Solid dispersions containing apoptosis promoting proteins

FIELD: medicine, pharmaceutics.

SUBSTANCE: pro-apoptotic solid dispersion contains a compound, e.g. ABT-263 taken in a substantially non-crystalline form to inhibit Bcl-2 proteins and dispersed in a solid binding substance containing (a) a pharmaceutically acceptable water-soluble polymer carrier and (b) a pharmaceutically acceptable surfactant. A method for preparing this solid dispersion involving dissolving the compound, polymer carrier and surfactant in an acceptable dissolution medium and removing the dissolution medium to form the solid binding substance containing the polymer carrier and surfactant and possessing a compound dispersed therein in the substantially non-crystalline form.

EFFECT: solid dispersion is orally applicable in the individual in need thereof for treating a disease characterised by the overexpression of one or more anti-apoptotic Bcl-2 proteins, eg a malignant new growth.

22 cl, 6 ex, 2 tbl, 3 dwg

 

The present application claims priority on the provisional application U.S. No. 61/185105 registered 8 June 2009.

Give a cross reference to the following co-registered application USA, contains the object of the invention related to the present application: serial No. 12/796000 registered 8 June 2010, titled "Pharmaceutical dosage form for oral administration of a Bcl-2 family inhibitor", whose priority is claimed on provisional application U.S. serial No. 61/185130 registered 8 June 2009.

A full description of each of the aforementioned applications include in this document by reference.

Field of the INVENTION

The present invention relates to solid dispersions containing promotes apoptosis agent, to pharmaceutical dosage forms containing such dispersions, to a process for preparing such dispersions and dosage forms and to methods of their use for the treatment of diseases characterized by sverkhekspressiya antiapoptotic protein family Bcl-2.

Background of the INVENTION

Avoidance of apoptosis is the hallmark of malignant tumors (Hanahan &Weinberg (2000) Cell 100:an excerpt) p. 57-70). Malignant cells must overcome continuous exposure to cellular stress such as DNA damage, activation of oncogenes, the passage of broken cells DNA.�cycle and hard microenvironment, causing normal cells to undergo apoptosis. One of the primary means by which malignant cells escape apoptosis, is increasing regulation of the antiapoptotic protein family Bcl-2.

Describe connections occupying the BH3-binding cleft proteins Bcl-2, for example Bruncko et al. (2007) J. Med. Chem. 50:641-662. These compounds include N-(4-(4-((4'-chloro-(1,1'-biphenyl)-2-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene-sulfonamide, also known as ABT-737, having the formula:

ABT-737 binds proteins of the family of Bcl-2 (in particular, Bcl-2, Bcl-XLand Bcl-w with high affinity (Ki<1 nm). He shows a solitary activity against small cell lung cancer (SCLC) and malignant neoplasms of lymphoid tissue and enhances the proapoptotic effects of other chemotherapeutic agents. ABT-737 and related compounds and methods for producing such compounds described in the published patent application U.S. No. 2007/0072860 Bruncko et al.

Recently identified an additional group of compounds having high affinity binding to proteins of the family of Bcl-2. These compounds and methods for their preparation described in the published patent application U.S. No. 2007/0027135 Bruncko et al. (in this document "publication '135"), in full�m the volume of which is incorporated herein by reference, and, as you can see from the formula below, they are structurally related ABT-737.

In the publication '135 indicate that, while the previously known inhibitors of protein family Bcl-2 can have a strong cell efficiency or severe systemic exposure after oral administration, they do not possess both properties simultaneously. A typical measure of cell the effectiveness of a compound is the concentration causing 50% cell effect (EC50). A typical measure of systemic exposure after oral administration of the compounds is the area under the curve (AUC) obtained by plotting the concentration of compound in the plasma depending on the time elapsed since oral administration. Previously known compounds, as indicated in the publication '135, have a low ratio of AUC/EC50that means that they are not orally effective. In contrast, indicate that the compounds with the above formula exhibit enhanced properties in terms of cell efficiency and systemic exposure after oral administration, resulting in a much higher ratio of AUC/EC50than the one used for the previously known compounds.

One compound, specified in the publication '135 as "Example 1" is N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexa-1-EN-1-yl)methyl)piperazine--yl)benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl) benzosulfimide, also known as ABT-263. The compound has a molecular weight of 974,6 g/mol and has the formula:

ABT-263 binds Bcl-2 and Bcl-XLwith high affinity (<1 nm) and is believed to have similarly high affinity to Bcl-w. His attitude AUC/EC50indicate in the publication '135 as 56, more than an order of magnitude higher than specified for ABT-737 (4,5). To determine the AUC for the publication '135 each compound was administered to rats in a single dose 5 mg/kg via oral probe as a solution of 2 mg/ml in a solvent of 10% DMSO (dimethyl sulfoxide) in PEG-400 (polyethylene glycol with an average molecular weight of approximately 400).

In the publication '135 not indicate oral bioavailability (expressed, for example, the AUC after oral administration as a percentage of AUC after intravenous administration), but from it we can conclude that it is significantly greater for ABT-263, than to ABT-737.

Recently, Tse et al. (2008)Cancer Res.68(9):3421-3428, reported in the supplementary data to the article that the model dogs oral bioavailability of a solution of ABT-263 in PEG-400/DMSO was 22.4%, and the solution of ABT-263 in 60% Phosal™ PG (phosphatidylcholine + propylene glycol), 30% PEG-400 and 10% ethanol accounted for 47.6%.

Oxidative reactions are an important degradation pathway of medicines, especially in the preparation in solution. OK�slania can occur through a number of ways, including acatalasemia autookislenia substrate by molecular oxygen, photolytic initiation, hemolytic temperature cleavage and catalysis by metals. Various functional groups show individual sensitivity to oxidation. In particular, the thioethers can degrade by cleavage of hydrogen in α-position to the sulfur atom or the addition of α-peroxyl radical directly or via one-electron transfer process, converting the sulfide in culpin, sulfone or sulfoxide (Hovorka & Schöneich (2001)J. Pharm. Sci 90:253-269).

It is shown that (phenylsulfanyl)methyl group, belonging to the compounds described in the publication '135, including ABT-263, has a thioether bond, susceptible to oxidation, for example, in the presence of oxygen or reactive oxygen species such as superoxide, hydrogen peroxide or hydroxyl radicals. The publication '135 includes antioxidants in an extended sheet of excipients specified as applicable for the introduction described in this document connections.

However, it will be favorable pharmaceutical compositions less susceptible to oxidation of the active ingredient. Additionally, a favorable composition will be capable of a higher dosage of the active ingredient than in the compositions of the solution in the publication '135 or Ts et al. (2008) above. In addition, liquid formulations, as described in the publication '135 and Tse et al. (2008) above may be unpleasant for oral administration to the taste or other reasons, and for these reasons, there may be problems with patient compliance with the regimen; thus, favorable are solid compositions.

Very low solubility compounds from the publication '135, including ABT-263, in water poses a challenge to the originator of the recipe, especially if there is a need to maintain acceptable oral bioavailability, is strictly dependent solubility in the aqueous environment of the gastrointestinal tract. To solve the problem of low oral bioavailability in this area offer various solutions. For example, in Sharma &Joshi (2007)Asian Journal of Pharmaceutics1(1):9-19 discuss various strategies of increasing the solubility in solid dispersions. To obtain solid dispersions in this regard, describe the method of solvent evaporation, referred to as an example of a solid dispersion etoricoxib obtained by the method comprising dissolving polyethylene glycol (PEG), polyvinylpyrrolidone (PVP or povidone) and the active ingredient 2-propanol.

Specific type of disease that requires improved methods of therapy, is a non-Hodgkin's lymphoma (NHL). NHL is the sixth most spreaded�common type of new cancer in the USA and has a place mainly in patients aged 60-70 years. NHL is not a separate disease, but a family of related diseases that are classified based on several characteristics, including clinical and histological signs.

One way of classification is shared by various histological subtypes into two broad categories on the basis of the disease, i.e. whether the disease is slowly developing or aggressive. Basically, slow-growing subtypes develop slowly and are usually incurable, while aggressive subtypes are growing rapidly and are potentially curable. Follicular lymphomas are the most common slow-growing subtype, diffuse large cell lymphomas are the most common aggressive subtype. The oncoprotein Bcl-2 in the source described in non-Hodgkin B-cell lymphoma.

Treatment of follicular lymphoma typically consists of based on natural substances or combination chemotherapy. Common used combination treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), as well as combined treatment with rituximab, cyclophosphamide, vincristine and prednisone (RCVP). Also used monotherapy with rituximab (directed at CD20, phosphoprotein constantly expressed on the surface of B-cells) or fludarabine. The addition of rituximab to chemotherapy regimens can provide improved speed of response and improved progression-free survival.

For the treatment of trudnootdelema treatment or relapsed NHL means you can apply for radioimmunotherapy, the high doses of chemotherapy and stem cell transplants. At present there is no approved treatment regimens, leading to a cure, and in the current guidelines recommend to treat patients during clinical trials, even in the condition of the first line.

Treatment of patients with extensive aggressive B-cell lymphoma, first-line, usually consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), or adjusted-dose etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R).

Most lymphomas respond to any source of data methods of therapy, but tumors typically recur, and eventually become trudnootdelema treatment. With the increase of the quantity received by patients treatment regimens becomes more resistant to chemotherapy diseases. The average response to first line treatment is approximately 75%, 60% - on the second line, 50% on the third line and approximately 35-40% on the fourth-line therapy. Assume that the velocity is�and response approaching 20% with the only means in the condition of multiple recurrent disease are positive, and serve as the basis for further research.

Modern chemotherapeutic agents have shown anti-tumor response by inducing apoptosis through multiple mechanisms. However, many tumors eventually become resistentie to these tools. In the analysis of short-term survival ofin vitroand, recently,in vivoit was shown that Bcl-2 and Bcl-XLattach a resistance to chemotherapy. This suggests that if we can develop improved therapies aimed at suppressing the function of Bcl-2 and Bcl-XLit is possible to successfully overcome resistance to chemotherapy.

Promotes apoptosis drugs targeting proteins of the family of Bcl-2, such as Bcl-2 and Bcl-XLbest to enter on the treatment regimen that provides continuous, for example, daily, replenishing the concentration in the plasma to maintain the concentration within a therapeutically effective range. This can be achieved daily parenterally, e.g., intravenously (i.v.) or intraperitoneal (i.p.) introduction. However, the daily parenteral administration is often impractical in a clinical setting, in particular for an outpatient�V. To increase the clinical applicability of promoting apoptosis means, for example, chemotherapeutic agents for patients with malignant tumors, will be highly desirable solid dosage form with acceptable oral bioavailability. Such dosage form and regimen for oral administration will represent an important advancement in the treatment of many types of malignancies, including NHL, and will be more ways to facilitate the combined treatment with other chemotherapeutic agents.

Summary of the INVENTION

Currently provide solid dispersion containing, essentially, non-crystalline, for example amorphous form of the compound of the formula I:

where:

X3is chlorine or fluorine; and

(1) X4is azepin-1-yl, morpholine-4-yl, 1,4-oxazepan-4-yl, pyrrolidin-1-yl, -N(CH3)2, -N(CH3)(CH(CH3)2), 7-azabicyclo[2.2.1]heptane-7-yl or 2-ox-5-azabicyclo[2.2.1]hept-5-yl; and R0is

where

X5is-CH2-, -C(CH3)2- or-CH2CH2-;

X6and X7both are-H or methyl radicals; and

X8is fluorine, chlorine, bromine or iodine;

or

() X 4is azepin-1-yl, morpholine-4-yl, pyrrolidin-1-yl, -N(CH3)(CH(CH3)2) or 7-azabicyclo[2.2.1]heptane-7-yl; and R0is

where X6, X7and X8are listed above; or

(3) X4is a morpholine-4-yl or-N(CH3)2; and R0is

where X8is the above;

or its pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite; dispersed in a solid binder containing (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant.

In addition, provide solid deliver oral dosage form comprising a solid dispersion, optionally together with one or more additional excipients.

In addition, provide a method of producing a solid dispersion as described above.

The method includes:

(a) dissolving an active pharmaceutical ingredient (API), comprising (i) a compound of formula I or its pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite; (ii) a pharmaceutically acceptable water-soluble polymeric carrier and (iii) pharmaceutically acceptable surface treatments�-active agent in a suitable solvent; and

(b) removing the solvent to obtain a solid resin binder comprising a polymeric carrier and the surfactant and having the compound or its salt, prodrug, salt of a prodrug or metabolite, dispergirovannykh in it, essentially, in non-crystalline form.

A compound present in the final solid dispersion may be in the same chemical form (e.g., neutral base or salt), and the API used to retrieve it. Alternatively, the method includes one or more additional stages, where the connection is turned from the neutral grounds in salt, or Vice versa. In a specific embodiment, the implementation of the API is a salt, for example a crystalline salt of a compound of formula I, and the final solid dispersion contains a compound in the form of neutral grounds. In this embodiment of the method further includes adding the base to the removal of the solvent for the conversion of salt to the neutral base and, optionally, extraction by-product of such transformation (e.g., a by-product in the form of salt) from the resulting mixture.

In addition, provide a solid dispersion obtained as described above.

In addition, provide a method of treating a disease characterized by apoptotic dysfunc�the Oia and/or sverkhekspressiya antiapoptotic protein family Bcl-2, including oral administration suffering from the disease to the individual a therapeutically effective amount of a solid dispersion as described above, or one or more solid dosage forms containing such a dispersion. Examples of such diseases include many neoplastic diseases, including malignancy. Specific illustrative type of cancer that can be treated by the present method is non-Hodgkin's lymphoma (NHL). Another specific illustrative type of cancer that can be treated by the present method, is chronic lymphocytic leukemia. Another specific illustrative type of cancer that can be treated by the present method, is acute lymphocytic leukemia, for example, in children.

According to any one of the described above embodiments of the invention the compound of formula I is illustrative ABT-263 or its pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite, e.g., a neutral base of ABT-263 or bis-hydrochloride salt of ABT-263 bis-HCl ABT-263).

In addition, provide a method for maintaining in bloodstream of a human malignant tumor, for example, NHL suffering of the patient, a therapeutically effective�active concentration of ABT-263 and/or one or more of its metabolites in plasma, comprising oral administration to the individual of the solid dispersion of ABT-263 or its pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite (e.g., a neutral base of ABT-263 or a bis-HCl ABT-263) in essentially non-crystalline form in a binder containing a pharmaceutically acceptable water-soluble polymeric carrier and a pharmaceutically acceptable surfactant in the amount of a dosage equivalent of from about 50 to about 500 mg of equivalent neutral base of ABT-263 per day, with an average interval between doses of the drug approximately 3 hours to about 7 days.

Additional embodiments of the invention, including the more specific aspects of the above, will be or will become apparent from the following detailed description.

BRIEF description of the DRAWINGS

Fig. 1 is a graphical representation of the effects of various surfactants on the dissolution rate of solid dispersions containing bis-HCl ABT-263, as described in Example 3.

Fig. 2 is a graphical representation of the effects of various surfactants on the dissolution rate of solid dispersions containing a neutral base of ABT-263 as described in Example 3.

Fig. 3 is a graphical pre�the representation of effects of various polymer carriers on the dissolution rate of solid dispersions, containing bis-HCl ABT-263, as described in Example 4.

DETAILED DESCRIPTION

Solid dispersion according to the present description contains the active ingredient essentially in non-crystalline or amorphous form, as a rule, being more soluble than the crystalline form. The term "solid dispersion" herein includes systems having small particles of one phase, dispergirovannykh to another solid phase. More specifically, the present solid dispersions contain one or more active ingredients dispersed in an inert carrier or binder in the solid state, and may be obtained by heating or azeotropic method or combination of heat and azeotropic method. The present invention azeotropic method, as described herein, is particularly preferred to avoid the risk of thermal decomposition of the active ingredient when exposed to temperatures required for heating the polymer carrier.

"Amorphous form" refers to a particle without a definite structure, i.e., no crystalline structure.

The term "essentially non-crystalline" herein means that when the x-ray diffraction analysis see no more than about 5%, e.g. not more than about 2%, or not more� than approximately 1% degree of crystallization. In a specific embodiment, the implementation in a single x-ray analysis or polarization microscopy, or both ways, don't see defined crystallization.

Compounds of formula I, including their salts, prodrug, salt of a prodrug and metabolites used in this document generally have very low solubility in water, e.g., less than about 100 μg/ml, in most cases, less than about 30 μg/ml. the Present invention may be particularly beneficial to medicines is essentially insoluble in water, i.e. having a solubility of less than approximately 10 μg/ml, because the method of the invention improves the conventional saturation of a solution of such poorly soluble active ingredient. Examples of such active ingredients are, for example, medicinal substances of class IV of the Biopharmaceutical classification system (BCS), characterized by low solubility and low permeability (see, "Waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system", U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000). It should be understood that the solubility of many compounds is pH-dependent; in the case of such compounds for solubility in this document conforms to the�esthet physiological pH, for example, a pH from about 1 to about 8. Thus, in various embodiments, the drug has a solubility in water at least at some point in the pH range of from about 1 to about 8, less than about 100 μg/ml, e.g., less than about 30 μg/ml, or less than approximately 10 μg/ml. as an illustration, ABT-263 has a solubility in water of less than 4 µg/ml at pH 2.

Solid dispersion of the present invention contain as active ingredient a compound of formula I, as defined above, or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite of such a compound. Not necessarily, they may additionally contain a second active ingredient, e.g., a therapeutic agent, applicable to combined treatment with a compound of formula I, as described herein below.

In one of the embodiments of the compound has formula I, where X3is fluoride.

In an additional embodiment of the compound has the formula I, where X4is a morpholine-4-yl.

In yet another additional embodiment of the compound has the formula I, where R0is

where X5is-O-, -CH2-, -C(CH3 )2- or-CH2CH2-; X6and X7both are-H or methyl radicals; and X8is fluorine, chlorine, bromine or iodine. To illustrate this embodiment of the X5may be-C(CH3)2-, and/or each of X6and X7may be-H, and/or X8may be chlorine.

In yet another additional embodiment of the compound has the formula I, where R0is

where X5is-O-, -CH2-, -C(CH3)2- or-CH2CH2-; X6and X7both are-H or methyl radicals; and X8is fluorine, chlorine, bromine or iodine. To illustrate this embodiment of the X5may be-C(CH3)2-, and/or each of X6and X7may be-H, and/or X8may be chlorine.

In yet another additional embodiment of the compound has the formula I, where X3is fluorine, and X4is a morpholine-4-yl.

In yet another additional embodiment of the compound has the formula I, where X3is fluorine, and R0is

where X5is-O-, -CH2-, -C(CH3)2- or-CH2CH2-; X6and X7both are-H or m�subsector radicals; and X8is fluorine, chlorine, bromine or iodine. To illustrate this embodiment of the X5may be-C(CH3)2-, and/or each of X6and X7may be-H, and/or X8may be chlorine.

In yet another additional embodiment of the compound has the formula I, where X4is a morpholine-4-yl, and R0is

where X5is-O-, -CH2-, -C(CH3)2- or-CH2CH2-; X6and X7both are-H or methyl radicals; and X8is fluorine, chlorine, bromine or iodine. To illustrate this embodiment of the X5may be-C(CH3)2and/or each of X6and X7may be-H, and/or X8may be chlorine.

In yet another additional embodiment of the compound has the formula I, where X3is fluorine, X4is a morpholine-4-yl, and R0is

where X5is-O-, -CH2-, -C(CH3)2- or-CH2CH2-; X6and X7both are-H or methyl radicals; and X8is fluorine, chlorine, bromine or iodine. To illustrate this embodiment of the X5may be-C(CH3)2-,and/or each of X 6and X7may be-H, and/or X8may be chlorine.

Compounds of formula I may contain asymmetrically substituted carbon atoms in the R - or S-conformation; such compounds may be present as racemates or in excess of one conformation over another, for example, in the enantiomeric ratio of at least about 85:15. The connection can be essentially enantiomerically pure, for example, having an enantiomeric ratio of at least about 95:5, or in some cases at least about 98:2 or at least about 99:1.

Compounds of formula I can alternatively or additionally contain carbon-carbon double bond or carbon-nitrogen double bond in the Z - or E-conformation, the term "Z" refers to a conformation where the Deputy is greater on the same side of this double bond and the term "E" refers to a conformation where more Deputy is on the other sides of the double bond. The connection may alternatively be present as a mixture of Z - and E-isomers.

Compounds of formula I can alternatively or additionally exist as tautomers or their equilibrium mixtures, where the proton shifts from one atom to another. Examples of tautomers, as an illustration, include keto-enol, phenol-�UTB, oxime-nitroso, nitro-ACI, Yiming-enamin, etc.

In some embodiments, the compound of formula I is present in the solid dispersion in the form of its parent compound, independently or in combination with salt or Pro-drug form of the connection.

Compounds of formula I can form acid salts of accession, the basic salts of accession or zwitterionic. Salts of compounds of formula I can be obtained by extraction or subsequent cleaning compounds. Acidic salts of accession are those obtained by reaction of a compound of formula I with acid. For example, in the composition of the invention can be applied salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzolsulfonat (besylate), bisulfate, butyrate, comfort, camphorsulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonic, methanesulfonate, naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, pyruvate, thiocyanate, trichloroacetate, triptorelin, para-toluensulfonate and undecanoate of a compound of formula I. Similarly, we can apply basic salts of accession, including those obtained by reaction of compounds bicarbonate, ka�bantom, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.

The compound of formula I, typically, has several protonirovannymi nitrogen atoms and, thus, capable of forming acid salts of accession with several, for example, approximately from 1.2 to about 2, from about 1.5 to about 2, or about 1.8 to about 2, equivalents of acid per equivalent connection.

Similarly, ABT-263, may form acid salts of accession, the basic salts of accession or zwitterionic. Salt of ABT-263 can be obtained by extraction or subsequent cleaning compounds. Acidic salts of accession, resulting from the reaction of ABT-263 with an acid include the above. Similarly, we can apply basic salts of accession, including the above. ABT-263 has at least two protonirovannymi nitrogen atoms and, thus, capable of forming acid salts of accession with several, for example, approximately from 1.2 to about 2, from about 1.5 to about 2, or about 1.8 to about 2, equivalents of acid per equivalent connection.

As an illustration, in the case of ABT-263 can be formed bis-salts, including, for example, bis-hydrochloride (bis-HCl) and bis-hydrobromide (bis-HBr salt).

For example, bis-HC ABT-263, having a molecular weight of 1047,5 g/mol and is represented by the formula

you can get a variety of ways, for example, in a way that can be described as follows.

Get a neutral base of ABT-263, to illustrate, as described in Example 1 above cited publication of the patent application U.S. No. 2007/0027135, detailed description of which is incorporated herein by reference. A suitable mass of the neutral base of ABT-263 is dissolved in ethyl acetate. A solution of hydrochloric acid in ethanol (for example, approximately 4.3 kg of HCl in 80 g EtOH) was added to a solution of ABT-263 in an amount that provides at least 2 mol of HCl per mole of ABT-263 and enough EtOH (at least approximately 20 volumes) for crystallization of the resulting salt of bis-HCl ABT-263. The solution was heated to approximately 45°C with stirring, and add the crystals-priming as a suspension in EtOH. After approximately 6 hours the resulting suspension was cooled to about 20°C for about 1 hour, and stirred at this temperature for about 36 hours. The suspension was filtered to recover a crystalline solid, which is an ethanol solvate of bis-HCl ABT-263. During drying of solids under the action of vacuum and nitrogen with moderate stirring during� about 8 days to get dried white crystals of bis-HCl ABT-263. This material is suitable as an API for obtaining the composition of the bis-HCl ABT-263 or (by adding a step of conversion of salt into the base in the method of producing a solid dispersion) of the neutral base of ABT-263 of the present invention.

The term "neutral ground" is used for convenience herein to refer to the original connection, at the same time realizing that the original connection is, strictly speaking, zwitterions and, thus, acting like a real Foundation.

Compounds of formula I and methods for producing such compounds described in the above cited publication of the patent application U.S. No. 2007/0027135 and/or in the above cited publication of the patent application U.S. No. 2007/0072860, each of which is fully incorporated herein by reference. The terms for the substituents used in the present document specify precisely how in those publications.

Compounds of formula I having the group-NH-C(O)OH, -OH or-SH, may be attached thereto forming a prodrug group that can be removed by metabolic meansin vivoto release the original connection with free groups,- NH, -C(O)OH, -OH or-SH. You can also apply salt of the prodrug.

Without limitation to theory, it is believed that therapeutic efficacy of the compounds of formula I is caused, at m�re, in part, their ability to bind to protein family Bcl-2, such as Bcl-2, Bcl-XLor Bcl-w in a way that inhibits the anti-apoptotic action of the protein, for example, occupying the BH3-binding cleft of the protein. Generally, it is desirable to select a compound having high affinity binding to protein family Bcl-2, for example, Kinot more than about 5 nm, preferably not more than approximately 1 nm.

Solid dispersion, as provide herein, contains any specific compound described in the publication '135, definitely include as an embodiment of the present invention.

In a more specific embodiment, the implementation, the composition comprises ABT-263 or its salt, prodrug, salt of a prodrug or metabolite. In another more specific embodiment, the implementation, the composition contains the source compound ABT-263, (i.e., neutral base) or a salt, prodrug or salt of prodrug. In another more specific embodiment, the implementation, the composition comprises a neutral base of ABT-263 or its salt. In even more specific embodiment of the composition comprises a neutral base of ABT-263 or a bis-HCl ABT-263.

Bis-HCl ABT-263 due to its crystalline nature, as a rule, is more suitable for use as an API than neutralmeasure ABT-263, received for publication '135 in an amorphous or glassy solid state. However, there may be advantages in providing a composition of solid dispersion of ABT-263, where ABT-263 is in the form of neutral grounds, because the drug will be less prone to crystallization inside the train or immediately after release from him. Thus, in another more specific embodiment of the composition comprises a neutral base of ABT-263. Note that in this embodiment, the implementation is not necessary to form a neutral base of ABT-263, is used as the API in the composition.

The compound of formula I or its salt, prodrug, salt of a prodrug or metabolite present in the solid dispersion according to the invention in quantities that may be therapeutically effective when the composition is administered to the needy in this individual on the appropriate treatment regimen. The size of the dosage in this document expressed as the number of equivalent of the starting compound (equivalent neutral grounds), unless the context otherwise requires. Normally, a single dose (the number entered at one time) that can be entered with an appropriate frequency, e.g., two times a day to once a week, is from about 10 to about 1000 mg per�animosty from the compounds being considered. If the frequency of administration is once a day (q.(d.), single dose and daily dose are the same. As an illustration, for example, if a drug is ABT-263, a single dose typically is from about 25 to about 1000 mg, more typically, from about 50 to about 500 mg, e.g., about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450 or about 500 mg. If the dosage form contains shell capsule comprising a solid dispersion, or a tablet, where the solid dispersion amount with other ingredients, the single dose can be delivered in a dosage form for a single injection or multiple dosage forms, most typically from 1 to about 10 dosage forms.

The higher the dose, the more desirable it becomes to provide a solid dispersion having a relatively high concentration of the drug. Typically, the concentration of drug in the solid dispersion is at least about 1%, e.g., from about 1% to about 50% by weight of equivalent neutral grounds, but acceptable or achievable in specific conditions�x can be lower and higher concentrations. As an illustration, for example, if a drug is ABT-263, the concentration of the drug in various embodiments is at least about 2%, e.g., from about 2% to about 50%, or at least about 5%, e.g., from about 5% to about 40%, e.g. about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% or about 40% mass equivalent neutral grounds.

The main component of the binder of the drug solid dispersion is a polymer, which is hydrophilic or water-soluble, at least during part of the pH scale, more specifically at a pH present in the gastrointestinal tract (GI), or a combination of such polymers. The polymer or mixture of polymers applicable herein, are solid at ambient temperature and, in the interests of good storage stability in the temperature range should remain solid even at the high temperatures normally encountered in storage, transportation and use of the drug. The applicable property of the polymer, determining its applicability in the present paper, therefore, is its glass transition temperature (Tg). Fittingly�e water-soluble polymers include, as non-limiting examples, those with Tgat least about 50°C, more specifically from about 80°C to about 180°C. Methods for determining the values of Tgorganic polymers described, for example, Sperling, ed. (1992)Introduction To Physical Polymer Science, 2nd edition, John Wiley & Sons, Inc.

Non-limiting examples of polymeric carriers that are applicable in the present document include:

- homopolymers and copolymers of N-vinylacetate, in particular, homopolymers and copolymers of N-vinylpyrrolidone, for example, the homopolymer of polyvinylpyrrolidone (PVP or povidone) and copolymers, such as containing monomers N-vinylpyrrolidone and vinyl acetate (copovidone) or N-vinylpyrrolidone and finalproject;

- esters of cellulose and cellulose ethers, in particular methylcellulose, ethylcellulose, (hydroxyalkyl)cellulose, such as hydroxypropyl cellulose, (hydroxyalkyl)alkyl cellulose, such as hydroxypropylmethyl cellulose (HPMC or polymer), phthalates, and succinates of cellulose, such as acetate cellulose phthalate, phthalate of hydroxypropylmethylcellulose, succinate of hydroxypropylmethylcellulose acetate and succinate of hydroxypropylmethylcellulose (HPMC-AS);

- oxides of high molecular polyalkylene, such as polyethylene oxide, polypropyleneoxide and copolymer ethylene oxide and propylenes�Yes (poloxamer);

- polyacrylates and polymethacrylates, such as copolymers of methacrylic acid/ethyl acrylate, copolymers of methacrylic acid/methyl methacrylate, copolymers of butyl methacrylate/2-dimethylaminoethylmethacrylate, poly(hydroxyethylacrylate) and poly(hydroxyethylmethacrylate);

- polyacrylamides;

- polymers of vinyl acetate, such as copolymers of vinyl acetate and crotonic acid, partially hydrolyzed polyvinyl acetate (also referred to as partially saponified "polyvinyl alcohol"), and polyvinyl alcohol;

- oligo - and polysaccharides, such as carragenan, galactomannans and xanthan gum;

and a mixture of two or more of them.

In one of the embodiments of the binder solid dispersion contains one or more polymeric carriers selected from the group consisting of copovidone, povidone and HPMC-AS. A specific example applicable copovidone is composed of approximately 60% of the monomers N-vinylpyrrolidone and about 40% of vinyl acetate monomers. A specific example applicable povidone is such, having a K-value (measure of viscosity of an aqueous solution of povidone) of approximately 30.

One or more polymer carriers, as a rule, are, in General, from about 20% to about 90%, e.g., from about 40% to about 85%, by mass� solid dispersion.

After oral administration and effects of gastrointestinal GI juice, but is not limited to theory, it is believed that provide a suitable rate of release and the inhibition of crystallization or recrystallization of the active ingredient through the interaction between the polymer carrier and a surface-active substance in the solid dispersion, thus making possible bioabsorption.

Particularly suitable as surfactants herein are the pharmaceutically acceptable non-ionic surfactants, in particular having a value hydrophilic-lipophilic balance (HLB) of from about 12 to about 18, for example, from about 13 to about 17, or from about 14 to about 16. The HLB system (see Fiedler (2002)Encyclopedia of Excipients, 5th edition, Aulendorf: ECV-Editio-Cantor-Verlag) attributes numeric values to surfactants, with lipophilic substances receiving lower HLB values and hydrophilic substances receiving higher HLB values.

Non-limiting examples of nonionic surface-active agents applicable in the present document include:

- derivatives of polyoxyethylene kasturbha oils, such as PEG-35 castor oil (e.g. Cremophor EL™ BASF Corp. or equivalent product), PEG-40 hydrogenise�created castor oil (for example, Cremophor RH™ 40 or equivalent product) and PEG-60 hydrogenated castor oil (e.g. Cremophor RH™ 60 or equivalent product);

- monoether fatty acids and sorbitan, for example, sorbitan monooleate (e.g. Span™ 80 or equivalent product), sorbitan monostearate (e.g. Span™ 60 or equivalent product), sorbitan monopalmitate (e.g. Span™ 40 or equivalent product) and sorbitan monolaurate (e.g. Span™ 20 or equivalent product);

- monoether fatty acids and polyoxyethylenesorbitan (Polysorbate), such as PEG-20 sorbitan monooleate (Polysorbate 80, e.g., Tween™ 80 or equivalent product), PEG-20 sorbitan monostearate (Polysorbate 60, for example, Tween™ 60 or equivalent product), PEG-20 sorbitan monopalmitate (Polysorbate 40, for example, Tween™ 40 or equivalent product) or PEG-20 sorbitan monolaurate (Polysorbate 20, for example, Tween™ 20 or equivalent product);

- poloxamer, such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 388 or poloxamer 407;

- α-tocopherylacetate succinate (TPGS or vitamin E polyethylene glycol succinate, see U.S. National Formulary); and mixtures of two or more of them.

One or more surfactants generally comprise, in General, from about 2% to about 25%, e.g., from about 5% to about 20% by weight of solid di�of Persia.

Pharmaceutical form according to the invention can consist essentially, or consist of a solid dispersion as described above. However, in some embodiments, a dosage form contains additional excipient, and requires additional processing solid dispersion. For example, the solid dispersion can be crushed into a powder and to fill a capsule shell or to give form or extruding to form a tablet with additional excipients, as is commonly used in these dosage forms.

Thus, deliver oral solid dosage forms of the invention include, as non-limiting examples, capsules, dragees, granules, pills, powders and pills. Commonly used for the preparation of such dosage forms, excipient include encapsulating material or composition additives such as absorption accelerators, antioxidants, binding tools, buffers, covering tools, dyes, diluents, means to improve disintegration, emulsifiers, extenders (extenders), fillers, fragrances, humectants, lubricants, preservatives, propellants, mould release, sterilizing agent, sweeteners, soljubilizatory and mixtures thereof. Specific examples of excipients include agar, alginic acid, aluminum hydroxide, benzyl, 13-butyleneglycol, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, ethanol, ethyl acetate, ethylcarbonate, ethylcellulose, ethyl laurate, ethyloleate, gelatin, wheat germ oil, glucose, glycerol, peanut oil (groundnut oil), isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, olive oil, peanut oil (peanut oil), potassium phosphate salts, potato starch, propylene glycol, talc, tragacanth gum, water, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium lauryl sulphate, sodium phosphate salts, soybean oil, sucrose, tetrahydrofurfuryl alcohol mixtures.

A method of obtaining a solid dispersion with a solvent, as described above, comprises dissolving the API, the polymer carrier and a surfactant in a suitable solvent; and removing the solvent to obtain a solid dispersion. Not necessarily, if the API is in salt form, and desirable is the provision of a solid dispersion of the drug in the form of a neutral substrate, the substrate is added before removal of the solvent for the action to turn the API into its corresponding neutral basis. For example, if the API is a bis-HCl ABT-263, the addition of bases, such as sodium hydroxide (NaOH), hydroxide ka�Oia (KOH), sodium bicarbonate (NaHCO3), potassium bicarbonate (KHCO3) or ammonium bicarbonate (NH4HCO3), in the amount of at least 2 moles per mole of the API may result in the transformation API to the neutral base of ABT-263. By-product inorganic salt, as an illustration, NaCl, KCl or NH4Cl, can be left in the product or, optionally, to extract to remove the solvent.

At the stage of dissolution can add various components in any order. For example, each ingredient can be added to the solvent separately and then dissolve in it. Alternatively, a polymeric carrier and/or surface-active agent can be pre-mixed with the API and then the resulting mixture is added to the solvent. However, as a rule, is generally accepted, if the method involves the transformation of salt into a neutral basein situfirst add salt API and base in the solvent, and then (optionally, after extraction by-product salt) adding the polymer carrier and a surfactant.

Essentially, you can apply any solvent provided that it is effective for dissolving the active ingredient, the polymer carrier and a surfactant. Non-limiting examples of solvents that may be applicable include meth�Nol, ethanol, acetone and mixtures thereof. Optionally, you can enable Aristotel.

If the desired extraction is a by-product in the form of a salt, such as NaCl, KCl or NH4Cl, before removal of the solvent, it is possible to choose a solvent, provided that the by-product salt is insoluble, thus making possible the extraction of by-product salt by filtration.

Removal of the solvent can be performed by application of heat, vacuum or a combination thereof. If the applied heat is generally preferable to avoid excessive glass-transition temperature (Tg) a polymer binder. For most purposes, appropriate is heated at a temperature of from about 50°C to about 80°C, for example, from about 55°C to about 75°C. After removal of the solvent the resulting preparation was cooled (if necessary) to the ambient temperature.

Additional details of the method can be found in the illustrative methods of Examples 1 and 2 below.

The terms "deliver oral", "oral introduction" and "orally administered" herein refer to the introduction to the individual through the mouth (p.o.), i.e. the introduction, in which the composition immediately swallow, for example, with a suitable volume of water or other potable liquid. "Oral BB�vision" is separated herein from intraoral administration, for example, sublingual or buccal administration or local injection of tissues of the oral cavity such as periodontal tissue, not directly involved in the ingestion of the composition.

To provide a solid dispersion or dosage forms with acceptable bioabsorable after oral administration, it is necessary to choose the form of the active ingredient (e.g., neutral base or salt), a polymer carrier (media), a surface-active substance (substances) and other optional ingredients and must be applied relative amounts of these components. This bioabsorption can be confirmed, for example, pharmacokinetic (PK) profile of solid dispersion or dosage forms, more specifically, by Cmaxor AUC, for example, AUC0-24or AUC0-when a specific dose or range of doses. As an illustration, the bioavailability can be expressed as a percentage, for example with the use of F-criterion, which is calculated AUC for the oral delivery of the test composition as a percentage of AUC for intravenous (i.v.) bring medication in an appropriate solvent, taking into account any differences between oral and i.v. doses.

Bioavailability can be determined by PK studies in humans or any �odchodami model types. For present purposes, as a rule, is a suitable model of a dog, as an illustration, described in Example 5 below. In various illustrative embodiments, when the drug is ABT-263, the composition of the invention exhibit oral bioavailability of at least about 15%, at least about 20%, at least about 25% or at least about 30% to about 50% or more on the model in dogs when administered as a single dose of about 2.5 to about 10 mg/kg for the hungry or nemolodymi animals.

Included in this document compositions, including the compositions described in General or with restrictions in this paper are applicable for oral deliver the individual drugs, which is a compound of formula I or its pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite. Thus, the method of the invention for delivery of such drugs to the individual includes the oral administration of a composition as described above.

The individual can be a man or not belonging to the human animal (e.g., agriculture, contained in the zoo, work animals or animal companion, or lab�Torno animals used as a model), but in an important embodiment of the individual is the person requiring the medication, for example, for treatment of a disease characterized by apoptotic dysfunction and/or sverkhekspressiya anti-apoptotic protein family Bcl-2. A man can be a man or a woman of any age. The patient is an adult, but the method of the invention can be used for the treatment of childhood malignancies, such as leukemia, e.g. acute lymphocytic leukemia in children.

Normal composition is administered in an amount that provides a therapeutically effective daily dose of drug. The term "daily dose" herein means the amount of drug introduced into the day, regardless of the frequency of administration. For example, if an individual receives a single dose of 150 mg twice a day, the daily dose is 300 mg. it Should be understood that the use of the term "daily dose" does not imply that a particular dosage of the drug be sure to enter once per day. However, in the specific embodiment of the frequency of administration of the drug is once a day (q.(d.), in this embodiment, the implementation of the daily dose and dose are the same.

What is the treatment�CI effective dose, depends on the specific compound, the individual (including the type and body weight of the individual), the disease being treated (e.g., a specific type of cancer), stage and/or severity of the disease, the individual resistance of the individual to the connection, enter the connection as monotherapy or in combination with one or more other drugs, for example, other chemotherapeutic agents for the treatment of malignant neoplasms and other factors. Thus, the daily dose may vary in a wide range, e.g., from about 10 to about 1000 mg. higher or lower daily doses may be appropriate in specific situations. It should be understood that the enumeration herein "therapeutically effective" dose herein does not necessarily require that the drug was therapeutically effective if administered only a single dose; generally, therapeutic efficacy depends on the composition introduced repeatedly by the scheme of treatment, including the appropriate frequency and duration of administration. Highly preferred is that, while selected daily dose is sufficient to provide the benefits in terms of treatment W�kacestvennogo neoplasms, it should not be sufficient to cause adverse side effects in unacceptable or unbearable degree. The appropriate therapeutically effective dose can be selected by the physician of ordinary skill, without undue experimentation, based on the description herein and the prior art cited in this document, taking into account factors such as those listed above. The doctor, for example, may begin treatment of the patient with malignant tumor with a course of therapy with a relatively low daily dose and pick up a higher dosage over a period of days or weeks to reduce the risk of adverse side effects.

As an illustration, a suitable dose of ABT-263, typically comprise from about 25 to about 1000 mg/day, more typically, from about 50 to about 500 mg/day or from about 200 to about 400 mg/day, for example, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450 or about 500 mg/day, administered with an average interval between doses from about 3 hours to about 7 days, for example, from about 8 hours to about 3 days, or from about 12 hours�in approximately 2 days. In the majority of cases, the treatment regimen with the introduction of once a knocks (q.(d.).

"The average interval between doses" in this document is defined as the period of time such as one day or one week, divided by the number of single doses administered for a given period of time. For example, if the drug is administered three times a day, about 8 o'clock in the morning, around noon and around 6 PM, the average interval between doses is 8 hours (24-hour time span divided by 3). In order to determine the average interval between doses, when the drug accounted as separate dosage form such as a tablet or capsule, many (for example, approximately from 2 to 10) dosage forms administered simultaneously, consider a single dose.

If drug compound is ABT-263, for example, in the form of a neutral base of ABT-263 or a bis-HCl ABT-263, in some embodiments, the implementation can choose the daily dosage of the drug and the interval between doses to maintain the concentration of ABT-263 in plasma in the range of approximately 0.5 to approximately 10 μg/ml. Thus, during the course of therapy of ABT-263 on such modalities of implementation of the steady-state maximum plasma concentration (Cmax) generally should not exceed priblisitelno µg/ml and steady-state minimum plasma concentration (Cmin) generally should not fall below about 0.5 μg/ml. in addition, it is desirable to choose the daily dosage of the drug and the average interval between doses in the ranges shown above, effective to ensure a relationship of Cmax/Cminnot more than about 5, for example not more than about 3 at steady state. It should be understood that longer intervals between doses tend to lead to large relations Cmax/Cmin. As an illustration, when steady state Cmaxconstituting from about 3 to about 8 μg/ml, and Cminconstituting from about 1 to about 5 ug/ml ABT-263 can be set this way. The values of Cmaxand Cminat steady state can be set in the PK study, for example, carried out according to standard protocols, including as non-limiting examples of such, are approved by the regulatory institution such as the U. S. Food and Drug Administration (FDA).

If the composition is in the form of a capsule, one to a small number of capsules can be swallowed whole, usually with the help of water or other digestible liquid to facilitate swallowing. Suitable materials shells of capsules incl�Ute, as non-limiting examples, gelatin (in the form of hard gelatin capsules or soft elastic gelatin capsules), starch, carrageenan and HPMC.

Because people believe that the composition of the present invention exhibit only a slight effect on food introduction according to the present variant of the implementation can be carried out with or without food, i.e., on an empty stomach or with meals. Generally, it is preferable to introduce these songs to the patient on an empty stomach.

The composition of the invention suitable for use in monotherapy or in combined treatment with, for example, other chemotherapeutic agents or ionizing radiation. A particular advantage of the present invention is that it makes it possible for oral administration once a day, the regimen, which is convenient for the patient undergoing other treatment administered oral drugs in the regimen once a day. Oral administration is easily performed by the patient or the person providing care and treatment to the patient's home; it is also a convenient way of introduction for patients in the hospital or in institutions for permanent residence and medical care.

Methods of combined treatment, as an illustration, include the introduction of the composition according to the present from�bretania, for example, such a composition comprising ABT-263, simultaneously with one or more of bortezomib, carboplatin, cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel, doxorubicin, etoposide, fludarabine, irinotecan, paclitaxel, rapamycin, rituximab, vincristine, etc., for example, polytherapy, such as CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), RCVP (rituximab + cyclophosphamide + vincristine + prednisone), R-CHOP (rituximab + CHOP) or DA-EPOCH-R (adjusted dose of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab).

The composition according to the invention, for example, such a composition comprising ABT-263, you can type in the combined treatment with one or more therapeutic agents that include, as non-limiting examples of alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotic tools, antiproliferative funds, antiviral agents, inhibitors of Aurora kinases, others promote apoptosis means (for example, inhibitors of Bcl-xL, Bcl-w and Bfl-1), activators of the way of death receptors, inhibitors of the kinase Bcr-Abl, BiTE antibodies (bispecific activator of T-cells), conjugates of the antibody-drug, biological response modifiers, inhibitors of cyclin-dependent kinase (CDK) inhibitors of cell CEC�and, inhibitors of cyclooxygenase-2 (COX-2), binding proteins with dual variable domain (DVD), inhibitors of the receptor of epidermal growth factor 2 (ErbB2 or HER/2neu), inhibitors of growth factors, inhibitors of heat shock protein (HSP)-90 inhibitors kistanova deacetylase (HDAC), to hormonal therapy, immunological tools, inhibitors of apoptotic proteins (IAPS), intercalating antibiotics, kinase inhibitors, inhibitors of kinesin, JAK2 inhibitors, inhibitors of target of rapamycin mammalian (mTOR), microRNA, inhibitors of the mitogen-activated extracellular regulated signal kinase (MEK), multivalent binding proteins, non-steroidal anti-inflammatory drug (NSAID), inhibitors of poly-ADP (adenosine diphosphate)-ribosomally (PARP), a platinum chemotherapeutic agents, inhibitors of Polo-like kinase (Plk) inhibitors phosphoinositide-3-kinase (PI3K), proteasome inhibitors, purine analogs, pyrimidine analogs, inhibitors tyrosinekinase receptors, retinoids, deltoids, plant alkaloids, small inhibitorsa ribonucleic acids (miRNAs), topoisomerase inhibitors, inhibitors of ubiquitinate, etc.

Of BiTE antibodies are bispecific antibodies that direct T-cells to attack the cancer cells by simultaneously binding the two cells. Then T-Claix�ka attacks target the malignant cell. Examples of BiTE antibodies include, as non-limiting examples, adecatumumab (Micromet MT201), blinatumomab (Micromet MT103), etc. Without limitation to theory, one mechanism by which T cells cause apoptosis of the target cancer cells, exocytosis is the component of cytolytic granules, including perforin and Grasim B. In this regard, it was shown that Bcl-2 attenuates the induction of apoptosis and perforin, and grannymom B. These data suggest that the inhibition of Bcl-2 may enhance the cytotoxic effects called T-cells by the action of malignant cells (Sutton et al. (1997)J. Immunol.158:5783-5790).

MiRNAs are molecules with bases endogenous RNA or chemically modified nucleotides. Modifications do not eliminate cellular activity, but more often gives increased stability and/or increased cell efficiency. Examples of chemical modifications include phosphorothioate group, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethylamine, combinations thereof, etc. MiRNAs may have different length (e.g., 10-200 BP) and structures (e.g., hairpins, one/two chains, pipelinename, single-strand breaks/passes, pairings complementary reason), and they undergo processing in the cells to guarantee� active silencing of the gene. Double-stranded miRNAs (dcrk) can have the same number of nucleotides in each chain (blunt ends) or asymmetric ends (sticky ends). A sticky end in 1-2 nucleotides can be present on the sense and/or antisense chain, and also be present at the 5' and/ or 3'ends of this circuit. For example, it is shown that miRNAs targeting Mcl-1, enhances the activity of ABT-263 or ABT-737 in various tumor cell lines (Tse et al. (2008) Cancer Res. 68:3421-3428 and references therein).

Multivalent binding proteins bind proteins containing two or more antigen-binding sites. Multivalent binding proteins constructed so that they have three or more antigen-binding sites and, as a rule, are not natural antibodies. The term "multispecific binding protein" means a binding protein capable of binding two or more related target. Binding proteins with dual variable domain (DVD) are tetravalent or multivalent binding proteins containing two or more antigen-binding sites. These DVDs can be monospecificity (i.e., capable of binding one antigen) or multispecificity (i.e. capable of binding two or more antigens). Binding proteins with a DVD containing two polypeptide heavy chain of DVD and two polypeptide light chain V (d) is referred to as DVD-Ig. Each half DVD Ig polypeptide contains the heavy chain DVD polypeptide light chain DVD and two antigen-binding site. Each binding site contains a variable domain of the heavy chain variable domain and light chain total of 6 CDRs involved in antigen binding, antigen-binding site.

Alkylating agents include altretamin, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, Cloretazine™ (laromustine, VNP 40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, metabolical, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, treosulfan, trofosfamide, etc.

Angiogenesis inhibitors include inhibitors of the receptor of epidermal growth factor (EGFR), inhibitors of endothelial-specific tyrosinekinase receptor (Tie-2) inhibitors receptor insulin-like growth factor-2 (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase -9 (MMP-9) inhibitors of the receptor platelet-derived growth factor (PDGFR), the analogues of thrombospondin, inhibitors tyrosinekinase receptor growth factor vascular endothelial (VEGFR), etc.

Antimetabolites include Alimta ® (pemetrexed, denetria, LY231514, MTA), 5-azacytidine, Xeloda™ (capecitabine), carmofur, eustat™ (cladribine), Clofarabine, cytarabine, ocfosfate cytarabine, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethinyl-1-β-D-ribofuranosylpurine-4-carboxamide), enocitabine, ethenicity, fludarabine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, Gemzar™ (gemcitabine), hydroxyurea, Alkeran ® (melphalan), mercaptopurine, 6-mercaptopurine ribozid, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, political, pentostatin, raltitrexed, ribavirin, S-1, triapin, trimetrexate, TS-1, tianfuan, tegafur, vidarabine, UFT, etc.

Antiviral agents include ritonavir, gidroksihlorohina, etc.

Inhibitors of Aurora kinases include ABT-348, AZD-1152, MLN-8054, VX-680, Aurora A-specific inhibitors of kinases, Aurora B-specific inhibitors of kinases pan-inhibitors of Aurora kinases, etc.

Inhibitors of protein family Bcl-2, other than ABT-263 or compounds of formula I herein include AT-101 ((-)gossypol), which aims to Bcl-2 antisense oligonucleotide Genasense™ (G3139 or oblimersen), IPI-194, IPI-565, ABT-737, GX-070 (obatoclax), etc.

Inhibitors of kinases Bcr-Abl include dasatinib (BMS-354825), Gleevec™ (imatinib), etc.

The CDK inhibitors include AZD-5438, BMI-1040, BMS-387032, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202 or R-roscovitine), ZK-304709, etc.

The COX-2 inhibitors include ABT-963, Arcoxia™ (etoricoxib), Bextra™ (valdecoxib), BMS-347070 Celebrex™ (celecoxib), COX-189 (lumiracoxib), CT - 3, Deramaxx™ (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylbenzoyl)-1H-pyrrol, MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, Vioxx™ (rofecoxib), etc.

EGFR inhibitors include ABX-EGF, immunoliposome against EGFR, EGF vaccine, EMD-7200, Erbitux™ (cetuximab), HR3, IgA antibodies, Iressa™ (gefitinib), Tarceva™ (erlotinib or OSI-774), TP-38, fused EGFR protein, Tykerb™ (lapatinib), etc.

Inhibitors of ErbB2 receptor include CP-724714, CI-1033 (canertinib), Herceptin™ (trastuzumab), Tykerb™ (lapatinib), Omnitarg™ (2C4, pertuzumab), TAK-165, GW-572016 (infamis), GW-282974, EKB-569, PI - 166, dHER2 (vaccine against HER2), APC-8024 (vaccine against HER2), bespecifically antibody against the HER/2neu, B7.her2IgG3, trifunctional bespecifically antibodies AS HER2, mAB AR-209, mAB 2B-1, etc.

Inhibitors of kistanova deacetylase include depsipeptide, LAQ-824, MS-275, trioxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid, etc.

Inhibitors of HSP-90 include 17AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, Mycograb™ (recombinant human antibody to HSP-90), nab-17AAG, NCS-683664, PU24FC1, PU-3, radicial, SNX-2112, STA-9090, VER-49009, etc.

Inhibitors of apoptotic proteins include HGS-1029, GDC-0145, GDC-0152, LCL-161, LBW-242, etc.

Conjugates of the antibody - drug include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti-CD22-MCC-DMl, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19A, SGN-35, SGN-75, etc.

Activators the way of death receptors include TRIL and antibodies or other means, aimed at TRAIL or death receptors (e.g., DR4 and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762, trastuzumab, etc.

Inhibitors include kinesin Eg5 inhibitors such as AZD-4877, and ARRY-520, CENPE inhibitors such as GSK-923295A, etc.

The JAK2 inhibitors include CEP-701 (resourcelib), XL019, INCB-018424, etc.

The MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059, etc.

The mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive inhibitors of TORC1/TORC2, including PI-103, PP242, PP30, and Torin 1, and so on.

Nonsteroidal anti-inflammatory drugs include Amigesic™ (salsalate), Dolobid™ (diflunisal), Motrin™ (ibuprofen), Orudis™ (Ketoprofen), Relafen™ (nabumetone), Feldene™ (piroxicam), cream ibuprofen, Aleve™ and Naprosyn™ (naproxen), Voltaren™ (diclofenac), Indocin™ (indomethacin), Clinoril™ (sulindac), Tolectin™ (tolmetin), Lodine™ (etodolac), Toradol™ (Ketorolac), Daypro™ (oxaprozin) etc.

The PDGFR inhibitors include CP-673451, CP-868596, etc.

Platinum chemotherapeutic agents include cisplatin, Eloxatin™ (oxaliplatin), heptaplatin, lobaplatin, nedaplatin, Paraplatin ® (carboplatin), picoplatin, satraplatin, etc.

Inhibitors of Polo-like kinases include BI-2536, etc.

Inhibitors phosphoinositide-3-kinase include wortmannin, LY-294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866, GDC-0941, BGT226, BEZ235, XL765, etc.

Analogs of thrombospondin on�fer ABT-510, ABT-567, ABT-898, TSP-1, etc.

The VEGFR inhibitors include Avastatin™ (bevacizumab), ABT-869, AEE-788, Angiozyme™ (inhibiting angiogenesis is a ribozyme (Ribozyme Pharmaceuticals (Boulder, CO) and Chiron (Emeryville, CA)), axitinib (AG-13736), AZD-2171, CP-547632, IM-862, Macugen™ (pegaptanib), Nexavar™ (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK-787 or ZK-222584), Sutent™ (sunitinib or SU-11248), VEGF trap, Zactima™ (vandetanib or ZD-6474), etc.

Antibiotics include intercalating antibiotics such as aclarubicin, actinomycin D, amrubicin, annamycin, Adriamycin™ (doxorubicin), Blenoxane™ (bleomycin), daunorubicin, Caelyx™ and Myocet™ (liposomal doxorubicin), elsamitrucin, epirubicin, Parubiy, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimulater, streptozocin, Valstar™ (valrubicin), zinostatin, etc.

Inhibitors of topoisomerases include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, bicategory, belotecan, BN-80915, Camptosar™ (irinotecan hydrochloride), camptothecin, Cardioxane™ (dexrazoksana), diflomotecan, edotecarin, Ellence™ and Pharmorubicin™ (epirubicin), etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, oracin, parabolin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluprost, topotecan, etc.

Antibodies include Avastin™ (bevacizumab), CD40-specific antibodies, chTNT-1/B, denosumab, Erbitux™ (cetuximab), Humax-CD4™ (zanolimumab), IGF1R-special�ary antibodies, lintuzumab, Panorex™ (edrecolomab), Rencarex™ (WX G250), Rituxan™ (rituximab), ticilimumab, trastuzumab, CD20 antibodies types I and II, etc.

Remedies for hormonal therapy include Arimidex™ (anastrozole), Aromasin™ (exemestane), arzoxifene, Casodex™ (bikalutamid), Cetrotide™ (cetrorelix), degarelix, deslorelin, Desopan™ (trilostane), dexamethasone, Drogenil™ (flutamide), Evista™ (raloxifene), Afema™ (fadrozole), Fareston™ (toremifene), Faslodex™ (fulvestrant), Femara™ (letrozole), formestane, glucocorticoids, Hectorol™ (doxercalciferol), Renagel™ (sevelamer carbonate), lasofoxifene, leuprolide acetate, Megace™ (megestrol), Mifeprex™ (mifepristone), Nilandron™ (nilutamid), tamoxifen, including Nolvadex™ (tamoxifen citrate), Plenaxis™ (abarelix), prednisone, Propecia™ (finasteride), elastan, Suprefact™ (buserelin), growth hormone-releasing factor, luteinizing hormone (LHRH), including Trelstar™ (triptorelin), histrelin, including Vantas™ (gostraliruyu implant), Modrastane™ (trilostane), and Zoladex™ (goserelin), etc.

Deltoids and retinoids include seocalcitol (EB 1089 or CB 1093), lexicality (KH1060), fenretinide, Panretin ® (alitretinoin), tretinoin, including Atragen™ (liposomal tretinoin), Targretin™ (bexarotene), LGD-1550 and so on.

PARP inhibitors include ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, etc.

Plant alkaloids include vincristine, vinblastine, vindesine, vinorelbine, etc.

The proteasome inhibitors include Velcade ® (Bo�tezaab), MG132, NPI-0052, PR-171, etc.

Examples of immunological tools include interferons and other immunity-boosting tools. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, Actimmune™ (interferon gamma-1b), interferon gamma-n1, combinations thereof, etc. Other tools include Alfaferone (IFN-α), BAM-002 (oxidized glutathione), Beromun™ (tasonermin), Bexxar™ (tositumomab), Campath™ (alemtuzumab), CTLA4 (antigen cytotoxic lymphocytes 4), dacarbazine, denileukin, epratuzumab, Granocyte™ (lenograstim), lentinan, leukocyte interferon alpha, imiquimod, MDX-010 (anti-CTLA-4), a vaccine against melanoma, mitooma, molgramostim, Mylotarg™ (gemtuzumab ozogamicin), Neupogen™ (filgrastim), Onco VAC-CL, Ovarex™ (oregovomab), pemtumomab (Y-muHMFGl), Provenge™ (sipuleucel-T), sargramostim, sizofiran, teceleukin, Theracys™ (BCG or Bacillus Calmette-Guerin), ubenimex, Virulizin™ (immunotherapeutic agent, Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama or SSM), WF-10 (tetrachlorodecaoxide or TCDO), Proleukin™ (aldesleukin), Zadaxin™ (thymalfasin), Zenapax™ (impact), Zevalin™ (90Y-ibritumomab tiuxetan), etc.

The biological response modifiers are tools that modify defense mechanisms of living organisms or biological responses such as survival, growth or differentiation of tissue cells so that they possess antitumor activity of�Yu, and include baptisms, lentinan, sizofiran, picibanil, PF-3512676 (CpG-8954), ubenimex, etc.

The pyrimidine analogs include cytarabine (citizenerased, ara C or arabinose C), doxifluridine, Fludara™ (fludarabine), 5-FU (5-fluorouracil), floxuridine, Gemzar™ (gemcitabine), Tomudex™ (raltitrexed), triacetyluridine, Troxatyl™ (troxacitabine), etc.

Purine analogs include Lanvis™ (thioguanine), Purinethol™ (mercaptopurine), etc.

Antimitotic funds include batubulan, epothilone D (KOS-862), N-(2-((4-hydroxy-phenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS-247550), paclitaxel, Taxoter™ (docetaxel), larotaxel (PNU-100940, RPR-109881 or XRP-9881), patupilone, vinflunine, ZK-EPO (synthetic epothilone), etc.

Inhibitors of ubiquitinate include MDM2 inhibitors, such as nutlins, NEDD8 inhibitors, such as MLN4924, etc.

The compositions of the present invention can also be used as radiosensitisation, increasing efficiency of radiation therapy. Examples of radiation therapy include, as non-limiting examples, the outer remote radiotherapy (XBRT), remote therapy (teletherapy), brachytherapy, contact radiation therapy introduction radiation sources in the affected organ, contact radiation therapy with the introduction of a liquid radiation source in the affected organ (unsealed source radiotherapy), etc.

Additionally or alternatively, �oppoziciu of the present invention can be entered in the combined treatment with one or more antitumor or chemotherapeutic agents, selected from Abraxane™ (ABI-007), ABT-100 (inhibitor farnesyltransferase), Advexin™ (vaccine Ad5CMV-p53 or contusugene ladenovec), Altocor™ or Mevacor™ (lovastatin), Ampligen™ (poly(I)-poly(C12U), a synthetic RNA), Aptosyn™ (exisulind), Aredia™ (pamidronic acid), Arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene), Avage™ (tazarotene), AVE-8062 (derived combretastatin), BEC2 (mitumba), cachectin or cachexin (tumor necrosis factor), Canvaxin™ (vaccine against melanoma), CeaVac™ (vaccine malignant neoplasm), Celeuk™ (celmoleukin), histamine, including Ceplene™ (histamine dihydrochloride), Cervarix™ (adsorbed vaccine against the human papilloma virus (HPV) containing AS04 adjuvant), CHOP (Cytoxan™ (cyclophosphamide) + Adriamycin™ (doxorubicin) + Oncovin™ (vincristine) + prednisone), combretastatin A4P, Cypat™ (cyproterone), DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a linker His-Ala with epidermal growth factor), dacarbazine, dactinomycin, Dimericine™ (liposomal lotion T4N5), 5,6-dimethylxanthene-4-acetic acid (DMXAA), discodermolide, DX-8951f (exatecan mesylate), eniluracil (itineraria), squalamine, including Evizon™ (squalamine lactate), enzastaurin, EPO-906 (epothilone B), Gardasil™ (quadrivalent recombinant vaccine against human papillomavirus (types 6, 11, 16, 18)), Gastrimmune™, Genasense™ (�oblimersen), GMK (vaccines based on conjugate was), GVAX™, a vaccine against prostate cancer), halofuginone, histrelin, gidroksicarbamida, ibandronova acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin of besudotox), IL-13-exotoxinPseudomonas, interferon-α, interferon-γ, Junovan™ and Mepact™ (mifamurtide), lonafarnib, 5,10-methylentetrahydrofolate, miltefosine (hexadecylphosphocholine), Neovastat™ (AE-941), Neutrexin™ (trimetrexate of glucuronate), Nipent™ (pentostatin), Onconase™ (ranpirnase, the enzyme ribonuclease), Oncophage™ (vitespen, vaccines against melanoma), OncoVAX™ (vaccine IL-2), Orathecin™ (rubitecan), Osidem™ (based on cell antibodies medicines), Ovarex™ MAb (monoclonal mouse antibody), paclitaxel albumin-stabilized nanoparticle paclitaxel, Pandimex™ (aglionby saponins from a ginseng, comprising 20(S)-protopanaxadiol (aPPD) and 20(S)-protopanaxatriol (aPPT)), panitumumab, Panvac™-VF (research vaccine malignant neoplasm), pegaspargase, of peginterferon Alfa (PEG interferon A), phenoxodiol, procarbazine, reumatica, Removab™ (catumaxomab), Revlimid ® (lenalidomide), RSR13 (efaproxiral), Somatuline™ LA (lanreotide), Soriatane™ (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), Targretin™ (bexarotene), Taxoprexin™ (docosahexaenoic acid (DHA) + paclitaxel), Telcyta™ (infospeed, TLK-286, Temodar™ (temozolamide), tesmilifene, tetrandrine, thalidomide, Theratope™ (vaccine STn-KLH), Thymitaq™ (nolatrexed dihydrochloride), TNFerade™ (adenovector: DNA carrier containing the gene for tumor necrosis factor-α), Tracleer™ or Zavesca™ (bosentan), TransMID-107R™ (KSB-311, diphtheria toxins), tretinoin (retina-A), Trisenox™ (arsenic trioxide), Ukrain™ (derivative of alkaloids from plants celandine), Virulizin™, Vitaxin™ (antibody against αvβ3), Xcytrin™ (motexafin gadolinium), Xinlay™ (atrasentan), Xyotax™ (paclitaxel poliglumex), Yondelis™ (trabectedin), ZD-6126 (N-acetilcolina-O-phosphate), Zinecard™ (dexrazoksana), zoledronic acid, zorubicin, etc.

In one of the embodiments of the composition according to the invention, for example, such a composition comprising ABT-263, is administered in therapeutically effective amounts to the needy in this individual to treat a disease in which sverkhekspressiya one or more of antiapoptotic protein Bcl-2, antiapoptotic protein Bcl-XLand antiapoptotic protein Bcl-w.

In another embodiment of the composition according to the invention, for example, such a composition comprising ABT-263, is administered in therapeutically effective amounts to the needy in this individual for the treatment of diseases characterized by abnormal cell growth and/or impaired apoptosis.

Examples of such diseases include,as non-limiting examples malignant neoplasm, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, malignant tumor of the head and neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of bone tissue, colon cancer, rectal cancer, anal cancer, stomach cancer, cancers of the gastrointestinal tract (stomach, colon and/or duodenal), chronic lymphocytic leukemia, acute lymphocytic leukemia, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma of soft tissue, cancer of the urethra, penile cancer, testicular cancer, hepatocellular cancer (hepatic and/or biliary duct), primary or secondary tumor of the Central nervous system, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, malignant neoplasms of lymphoid tissue by T-cell or B-cell origin, melanoma, multiple myeloma, cancer of the mouth, nemeskal�accurate lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and/or ureter, počečnokletočnyj carcinoma, carcinoma of the renal pelvis, neoplasm of the Central nervous system, primary lymphoma of the Central nervous system, nahodkinskuju lymphoma, spinal tumors, brainstem glioma, pituitary adenoma, cancer of the adrenal cortex, bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination.

In a more specific embodiment of the composition according to the invention, for example such a composition comprising ABT-263-containing solid dispersion, is administered in therapeutically effective amounts to the needy in this individual for the treatment of bladder cancer, brain tumor, breast cancer, tumors of the bone marrow, cervical cancer, chronic lymphocytic leukemia, acute lymphocytic leukemia, colon cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma, malignant neoplasms of lymphoid tissue by T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer or cancer of the spleen.

According to any one of these options is implemented�of Tulane composition is administered as monotherapy or in combination therapy with one or more additional therapeutic agents.

For example, a method of treating mesothelioma, bladder cancer, pancreatic cancer, skin cancer, malignant neoplasms of the head and neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of cervix, carcinoma of the vagina, carcinoma of the vulva, bone tissue neoplasms, colon cancer, rectal cancer, anal cancer, stomach cancer, cancer of the gastrointestinal tract (stomach, colon and/or duodenal), chronic lymphocytic leukemia, acute lymphocytic leukemia, cancer of the esophagus, cancer of the small intestine, tumors of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, penile cancer, testicular cancer, hepatocellular cancer (hepatic and/or biliary duct), primary or secondary tumors of the Central nervous system, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, malignant neoplasms of lymphoid tissue by T-cell or B-cell origin, melanoma, multiple mie�ohms, oral cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and/or ureter, počečnokletočnyj carcinoma, carcinoma of the renal pelvis, neoplasias of the Central nervous system, primary lymphoma of the Central nervous system, non-Hodgkin's lymphoma, tumors of the spine, glioma of the brain stem, pituitary adenoma, cancer of the adrenal cortex, bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of the individual comprises administering to the individual therapeutically effective amounts of (a) the composition of the invention, for example, such a composition comprising ABT-263, and (b) one or more of etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib.

In specific embodiments, the composition according to the invention, for example, such a composition comprising ABT-263, is administered in therapeutically effective amounts to the needy in this individual in the combined treatment with etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in a therapeutically effective amount for the treatment of malignant tumors of lymphoid tissue, such as B-cell lymphoma or non-Hodgkin's lymphoma.

In other specific embodiments, �oppoziciu according to the invention, for example, such a composition comprising ABT-263, is administered in therapeutically effective amounts to the needy in this individual as monotherapy or with combination therapy with etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in a therapeutically effective amount for the treatment of chronic lymphocytic leukemia or acute lymphocytic leukemia.

The present invention also relates to a method for maintaining in bloodstream of a person with malignant neoplasm a therapeutically effective concentration of ABT-263 and/or one or more of its metabolites in plasma, comprising administering to the individual a solid dispersion of ABT-263 or its pharmaceutically acceptable salt, prodrug, salt of a prodrug or metabolite (e.g., neutral base of ABT-263 or ABT-263 bis-HCV) in essentially non-crystalline form in a binder containing a pharmaceutically acceptable water-soluble polymeric carrier and a pharmaceutically acceptable surfactant in the amount of the dosage the equivalent of from about 50 to about 500 mg ABT-263 per day, at an average interval between doses from about 3 hours to about 7 days.

What constitutes a therapeutically effective concentration in plasma depends, including, of concrete�Togo malignancy, available to the patient, the stage of severity and aggressiveness of malignant neoplasms and the desired outcome (e.g., stabilizing, reducing tumor growth, reduce tumor size, reduce the risk of metastasis, etc.). Highly preferred is that, while selected daily dose is sufficient to provide the benefits in terms of treatment of malignant neoplasms, it should not be sufficient to cause adverse side effects in unacceptable or unbearable degree.

For the treatment of malignant neoplasms, in General, and malignant neoplasms of lymphoid tissue, such as non-Hodgkin's lymphoma, in particular, in most cases, it is necessary to maintain the concentration of ABT-263 in plasma in the range of approximately 0.5 to approximately 10 μg/ml. Thus, during the course of therapy ABT-263 established Cmaxmainly, should not exceed about 10 μg/ml, and the steady-state Cminmainly, should not fall below about 0.5 μg/ml. in addition, it is desirable to choose the daily dosage of the drug and the average interval between doses in the ranges shown above, effective to ensure a relationship of Cmax/Cminnot more than about 5, for example not more than a few�about 3, at steady-state condition. It should be understood that longer intervals between doses tend to lead to large relations Cmax/Cmin. As an illustration, when steady state Cmaxconstituting from about 3 to about 8 μg/ml, and Cminconstituting from about 1 to about 5 ug/ml ABT-263 can be set this way.

The daily dosage of the drug, effective to maintain a therapeutically effective level of ABT-263 in plasma, is according to the present embodiment of the from about 50 to about 500 mg. In most cases, a suitable daily dosage of the drug is from about 200 to about 400 mg. To illustrate the daily dosage of the drug may be, for example, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450 or about 500 mg.

The average interval between doses, is effective to maintain a therapeutically effective level of ABT-263 in plasma is according to the present embodiment of the from about 3 hours to about 7 days. In most cases, a suitable average interval between doses is from about 8 cha�s to approximately 3 days, or from about 12 hours to about 2 days. Often suitable treatment scheme with the introduction of once daily (q.(d.).

As an illustration, in the present embodiment, the implementation of ABT-263 is present in the pharmaceutical composition in the form of a neutral base of ABT-263 or a bis-HCl ABT-263, more specifically a neutral base of ABT-263. As further indicated above, it is possible to apply any composition of ABT-263 of the present invention.

As in other embodiments, the present variant of the implementation can be carried out with or without food, i.e., on an empty stomach or with meals. Generally, it is preferable to introduce these songs to the patient on an empty stomach.

EXAMPLES

The following examples are only illustrative and do not limit the description in any way. Officially registered under the brand name of the ingredients used in the examples can be replaced with comparable ingredients from other suppliers include:

ProSolv™ HD90 from JRS Pharma: siliconized microcrystalline cellulose;

Span™ 20 from Croda International PLC: sorbitanoleat;

Tween™ 20 from Uniqema: surfactant Polysorbate 20;

Tween™ 80 from Uniqema: surfactant Polysorbate 80.

All quantities of ABT-263, including concentrations and doses specified in the examples, exp�reflect on the dose equivalent neutral grounds unless specifically stated otherwise. If ABT-263 is administered as a salt of bis-HCl, 1,076 mg bis-HCl ABT-263 provides 1 mg equivalent neutral base of ABT-263.

Example 1: Obtain solid dispersions bis-HCl ABT-263

Crystalline salt of bis-HCl ABT-263 was mixed with a surface-active substance and a water-soluble polymer in the following mass relations:

10,8% salt of ABT-263 (10% of the equivalent neutral ground), 10% surfactant; 79,2% polymer

21.5% of the salt of ABT-263 (20% of the equivalent neutral ground), 10% surfactant; 68,5% polymer

32.3% of salt of ABT-263 (30% of the equivalent neutral ground), 10% surfactant; 57,7% polymer

43% of the salt of ABT-263 (40% of the equivalent neutral ground), 10% surfactant; 47% polymer

In different series surfactant TPGS was, Span™ 20 or Tween™ 20. In various series, the polymer was copovidone (Kollidon™ VA 64), povidone K-30 or HPMC-AS.

In each case the mixture was dissolved in methanol. The methanol was removed at 65°C when exposed to a vacuum system using Genevac™, and allowed the resulting solid dispersion to cool to ambient temperature.

In each case, the solid dispersion is sieved through a mesh with 40 holes for receiving the powder with reduced particle size. Get then�shki was used to determine T gdifferential scanning calorimetry (DSC), determining the residual solvent and moisture thermogravimetric analysis (TGA), determine the degree of crystallization, and its lack of x-ray diffraction analysis of the powder (PXRD) and determine the physical stability when stored at 25°C/60% relative humidity (RH) and at 40°C/75% RH.

In each case, the solid dispersion powder was mixed with ProSolv™ HD90, croscarmellose sodium and sodium fumarate in a weight ratio of 82:15:2:1. The resulting mixture was filled hard gelatin capsules of size depending on the number of medicines, to obtain a single dose of 50 mg ABT-263. The capsules were tested for dissolution in a buffer with pH 6.5, containing 7.6 mm Tween™ 80, using USP apparatus II (see Example 3 below).

Found that all the tested solid dispersion of bis-HCl ABT-263, obtained as described above, have Tgin the range of 70-110°C. TGA showed that the variance copovidone/HPMC-AS had the least moisture content (2-4%), and variance of povidone, regardless of the used surfactant, had the highest moisture content (8-10%). PXRD showed the absence of crystallization, i.e., bis-HCl ABT-263 was amorphous in all solid dispersions. Only solid dispersion of bis-HCl ABT-263, obtained with HPMC-AS as a polymeric carrier, showed Priya�satisfactory stability when stored for one month. If you have used povidone or copovidone, observed the tendency to absorb moisture from the air in testing stability with open storage and at 25°C/60% RH and at 40°C/75% RH.

Example 2: Obtaining a solid dispersion of a neutral base of ABT-263

Crystalline salt of bis-HCl ABT-263 is dissolved in acetone and added NaOH to turn bis-HCl ABT-263 in neutral basis. A byproduct NaCl precipitated and was removed by filtration.

To obtain the solution of neutral base of ABT-263 in acetone was added a surfactant and a water-soluble polymer in the following mass relations:

10% neutral base of ABT-263; 10% of a surfactant; 80% polymer

20% of the neutral base of ABT-263; 10% of a surfactant; 70% polymer

30% of the neutral base of ABT-263; 10% of a surfactant; 60% polymer

40% of the neutral base of ABT-263; 10% of a surfactant; 50% polymer

In different series surfactant TPGS was, Span™ 20 or Tween™ 20. In various series, the polymer was copovidone (Kollidon™ VA 64) or HPMC-AS.

The acetone was removed at 65°C when exposed to a vacuum system using Genevac™, and allowed the resulting solid dispersion to cool to ambient temperature.

In each case, the solid dispersion is sieved through a mesh with 4 holes for receiving the powder with reduced particle size. The obtained powders as in Example 1 was used to determine Tgthrough DSC, determination of residual solvent and moisture by TGA, determine the degree of crystallization or its lack by PXRD and determine the physical stability when stored at 25°C/60% RH and at 40°C/75% RH.

In each case, the solid dispersion powder was mixed with ProSolv™, croscarmellose sodium and sodium fumarate in a weight ratio of 82:15:2:1. The resulting mixture was filled hard gelatin capsules of size depending on the number of medicines, to obtain a single dose of 50 mg ABT-263. The capsules were tested for dissolution in a buffer with pH 6.5, containing 7.6 mm Tween™ 80 (see Example 3 below).

Found that all the tested solid dispersion of a neutral base of ABT-263, obtained as described above, have Tgin the range of 70-110°C. TGA showed that the variance of copovidone and HPMC-AS had low moisture content (2-4%). PXRD showed the absence of crystallization, i.e., the neutral base of ABT-263 was amorphous in all solid dispersions. Solid dispersion of a neutral base of ABT-263, received copovidone or HPMC-AS as a polymeric carrier, showed acceptable storage stability for one month without any signs of absorption of moisture from the air.

Example 3: Profiles �of stvorenja solid dispersions

Characteristic profiles of dissolution (drug release) in buffer with pH 6.5, containing 7.6 mm Tween™ 80 is shown in Fig. 1 (bis-HCl ABT-263) and Fig. 2 (neutral base of ABT-263).

As shown in Fig. 1, when the filling level of the drug 20%, solid dispersion of bis-HCl ABT-263 with 68,5% copovidone and 10% TPGS showed a moderate rate of release of the drug, staying on the release of approximately 80%. The release of similar dispersions that Span™ 20 or, in particular, Tween™ 20 as a surfactant was slower.

In contrast, as shown in Fig. 2, at the same level of filling drug 20% solid dispersion of a neutral base of ABT-263 with 70% copovidone and 10% Tween™ 20 or TPGS showed fast drug release. Only surfactant Span™ 20 led to a slower release in the case of dispersion of a neutral base.

The rate of release was dependent on the filling level of the drug in the dispersion compositions and bis-HCl ABT-263, and neutral grounds, 20% of the variance, demonstrating a more rapid release than 30% or 40% of the variance in both cases.

Unlike similar solid dispersion obtained from the neutral base of ABT-263, a solid�th dispersion, containing bis-HCl ABT-263, copovidone and Tween™ 20, showed the formation of the shell. Consider that the formation of membranes caused by deposition of the drug on the surface of the capsule filler.

In a separate study of solid dispersion of bis-HCl ABT-263 in the binder copovidone with replacement of 5% of copovidone in HPMC-AS and without it, showed slower drug release in the presence of HPMC-AS.

Example 4: Effect of the polymer medium on the dissolution profile of the variances bis-HCl ABT-263

Solid dispersion with various polymeric carriers were tested for the influence of polymer carriers on the dissolution rate. Four solid dispersions were obtained with the salt of the bis-HCl ABT-263 (20% of the equivalent neutral grounds), 10% TPGS and the following polymeric carriers:

only povidone

50% povidone + 50% copovidone

25% povidone + 75% copovidone

only copovidone

The dissolution profiles of the four solid dispersions are shown in Fig. 3. The rate of release of the drug increased with increasing level of povidone.

Example 5: Pharmacokinetics dispersions bis-HCl ABT-263 on models dogs

The pharmacokinetics of a single dose of two solid dispersions of ABT-263 was evaluated on non-fasting dogs breed Beagle (n = 6) after oral dose of 50 mg/kg followed by 10 ml of water. Prior to the introduction of doses� and through 0,25, 0,5, 1, 1,5, 2, 3, 4, 6, 9, 12, 15 and 24 hours after administration from the jugular vein of each animal received a series of blood samples with heparin. Blood plasma was separated by centrifugation (2000 rpm for 10 minutes at approximately 4°C) and allocated ABT-263 with the use of protein precipitation by acetonitrile.

Comparing two solid dispersion of bis-HCl ABT-263 (those of Example 4 containing only povidone or only copovidone). Powder dispersion was mixed with ProSolv™ HD90, croscarmellose sodium and sodium fumarate in a weight ratio of 82:15:2:1 and the mixture is filled capsules.

ABT-263 and the internal standard were separated from each other and from jointly allocated impurities in column (50×3 mm Keystone Betasil CN™ 5 µm mobile phase acetonitrile/0.1% of trifluoroacetic acid (50:50 by volume) at a flow rate of 0.7 ml/min. the Analysis was performed at the biomolecular mass analyzer Sciex API3000™ with heated contact surface of the nozzle. Peak area of ABT-263 and internal standard were determined with the use of the software Sciex MacQuan™. The concentration of each sample of the drug in plasma was calculated by linear regression analysis (unweighted) the relationship of the areas of peaks (original/internal standard) of labeled standards of blood plasma against the concentration by the method of least squares. Provided Dan�s on plasma concentrations to build multiexponential curve with the use of WinNonlin 3 (Pharsight).

Area under the curve of plasma concentration-time from 0 to t hours (time of the last measured plasma concentration) post-dose (AUC0-t)calculated using linear trapezoid rule for profiles "plasma concentration-time". The residual area extrapolated to infinity, determined as the final plasma concentration (Ct), is divided into a finite rate constant of elimination (β), was added to AUC0-tto obtain the total area under the curve (AUC0-∞). The bioavailability was calculated as normalized by dose AUC0-∞when introduced oral dose divided by the corresponding value obtained when i.v. (IV) the imposed dose, administered as a slow bolus in the jugular vein under light ether anesthesia.

The PK parameters for dispersions only with povidone and copovidone are presented in table 1.

Table 1
The PK parameters of solid dispersion compositions in dogs (n=6)
CompositionCmax
mcg/ml
Cmax/D
µg/ml per mg/kg
Tmax
watch
AUC
μg·h/ml
AUC/D
μg·h/ml per mg/kg
F%
Povidone5,61,169,839,37,9A 16.4
Copovidone9,61,784,564,911,924,7

Although the Example 4 shows that the dispersion of bis-HCl ABT-263, obtained with povidone provides the best rate of release than with copovidone, she has the worst bioavailability in this study on dogs than a comparable dispersion that is obtained copovidone.

Example 6: Pharmacokinetics of illustrative solid dispersions on models dogs

The pharmacokinetics of a single dose of two solid dispersions of ABT-263 was evaluated on non-fasting dogs breed Beagle (n = 6), following the same Protocol as in Example 5. Got two solid dispersion of ABT-263 (Dispersion I and II). The variance of I, obtained essentially according to the method of Example 2 contained 10% neutral base of ABT-263, 10% TPGS and 80% of copovidone. For getting the Composition I of the powder dispersion filled capsules without any additional components. Dispersion II, obtained essentially according to the method of Example 1, �won 13,11% bis-HCl ABT-263 (12,18% of the equivalent neutral base), 15% TPGS and 71.89% of povidone. To obtain Composition II powder dispersion was mixed with ProSolv™ HD90, chromalveolata sodium and sodium fumarate in a weight ratio of 82:15:2:1 and the mixture is filled capsules.

The PK parameters for Compositions I and II are presented in table 2.

Table 2
The PK parameters of solid dispersion compositions in dogs (n=6)
CompositionCmax
mcg/ml
Cmax/D
µg/ml per mg/kg
Tmax
watch
AUC
μg·h/ml
AUC/D
μg·h/ml per mg/kg
F%
I7,51,508,559,011,224,6
II6,41,247,839,27,416,3

The dispersion of the bis-HCl ABT-263 (Composition II), obtained with the povidone, possessed poorer bioavailability in this study on dogs than the variance neutralization�professional the base of ABT-263 (Composition I), get with copovidone.

1. Solid dispersion for injection of Pro-apoptotic compounds containing, essentially, in a noncrystalline form of the compound N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexa-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl) benzolsulfonat (ABT-263) or its pharmaceutically acceptable salt; dispersed in a solid binder containing (a) at least one pharmaceutically acceptable water-soluble polymeric carrier containing homopolymer and/or copolymer of N-vinylacetate, and (b) at least one pharmaceutically acceptable surfactant containing α-tocopherolacetate succinate.

2. Solid dispersion according to claim 1, wherein the compound of formula I is a neutral base of ABT-263 or a bis-HCl ABT-263.

3. Solid dispersion according to claim 1 or claim 2 where the compound is present in amounts equivalent neutral base of ABT-263 from 5% to 40% by mass.

4. Solid dispersion according to claim 1, wherein the at least one polymeric carrier is present in an amount of from 40% to 85% by mass, and at least one surfactant is present in an amount of from 5% to 20% by mass.

5. Solid dispersion according to claim 1, wherein the at least one polymeric carrier is selected from the group comp�of the present of copovidone povidone and mixtures thereof.

6. Solid dispersion according to claim 1, further comprising one surfactant selected from the group consisting of derivatives of polyoxyethylene castor oil, monoufia fatty acids and sorbitan, polysorbates, poloxamers and mixtures thereof.

7. A method of obtaining a solid dispersion that includes:
(a) dissolving an active pharmaceutical ingredient (API), (i) containing N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexa-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl) benzolsulfonat (ABT-263) or its pharmaceutically acceptable salt; (ii) at least one pharmaceutically acceptable water-soluble polymeric carrier containing homopolymer and/or copolymer of N-vinylacetate, and (iii) at least one pharmaceutically acceptable surfactant containing α-tocopherolacetate succinate in a suitable solvent; and
(b) removing the solvent to obtain a particulate binder containing at least one polymeric carrier and at least one surfactant and having the compound or its salt, dispergirovannykh in it, essentially, in non-crystalline form.

8. A method according to claim 6 or claim 7, where the API contains the compound ABT-263 in the form �Oli and the method further includes the transformation of that form salts in the form of a neutral base to remove the solvent.

9. A method according to claim 8, where the specified transformation involves the addition of a base.

10. A method according to claim 8, wherein the salt form is dissolved in a solvent and turn in it to form a neutral base to add at least one polymeric carrier and at least one surfactant.

11. A method according to claim 8, further comprising extraction of the by-product of the specified transformation in the form of a salt to the removal of the solvent.

12. A method according to claim 8, where the solvent removed by heating and/or exposure to vacuum.

13. A method according to claim 8, wherein the solvent includes methanol, ethanol or acetone.

14. Orally delivered pharmaceutical dosage form containing a solid dispersion according to any one of claims. 1-6.

15. The application of solid dispersion according to any one of claims. 1-6 to obtain drugs for the treatment of a disease characterized by apoptotic dysfunction and/or sverkhekspressiya antiapoptotic protein family Bcl-2, where the drug is injected suffering from oral disease the individual.

16. The use according to claim 15, where the disease is a neoplastic disease.

17. The use according to claim 16, where the neoplastic disease is selected from the group consisting of malignancies, mesothelioma, bladder cancer, pancreatic cancer W�Lesa skin cancer, malignant neoplasms of the head and neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of cervix, carcinoma of the vagina, carcinoma of the vulva, bone tissue neoplasms, colon cancer, rectal cancer, anal cancer, stomach cancer, cancer of the gastrointestinal tract (stomach, colon and/or duodenal), chronic lymphocytic leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of the small intestine, tumors of the endocrine system, thyroid cancer, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, penile cancer, testicular cancer, hepatocellular cancer (hepatic and/or biliary duct), primary or secondary tumors of the Central nervous system, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, malignant neoplasms of lymphoid tissue T-cell or b-cell origin, melanoma, multiple myeloma, oral cancer, non-small cell lung cancer, prostate cancer, malkoc�etozhnogo lung cancer, cancer of the kidney and/or ureter, počečnokletočnyj carcinoma, carcinoma of the renal pelvis, neoplasias of the Central nervous system, primary lymphoma of the Central nervous system, non-Hodgkin's lymphoma, tumors of the spine, glioma of the brain stem, pituitary adenoma, cancer of the adrenal cortex, bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination.

18. The use according to claim 16, where the neoplastic disease is a malignant neoplasm of lymphoid tissue.

19. The use according to claim 18, where the malignancy of lymphoid tissue is non-Hodgkin lymphoma.

20. The use according to claim 16, where the neoplastic disease is a chronic lymphocytic leukemia or acute lymphocytic leukemia.

21. The use according to any one of claims. 15-20, where the compound of formula I in the input solid dispersion is ABT-263 or its pharmaceutically acceptable salt, and where the solid dispersion is administered in a dose of from about 50 to about 500 mg of equivalent neutral base of ABT-263 per day, with an average interval between doses from about 3 hours to about 7 days.

22. The use according to claim 21, where the composition is administered once daily at a dose of from about 200 to about 400 mg of equivalent neutral base of ABT-263 in �ducks.



 

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