics, 4 (3), 301 -309, 2007. An Overview of Pharmaceutical Cocrystals as Intellectual Property: Andrew V. Trask Theme Article - Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement

MRS Bulletin, Nov 2006, Vol. 31, William Jones, W.D. Samuel Motherwell, and Andrew V. Trask

WO/2008/054609) DISSOLUTION AND PRECIPITATION OF COCRYSTALS WITH IONIZABLE COMPONENTS

Inhibitors of tyrosine kinases in CML therapy

Erlotinib

Imatinib Lapatinib

Sorafenib

Sunitinib

Tipifarnib

Scheme 1. Studied inhibitors of tyrosine kinase: Axitinib Bosutinib , Cediranib Dasatinib Erlotinib Gefitinib Imatinib Lapatinib, Lestaurtinib , Nilotinib Semaxanib, Sunitinib, Vandetanib

With chronic myelogenous leukaemia (CML) a new era started in 1998, when the first inhibitor of tyrosine kinases Imatinib (Glivec) was introduced into practice. Now, more drugs belonging to this group are being introduced. One of them, Dasatinib (Sprycel) is already commonly available also in the Czech Republic, another one, Nilotinib (Tasigna) should be put into practice this year. While Nilotinib issues from the original Imatinib, Dasatinib is conceived a little differently. It has a different safety profile and mainly a higher number of kinases it blocks

Imatinib, characteristic 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. 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. One of the problems of 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. In the first group, Imatinib does not inhibit Bcr-Abl kinase at all or inhibits it in an insufficient manner. On the molecular level 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. In the Czech Republic it is available under the trade name Glivec (Novartis).

Mechanism of the effect

The mechanism of the effect of IM has been best investigated in BCR/ABL-positive cells. IM interacts with the Bcr/Abl (ρ210) 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. So 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.

Pharmacological characteristics

After oral ingestion 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. In plasma IM is virtually completely bound to proteins, especially albumin. 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/m2, which correspond to the dose of 400 to 600 mg in adults. Similarly, there are no limitations in elderly persons. In adults, no need to adjust the dose to the weight or body surface of the patient is normally specified; however, some cases of obese patients with a weight exceeding 100 kg have been described where an increase of the dose led to success of the therapy, which had been unsuccessful so far. Considerable accumulation does not even occur in patients with slight renal insufficiency. It has been proved that a kidney disorder increases exposure of the drug and reduces its elimination, but in the absolute majority of cases this fact does not lead to the necessity to reduce dosing. However, one must proceed very carefully in the case of patients with liver insufficiency. A significant disorder of the liver function may increase exposure of the drug by up to 50%.

Experiments with animals have also proved that EvI has considerable teratogenic characteristics and is excreted significantly into breast milk. It is true that several cases when patients successfully bore the full term and gave birth to healthy children after being treated with IM have been described; however, contraception is standardly recommended to women in the fertile age during the treatment. If the patient becomes pregnant, an alternative treatment must be started (e.g. interferon-a) or abortion must be indicated. Breastfeeding during EVI treatment is not recommended.

Drug interactions

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), or inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, erythromycin, ciclosporin or clarithromycin) administered in parallel may lead to an increase or decrease of metabolism of the drug and thus secondarily to a reduction or increase of its concentrations in the plasma. Care is also necessary in the cases of drugs that are a substrate of the CYP3A4 isoenzyme. For example, administration of EVI together with simvastatin increases the maximum concentration of this drug to twice the value and reduces its clearance by 70%.

Dosage and method of administration

With haematological malignities 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

So far a series of crystalline forms of Imatinib have been described.

WO07023182 Novartis - Delta and epsilon crystal forms of imatinib mesylate WO07059963A1 Novartis - F, G, H, I and K crystal forms of imatinib mesylate WO9903854A1 Novartis - Crystalline form beta of imatinib mesylate WO06024863A1 Cipla - Imatinib mesylate: Preparation of form alpha, form alpha; Stable crystal form; Stable crystal form of needle crystals WO06048890A1 Sun - Alpha non needle shape form; Crystalline form of imatinib mesylate WO05077933A1 Natco - Form alpha2; Process for form beta imatinib mesylate WO06054314 Natco - Crystalline forms I and II; Composition containing I, II or mixture of imatinib mesylate WO04106326A1 HeteroDrugs - Crystalline form Hl; Imatinib mesylate hydrate

WO05095379B1 InstytutFarmPL - Preparation alpha form; "dimethanesulphonic" acid, crystalline form, form I, II, mixture

Description of preparation of the API and of formation of solid dispersions of Imatinib mesylate with the use of cellulose derivatives

WO 2008/1 12722 A2

PCT/US2008/056588

Reddy's Laboratories LTD.

Imatinib mesylate

The treatment scheme of chronic myelogenous leukaemia (CML) has principally changed in the last five years. Medicaments used for tens of years (hydroxyurea, interferon alpha) have been replaced by the inhibitor of tyrosine kinases Imatinib mesylate. Imatinib (Glivec®) has become the drug of first choice in patients with Ph positive CML for its high efficiency and low toxicity. Patients treated with Imatinib in an early chronic phase in the IRIS study, receiving standard doses of the medicament (400 mg a day p.o.) achieved a complete haematological response in 98% of cases and a complete cytogenetic response in 86% of cases. In the same study 93% of patients lived without progression into the accelerated phase or blastic reversal. The curve of zoogenic transplantations performed in the early chronic phase has steeply decreased since 2000. The goal of the treatment of chronic myelogenous leukaemia has also changed. While the best result of the hydroxyurea treatment was stabilization of the blood count and regression of hepatosplenomegaly, with interferon alpha a part of the patients achieved a cytogenetic response. Unlike interferon alpha, 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. Monitoring of the cytogenetic response (karyotype after 6 and 12 months and further once a year) and the molecular genetic response with quantitative RT-PCR methods in three-month intervals will make it possible to evaluate the quality of response to the treatment and to reveal the first signs of resistance or relapse in time. 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. At present, 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 (in 50- 90% of cases) 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. 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. The prognosis of patients with CML has significantly improved in the recent years; the reported calculated survival median is 13 years. Mutations in the area of the BCR-ABL fusion gene will probably become more significant for the selection of the treatment preparation in future. At present, selective inhibitors of BCR-ABL/T315I are being looked for. At the same time, combinations of old proven medicaments as well as new preparations with Imatinib are being tested.

Controlled release of the drug The term controlled drug release 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. The term 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). Longer effect of the pharmaceutical substance in the bio-phase is enabled by specific pharmaceutical auxiliary substances and/or special technological procedures, i.e. the dosage form, or a more complex dosage system. The preparations are often referred to as RETARD, CR or SR (Controlled Release, Slow Release). 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 2nd generation

Dosage forms of the 2nd 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. Depending e.g. on the used package they release the drug continually in the interval of 6-24 hours or discontinuously, i.e. in the specified part of GIT, after a certain time following the administration, or in two and more pulses. In the pharmaceutical market a number of preparations are available with the SR (slow release), MR (modified release), CR (controlled release), RET (retard) and other indications that offer several benefits as compared to conventional oral medicament forms due to their protracted (continual, slow) releasing of the pharmaceutical substance to the organism. These benefits mainly comprise administration of the medicament once a day, which significantly improves patient compliance, and elimination of fluctuation of the drug level in the blood. Thus, the therapy becomes more efficient and side effects of the drug are reduced. Theoretically, it would be suitable to prepare many oral drugs with protracted release. However, besides pharmaco-therapeutic reasons this is prevented by some physical-chemical and biological characteristics of drugs (solubility in the GIT environment, distribution coefficient, molecular size, metabolism, etc.). 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. Less suitable, but permissible, is also first order kinetics, where the highest amount of the drug is released after the administration and then the amount of the released drug per time unit decreases; the dependence of the total amount of released drug in time is logarithmic. These findings do not only apply to oral dosage forms with protracted release, but also to the other, e.g. to transdermal preparations with protracted release of the pharmaceutical substance that are very frequently used in neurology. Solid oral dosage forms of the 2nd 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.

Significance of the present patented solution and advantage over the state of the art:

API's represent extremely valuable "core" materials for the pharmaceutical industry. However, it is a well-known fact that at present more than a half of newly developed API's are classified as 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. Pharmaceutical 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.

The list is available on the FDA website: http://vm.cfsan.fda.gov/~dms/eafus.html

From this large group of excipients 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.

Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R. Systematic Analysis of the Probabilities of Formation of Bimolecular Hydrogen-Bonded Ring Motifs in

Organic Crystal Structures. New J. Chem. 1999, 23, 25-34.

Dey, A.; Kirchner, M. T.; Vangala, V. R.; Desiraju, G. R.; Mondal, R.; Howard, J. A. K. Crystal Structure Prediction of Aminols: Advantages of a Supramolecular Synthon Approach with Experimental Structures. J. Am. Chem. Soc. 2005, 127, 10545-10559

Andrew V. Trask, An Overview of Pharmaceutical Cocrystals as Intellectual Property

MoI Pharmaceutics, 4 (3), 301 -309, 2007.

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 bio availability than simple polymorphism together with IP protection of the product, it is obvious that dynamic development in this field will continue.

In our strategy we have gradually followed all the steps leading to the formation of a co- crystal as a crystalline molecular complex. Especially for the designed API-excipient (tecton) combinations the primary phenomenon was spectroscopically evaluated, namely formation of a complex in the solution, which subsequently leads to crystallization of the molecular complex or precipitation in the form of a solid dispersion.

Modern methods of crystal engineering and supramolecular chemistry open new possibilities, namely modification of the API surface with a suitably designed complexing partner, which modulates solubility and transport properties of the API in the solution and leads to the formation of co-crystals in the solid state. Their successful production is based on complementariness of functional groups of the selected excipient to the functional groups on the API surface. This strategy opens new possibilities for the formulation of API's with inconvenient physical- chemical parameters for pharmaceutical use. This approach has also more general validity than, e.g., production of salts, which necessarily requires an acidic or basic centre in the molecule of the API. Even though no such group is part of the API, inconvenient, e.g. dissolution, parameters can be solved by means of formation of co-crystals, in which multifunctional approach comprehensively taking into account the surface characteristics of the API will be applied. Thus, pharmaceutical co-crystals represent a new paradigm in the formulation strategy, which solves principal issues of both IP and physical-chemical characteristics of API's for the development of a dosage form. The improved characteristics concern hygroscopicity, solubility, dissolution kinetics, chemical morphological stability and, last but not least, transport characteristics of API's. As 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. NIR studies have also proved that our approach, based on the formation of co-crystals, leads to an increase of solubility of the API base or to modulation of solubility of API salts. Another important factor is achievement of both chemical and polymorphous stability, which we have tested by the NIR method. From the point of view of chemical production 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. Another factor, very important from the regulatory point of view, is that the formation of co- crystals does not involve formation of a covalent bond - this is the case of non-covalent system (supramolecules). Since no new chemical entity is formed, this is the case of a low-risk approach from the regulatory point of view. Accordingly, in the general sense, formation of API co-crystals can be perceived as the first formulation step leading to the desired physical-chemical characteristics of API's, allowing to achieve biological availability equal to the original preparation, or, on the contrary, modulation for controlled release. 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.

Disclosure of Invention:

An industrially applicable methodology for production of co-crystals and solid dispersions of inhibitors of tyrosine kinases with low- and high-molecular excipients has been elaborated. The entire method consists in addition of a solution of the API in the selected solvent to a solution of the excipient with complementary groups for binding to the surface determinants of the API. The primarily produced API-tecton complex subsequently provides co-crystals or an amorphous form of the API in the form of a solid dispersion. The prepared co-crystal or solid dispersion is isolated by filtration or centrifugation. The production of co-crystals or solid dispersion results in modification of the dissolution characteristics and in increase of the chemical and morphological stability of the API.

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.

Detailed description of the patent:

While a number of polymorphs of inhibitors of tyrosine kinases are known, the possibility of modifying physical-chemical characteristics of these API's by means of co-crystals has not been described yet. Alteration of physical-chemical characteristics for the given API provides the desired differences in dissolution characteristics, stability and bio-availability. The stability does not only concern chemical stability, but mainly polymorphous stability, since in the technology of production of a dosage form conversions of individual crystalline and the amorphous forms are often observed, leading to undesired changes in dissolution and bio-availability characteristics.

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.

In the complex of the active substance and the tecton 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, π-π 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.

As 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.

Of low-molecular tectons, 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.

Of polymeric tectons, substances selected from the group including alginic acids, pectins, alginic acid, polysaccharide carboxylic and sulfonated systems, beta glucan, ester pectins, polygalacturonic acid, sulfonated dextrans, chitosan salts, PEGylated chitosan, PVP, PEG, Pluronic, polylactides, polylactides-polyglycolides, 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.

For the selection of the partner for co-crystallization or production of a solid solution it has proved to be very useful if the selection is based on quantum chemical and molecular modelling of the inhibitor with selected excipients, wherein complementarity of hydrogen bonds of the active substance and the excipient is the main selection criterion.

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. In some cases, 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).

Sometimes it is convenient for optimal formation of the complex to add to the solution of the active substance and excipient a solution of an organic salt, usually KCl, or NaCl, which initiates crystallization of the API-excipient complex by increasing the ionic strength.

Crystallization is carried out in the temperature range of -80 °C to +120 0C.

The use of 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-complexed 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.

Examples of our approach and types of excipients are summarized in Table 1, together with the data of elementary composition.

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. Their preparation is based on a robust and scale-upable approach, wherein it is possible to achieve, by selection of the tecton, stabilization partner or partners and suitable crystallization or precipitation conditions (selection of the solvent, mixture of solvents, pH, ionic strength of the solution), the desired characteristics of the API, which-the API does not have without the modification. This holds good both for dissolution and stabilization characteristics. The entire process has several steps: - Designing a suitable partner for the API on the basis of knowledge of supramolecular chemistry, formation of non-covalent complexes based on spatial complementarity and complementarity of the functional groups of the API and tecton (excipient); - The formation of 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; - Isolation of co-crystals or solid dispersion (crystallization, precipitation, centrifugation, lyophilization, spray drying); - The 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. For high-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. This process is applicable both to salts and free bases of the studied API's as well as to API's without acido-basic functional groups. 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; - Its crystallization or precipitation; - Isolation of co-crystals or solid dispersion; - Drying; - Application for the production of a dosage form for oral administration, such as capsules, tablets, granules or powder. In this arrangement 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. The 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.

This approach is described in detail in the examples below.

Characterization of the produced complexes and co-crystals was performed by the NIR, ssNMR, Raman, FTIR, XRPD methods, as well as by elementary analysis.

The results of analyses of co-crystals and solid dispersions of kinase inhibitors with low- and high-molecular excipient, conducted by the IR, Raman, NIR ssNMR, XRPD and elementary analysis methods are shown in attached drawings.

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.

X-ray powder diffraction: The records presented were measured on an X 'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used CuKa (λ=1.542A), excitation voltage: 45 kV, anode current: 40 mA, measurement range: 4 - 40° 2Θ, increment: 0.008° 2Θ, irradiated part of the sample 10 mm; the measurement was carried out on a Si plate covered with PE foil.

NIR spectroscopy: The records presented were obtained using a Smart Near-IR UpDrift™ Nicolet™ 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. Brief Description of Drawings:

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 13C 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. The theoretical value of chemical shift of pure guanidine HCl is 164 ppm, while in the case of co- crystal with Imatinib the experimental value of chemical shift is 159 ppm.

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).

Examples

Describe the method of preparation, characterization and use of complexes and co-crystals of inibs, their amorphs and solid disperses with selected low- and high-molecular excipients. The method of preparation and characterization is documented by the following examples without being limited by them in any way.

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 250C 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.

Example 2 500 mg of Imatinib mesylate 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.

Example 3 1 mmole of Lapatinib ditosylate was dissolved in water (10-50 ml), then a solution of 1-10 molar equivalents 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 Lapatinib ditosylate with guanidine hydrochloride) was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.

Example 4 500 mg of Imatinib mesylate 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. Example 5 500 mg of Imatinib mesylate 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 250C 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.

Example 6 500 mg of Imatinib mesylate 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 250C 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 20-300C 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 250C, 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 20-300C and characterized.

Example 8 500 mg of Imatinib mesylate 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 250C 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 0C and characterized.

Example 9 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then a solution of 2 to 50 molar equivalents of lactose (in 3-15 ml of water) was added at the temperature of 250C, then 20-50 ml of EtOH and 1-10 ml of a IM solution of KCl were added; this mixture was left to crystallize at 0-25 0C for 1-24 hours. The product (co-crystals of Imatinib mesylate with lactose) was aspirated and dried in vacuo at a temperature of 20-30 0C and characterized. Example 10 1 mmole of Sunitinib was dissolved in water (10-50 ml), then a solution of 1-20 molar equivalents of fructose and lactose (in 3-150 ml of water) was added at the temperature of 25°C, then 0-50 ml of EtOH were added and subsequently 1 - 100 ml of a IM solution of NaCl, KCl or possibly other salts of strong acids and bases; this mixture was left to crystallize at 0-25°C for 1-24 hours. The product (co-crystals of Sunitinib with a saccharide) was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.

Example 11 500 mg of Imatinib mesylate 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.

Example 12 500 mg of Imatinib mesylate were dissolved in MeOH (10-50 ml) and placed in an autoclave together with 200 mg of polylactide-polyglycolide, then solid CO2 (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.

Example 13 500 mg of Imatinib mesylate 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 250C; 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.

Example 14 500 mg of Imatinib mesylate 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 250C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20- 30°C and characterized.

Example 15 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then a 1% solution of beta glucan (in 3-15 ml) was added at the temperature of 250C; 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- 300C and characterized.

Example 16 500 mg of Imatinib mesylate 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 0C and characterized.

Example 17 1500 mg of Imatinib base were dissolved in MeOH (10-50 ml), then a 1% solution of beta glucan (in 30-150 ml) was added at the temperature of 25°C; the mixture was stirred at the laboratory temperature and then it was left to crystallize (precipitate) at 250C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0C and characterized.

Example 18 500 mg of Imatinib mesylate 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 0C 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 250C, 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 20-300C 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 250C, 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 0C and characterized.

Example 2 1 500 mg of Imatinib mesylate 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 250C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.

Example 22 500 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 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 0C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0C 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 200C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20- 300C and characterized.

Example 24 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of alginic acid was added at the temperature of 250C, followed by a solution of PVP (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°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 250C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30°C and characterized.

Example 26 500 mg of Imatinib mesylate 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 20-300C and characterized.

Example 27 500 mg of Imatinib mesylate 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 200C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-

3 O0C 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 200C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0C 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 Sunitinib were dissolved in MeOH (10-50 ml), then an aqueous solution of 250 mg of lactose was added at the temperature of 25°C. This mixture was left to crystallize at 20°C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30°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 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 250C. This mixture was left to crystallize at 2 O0C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-300C and characterized.

Example 31 500 mg of Imatinib mesylate were dissolved in water (10-50 ml), then an aqueous solution of 150 mg of ascorbic acid (in 3-15 ml) was added at the temperature of 25°C; this mixture was left to crystallize at 100C for 1-24 hours. The product was aspirated and dried in vacuo at a temperature of 20-30 0C and characterized. A higher chemical stability of the co-crystals in comparison with the non-modified API was proved by the HPLC and NIR methods following stress tests. The HPLC analysis was conducted using the method described in the literature:

Experimental design in reversed-phase high-performance liquid chromatographic analysis of imatinib mesylate and its impurity. Medenica, M.; Jancic, B.; Ivanovic, D.; Malenovic, A.: Journal of Chromatography, A (2004), 1031(1-2), 243-248; Reversed-phase liquid chromatography analysis of imatinib mesylate and impurity product in Glivec capsules. Ivanovic, D.; Medenica, M.; Jancic, B.; Malenovic, A.:Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences (2004), 800(1-2), 253-258 Development and validation of a stability indicating RP-LC method for determination of imatinib mesylate. Bende, Girish; Kollipara, Sivacharan; Kolachina, Venugopal; Saha, Ranendra.: Chromatographia (2007), 66(11/12), 859-866. Table 1 Results of the elementary analysis for co-crystals in solid dispersion of Imatinib mesylate (IMA) and other kinase inhibitors with selected low- and high-molecular excipients. Formation of complexes for kinase inhibitors both in the form of bases and corresponding salts with selected proposed excipients was studied.

CHN analyses were conducted on an Elementar vario EL III instrument made by the Elementar Company. Accuracy of the method has been determined by the manufacturer for a parallel analysis of 5 mg of 4-amino-benzene sulfonic acid standard in the CHNS module to be < 0.1% abs. for each element. Claims

1. Complexes of inhibitors of tyrosine kinases, in which at least one tyrosine kinase inhibitor is in a complex with a water-soluble excipient, or tecton, wherein the complex is constituted by supramolecular bonds between the surface determinants of the said inhibitor and the complementary groups of the tecton and wherein the molar proportion of the inhibitor and a monomelic tecton or the proportion of the inhibitor and the number of monomeric units of a polymeric tecton is 1 : 1 to 0.1 : 99.9.

2. The complexes according to claim 1, wherein the supramolecular bonds are constituted by hydrogen bonds.

3. The complexes according to claim 2, wherein the complementarity of the hydrogen bonds is determined by quantum chemical and molecular modelling.

4. The complexes according to any one of the preceding claims, wherein the respective kinase inhibitor is selected from the group comprising Axitinib, Bosutinib, Cediranib, Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sunitinib, Vandetanib, Sorefenib, and Tipifarnib.

5. The complexes according to claim 2, wherein Imatinib is used as the kinase inhibitor.

6. The complexes according to any one of the preceding claims, wherein the tecton is of a monomeric character and the complexes exhibit crystalline arrangement.

7. The complexes according to claim 6, wherein the tectons are selected from the group comprising hydrochlorides of amines or amides, and mono- or oligosaccharides.

8. The complexes according to claims 6-7, in which the tectons are low-molecular substances selected from the group comprising 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, and surfactants-excipients, such as tween 80.

9. The complexes according to claims 1-5, in which the tectons are polymeric substances.

10. The complexes according to claim 9, wherein the tectons are selected from the group comprising alginic acids, pectins, alginic acid, polysaccharidic carboxylic and sulfonated systems, beta glucan, ester pectins, polygalacturonic acid, sulfonated dextrans, chitosan salts, PEGylated chitosan, PVP, PEG, and Pluronic. 11. The complexes according to claim 10, wherein the tectons are selected from the group comprising alginic acids, pectins, and beta glucan.

12. The complexes according to claim 11, which are of a crystalline nature.

13. The complexes according to claim 11, which are of an amorphous nature.

14. The complexes according to any one of the preceding claims, wherein the kinase inhibitors contained therein are in the form of salts.

15. The complexes according to claim 14, wherein the kinase inhibitors present therein are salts with an alkyl or aryl sulfonic acid, hydrochloric, sulfuric, phosphoric, formic, acetic, oxalic, tartaric, citric or fumaric acids, preferably with methane sulfonic acid.

16. The complexes according to any one of the preceding claims, which are constituted by the active substance and two complementary tectons, which are at the same time complementary to the surface of the active substance.

17. The complexes according to claim 16, wherein a mixture of a low- and high-molecular tectons is used.

18. The complexes according to any one of claims 1-17, wherein at least two active substances are present.

19. The complexes according to any one of the preceding claims, wherein the tyrosine kinase inhibitors are complexed in solid dispersions by means of excipients selected from alginic acid, pectins, beta glucan and other polysaccharides according to any one of the preceding claims in an amorphous form.

20. The complexes according to any one of the preceding claims, wherein the tyrosine kinase inhibitors are complexed in solid dispersions by means of excipients selected from alginic acid, pectins, beta glucan and other polysaccharides according to any one of the preceding claims in a crystalline amorphous form containing 1-99 % of the crystalline form.

21. Use of the complexes according to any one of the preceding claims for the preparation of a pharmaceutical composition.

22. The use according to claim 21, wherein the resulting pharmaceutical composition is destined for treatment of chronic myelogenous leukaemia (CML), acute lymphoblastic leukaemia (ALL), gastrointestinal stromal tumour, chronic eosinophilic leukaemia, or hypereosinophilic syndrome and systemic mastocytosis.

23. The use according to claim 21, wherein the said composition further contains fillers selected from soluble mono-, oligo- or polysaccharides, or insoluble polysaccharides.

24. The use according to any one of claims 21-23, wherein the formed composition exhibits controlled release.

25. The use according to any one of claims 21-24 for a composition with directed release, wherein the kinase inhibitor is preferentially released in leukaemic cells.

26. A method for the preparation of the complexes according to claims 1-20 in the form of co-crystals or solid solutions of the active substance with the selected excipient, characterized in that use is made of supramolecular, non-covalent interactions, based in a combined way or individually on hydrogen bonds, hydrophobic interactions, use of van der Waals forces, π-π interactions, interactions of halogens, or coordination or dipole-dipole interactions.

27. The method according to claim 26, characterized in that at least one tyrosine kinase inhibitor or its salt with low-molecular excipients is subjected to co-crystallization, the composition of the co-crystal being controlled by the molar proportion of the active substance-excipient.

28. The method according to claim 26, characterized in that at least one tyrosine kinase inhibitor or its salt with high-molecular excipients is subjected to co-crystallization, the composition of the complexes being controlled by the molar proportion of the active substance-excipient.

29. The method according to claim 26, characterized in that the selection of the partner for the co-crystallization is based on quantum chemical and molecular modelling of the inhibitor with selected excipients, wherein complementarity of hydrogen bonds of the active substance and excipient is the main selection criterion.

30. The method according to claim 29, characterized in that the resulting theoretical design is verified by spectroscopic study using FTIR and/or NMR spectra.

31. The method according to any one of claims 26-30, characterized in that the molar proportion of the tyrosine kinase inhibitor : excipient is 0.1- 50 : 99.9- 50. 32. The method of preparation of complexes of tyrosine kinase inhibitors according to claims 26-31 with low-molecular and/or high-molecular excipients, characterized in that the solvent used for the preparation is water.

33. The method according to any one of claims 26-32, characterized in that the solvent used is a mixture of water and an organic solvent, preferably ethanol.

34. The method according to claim 33, characterized in that the solvent used is a mixture of water and an organic solvent, preferably ethanol, and of a selected buffer for optimal pH for the production of the active substance - excipient complex.

35. The method according to any one of claims 26-31, characterized in that the solvent used is an organic solvent, preferably an ROH alcohol having 1 to 8 carbon atoms in the R residue, a bipolar aprotic solvent, a mixed organic solvent, preferably EtOH and DMSO, or supercritical liquids (liquid carbon dioxide with 1 to 10% of EtOH).

36. The method according to claim 26 for the preparation of co-crystals and dispersion of Imatinib mesylate, characterized in that a solution of an inorganic salt, especially KCl or NaCl, which initiates crystallization of the Imatinib mesylate - excipient complex by increasing the ionic strength, is added to the solution of Imatinib mesylate and the excipient for the formation of the co-crystals.

37. The method according to any one of claims 26-36, characterized in that the crystallization temperature is in the range of -80 °C to +120 °C.

38. The method according to any one of the preceding claims, characterized in that the low-molecular substances for the formation of co-crystals are selected from the group comprising mono- and oligosaccharides with 1 to 9 monomelic units, ascorbic acid, vitamins A and E, amino acids, guanidine and its derivatives, urea, thiourea, aminosaccharides, amides of aliphatic and aromatic acids, sulfoamides and/or surfactants-excipients, such as tween 80.

39. The method according to claim 26 for the preparation of solid dispersion of Imatinib mesylate with polymeric excipients such as PVP, PEG, a mixture of synthetic polymers and natural PVP, PEG and/or Pluronic in combination with a substance from the group comprising chitosan, alginic acid, pectins and ester-modified pectins, preferably benzyl esters, characterized in that the polymeric excipient is subjected to co-precipitation with the given inib from an aqueous solution having selected pH or from a water - organic solvent mixture.

40. A method of characterization of co-crystals and dispersions in the solid state by means of a combination of the ssNMR, XRPD, Raman, FTIR, raman, NIR, elementary analysis methods; the complexes in a solution being characterized with Raman spectroscopy and 1H ,13C 15N- NMR 1 D and 2D spectra.

41. Use of the complexes according to claims 1-20 for stabilization of the tyrosine kinase inhibitors used in the pharmaceutical industry as active substance.

42. Use of co-crystals and solid dispersions of the tyrosine kinase inhibitors according to claim 1 for stabilization of tyrosine kinase inhibitors used in the pharmaceutical industry as active substances.

43. Use of the complexes according to claims 1-20 for modulation of solubility and transport characteristics of tyrosine kinase inhibitors.

44. Co-crystals of Imatinib mesylate and other tyrosine kinase inhibitors for use in formation of combinations with other drugs, wherein no chemical interaction of two active substances occurs and thus formation of possible impurities is prevented.

45. The complexes according to any of claims 1 to 20, wherein the tyrosine kinase inhibitors are complexed in solid dispersions by means of excipients selected from alginic acid, pectins, beta glucan and other polysaccharides according to claim 10 in the crystalline form.