Abt-263 capsule

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular, described is a capsule, containing a capsule envelope, which includes an encapsulated liquid solution of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)3-(morpholin-4-yl)-1-(phenylsulphanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulphonyl)benzenesulphonamide (ABT-263) or its bis-hydrochloride salts in a non-ethanol carrier. As filling agents used are: a phospholipid, a solubilising agent for the phospholipid, selected from glycols, glycolides, glycerides and their mixtures, a surface-active substance of a non-phospholipid type and a sulphur-containing antioxidant in an amount, effective for the reduction of oxidising ABT-263 degradation in storage. The sulphur-containing antioxidant is selected from sulphites, bisulphites, metabisulphites and thiosulphites and their mixtures. A method of the capsule obtaining is also described. The capsule is used for treating a disease, characterised by the overexpression of one or several anti-apoptotic proteins of the Bcl-2 family, for instance, cancer.

EFFECT: invention provides a long storage term for the said capsule.

33 cl, 3 dwg, 20 tbl, 14 ex

 

This application claims the priority of provisional patent application U.S. ser. No. 61/289289, filed December 22, 2009, the complete disclosure of which is incorporated into this description by reference.

Is cross-referenced to the following patent applications U.S. that contains a subject invention related to the present application: Ser. No. 12/770122 entitled "Lipid of the finished dosage form of the promoter of apoptosis", filed on April 29, 2010; Ser. No. 12/770174, entitled "Stabilized lipid finished dosage form of the promoter of apoptosis", filed on April 29, 2010; and Ser. No. 12/770299 entitled "the Finished dosage form for oral administration of a promoter of apoptosis", filed on April 29, 2010

Area of technology

The present invention relates to apoptosis-stimulating agent ABT-263, finished dosage forms, containing ABT-263, and methods of their use for the treatment of diseases characterized by sverkhekspressiya protivoepilepticheskih protein family Bcl-2. In particular, this invention relates to encapsulated finished dosage forms used for oral administration of ABT-263 to a subject in need of such introduction.

Characteristic of prior art

Evasion of apoptosis is a marker of malignancies (Hanahan &Weinberg (2000) Cell 100:5770). Cancer cells must overcome the continuous bombardment of cellular stress such as DNA damage, activation of oncogenes, abnormal cell cycle progression and rigid microenvironment that can cause normal cells to apoptosis. One of the main ways by which cancer cells avoid apoptosis is positive regulation protivoepilepticheskih protein family Bcl-2.

Compounds that occupy BH3 binding groove of proteins Bcl-2, have been described, for example, Bruncko et al. (2007)J. Med. Chem.50:641-662. These compounds included 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-nitrobenzenesulfonamide, otherwise known as ABT-737, which has the formula:

ABT-737 binds with high affinity (<1 nm) protein family Bcl-2 (in particular, Bcl-2, Bcl-XLand Bcl-w). This compound shows menuactivity against small cell lung cancer (SCLC) and lymphoplasma, and potentiates the Pro-ipoptions of the action of other chemotherapeutic agents. ABT-737 and related compounds and methods for producing such compounds are disclosed Bruncko et al. the publication of the patent application U.S. No. 2007/0072860.

Was recently identified a number of additional link�, possessing high binding affinity to proteins of the family of Bcl-2. These compounds and methods for their preparation are disclosed Bruncko, etc. in the publication of the patent application U.S. No. 2007/0027135 (in the present description "the'135 publication"), incorporated into this description in full by reference, and these compounds, as can be seen from their formulas are structurally related ABT-737.

One compound, identified as "Example 1" in the publication '135, N represents-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzolsulfonat, otherwise known as ABT-263. This compound has a molecular weight 974,6 g/mol and has the formula:

There are messages from Tse et al. (2008) Cancer Res. 68:3421-3428 and, in addition, supplementary data, available fromCancer Researchonline(cancerres.aacrjournals.org/),about pharmacokinetic animal studies of ABT-263, synthesized as described in the publication '135. The drug received in the form of a solution in 10% dimethyl sulfoxide (DMSO) in polyethylene glycol (PEG) 400 or in a mixture of 10% ethanol/30% PEG400/60% Phosal 50 PG™.

In the publication '135 not reported, the bioavailability after oral administration of the drug (expressed, for example, by means of AUC after oral administration in in�de % AUC after intravenous administration), however, this publication follows that the bioavailability in oral administration is significantly higher for ABT-263, than to ABT-737. However, further increase bioavailability in oral administration would be useful. In this area have proposed different solutions to solve the problem of low bioavailability of the drug when administered orally. For example, Lacyet al. in U.S. patent 5645856 propose the formulation of hydrophobic drugs with (a) oil, (b) hydrophilic surface-active substance and (c) a lipophilic surface-active substance, which significantly reduces the inhibitory effect of the hydrophilic surfactant onin vivolipolysis oils, such as lipolysis, as they say, is the factor that stimulates the bioavailability of the medication. To numerous classes listed hydrophilic surfactants include phospholipids such as lecithins.

U.S. patent 6267985, Chen & Patel, aimed, inter alia, a pharmaceutical composition comprising (a) triglyceride, (b) a carrier comprising at least two surfactants, one of which is hydrophilic, and (c) a therapeutic agent, which is able to solubilisates in the triglyceride, the carrier, or both. The patent indicates �the triglyceride and surfactants should be present in quantities which ensure the formation of a transparent aqueous dispersion when the composition is mixed with an aqueous solution under certain conditions. Among the extensive separate lists illustrative of the ingredients mentioned here "glyceryltrinitrate/capret" as the triglyceride and surfactants phospholipids, including phosphatidylcholine.

Patel &Chen in U.S. patent 6451339 indicate deficiencies in the presence of triglycerides in the compositions, and such compositions essentially contain triglycerides, but which also give a transparent aqueous dispersion.

Patel &Chen in U.S. patent 6309663 offer pharmaceutical compositions containing a combination of surfactants, which reportedly enhances bioabsorption hydrophilic therapeutic agent.Among illustrative surfactants again are the phospholipids, such as phosphatidylcholine.

Fanaraet al. in U.S. patent 6464987 offer liquid pharmaceutical composition containing the active substance, from 3% to 55% of the mass. phospholipid, from 16% to 72% of the mass. solvent, and from 4% to 52% of the mass. fatty acids. In particular, examples are compositions comprising Phosal 50 PG™ (mainly comprising phosphatidylcholine and propylene glycol), in some cases together with Phosal 53 MCT� (mostly including phosphatidylcholine and medium chain triglycerides). Such compositions, as reported, are able to instantaneous gelation in the presence of the aqueous phase and make it possible to realize controlled release of the active substance.

Leonardet al.in U.S. patent 5538737 offer capsule containing an emulsion of “water in oil”, in which a water-soluble salt of the drug dissolved in the aqueous phase of the emulsion and in which the oil phase comprises an oil and an emulsifying agent. To mentioned oils are medium chain triglycerides; among mentioned emulsifying agents, phospholipids, such as phosphatidylcholine. According to various examples cited in the document, use Phosal 53 MCT™, which contains phosphatidylcholine and medium chain triglycerides.

Waranis & Leonard in U.S. patent 5536729 offer oral drug,containing rapamycin at a concentration of from about 0.1 to about 50 mg/ml, in a medium comprising a solution of phospholipid. It is established that the preferred pharmaceutical composition can be obtained using Phosal 50 PG™ in the form of a solution of phospholipid. Alternative mentioned solution of phospholipid is a Phosal 50 MCT™.

Harrisonetc. in U.S. patent 5559121 offer oral preparation containing rapamycin, PR� a concentration of from about 0.1 to about 100 mg/ml, in the media, including N,N-dimethylacetamide and a solution of phospholipid. Examples of more preferred embodiments, as shown, are those obtained using Phosal 50 PG™. Alternative mentioned solution of phospholipid is a Phosal 50 MCT™.

The publication of the patent application U.S. No. 2007/0104780 Liparietc.reveal that the drugs are small molecule (defined in this context as having a molecular weight, excluding counterions in the case of salts, not more than about 750 g/mol, typically not more than about 500 g/mol), which has a low solubility in water,can be formulated in the pharmaceutical composition is a solution, in essentially non-aqueous carrier comprising at least one phospholipid and a pharmaceutically acceptable solubilizers tool. The solution, when mixed with the aqueous phase, as reported, forms degelatinized essentially opaque fluid [fluid] variance. Illustrative in this context describes pharmaceutical compositions of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869, an inhibitor proteincontaining), comprising Phosal 53 MCT™ and other ingredients.

Recently, a clinical trial of ABT-263 Krivoshik was revealed in the publication of the patent application U.S. No. 2009/0149461, �otara included in this description in full by reference without acknowledgement that it is prior art to this invention. Product intended for administration described in this document as "powder for oral solution (2.0 grams/vial equivalentbase, 25 mg/ml when mixed), and diluents for preparation of a solution identified as "Phosal® 53 medium chain triglyceride (MCT), 120 grams/vial" and "alcohol (ethanol), dehydrated, USP/EP/JP 200 proof [i.e., 100% pure alcohol]”.

Specific type of disease that requires the development of improved treatment methods, is negotinska lymphoma (NHL). NHL is the sixth most common type of new malignancies in the United States and occurs mostly in patients 60-70 years of age. NHL is not a separate disease but a family of related diseases that classify on the basis of certain characteristics, including the characteristic clinical signs and histology.

One method of classification accommodates different histological subtypes into two main categories, based on the pathogenesis of the disease, i.e., whether the disease is indolent or aggressive. In General, indolent subtypes develop slowly and usually are curable, whereas aggressive subtypes develop quickly and are potentsialzavisimye. Follicular lymphoma is the most common indolent subtype, diffuse large cell lymphomas are the most common aggressive subtype. The oncoprotein Bcl-2 was originally described in connection with nakhodinskii b-cell lymphoma.

Treatment of follicular lymphoma usually consists of treatment associated with biological agents or combination chemotherapy. Traditionally used a combination treatment of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), as well as combined treatment with rituximab, cyclophosphamide, vincristine and prednisone (RCVP). In addition, the use of rituximab monotherapy (targeting CD20, phosphoprotein uniformly expressed on the surface of b-cells) or fludarabine. The addition of rituximab in the treatment with chemicals can help improve the response rate and the increase in the remission period.

For the treatment of refractory or recurrent nakhodinskii lymphoma can be used radioimmunotherapeutic funds, chemotherapy using drugs high dose and stem cell transplants. Currently, there are no proven sanctioned by medical schemes, which would provide treatment, and current recommendations func�Ute patients treated in a clinical trial, even when treatment is the drug of first choice.

Treatment the drug of first choice patients with aggressive large cell [b-cell] lymphoma usually consists of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), or dose-controlled etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R).

The majority of lymphomas initially responds to any one of these treatments, however, the tumors usually recur and eventually become refractory. Since the number of courses of treatment the patient increases, the disease becomes more resistant to chemotherapy. The average response to the first course of treatment is approximately 75%, for the second course of treatment 60% on the third course of treatment 50%, and the fourth treatment approximately 35-40%. Consider that your response rate, reaching 20% in monotherapy in the case of multiple recurrences, are positive and deserve further study.

Other neoplasms that require the development of improved methods of treatment include leukemias, such as chronic lymphocytic leukemia (NHL, B-cell lymphoma and acute lymphocytic leukemia.

Chronic lymphoid leukemia (CLL) represents the most common type of leukemia. CLL is mainly�zoom, a disease of adults, with more than 75% of newly diagnosed people are aged over 50 years, however, in rare cases, the disease is found in children. Combined chemotherapy are common treatment, for example, fludarabine with cyclophosphamide and/or rituximab, or more false combinations such as CHOP or R-CHOP.

Acute lymphocytic leukemia, also known as acute lymphoblastic leukemia (ALL) is primarily a disease of childhood, once essentially zero survival rate, but now with the survival rate up to 75% with combined chemotherapy, similar to those mentioned above. However, there is still a need to develop new therapies, which would further improve survival rates.

Modern chemotherapeutic agents exert their antitumor activity by inducing apoptosis through a variety of mechanisms. However, many tumors eventually become resistant to these drugs. Bcl-2 and Bc1-Xl have been shown to impart resistance to chemotherapy in trials for short-term survival in conditions ofin vitroand, suck recently, in terms ofin vivo. This suggests that such resistance to chemotherapy could be successfully overcome in kucherlapati advanced ways of treatment, aimed at the suppression of the functioning of Bcl-2 and Bcl-XL.

Summary of being inventions

To date, as drugs ABT-263, which can be used for oral administration were disclosed only drugs ABT-263 in the form of a diluted liquid,including, for example, a solution of ABT-263 in 10% DMSO in PEG 400 or in a mixture of 10% ethanol/30% PEG 400/60% Phosal 50 PG™, which have been applied for the introduction of Tseetc.(2008),as mentioned aboveor 25 mg/ml solution of ABT-263 in Phosal 53 MCT™ and ethanol, disclosed in the above-identified patent application publication No. 2009/0149461 ("publishing '461").

Separate dosage form such as capsule, has advantages in comparison with liquid in the sense that the dose of the drug is strictly defined in advance, such a dosage form is easier to introduce, enabling the patient to more strictly comply with therapeutic recommendations, and assumes a longer shelf life. In addition, if the active ingredient or any of the filler has an unpleasant taste, encapsulating pharmaceutical composition to avoid this feeling in the patient. Known conclusion liquid pharmaceutical compositions, for example, in gelatin capsules; however, ABT-263 is in this respect some of the problems.

In PHE�o typical standardized doses of ABT-263 for the most part the readings are relatively high (up to about 500 mg or more), which means that a diluted solution of ABT-263, such as 25 mg/ml solution discussed in the publication '461, cannot be represented in the form of a capsule suitable for use. Even doses of 200 mg may require 8 large (1 ml) capsules, with each containing 25 mg ABT-263. Poor solubility of ABT-263 in most of pharmaceutically acceptable solvents was explained by the inability to date of the development of a more concentrated solution, demonstrating acceptable stability during storage.

Secondly, despite the fact that ABT-263 can be dissolved in the products on the basis of a phospholipid, such as Phosal 50 PG™, and Phosal 53 MCT™, the resulting solutions are highly viscous, if they do not add to the reduction of the viscosity agent, such as ethanol. Ethanol and other lowering the viscosity of the funds, such as glycerin, is incompatible with most of the material of the capsule shell, in particular, materials of hard shell capsules, e.g. hard gelatin shell capsules.

Thirdly, it was found that ABT-263 is sensitive to oxidation with the formation of degradation products including sulfoxides. This is not necessarily a serious problem for �Reparata in liquid form, which can be cooked for immediate admission, but pre-manufactured dosage forms such as capsule, oxidative degradation can mean an unacceptably short shelf life medicines. Therefore, it is important the inclusion of an antioxidant in a liquid pharmaceutical composition to ABT-263, designed to encapsulate; however, as shown in this context, many of the commonly used antioxidants are ineffective to prevent the formation of sulfoxides in the pharmaceutical compositions of ABT-263.

So, at the moment it was discovered that in practice the implementation of the present invention described in this context, it is possible to encounter a number of problems associated with obtaining pharmaceutically acceptable formulations of ABT-263 in the form of capsules filled with liquid drug solution.

In one embodiment, the present invention provides a pharmaceutical capsule containing capsule shell containing within itself encapsulated in an amount of not more than about 1000 mg per capsule, liquid solution of ABT-263 or its pharmaceutically acceptable salt at a concentration equivalent of the free base of ABT-263, at least about 40 mg/ml in essentially metanolom media that comprises as pharmaceutically acceptable�'s fillers:

at least one phospholipid,

at least one solubilizers agent for at least one phospholipid selected from the group consisting of glycols MH, glycolide, glycerides and mixtures thereof,

at least one surface-active substance apostolidou of nature, and

at least one sulfur-containing antioxidant in an amount effective to reduce oxidative degradation of ABT-263 when stored.

In a more specific embodiment, the ABT-263 is present in the capsule in the form of the free base in contrast to the salt form.

In another more specific embodiment, the sulfur-containing antioxidant is poorly soluble in lipids; therefore, the introduction of an antioxidant in the form of an aqueous feed solution, the encapsulated liquid solution according to this embodiment contains water. The presence of too larger amounts of water can threaten the physical stability of the liquid on the basis of the lipid solution, and, in addition, may contribute to the increase in the rate of formation of sulfoxides, denying the benefit of adding an antioxidant. Therefore, it is important that the encapsulated liquid solution in accordance with the option contained not more than about 1% of the mass. water.

A limit on the number of sulfur-containing antioxidant, imposed a limit on the water content, with�sdet additional difficulties. Typically, structuresa antioxidants reduce the formation sulfoxide by-products of the drug by acting as competitive substrates for oxidative substances, such as peroxides; this method usually requires that the antioxidant is present in amount of at least approaching the molar equivalence with respect to the number of the medicine. Unexpectedly, the authors found that when molar ratio is 1:20 or even lower relative to the concentration of ABT-263, some structuresa antioxidants display a marked effectiveness in reducing the rate of formation of sulfoxides in different storage conditions. A suitable structuresa antioxidants according to this embodiment include, without limitation, sulfites, bisulfite, metabisulfite and thiosulfate.

Illustrative prototype capsule according to the present embodiment contains the shell of hard gelatin capsules of size 0, which encloses within itself a liquid solution, which contains:

about 50 mg of the free base of ABT-263,

about 150 mg of phosphatidylcholine,

about 75 mg of medium chain triglycerides,

about 90 mg medium chain mono - and diglycerides,

about 90 mg of a surfactant, Polysorbate 80,

about 0.25 mg of sodium metabisulphite or ka�Oia,

about 0.025 mg of EDTA (ethylenediaminetetraacetic acid, a chelating agent) or its salts, and

about 2.5 mg of water.

In another embodiment, the present invention provides a method of producing capsules described above, including:

dissolution of API (active pharmaceutical ingredient), which mainly consists of ABT-263 or salts thereof in at least one of the phospholipid and solubilizing agent with obtaining a lipid solution,

a mixture of surfactants apostolidou nature with solubilizers agent or lipid solution,

the dissolution of poorly lipid-soluble sulfur-containing antioxidant in water to obtain aqueous feed solution,

mixing an aqueous feed solution with the lipid solution to obtain a liquid solution to be encapsulated, and

encapsulation of the liquid solution in the shell of the capsule.

In another embodiment, the present invention provides a method of treating diseases characterized by dysregulation of apoptosis and/or sverkhekspressiya protevoepilepticescoe protein family Bcl-2, comprising the oral administration to a subject suffering from the disease a therapeutically effective amount of ABT-263, which is described in this context, the capsule comprising encapsulated inside the liquid. Examples of such diseases include m�OIG neoplasms, including different types of cancer. Specific illustrative type of cancer that can be treated according to the present method, is non-Hodgkin's lymphoma. Another specific illustrative type of cancer that can be treated according to the present method, is chronic lymphocytic leukemia (CLL). The following specific illustrative type of cancer that can be treated according to the present method, is the acute lymphocytic leukemia (ALL), for example the patient is a child.

In another embodiment, the present invention provides a method for maintaining in bloodstream of a cancer patient, for example, a patient with non-Hodgkin lymphoma, CLL or ALL, a therapeutically effective plasma concentration of ABT-263 and/or one or more of its metabolites, comprising administering to the subject one to some set of capsules containing ABT-263, obtained as described in this context, dosed in an amount of from about 50 to about 1000 mg ABT-263 per day, at an average interval between doses of the drug from about 3 hours to about 7 days.

In accordance with the above-mentioned methods, the input illustrative capsule can be a prototype capsule, as described above, or another capsule according to the invention, which is oral, in essence, is the bioequivalent of the foregoing.

Additional�Uo embodiments of the invention, including more specific aspects of the options presented above, can be found in, or become apparent from the following detailed description.

Brief description of the drawings

Fig. 1 is a schematic phase diagram of solutions of the free base of ABT-263 in a triple "IPT" lipid systems, described in Example 8. The shaded area in the graph represents a region of the optimized final formulation of the composition of the drug.

Fig. 2 is a schematic phase diagram of solutions of the free base of ABT-263 in a triple "IST" lipid systems, described in Example 8. The shaded area in the graph represents a region of the optimized final formulation of the composition of the drug.

Fig. 3 is a graph of the average plasma concentration of ABT-263 after the introduction of people, cancer patients, capsules with liquid drug solution according to the invention in comparison with the pharmaceutical composition, lipid drug solution described in Example 14.

Detailed description of the invention

The present invention offers a finished dosage form of ABT-263 or its salts in the form of capsules with liquid drug solution that is suitable for oral administration. The terms "oral administration" and "oral permission" in this context, refers to th� the subject of inside(p.o.), i.e., the introduction, in which the composition of the drug immediately swallowed, for example, using a suitable volume of water or suitable for drinking liquids. "Oral administration" is different in this context from intraoral administration, e.g., sublingual or buccal administration, or topical application to tissue of the oral cavity such as periodontal tissue, which includes immediate ingestion of the composition of the drug.

"ABT-263" in this context refers to the compound N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)-3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide. In the form of its parent compound, ABT-263 has the formula:

In some embodiments, ABT-263 is present in the product in the form of its parent compound. The term "free base" is used in this context for convenience of description, refers to the parent compound, recognizing that the parent compound is a, strictly speaking, a zwitterionic compound and, therefore, does not always behave as a true base.

ABT-263 can form additive salt of the acid additive salts of the bases or zwitter-ions. Salts of compounds of Formula I can get�you during selection or after cleaning compounds. Additive acid salts are salts resulting from the reaction of ABT-263 with acid. For example, 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-, malate-, mesitylenesulfonic-, methanesulfonate, naphthalenesulfonate-, nicotinate-, oxalate, pamoate, pectinate-, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate-, trichloracetate, triptorelin-, para-toluensulfonate - and undecanoate salt of ABT-263 can be used in the composition of the preparation according to the present invention. Similarly, can be used additive salts of the bases, including salts obtained by the reaction of ABT-263 with bicarbonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium.

ABT-263 has at least two protonium nitrogen atoms and, consequently, are capable of forming additive salts of acids with more than one, for example, from about 1.2 to about 2, from about 1.5 to about 2 or from about 1.8 to about 2, equivalents of acid per equivalent of ABT-263.

Illustrative, can be obtained bybis-salt of ABT-263, on�tea, for example,bis-hydrochloride (bis-HCl) andbis-hydrobromide (bis-HBr) salts.

For example, ABT-263bis-HCl is represented by the formula

can be obtained in various ways, for example, the method may be broadly described as follows.

The free base of ABT-263 get illustrative, as described in Example 1 of the above-identified publication of the patent application U.S. No. 2007/0027135, the complete disclosure of which is incorporated into this description by reference. A suitable weight of the free 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 moles of HCl per mole of ABT-263 and a sufficient amount of EtOH (at least about 20 vol.) for crystallization of the received ABT-263bis-HCl salt. The solution was heated to about 45°C under stirring and add a seed crystal in the form of a slurry in EtOH. After about 6 hours, the resulting slurry was cooled to about 20°C for approximately 1 hour and stirred at the same temperature for about 36 hours. The slurry was filtered, separating crystalline solid, which is an ethanol solvate ABT-263bis-HCl. Drying of this solid under vacuum and a nitrogen atmosphere at a moderate of paramashiva�AI for about 8 days gives white crystals desolvation ABT-263 bis-HCl. This substance is appropriate for producing a finished dosage form ABT-263bis-HCl of the present invention.

Thus, the capsule of the present invention comprises the free base of ABT-263 or its pharmaceutically acceptable salt, for example, ABT-263bis-HCl. In a more specific embodiment, the composition of the drug includes the free base of ABT-263.

As indicated above, the free base of ABT-263 can be obtained by the method described in Example 1 of the above-identified publication '135. The product of this method is amorphous glassy solid. From this product you can get powder, for example, using the methods of freeze drying, spray drying or precipitation. This powder can be used as an API to obtain capsules of the present invention; however, in the future will be found preferableas the API crystalline form of the free base of ABT-263. These crystalline forms include solvates and crystalline forms, not containing in its structure of the solvent.

Solvates of the free base of ABT-263 can be obtained as described below. The original product can be any shape in the solid state of the free base of ABT-263, including the amorphous form obtained in accordance with the publication '135.

The measured amount of freely�on the base of ABT-263 (as indicated, can be used any solid state form) suspended in any number of solvents or mixtures of solvents, including, without limitation, 2-propanol, 1-propanol, a mixture of ethyl acetate/ethanol 1:3 vol./vol., a mixture of methyl acetate/hexane 1:1 vol./vol., chloroform, methanol, a mixture of 1,4-dioxane/hexane 1:2 vol./vol., toluene and benzene. The resulting suspension was stirred at ambient temperature while protecting it from light. After a period of time sufficient for the solvation of the free base of ABT-263 in each case, the crystals are collected by filtering centrifugation. The obtained solvate can be characterized by using x-rays diffraction with x-ray photography according to the method of powder (PXRD), for example, using G3000 diffractometer (Inel Corp., Artenay, France), equipped with sensitive diregiovani reflection detector and optics of the beam of parallel rays. Diffractometer installed the tube with a copper anode (1.5 kW sharp focus), the mode of operation of the device 40 kV and 30 mA. Monochromatic primary radiation beam is provided by a germanium monochromator. The diffractometer is calibrated using a fading beam in the range of one degree. Calibration control using the position of the line of standard silicon powder (NIST 640c). The device operates using the computer, using the program�mnoe the Symphonix software (Inel Corp., Artenay, France), and the data are analyzed using Jade software (version of 6.5, Materials Data, Inc., Livermore, CA). The sample charged in an aluminum objectoperation and align the slide.

Desolately ethyl acetate/ethanol solvate, for example, by air drying, provides a solvent-free, crystalline form of the free base of ABT-263. Reflexes PXRD for the free base of ABT-263 of I are listed in Table 1. Powder diffraction pattern having reflex, mainly such as indicated in the present description, can be used to identify the crystalline free base of ABT-263, in particular, of the free base of ABT-263 Form I. the Expression "mainly are as stated" in this context means the presence of reflexes which are shifted not more than about 0.2°2θ from the specified position.

Table 1
The list of PXRD reflexes: solvent-free crystalline polymorphic form I of the free base of ABT-263
The reflex position (°2θ)
6,21
6,72
9.66 as per
10,92
Of 11.34
12,17
Of 14.28
16,40
16,95
17,81
18,03
18,47
For 19.32
20,10
21,87

Desolate most of the solvates, including solvates of 1-propanol, 2-propanol, methanol, benzene, toluene, mixtures of dioxane/hexane, a mixture of methyl acetate/hexane and chloroform, gives a solvent-free crystalline form of the free base of ABT-263, which, as shown by PXRD, is identical crystalline form obtained by desolately solvate of ethyl acetate/ethanol.

Desolately solvates of pyridine and anisole gives not containing RA�solvent crystal form of the free base of ABT-263, which, as shown by PXRD, differs from the form obtained by desolately ethyl acetate/ethanol solvate. The crystal form obtained as a result of desolvation of the solvate of pyridine and anisole, designated Form II. Reflexes PXRD for Form II free base of ABT-263 are listed in Table 2. Powder diffraction pattern having peaks, mainly such as indicated in this context, can be used to identify the crystalline free base of ABT-263, in particular, Form II free base of ABT-263.

Table 2
List of reflexes PXRD: solvent-free crystalline polymorphic form II free base of ABT-263
The reflex position (°2θ)
5,79
At 8.60
9,34
10,79
11,36
11,59
To 12.76
13,23
13,73
14,01
14,72
15,00
16,28
Is 17.07
17,48
's 18.75
19,34
Equal to 19.71
20,56
21,35

Reflexes PXRD, especially characteristic of Form I of the free base of ABT-263, in particular, distinguishing the Form I from Form II include reflexes when 6,21, 6,72, 12,17, 18,03 and 20,10°2θ, in each case, ±0,2°. In one embodiment, Form I of the free base of ABT-263 is characterized at least by reflex in any one or more of these provisions. In another embodiment, Form I of the free base of ABT-263 is characterized at least by reflex in each of the e�their provisions. In another embodiment, Form I of the free base of ABT-263 is characterized by reflex in each position, are presented in Table 1.

Reflexes PXRD, especially characteristic of Form II free base of ABT-263, in particular, distinguishing the Form II from Form I include reflexes when 5,79, 8,60, of 12.76, 15.00 and 20,56°2θ, in each case, ±0,2°2θ. In one embodiment, Form II free base of ABT-263 is characterized at least by reflex in any one or more of these provisions. In another embodiment, Form II free base of ABT-263 is characterized at least by reflex in each of these provisions. In another embodiment, Form II free base of ABT-263 is characterized by reflex in each position, are presented in Table 2.

Any of the crystalline forms of the free base of ABT-263, including solvated forms, can be used as an API to obtain capsules of the present invention. However, for this purpose is generally preferable solvent free form, such as Form I and Form II.

Metered quantities in this context are expressed as amounts equivalent to the free base, unless the context otherwise agreed. Typically, uniform dose (the number entered at a time), which may be administered with suitable repeatability,for exampletwice a day one to two times a week, 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. Standardized dose can be delivered in the form of one capsule or for a set of capsules, for example, 1 to about 10 capsules, more typically from 1 to about 5 capsules.

The more uniform the dose, the more desirable it becomes the choice of the mixture of fillers, which would allow a relatively high concentration of the drug in the solution based on it. A suitable concentration of ABT-263 is at least about 40 mg/ml,for examplefrom about 50 to about 200 mg/ml, e.g., about 50, about 75, about 100, about 125, about 150, or about 200 mg/ml Based on the weight ratio wt./wt., a suitable concentration of ABT-263 is at least about 4%,for examplefrom about 5% to about 20%, e.g., about 5%, about 7.5%, about 10%, about 12.5%, about 15% or about 20% of the mass.

In the capsule of the present invention, ABT-263 is "in solution" in the encapsulated liquid. It should be obvious that this means that ABT-263, essentially entirely, is in solution, i.e. that only a small part of ABT-263, for example, not more than about 2%, or not more than about 1%, is in solid (for example, crystalline) form, regardless of whether it is dispersed, for example, in the form of a suspension or not. From a practical point of view, this means that ABT-263 can be normally included in the final composition of the drug at a concentration below the limit of its solubility in the mixture of the used fillers. It should be obvious that the limit of solubility may depend on temperature, and, therefore, the choice of a suitable concentration should take into account the temperature range in which, probably, the composition of the drug will be stored, transported and used.

Encapsulated liquid represents "essentially, bisethanol" liquid, i.e., not containing ethanol, or containing such an amount of ethanol that is too small to ensure that, from a practical point of view, materially adversely affect the operation or properties of the capsule. In particular, the amount of ethanol that is present must be below the threshold concentration at which the integrity of the shell of the capsule is compromised. Typically, the encapsulated liquid contains from zero to less than about 5 wt%. ethanol. This is especially important when using a hard shell capsules, for example, in the case of a capsule with a hard shell gelatin or hydroxypropylmethylcellulose (HPMC). The soft shell capsules, such as soft shell-based gelatin or the collapse�Ala, containing plasticizer, can tolerate somewhat higher amount of ethanol. Some pre-mixed products on the basis of the phospholipid used in this context, contain a small amount of ethanol, which have no adverse effect even on a hard gelatin capsule; e.g., Phosal 53 MCT™ may contain up to about 6% ethanol. When using, illustratively, in an amount not exceeding about 75% wt., based on the weight of the encapsulated liquid, Phosal 53 MCT™, as shown, brings ethanol in an amount not exceeding about 4.5 wt.%, by weight of the encapsulated liquid that leaves the encapsulated liquid in essentially basemanager" state, as defined in this context.

In most embodiments, the encapsulated liquid is also "essentially anhydrous" liquid, i.e., water containing, or containing an amount of water which is too small to ensure that, from a practical point of view, materially adversely affect the operation or properties of the capsule. Typically, the encapsulated liquid contains at least from zero to less than about 5 wt%. water. It should be obvious that some used in this context, the ingredients can bind small amounts �odes on or within their molecules or supramolecular structures; this bound water, if present, has no effect on "essentially anhydrous" the nature of the carrier, defined in the present description. In addition, in accordance with those embodiments that use is poorly lipid-soluble antioxidant, as a rule, requires a small amount of water, usually not exceeding about 1% by weight. by weight of the encapsulated liquid.

As mentioned above, the encapsulated liquid contains,inter aliais a phospholipid, and a pharmaceutically acceptable solubilizers agent to phospholipid. It should be obvious that the reference, singly, or a phospholipid solubilizers agent or other ingredient of the pharmaceutical composition in this context includes a lot of them; thus, in the present description undoubtedly provides and combinations, such as mixtures of more than one phospholipid, or more than one solubilizing agent. Solubilizers agent or combination solubilizing agent and the phospholipid may also contribute to the dissolution of ABT-263, and other ingredients such as surfactant apostolidou of nature.

You can use any pharmaceutically acceptable phospholipid or mixture of phospholipids. In General, these phospholipids are esters of phosphoric acid, which provide children with hi�raise phosphoric acid, fat(s) acid(s), alcohol and a nitrogenous base. Pharmaceutically acceptable phospholipids may include, without limitation, phosphatidylcholine, phosphatidylserine and phosphatidylethanolamine. In one embodiment, the composition of the product contains phosphatidylcholine obtained, for example, from natural lecithin. Can be used any source of lecithin, including sources of animal origin such as egg yolk, however, usually preferred sources of plant origin. Soy is an especially rich source of lecithin, which may give phosphatidylcholine for use in the present invention.

Illustrative suitable amount of phospholipid is from about 15% to about 60%, e.g., from about 20% to about 45 wt.%, by weight of the encapsulated liquid, although in some situations, the phospholipid can be used in higher and smaller amounts.

The ingredients used as components solubilizing agent include glycols, glycolide and glycerides.

Glycols are usually suitable only in cases where must be used for soft shell capsules, and glycols tend to incompatibilities with hard shells, such as a hard gelatin shell. Suitable glycols for soft capsules according to the invention include propylenglycol� and polyethylene glycols (PEG), having a molecular weight from about 200 to about 1000 g/mol,for example, PEG 400, which has a mass-average molecular weight of about 400 g/mol. Such glycols can provide relatively high solubility of ABT-263; however, in some cases, while in solution in the presence of glycols, ABT-263 can exhibit chemical degradation, for example, the formation of sulfoxides, to some extent. This can be seen as changes in the color of the solution with time. The higher the glycol content in the media, the greater may be the tendency of ABT-263 to degradation. In one embodiment, therefore, one or more glycols are present in a total amount of glycol is at least about 1%, but less than about 50%, e.g., less than about 30%, less than about 20%, less than about 15%, or less than about 10 wt.%, by weight of the encapsulated liquid. In another embodiment, the media essentially does not contain glycol.

Glycolide are glycols, such as propylene glycol or PEG, esterified with one or more organic acids, for example, medium - to long-chain fatty acids. Suitable examples include products of propilenglikolmonostearata, propilenglikolmonostearata and propilenglikolstearat, such as, for example, Capmul PG-8™, Capmul PG-12™ and Capmul PG-2L™, respectively, from Abitec Corp., and about�UKTI, essentially equivalent.

Suitable glycerides include, without limitation, medium - to long-chain mono-, di - and triglycerides. The term "medium chain" in this context refers to hydrocarbon chains, which, individually, contain more than about 6 and less than about 12 carbon atoms, including, for example, With8to p10chain. Thus, glycerine products containing chains of capric and Caprylic acids,for examplemono-, di - and/or triglycerides of Caprylic/capric acids, are examples of "medium chain" glycerine products in this context. The term "long-chain" in this context refers to hydrocarbon chains, separately containing at least about 12, for example from about 12 to about 18, carbon atoms, including, for example, laureline, meritline, catilinae, steriline, realnye, linoleyl and linoleyl chain. Hydrocarbon group with a chain length in the above range, soderjaschiesya in glycerine products, can be saturated, mono - or polyunsaturated.

In one embodiment, the encapsulated liquid contains, as a main component solubilizing agent, one or more medium chain triglycerides. A suitable example of a medium chain triglyceride product is a fun� triglyceride product of Caprylic/capric acids, for example, Captex 355 EP™ from Abitec Corp. and products are essentially equivalent to the above. Optionally, as an additional principal component solubilizing agent of this option, the encapsulated liquid further comprises one or more medium chain mono - and/or diglycerides. A good example of such a component is a mono - and diglyceride product of Caprylic/capric acids, such as, for example, Imwitor 742™ from Sasol Germany GmbH and the products are essentially equivalent to the above.

In cases where one or more glycerides are present as the main component solubilizing agent, a suitable total amount of glycerides involves the amount effective to solubilize the phospholipid and, in combination with other fillers, effective for the maintenance of ABT-263 in solution. For example, glycerides, such as medium chain mono-, di - and triglycerides may be present in the total amount of glycerides is from about 15% to about 60%, e.g., from about 20% to about 45 wt.%, by weight of the encapsulated liquid, although in some situations can be used and higher and lower amounts. In one embodiment, the encapsulated liquid contains from about 7% to about 30%, e.g., from about 10% to about 25 wt%. medium chain trigly�of Eridu and from about 7% to about 30%, for example, from about 10% to about 25 wt%. medium chain mono - and diglycerides.

Handy when for use in the compositions of the present invention are available pre-mixed products containing appropriate combination of phospholipid/solubilizers agent. It is emphasized that, while the present invention encompasses compositions containing drug, these products, these compositions does not impose any restrictions. Pre-blended phospholipid products/solubilizers agent can be useful for improving the ease of obtaining compositions of the preparation according to the invention.

An illustrative example of the pre-mixed product phospholipid + solubilizers agent is Phosal 53 MCT™, available from Phospholipid GmbH, which contains, in wt.%, not less than 53% phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 29% medium chain triglycerides, 3-6% (typically about 5%) of ethanol, about 3% mono - and diglycerides from sunflower oil, about 2% oleic acid, and about 0.2% ascorbyl palmitate.

Another illustrative example is Lipoid S75™, available from Lipoid GmbH, which contains, % mass, not less than 70% of phosphatidylcholine in solubilities system. This product can be optionally mixed with triglycerides, for example, �ri a weight ratio of 30/70, to give product ("Lipoid S75™ MCT"), containing, wt.%, not less than 20% of phosphatidylcholine, 2-4% of phosphatidylethanolamine, not more than 1.5% of lysophosphatidylcholine, and 67-73% medium-chain triglycerides.

Another illustrative example of the pre-mixed product phospholipid + solubilizers agent, in this case only suitable for soft capsules according to this invention is Phosal 50 PG™, available from Phospholipid GmbH, which contains, by weight, not less than 50% phosphatidylcholine, not more than 6% lysophosphatidylcholine, about 35% propylene glycol, about 3% mono - and diglycerides from sunflower oil, about 2% of fatty acids of soybean, about 2% of ethanol, and about 0.2% ascorbyl palmitate.

Phosphatidylcholine component of each of these pre-mixed products derived from soy lecithin. Products that have a basically equivalent to the composition, can be obtained from other suppliers. The product having "substantially equivalent composition" in this context means that this product has a composition quite similar to that of a reference composition according to the list of incoming ingredients and relative amounts of ingredients, not showing because of this, in practice, no difference in properties associated with the use of this product in this context.

Encapsulated liquid additional�but contains a pharmaceutically acceptable surfactant apostolidou nature. The person skilled in the art can select a suitable surfactant for use in the capsule of the present invention, based on the information available in the present description. Such a surfactant may perform various functions, including, for example, increased dispersion of encapsulated liquid upon release from the capsule into an aqueous medium of the gastrointestinal tract. Thus, in one embodiment, a surfactant apostolidou nature is a dispersing and/or emulsifying agent, which enhances the dispersion and/or emulsification of the capsule in real or simulated gastrointestinal fluid. Illustrative surfactant, such as Polysorbate (polyoxyethylenesorbitan ester),for example, Polysorbate 80 (available, e.g., Tween™ 80 from Uniqema), can be introduced in an amount of from about 7% to about 30%, e.g., from about 10% to about 25%, by weight of the encapsulated liquid.

ABT-263 susceptible to degradation, with the formation of sulfoxides, in an oxidizing environment; therefore, it is desirable to include an antioxidant in the composition of the drug. The antioxidants used in pharmaceutical compositions, are often remedies that inhibit the generation of re�x varieties such as triplet or singlet oxygen, superoxide, peroxide and free hydroxyl radicals, or tools that capture these oxidative species as they are generated. Examples of commonly used antioxidants of these classes include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), remineralised, tocopherol, propylgallate, ascorbic acid and ascorbyl palmitate. We find, however, that at least some commonly used antioxidants are ineffective for the protection of ABT-263 against excessive formation of sulfoxides in the encapsulated liquid pharmaceutical compositions for the encapsulation described in this context.

For example, BHA, added at 0.2 wt%. 15% of the mass. a solution of the free base of ABT-263 in the environment indicated in the given context "IPT-253" (20% Imwitor 742™, 50% Phosal 53 MCT™, 30% Tween™ 80), as observed, has no effect on the formation of sulfoxides in a 4-week study on stability at 40°C without blowing nitrogen free space above the liquid, as shown in Table 3. A full report on this study is presented in Example 7 in the present description.

Table 3
The effect of 0.2% BHA on the formation of sulfoxide ABT-263 in IPT-253 solution
Time (weeks)The total sulfoxides,%
without antioxidant0,2% BHA
0Not detectable0,06
10,260,29
20,470,49
30,560,58
40,670,68

Antioxidants that, in contrast, proved to be effective, are structuresa compounds, including compounds of the formula

where

n is 0, 1 or 2;

Y1represents S;

Y2represents NHR1OH or H, where R1represents an alkyl or alkylaryl;

Y3represents COOR2or CH2OH, where R2represents H or alkyl; and

R3represents H or al�Il;

where alkyl groups are independently optionally substituted by one or more substituents, independently selected from the group consisting of carboxyl, alkylcarboxylic, alkoxycarbonyl, amino and alkylcarboxylic; their pharmaceutically acceptable salt; or, where Y1is an S and R3represents H, -S-S - dimer or pharmaceutically acceptable salt of such a dimer; or a compound of formula

where

Y represents S or S-S; and

R4and R5independently selected from H, alkyl and (CH2)nR6where n is 0-10 and R6is arylcarbamoyl, alkylsulphonyl, alkoxycarbonyl, carboxyl or CHR7R8- substituted alkyl, where R7and R8are independently CO2R9, CH2OH, hydrogen or NHR10where R9represents H, alkyl, substituted alkyl or arylalkyl and R10represents hydrogen, alkyl, alkylaryl or alkoxycarbonyl.

Deputy "alkyl" or "alkyl" or "alkoxy" group, forming part of the substituent is a group containing from 1 to about 18 carbon atoms and may be straight or branched chain. "Aryl" group, forming part of the substituent is a phenyl group, unsubstituted or substituted by one or carried�alkimi hydroxy, alkoxy or alkyl groups.

R1represents, illustratively, C1-4alkyl (for example, methyl or ethyl) or (C1-4alkyl)carbonyl (for example, acetyl).

R2represents, illustratively, H or C1-18alkyl, e.g., methyl, ethyl, propyl (for example,n-propyl or isopropyl), butyl (for example,n-butyl, isobutyl ort-butyl), octyl (for example,n-octyl or 2-ethylhexyl), dodecyl (for example, SLS), tridecyl, tetradecyl, hexadecyl or octadecyl (for examplestearyl).

R3represents, typically, H or C1-4alkyl (e.g. methyl or ethyl).

Sulfur-containing antioxidant of any of the above formulas can represent, for example, natural or synthetic amino acid or its derivative, such as alkyl ether or N-acyl derivative, or salt of such an amino acid or derivative. In cases where the amino acid or its derivative is obtained from a natural source, it is usually in the L-configuration; however, it is clear that, if necessary, D-isomers and mixtures of D,L-isomers can be replaced.

Non-limiting examples of such sulfur-containing compounds used in the present description, include β-allylmercaptocysteine, cysteine, cystine, homocysteine, methionine, thiodiglycolic acids�, thiodipropionate acid, diglycerin, and their salts, esters, amides and thio-ethers; and combinations thereof. In particular, one or more of such compounds can be selected from N-acetylcysteine, butyl ether of N-acetylcysteine, dodecyl ether of N-acetylcysteine ethyl ester of N-acetylcysteine methyl ester of N-acetylcysteine, octyl ester of N-acetylcysteine, propyl ester of N-acetylcysteine, stearyl ester of N-acetylcysteine, tetradecanol ester of N-acetylcysteine, tridecylalcohol ester of N-acetylcysteine, N-acetylmethionine reduce, butyl ether N-acetylmethionine reduce, dodecyl ester of N-acetylmethionine reduce, the ethyl ester of N-acetylmethionine reduce, methyl ester N-acetylmethionine reduce, octyl ester of N-acetylmethionine reduce, propyl ester of N-acetylmethionine reduce, stearyl ester of N-acetylmethionine reduce, tetradecanol ester of N-acetylmethionine reduce, tridecylalcohol ester of N-acetylmethionine reduce, cysteine, butyl ester of cysteine, dodecyl ester of cysteine, ethyl ester of cysteine, methyl ester of cysteine, octyl ester of cysteine, propyl ester of cysteine, stearyl ester of cysteine, tetradecanol ester of cysteine, tridecylalcohol ester of cysteine, cystine, dibutyl ether cystine, di(dodecyl) ester of cystine, diethyl ether cystine, dimethyl ester of cystine, dioctyl ester of cystine, depoprovera e�Ira cystine, distrilog of cystine ester, di(tetradecyl)new ester of cystine, di(tridecyl)new ester of cystine, N,N-deacetylation, dibutyl ether N,N-deacetylation, diethyl ether N,N-deacetylation, di(dodecyl)new ether N,N-deacetylation, dimethyl ether N,N-deacetylation, dioctyl ester of N,N-deacetylation, DIPROPYLENE ether N,N-deacetylation, DISTEARYL ether N,N-deacetylation, di(tetradecyl)new ether N,N-deacetylation, di(tridecyl)new ether N,N-deacetylation, dibutyltindilaurate, dibutyltindilaurate, di(dodecyl)thiodiglycol, di(dodecyl)thiodipropionate, diethylthiocarbamate, diethylthiophosphate, dimethylterephthalate, dimethyldicarbonate, dioctyladipate, dioctyladipate, dipropyleneglycol, dipropylthiocarbamate, distearyldimethyl, distearyldimethylammonium, di(tetradecyl)thiodiglycol, di(tetradecyl)thiodipropionate, homocysteine, butyl ether of homocysteine, dodecyl ether of homocysteine, the ethyl ester of homocysteine, methyl ester of homocysteine, octyl ester of homocysteine, propyl ether of homocysteine, stearyl ester of homocysteine, tetradecanol ether of homocysteine, tridecylalcohol ether of homocysteine, methionine, butyl ester of methionine, dodecyl ester of methionine ethyl ester of motion�on, methyl ester of methionine, octyl ester of methionine propyl ester of methionine, stearyl ester of methionine, tetradecanol ester of methionine, tridecylalcohol ester of methionine, S-methylcysteine, butyl ether S-methylcysteine, dodecyl ester S-methylcysteine, the ethyl ester of S-methylcysteine, methyl ester S-methylcysteine, octyl ester of S-methylcysteine, propyl ester S-methylcysteine, stearyl ether S-methylcysteine, tetradecanol ether S-methylcysteine, tridecylalcohol ether S-methylcysteine, thiodiglycolic acid, thiodipropionic acid, diglycerin, isomers and mixtures of isomers, and their salts.

Salts of the above compounds may represent additive salts of acids such as 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-, malate-, mesitylenesulfonic-, methanesulfonate-, naphthalenesulfonate-, nicotinate, oxalate, pamoate, pectinate-, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate-, trichloracetate, triptorelin-, para-toluensulfonate - and undecanoate salt.

Without going into the details of any of those�theoretical studies, usually believe that structuresa antioxidants,such as those illustrated above, protect ABT-263 due to the fact that they, themselves, are more easily oxidized and, therefore, they are oxidized preferable in comparison with ABT-263. In General, for this method of functioning to ensure a reasonable degree of protection, the antioxidant should be present in considerable quantity, for example, at a molar ratio relative to ABT-263, is at least about 1:10. In some embodiments, the molar ratio of antioxidant to ABT-263 is from about 1:10 to about 2:1,for examplefrom about 1:5 to about 1.5:1. The best results can sometimes be obtained when the mole ratio is approximately 1:1,i.e.,from about 8:10 to about 10:8.

Despite the antioxidant efficiency of sulfur-containing antioxidants aforementioned formulas, the authors determined that, when molar ratio is approximately 1:1, the above antioxidants tend to give solutions that become turbid during storage, when ABT-263 is used in the form of its free base. For solutions containing ABT-263 in the form of hisbis-HCl salt, this trend is absent or at least less visible.

However, another surprising discovery was that the free base of ABT-263 as was� detected, less susceptible to the formation of sulfoxides than ABT-263bis-HCl in the composition of the drug in the lipid solution (but in the absence of antioxidant), as shown in Table 6 (lookExample 3 below). Solvent system in solution And represents Phosal 53 MCT™/ethanol, 9:1 vol./about.; and in solution B represents Labrafil M 1944 CS™/oleic acid/Polysorbate 80, 30%/40%/30%, mass. (Labrafil M 1944 CS™ from Gattefosse contains polyoxyethyleneglycol.) A three-week study was performed at 40°C without nitrogen purge space above the product.

Taking advantage of the opening, namely, thatABT-263 is less susceptible to the formation of sulfoxides, being in free base form than in the form of salt, the authors turned to another class of sulfur-containing antioxidants, namely, an inorganic antioxidant classes of sulfite, bisulfite, metabisulfite and thiosulfate. A complicating aspect is that these antioxidants are not sufficiently soluble in the lipid compounds and should be introduced into the solution to be encapsulated in the aqueous solution. The presence of water promotes the formation of sulfoxide in solutions of ABT-263, and it is this actionit was necessary to minimize. To limit the amount of added water, insufficient lipid-soluble antioxidants, one in�the approach of this invention, add at significantly lower concentrations than the concentration providing molar equivalence with respect to the concentration of ABT-263.

In those cases, when utilized poorly lipid-soluble antioxidant, such as sulfite, bisulfite, metabisulfite or thiosulfate, it is accompanied by the introduction into the solution for incapsulate water in an amount not exceeding about 1% wt., for example, from about 0.2 to about 0.8 wt%. The amount of the antioxidant of this type, which may be introduced in such a small amount of water, usually not more than about 0.2% wt., and is, for example, an amount of from about 0.02 to about 0.2 wt.%, or from about 0.05 to about 0.15% wt., by weight of the solution to be encapsulated.

To minimise the amount of water added to the pharmaceutical composition, it is desirable to obtain an antioxidant in the form of a relatively concentrated aqueous feed solution, e.g. a solution containing at least about 10 wt%. antioxidant. However, it was found that in cases where use of excessively concentrated stock solution (for examplearound 20% or higher), this can lead to undesirable precipitation of solids in the pharmaceutical composition. Suitable concentration of the antioxidant in the initial solution are usually 10% to about 18 wt.%, illustration�tive, about 15% of the mass.

According to this embodiment is used in antioxidants are sodium and potassium salts of sulfites, bisulfites, metabisulfites thiosulfate; in particular, metabisulfite of sodium and potassium.

Optionally, the final composition of the present invention further comprises a chelating agent. In some circumstances, a chelating agent such as ethylenediaminetetraacetic acid (EDTA or its salt), carvedilol, citric acid and its salts, choline citrate, tartaric acid and its salts, etc., may also improve the stability of the pharmaceutical composition during storage. Consider, without delving into theoretical justification that the chelating agent may enhance the antioxidant efficiency by means of isolation of metal ions that catalyze or otherwise stimulate oxidative degradation of pharmaceutical compounds.

In one embodiment, EDTA or its salt (for example, dvuhmatchevaya salt of EDTA or calcium dvuhmatchevaya salt of EDTA) is optionally added, for example, in an amount of from about 0.002 percent to about 0.02% of the mass. by weight of the solution to be encapsulated, EDTA can be added as an aqueous stock solution in the same manner as an antioxidant. Antioxidant, and EDTA can, if required, be added as components of one and the same initial solution.

Not�Jew, it was found that at very low concentrations is poorly lipid-soluble antioxidant such as sodium metabisulfite, considered in this context (typically the mole ratio of such antioxidant to ABT-263 according to the present embodiment is not more than about 1:20), the formation of sulfoxide remains within the allowable limits, as illustrated in Example 12 in the present description.

In addition, the formation of the sulfoxide can be minimized by selection of the ingredients of the pharmaceutical compositions having a low peroxide value. Peroxide value is a generally accepted characteristic of the pharmaceutical excipients, and it is usually expressed (as in this context) in units appropriate to milliequivalents peroxides per kilogram of filler (mEq/kg). Some fillers are, by nature, have a low peroxide value, but also others, for example, fillers, which contain unsaturated fatty acid, as for example, realnye residues and/or polyoxyethylene chain, can be sources of peroxides. In the case of Polysorbate 80, for example, the preferred choice of the source of Polysorbate 80, which has a peroxide value not more than about 5, for example, not greater than about 2. Suitable sources include Crillet 4HP™ and Super-Refined Tween 80™, both available from Croda.

Illustrat�EIT encapsulated liquid solution according to the present embodiment contains:

from about 5% to about 20 wt%. ABT-263 in free base form,

from about 15% to about 60 wt%. phosphatidylcholine,

from about 7% to about 30 wt%. medium chain triglycerides,

from about 7% to about 30 wt%. medium chain mono - and diglycerides,

from about 7% to about 30% surfactant Polysorbate 80,

from about 0.02% to about 0.2% of the mass. metabisulphite sodium or potassium,

from about 0,003% to about 0.01% EDTA or its salts, and

from about 0.2% to about 0.8% of water.

In the encapsulated solution may not necessarily be present and other fillers, provided that they have no adverse effect on storage stability, safety or therapeutic efficacy of the capsule to an unacceptable degree. However, in a more specific embodiment, the encapsulated liquid solution consists of the ingredients listed directly above.

Capsule shell can be any pharmaceutically acceptable material, including hard and soft gelatin. The size of the capsule's shell is selected in accordance with the amount of fluid that will be subject to encapsulation. For example, the shell of the capsules of size 0 can be used to encapsulate up to about 600 mg of the liquid and the shell CAPSA�s size 00 up to about 900 mg of the liquid.

The prototype capsule of the present invention comprises a hard gelatin capsule shell size 0, containing within itself the encapsulated liquid solution, which contains:

about 50 mg ABT-263 in free base form,

about 150 mg of phosphatidylcholine,

about 75 mg of medium chain triglycerides,

about 90 mg medium chain mono - and diglycerides,

about 90 mg of a surfactant Polysorbate 80,

about 0.25 mg of sodium metabisulphite or potassium,

about 0.025 mg EDTA or its salts, and

about 2.5 mg of water.

It should be borne in mind that the term "about" in the foregoing description of a prototype of the capsule means that the number may vary within normal manufacturing tolerances generally accepted in the pharmaceutical industry.

Limit chemical and physical stability that led to the development of a capsule according to the present invention, may bring additional problem associated with bioavailability when administered by mouth. Acceptable biological availability can be confirmed, for example, pharmacokinetic (PK) parameters, including maximum plasma concentration (Cmax) and area under the curve plasma concentration-time (AUC), calculated from zero to 24 hours, starting from the time the introduction�Oia (AUC 0-24), or from zero to infinity (AUC0-∞). Illustratively, the bioavailability can be expressed in percentage form, for example, using the parameter F, which calculates, in quantitative terms, the AUC for the oral delivery of the tested compositions of the drug in the form of a percentage of the AUC for intravenous (i.v.) bring medication in an appropriate solvent, taking into account any differences between oral and i.v. doses.

Bioavailability may be determined by PK studies in humans or any suitable type of model. For this purpose, is generally suitable model on the dog, which in the illustration is described in Example 11 below. In various illustrative embodiments, capsules of the present invention demonstrate the bioavailability of ABT-263 when administered orally, at least about 30%, at least 35% or at least 40%, up to or exceeding 50%, on the model of the dog, with the introduction of ABT-263 in the form of a single dose of from about 2.5 to about 10 mg/kg animals fasting or non-fasting animals.

In one example, the capsule contains ABT-263 in free base form or in salt form, and a filler selected in such a way as to ensure (a) the solubility of ABT-263, at least about 40 mg/g, for example at least about 50 mg/g, at least about 60 mg/g, at least about 70 mg/g, at least OK�lo 80 mg/g or at least about 100 mg/g, at about 25°C; and (b) the PK profile after oral administration of the composition of the drug on the model of the dog, demonstrating the bioavailability of at least about 30%.

In a separate embodiment, the capsule is a prototype capsule, as described above, or another capsule according to the invention, which is essentially bioequivalent of the foregoing.

The term "essentially bioequivalent" in this context means a demonstration, in the study of the Republic of Kazakhstan with the use of a single dose or multiple doses in humans in conditions on an empty stomach or without starvation, essentially equal to Cmaxand, essentially, identical to the exposure measured as AUC, for example AUC0-24or AUC0-∞.The composition of the drug to be compared against substantial similarity in bioequivalence, should be injected with the same dose or doses, expressed in the case of ABT-263 in the form of the equivalent of the free base. If you need to conduct the comparison using the research with the use of multiple doses, use the values of Cmaxand AUC in the steady state. In this context, Cmaxor AUC of the test composition is "essentially identical" if this option is not less than 80% and not more than 125% of the corresponding parameter for the reference composition.�and ( for example, prototype capsule described above).

The present invention is not limited to the method used to obtain capsules,included or described in this context. Can be used any suitable method of pharmacy. Illustratively, the capsule of the present invention can be obtained by a method comprising a simple mixture of cited ingredients, in which the order of addition is not critical, with the production of the liquid solution to be encapsulated, followed by encapsulating the liquid in the shell of a capsule, e.g. hard or soft gelatin capsule shell, to obtain capsules. It is noted, however, that if the phospholipid is used in its solid state, for example, in the form of soy lecithin, it is usually desirable to first solubilisate phospholipid with solubilizers agent, or a part of it. Then other fillers and ABT-263 can be added by simple mixing, with stirring, if appropriate. Using the pre-mixed product, comprising a phospholipid and solubilizers agent can simplify the composition of the drug. For example, the phospholipid can include phosphatidylcholine and solubilizers agent, previously mixed with it, may include medium chain triglycerides, as in the case of Phosal 53 MCT™ or Lipoid 75™ MCT. Illustratively, the pre-mixed product contains from about 50% to about 75% of phosphatidylcholine and from about 15% to about 30% MCTS.

In those cases, when the solution to be encapsulated contains poorly lipid-soluble sulfur-containing antioxidant such as sodium metabisulfite or potassium, the method needs to be adjusted. An illustrative method of producing capsules containing such solution includes the following stages.

API (active pharmaceutical ingredient), which consists mainly of the free base of ABT-263 or its pharmaceutically acceptable salt (for example, ABT-263bis-HCl) was dissolved in a medium containing a phospholipid and at least part solubilizing agent, to obtain a liquid solution of ABT-263. As noted above, the pre-mixed product containing phospholipid and solubilizers agent, can be used as the medium for dissolution of the API.

In those cases, when ABT-263 has to be entered in the final composition in the form of its free base as the API can be any form of the free base in solid state. However, in the future will be found preferable to use as the API crystalline form of the free base of ABT-263, for example, solvated or resolutionyou are crystal clear, stable�coy form. In a specific embodiment of this method, as the API used resolutionyou crystalline form such as Form I or Form II crystalline ABT-263, is described in this context.

Surfactant apostolidou nature and, optionally, the balance solubilizing agent, mixed with solubilizers agent (prior to or concurrent with the dissolution of the API) or with the lipid solution (after dilution API). As noted above, a surfactant apostolidou nature represents, illustratively, Polysorbate, such as Polysorbate 80. Balance solubilizing agent may be any of the same substance as part solubilizing agent used together with the phospholipid for dissolution of ABT-263; alternatively, the balance can be another substance. For example, some solubilizing agent used together with the phospholipid for dissolution of ABT-263 may include one or more medium chain triglycerides, and balance solubilizers funds, mixed at this stage, may include one or more medium chain mono - and diglycerides, for example the product of mono - and diglycerides of Caprylic/capric acids, such as Imwitor 742™.

Separately, poorly lipid-soluble sulfur-containing antioxidant is dissolved in water with the receiving water source �of astora. In accordance with the above explanation, usually considered suitable source solutions at a concentration from about 10% to about 18% of the mass.

The aqueous stock solution is mixed with a liquid solution, typically after adding a surfactant apostolidou nature, getting the grout to encapsulate.

At the final stage, the resulting liquid solution encapsulate in the shell of the capsule by any known method of encapsulation.

The composition of the drug described in this context, including the composition, in General, or song with some specificity, is used for oral delivery of ABT-263 entity. Accordingly, the method of the present invention for the delivery of ABT-263 subject comprises administering by mouth one to some set of capsules described above.

The subject can be a person or entity not belonging to the human race (for example, farm animal, animal that live in the zoo, working cattleor pet or laboratory animal used as a model), but in an important embodiment, the subject is the person that needs medication, for example, for the treatment of diseases characterized by dysregulation of apoptosis and/or sverkhekspressiya protevoepilepticescoe protein family Bcl-2. H�persons can be male or female of any age but typically it's a grown man.

The composition of the drug is usually administered in an amount that provides a therapeutically effective daily dose of ABT-263. The term “daily dose" in this context means the amount of drug introduced in the course of the day, regardless of the multiplicity of the introduction. For example, if the entity receives a uniform dose of 150 mg twice daily, then the daily dose is 300 mg. Obviously, the use of the term "daily dose" means a particular dosage amount that is subject to mandatory introduction of once a day. However, in a particular embodiment, the frequency of administration is once a day (every day q.(d.), and daily dose and uniform dose in this embodiment constitute one and the same.

What is stated is the fact that a therapeutically effective dose depends on the subject (including the type and body weight of the subject), disease (for examplethat specific type of cancer to be treated; stage and/or severity of the disease, tolerance of the individual subject to drug, regardless of whether it is during monotherapy, or in combination with one or more other drugs,for example, other chemotherapeutic agents for the treatment of cancer and other factors. Thus, the daily dose m�can vary over a wide range, for example, from about 10 to about 1000 mg. In specific situations may be appropriate higher or lower daily doses. It should be borne in mind that eating in this context, the term "therapeutically effective" dose not necessarily require that the drug proved to be therapeutically effective when administered only a single dose; typically, therapeutic efficacy depends on the composition of the drug, subject to the introduction of repeatedly according to therapeutic scheme, including the appropriate frequency and duration of administration. Mostit is preferable that along with the fact that the selected daily dose sufficient to provide beneficial effects, from the point of view of cancer treatment, this dose would be insufficient to provoke unwanted side effects to be unacceptable or unacceptable degree. A suitable therapeutically effective dose can be selected by a physician of middle category, without undue experimentation based on the disclosure of the essence of the invention and the prior art cited in the present description, taking into account the factors mentioned above. To reduce the risk of any unwanted side effects, the doctor may, for example, to start a course of treatment for cancer patients with a relatively small daily dose and further to pick up the dose in direction�of increase over the period of several days or weeks.

Illustratively, suitable doses of ABT-263 are usually between 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 the average interval between doses of the drug from about 3 hours to about 7 days, for example, from about 8 hours to about 3 days, or from about 12 hours to about 2 days. In most cases, a suitable regimen of the drug once a day (every day q.(d.).

The term "average interval between administration of medication" in this context is defined as the period of time such as one day or one week divided by the number of standardized doses, administered during this time period. For example, in cases where the drug is administered three times daily, approximately 8 to noon,around noonandabout 6 in the afternoon, the average interval between doses of the drug is 8 hours (time span of 24 hours divided by 3). One capsule or a set (for example, from 2 to about 10) capsules, administered at one time, considered as a uniform dose to determine the average interval between taking the drug.

The daily dosage amount and interval between doses l�drug funds, in some embodiments, be selected so as to maintain a plasma concentration of ABT-263 in the range from about 0.5 to about 10 μg/ml. Thus, in the course of treatment drug ABT-263 in accordance with the above embodiments, the stationary maximum plasma concentration (Cmax) should in General not exceed about 10 μg/ml, and the lowest stationary plasma concentration (Cmin) should in General not fall below about 0.5 μg/ml. In the future will be revealed the desirability of choice in the ranges presented above, this daily dosing of such amounts and the average interval between doses of medication that would be effective to obtain a ratio With themax/Sminnot higher than about 5, for example, not higher than about 3, in the stationary state. It should be understood that longer intervals between doses of the drug usually tend to lead to higher relationship Withmax/Smin. Illustratively, in a stationary state, according to the proposed method it is possible to target WithmaxABT-263 from about 3 to about 8 μg/ml and Cminfrom about 1 to about 5 μg/ml. Stationary value Withmaxand Cmincan be set when the PK study in humans, for example, carried out in accordance with�tvii with standard protocols including but not limited to protocols that are acceptable to regulatory agencies, such asThe FDA food and drug administrationAdministration (FDA).

One to some set of capsules can be swallowed whole immediately, usually with water or other suitable drink fluids that contributed to the process of swallowing.

Because of the composition of the preparation according to the invention typically detect only a small nutritious, introduction according to this embodiment of the present invention may be carried out with or without (taking) food,i.e.,not in the fasted state oron empty stomach.In most cases, preferably the introduction of the compositions of the drug of the present invention to a patient are not in the fasted state.

Without giving preference to any theoretical justification, it is believed that therapeutic efficacy of ABT-263 due, at least in part, by its ability to bind to protein family Bcl-2, such as Bcl-2, Bcl-XLor Bcl-w, in a sense, that leads to inhibition protevoepilepticescoe action of the protein, for example, as a result of occupying the BH3 binding groove of the protein.

In the following embodiments of the invention, a method of treating a disease characterized by violation �agularia apoptosis and/or sverkhekspressiya protevoepilepticescoe protein family Bcl-2, comprising administering to a subject suffering from the disease a therapeutically effective amount of ABT-263, which is described in this context, the capsule comprising encapsulated inside the liquid.

Finished dosage forms, capsules, according to the invention are suitable for use in monotherapy or in combination treatment, e.g. in combination with other chemotherapeutic agents or with ionizing radiation. A particular advantage of this invention is that it permits oral administration once a day, the scheme of administration of medication, which is convenient for the patient who undergoes the treatment of other orally administered drugs in the regimen of once a day. Oral administration is easily performed by the patient or a person caring for a sick patient at home; moreover, such an introduction is a convenient way of introduction for patients undergoing treatment in the hospital or in the aid environment at the place of residence.

Combined treatment, illustrative, include the introduction of a pharmaceutical composition of ABT-263 in conjunction with one or more of bortezomid, carboplatin, cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel, doxorubicin, etoposide, fludarabine, guide�oxidationin, of irinotecan, paclitaxel, rapamycin, rituximab, vincristine, etc., for example, together with polytherapy, such as CHOP (cyclophosphamide + hydroxydoxorubicin + vincristine + prednisone), RCVP (rituximab + cyclophosphamide + vincristine + prednisone), R-CHOP (rituximab + CHOP) or DA-EPOCH-R (dose-adjustable etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab).

The pharmaceutical composition of ABT-263 can be entered during combined treatment with one or more therapeutic agents that include, but are not limited to, inhibitors of the development of blood vessels, antiproliferative funds, other promoters of apoptosis (for example, inhibitors of Bcl-xL, Bcl-w and Bfl-1), activators of the path of the receptor of death, BiTE antibodies (bespecifically T-cell “societal”), binding proteins with two variable domains (DVDs), inhibitors of apoptosis proteins (IAPs), microRNA, inhibitors of mitogen-activated extracellular signal-regulated kinase, multivalent binding proteins, inhibitors of poly-ADP (adenosine diphosphate)-ribosomally (PARP), a small inhibitory ribonucleic acids (siRNAs), kinase inhibitors, inhibitors of receptor tyrosine kinase inhibitors, inhibitors ofaurorakinase, inhibitors of Polo-like kinase inhibitors, bcr-abl kinase, inhibitors of growth factor, COX-2 inhibitors, non-steroidal anti-protivovospalitel�nye drugs (NSAIDs), antimitotic funds, alkylating agents, antimetabolites; capable of intercalation antibiotics, platypodinae chemotherapeutic agents, inhibitors of growth factor, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, immunological tools, antibodies, hormonal therapies, retinoids, deltoids, plant alkaloids, inhibitors of proteasome, inhibitors of HSP-90 inhibitors discontiuation (HDAC), purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors, inhibitors of ErbB2 receptor, mTOR inhibitors, and other antitumor agents.

Inhibitors of the development of blood vessels include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TIE2 inhibitors, IGF1R inhibitors, inhibitors of matrix metalloproteinase 2 (MMP-2) inhibitors of matrix metalloproteinase 9 (MMP-9) and analogs of thrombospondin.

Examples of EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, cetuximab, EMD-7200, ABX-EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR protein, EGF-vaccine, immunoliposome against EGFR and lapatinib.

Examples of PDGFR inhibitors include, but are not limited to, CP-673451 and CP-868596.

Examples of VEGFR inhibitors include, but are not limited to, bevacizumab, sunitinib, sorafenib, CP-547632, axitinib, vandet�NIB, AEE788, AZD-2171, VEGF trap, vatalanib, pegaptanib, IM862, pazopanib, ABT-869 and angiozyme.

Inhibitors of protein family Bcl-2, in addition to ABT-263, include, but are not limited to, AT-101 ((-)gossypol), Genasense™ Bcl-2-targeting antisens-oligonucleotide (G3139 or oblimersen), IPI-194, IPI-565, ABT-737, GX-070 (obatoclax), etc.

Activators the way of death receptor include, but are not limited to, TRAIL, antibodies or other remedies that tweaking the death receptor (for example, DR4 and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab), HGS-1029, LBY-135, PRO-1762 and trastuzumab.

Examples of analogs of thrombospondin include, but are not limited to, TSP-1, ABT-510, ABT-567, and ABT-898.

Examples of inhibitors ofaurorakinases include, but are not limited to, VX-680, AZD-1152 and MLN-8054.

An example of an inhibitor of Polo-like kinase includes, but is not limited to, BI-2536.

Examples of inhibitors of bcr-abl kinase include, but are not limited to, imatinib and dasatinib.

Examples of platinum-containing means include, but are not limited to, cisplatin, carboplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin.

Examples of mTOR inhibitors include, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001, and AP-23573.

Examples of inhibitors of HSP-90 include, but are not limited to, geldanamycin, radicial, 17-AAG, KOS-953, 17-DMAG, CNF-101, CNF-1010, 17-AAG-nab, NCS-683664, efungumab, CNF2024, PU3, PU24FC1, VER-49009, IPI-504, SNX-2112 and STA-9090.

Examples of HDAC inhibitors include, but are not limited to, suberoylanilide, hydroxamic acid (SAHA), MS-275, valproic acid, TSA, LAQ-824, truoxin and depsipeptide.

Examples of MEK inhibitors include, but are not limited to, PD-325901, ARRY-142886, ARRY-438162 PD-98059.

Examples of CDK inhibitors include, but are not limited to, flavopiridol, MCS-5A, CVT-2584, seliciclib, ZK-304709, PHA-690509, BMI-1040, GPC-286199, BMS-387032, PD-332991 and AZD-5438.

Examples of COX-2 inhibitors include, but are not limited to, celecoxib, parecoxib, deracoxib, ABT-963, etoricoxib, lumiracoxib, BMS-347070, RS 57067, NS-398, valdecoxib, rofecoxib, SD-8381, 4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylbenzoyl)-1H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3 and SC-58125.

Examples of NSAID's include, but are not limited to, salsalate, diflunisal, ibuprofen, Ketoprofen, nabumetone, piroxicam, naproxen, diclofenac, indomethacin, sulindac, tolmetin, etodolac, Ketorolac, and oxaprozin.

Examples of inhibitors of ErbB2 receptor include, but are not limited to, CP-724714, canertinib, trastuzumab, pertuzumab, TAK-165, ionamin, GW-282974, EKB-569, PI-166, dHER2, APC-8024, bespecifically antibody B7.her2IgG3 against HER/2neu and HER2 trifunctional bespecifically antibodies, mAB AR-209 and mAB 2B-1.

Examples of alkylating agents include, but are not limited to, N-oxide nitrogen mustard, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melfa�EN, busulfan, metabolical, carboquone, thiotepa, ranimustine, nimustine, Cloretazine™ (laromustine), AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, KW-2170, mafosfamide, mitolactol, lomustine, treosulfan, dacarbazine and temozolomide.

Examples of antimetabolites include, but are not limited to, methotrexate, 6-mercaptopurine ribozid, mercaptopurine, 5-fluorouracil (5-FU), alone, or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine by ocfosfate, enocitabine, S-l, pemetrexed, gemcitabine, fludarabine, 5-azacytidine, kapecitabinom, cladribine, Clofarabine, decitabine, eflornithine, attentitive, the cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, the disodium pemetrexed, pentostatin, palettecolor, raltitrexed, triapine, trimetrexate, vidarabine, mycophenolic acid, ocfosfate, pentostatin, tesfalem, ribavirin, EICAR, hydroxyurea and deferoxamine.

Examples of antibiotics include, but are not limited to, capable of intercalation antibiotics, aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin (including liposomal doxorubicin), elsamitrucin, epirubicin, Parubiy, idarubicin, mitotic�n C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimulater, streptozocin, valrubicin, zinostatin and combinations thereof.

Examples of inhibiting topoisomerase funds include, but are not limited to, aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, amsacrine, dexrazoksana, diflomotecan, irinotecan HCl, edotecarin, epirubicin, etoposide, exatecan, bicategory, gimatecan, lurtotecan, oracin, BN-80915, mitoxantrone, parabolin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluprost and topotecan.

Examples of antibodies include, but are not limited to, rituximab, cetuximab, bevacizumab, trastuzumab, CD40-specific antibodies and IGF1R-specific antibodies, chTNT - 1/B, denosumab, edrecolomab, WX G250, zanolimumab, lintuzumab and ticilimumab.

Examples of hormonal therapies include, but are not limited to, sevelamer carbonate, elastan, luteinizing hormone-releasing factor, madrasta, exemestane, leuprolide acetate, buserelin, cetrorelix, deslorelin, histrelin, anastrozole, forlin, goserelin, degarelix, doxercalciferol, fadrozole, formestane, tamoxifen, arzoxifene, bikalutamid, abarelix, triptorelin, finasteride, fulvestrant, toremifene, raloxifene, trilostane, lasofoxifene, letrozole, flutamide, megestrol, mifepristone, nilutamid, dexamethasone, predniso� and other glucocorticoids.

Examples of retinoids or deltoidsinclude, but are not limited to, seocalcitol, lexicality, fenretinide, alitretinoin, tretinoin, bexarotene and LGD-1550.

Examples of plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine and vinorelbine.

Examples of inhibitors of proteasome include, but are not limited to, bortezomib, MG-132, NPI-0052 and PR-171.

Examples of immunological drugs include, but are not limited to, interferons and many other immunity-boosting tools. Interferons include interferon alpha, interferon alpha-2a, interferon Alfa-2b, interferon beta, interferon gamma-1a, interferon gamma-1b, interferon gamma-n1, combinations thereof. Other tools include filgrastim, lentinan, sizofiran, live BCG[BCG] vaccine, ubenimex, WF-10 (tetrachlorodecaoxide or TCDO), aldesleukin, alemtuzumab, BAM-002, dacarbazine, impact, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, a vaccine against melanoma, molgramostim, sargramostim, tasonermin, telekin, timalin, it, immunotherapeutic tool Virulizin™ from Lorus Pharmaceuticals, Z-100 (specific substance from Maruyama or SSM), Zevalin™ (90Y-ibritumomab tiuxetan), epratuzumab, mitooma, oregovomab, pemtumomab, Provenge™ (sipuleucel-T), telekin, Therocys™ (Bacillus Calmette-guérin), antibodies to cytotoxic� lymphocytoma antigen 4 (CTLA4) and the means capable of blocking CTLA4, such as MDX-010.

Examples of biological response modifiers are tools that modify defense mechanisms of living organisms or biological responses such as survival, growth or differentiation of tissue cells, stimulating them to acquire antitumor activity. Such means include, but are not limited to, christening, lentinan, sitapura, picibanil, PF-3512676 and ubenimex.

Examples of pyrimidine analogs include, but are not limited to, 5-fluorouracil, floxuridine, doxifluridine, raltitrexed, cytarabine, cytosine arabinoside, fludarabine, triacetyluridine, troxacitabine and gemcitabine.

Examples of purine analogs include, but are not limited to, mercaptopurine and thioguanine.

Examples of antimitotic funds include, but are not limited to, N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, paclitaxel, docetaxel, larotaxel, epothilone D, PNU-100940, batubulan, ixabepilone, patupilone, XRP-9881, vinflunine and ZK-EPO (synthetic epothilone).

Examples of radiotherapy include, but are not limited to, radiation therapy external beam (XBRT), external beam irradiation, close-focus radiation therapy, radiation therapy sealed radioactive sources and radiation therapy unshielded radioactive sources.

And�of tetela BiTE are bespecifically antibodies, who induce T-cells to attack cancer cells by simultaneously binding the two cells. Then T-cell attacking a cancer cell target. Examples of BiTE antibodies include, but are not limited to, adecatumumab (Micromet MT201), blinatumomab (Micromet MT103), etc. without going into too much theoretical discussion, one of the mechanisms by which T cells cause apoptosis of the cancer cell target is to exocytosis of cytolytic granule components, which include perforin and Grasim B. In this regard, Bcl-2, as shown, reduces the induction of apoptosis by perforin and grannymom B. These results indicate that inhibition of Bcl-2 may enhance cytotoxic effects, called T-cells, while targeting cancer cells (Sutton et al. (1997)J. Immunol.158:5783-5790).

SiRNAs are molecules containing grounds of endogenous RNA or chemically modified nucleotides. Modifications will not void cell activity, but rather gives increased stability and/or increased cellular activity. Examples of chemical modifications include phosphorothioate group, 2'-deoxynucleotide, 2'-OCH3-containing ribonucleotides, 2'-F-ribonucleotides, 2'-methoxyethyl the ribonucleotides, combinations thereof, etc. siRNAs can have varying lengths (for example, 10-200 base pairs) and structure (�of aprimer , “studs”, single-/double-stranded plots, loops, single-stranded breaks [“nick”]/breaks (nucleotide sequence), incorrect pairing of bases) and ProcessInput in cells, providing the active silencing of the gene. Double-stranded siRNAs (short RNA duplexes - dsRNA) can have the same number of nucleotides on each chain (“blunt ends) or asymmetric ends (“projections”). The ledge of 1-2 nucleotides can be present on Sens and antisens-chain and may be present at the 5' and/or 3'ends of the chain. For example, siRNAs targeting Mc1-1 has been shown to increase the activity of ABT-263 (Tse et al. (2008)Cancer Res.68:3421-3428,mentioned above, and references within).

Multivalent binding proteins are binding proteins that contain two or more binding sites of the antigen. Multivalent binding proteins, according to their design, have three or more binding sites of the antigen and usually antibodies are not of natural origin. The term "polyspecific binding protein" means a binding protein capable of binding two or more related or unrelated targets. Binding proteins with dual variable domain(DVD) represent tetravalent or multivalent binding proteins containing two or more sites communications�of ivania antigen. These DVDs can be monospecificity (i.e., capable of binding one antigen) or polyspecificity (i.e., capable of binding two or more antigens). DVD binding proteins comprising two DVD polypeptide heavy chains and two DVD light chain polypeptide, called immunoglobulins with dual variable domains [DVD Ig]. Each half DVD Ig polypeptide includes DVD heavy chain DVD polypeptide light chains, and two binding site of the antigen. Each binding site comprises the variable domain of the heavy chain variable domain and a light chain, while only 6 CDR-sites involved in binding of the antigen to the binding site of the antigen.

PARP inhibitors include, but are not limited to, ABT-888, olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, etc.

Additionally or alternatively, the pharmaceutical composition of the present invention can be entered during combined treatment with one or more antitumor agents selected from ABT-100, N-acetilcolina-O-phosphate, acitretin, AE-941, aglycone protopanaxadiol, Arglabin, arsenic trioxide; vaccines against HPV (human papilloma virus), absorbed on adjuvant AS04; L-asparaginase, atamestane, atrasentan, AVE-8062, bosentan, infospeed, Canvaxin™, catumaxomab, CeaVac™, celmoleukin, complestatin A4P, kontuaren of ladenovec, Cotara™, cyproterone, deso�scopoletin, dexrazoksana, N,N-diethyl-2-(4-(phenylmethyl)phenoxy)ethanamine, 5,6-dimethylxanthene-4-acetic acid, docosahexaenoic acid/paclitaxel, discodermolide, efaproxiral, enzastaurin, epothilone B, itineraria, exisulind, palamarev, Gastrimmune™, antitumor GMK vaccine, GVAX™, halofuginone, histamine, gidroksicarbamida, ibandronova acid, ibritumomab of tiuxetan, IL-13-PE38, inanimate, interleukin-4, KSB-311, lanreotide, lenalidomide, lonafarnib, lovastatin, 5,10-methylentetrahydrofolate, mifamurtide, miltefosine, motexafin, oblimersen, OncoVAX™, Osidem™ stabilized by albumin nanoparticles of paclitaxel, paclitaxel poliglumex, pamidronate, panitumumab, peginterferon Alfa, pegaspargase, phenoxodiol, poly(I)-poly(C12U), procarbazine, ranpirnase, reumatica, recombinant quadrivalent vaccines against HPV (human papilloma virus), squalamine, staurosporine, STn-KLH vaccine, T4 endonuclease V, tazarotene, 6,6',7,12 tetramethoxy-2,2'-dimethyl-1β-berbamine, thalidomide, TNFerade™,131I-involving tositumomab, trabectedin, treason, tumor necrosis factor, Ukrain™, a vaccine against vaccinia-MUC-1, L-valine-L-biobrain, Vitaxin™, vitespen, zoledronic acid and zorubicin.

In one embodiment, the composition of the preparation according to the invention are administered in therapeutically effective amounts to a subject in need this, �La treatment of the disease, during which sverkhekspressiya one or more of protevoepilepticescoe protein Bcl-2, protevoepilepticescoe protein Bcl-XLand protevoepilepticescoe protein Bcl-w.

In another embodiment, the composition of the preparation according to the invention are administered in therapeutically effective amounts to a subject in need of this, for treating diseases of abnormal cell growth and/or dysregulation of apoptosis.

Examples of such diseases include, but are not limited to, cancer, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix (any organ), carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, cancer of the anal [anal] region, stomach cancer, gastrointestinal (gastric, colorectal and/or duodenal), chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, cancer of the urethra, penile cancer, testicular cancer, hepatocellular (hepatic and/or biliary duct) cancer, primary or secondary tumor of the Central�ate system primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoplasma T-cell or β-cell origin, melanoma, multiple myeloma, cancer (cavity) mouth, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and/or ureter, carcinoma of the kidney, carcinoma of the renal pelvis, neoplasms [tumors] the Central nervous system, primary lymphoma of the Central nervous system, nahodkinskuju lymphoma, spinal tumors, glioma of the brain stem, adenoma of the pituitary gland, cancer of the adrenal cortex, gallbladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma or a combination thereof.

In a more specific embodiment, the composition of the preparation according to the invention are administered in therapeutically effective amounts to a subject in need of such introduction, for the treatment of bladder cancer, brain cancer, breast cancer, cancer of the bone marrow, cervical cancer (any organ), chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, mechanochemical cancer, lymphoblastic leukemia, follicular lymphoma, lymphoplasma T-cell or β-cell origin�of ardenia, melanoma, myeloid leukemia, myeloma, cancer (cavity) mouth, cancer of the ovary, non-small cell lung cancer, prostate cancer, small cell lung cancer or cancer of the spleen.

Under either of these options, the composition of the drug may be administered during combined treatment with one or more additional therapeutic agents.

For example, a method of treating mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix (any organ), carcinoma of the vagina, carcinoma of the vulva, bone cancer, colon cancer, rectal cancer, anal cancer [anal] region, stomach cancer, cancer, gastrointestinal (gastric, colorectal and/or duodenal ulcer), chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer 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 (hepatic and/or biliary duct) cancer, primary or secondary tumors of the Central nervous system, primary or secondary tumors g�Inal cord, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoplasma T-cell or β-cell origin, melanoma, multiple myeloma, cancer (cavity) mouth, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and/or ureter, vaginal cancer, carcinoma of the renal pelvis, neoplasms 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, gallbladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma or a combination thereof in a subject comprises administering to the subject therapeutically effective amounts of (a) the composition of ABT-263 according to the present invention, and (b) one or more of etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib.

In some embodiments, the composition of the preparation according to the invention are administered in therapeutically effective amounts to a subject in need of such introduction, during combined treatment with etoposide, vincristine, CHOP, rituximab, rapamycin, R-CHOP, RCVP, DA-EPOCH-R or bortezomib in a therapeutically effective amount�TVE, for the treatment of lymphoplasma, such as b-cell lymphoma or non-Hodgkin's lymphoma.

In addition, the present invention provides a method for maintaining in bloodstream of a cancer patient human a therapeutically effective plasma concentration of ABT-263 and/or one or more of its metabolites, comprising administering to the subject one to some set of capsules described in this context, in a dosage amount equivalent to about 50 to about 500 mg ABT-263 per day, at an average interval between doses of the drug from about 3 hours to 7 days.

What is stated is the fact that a therapeutically effective plasma concentration varies,inter aliafrom a specific type of cancer available cancer patient, stage of its development, severity and aggressiveness of the cancer, and the expected outcome of the treatment (for examplethe stabilization , reduction of tumor growth, reduction in tumor size, decrease risk of metastasis,etc.). Most preferably, along with the fact that the plasma concentration sufficient to provide beneficial effects from the point of view of cancer treatment, the same concentration would be insufficient to provoke harmful side effects to an unacceptable or unacceptable degree.

EXAMPLES

Following� examples are illustrative in respect of the invention and illustrate solved by the present invention the problems however, these examples should not be construed as limiting. Characterization of specific choices as adverse or not selected to receive the drug prototype does not necessarily mean that this option is ineffective or goes beyond the scope of this invention. The person skilled in the art on the basis of full disclosure in the present description, can get acceptable formulations, even using the ingredients presented in the present description, as suboptimal.

Example 1: the solubility of the parent compound ABT-263 and itsbis-HCl salt in lipid solvents

The solubility of the parent compound ABT-263 free base, crystalline Form I) and ABT-263bis-HCl salts were tested in the various lipid solvents and mixtures of solvents under ambient conditions. In this study, solvents marked with a trademark, if they are not identified above in the present description, consisted of the following (subject to availability, they may be replaced, in substance, equivalent products from other manufacturers):

Miglyol 810™ from Sasol: triglycerides of Caprylic/capric acids;

Capmul MCM™ from Abitec: glycerolipid/capret;

Captex 300™ from Abitec: triglycerides of Caprylic/capric acids;

Labrafil M 2125 CS™ from Gattefosse: Policia�langlinais linoleic acid;

Tween 20™ from Uniqema: Polysorbate 20;

Labrasol™ from Gattefosse: polyoxyethyleneglycol the caprylate/capret;

Cremophor RH40™: polyoxyethylene (40) hydrogenated castor oil.

"PE-91" is a Phosal 53 MCT™ + ethanol, 9:1, volume ratio. "LOT-343" is Labrafil M 1944 CS™ + oleic acid + Tween 80™, 30:40:30, mass.

The data on solubility are presented in Table 4. In some cases, marked in Table 4 with an asterisk (*), the solubility was initially high, however, when standing deposition occurred.

Table 4
Solubility (mg/g) of the parent compound ABT-263 and its bis-HCl salt in lipid solvents
SolventParent connection (Form I)bis-HCl salt
Corn oil<86<104
Sesame oil<75<80
Castor oil*>78,8
Miglyol 810™ <76<84
Lipoid S75™ MCT150-20048,9
Phosal 53 MCT™>300n.d.
Oleic acid>514<498
Imwitor 742™*>245
Capmul MCM™*>321
Capmul PG-8™*<43
Capmul PG-12™*<39
Captex 300™*<52
Labrafil M 1944 CS™>265<45
Labrafil M 2125 CS™>290<44
PEG-400>200>278
Propylene glycol*>337
Tween 20� >256>176
Tween 80™>256>125
Labrasol™>242>292
Cremophor RH40™>226n.d.
poloxamer 124>231<41
PE-91>25089
LOT-343>479n.d.
n.d. is not defined

Example 2: Miscibility of ternary systems of fillers with the parent compound ABT-263 and its bis-HCl salt

Ternary mixture consisting of two solvents and surfactants, were evaluated for Miscibility and solubility of the drug, using 20% of the mass. the free base of ABT-263 or 10 wt%. ABT-263 bis-HCl salt. Appreciate solvents include Labrafil M 1944 CS™, Imwitor 742™, oleic acid, Capmul PG-8™, Capmul PG-12™, Lauroglycol 90™ (propylene glycol-monolaurate, available from Gattefosse) and Phosal 53 MCT™. Estimated surfactants include Tween 80™, Cremophor RH40™ Gelucire 44/14™ (polyoxyethyleneglycol laurat, available from Gattefosse) and Labrasol™. The data presented in Table 5.

All the subjects of the ternary system of fillers, containing 10-20% Gelucire 44/14™, showed immiscibility. Most of the subjects of systems containing more than 20% Cremophor RH40™ also showed immiscibility. Only in some systems, where the fillers were mixed, ABT-263 in free base form or in the form of a bis-HCl salt was soluble at the test concentration.

Data for additional ternary systems containing fillers based on phosphatidylcholine shown in Example 8, Tables 10 and 11.

Example 3: Chemical stability of the free base of ABT-263 and its bis-HCl salt in lipid solution

There have been some preliminary studies on the stability under conditions that allow parallel comparison between lipid solutions of ABT-263 in the form of a bis-HCl salt and free base form. ABT-263 is dissolved in two separate systems of lipid excipients, Phosal 53 MCT™/ethanol (9:1, by volume; "PE-91) and Labrafil M 1944 CS™/oleic acid/Tween 80™ (30:40:30 by weight; "LOT-343"). In system was not included antioxidant, and in the course of the experiment did not perform the nitrogen purge space netproducts. After conditioning the samples at 40°C (stress conditions) for up to 3 weeks, the analysis on the total content of sulfoxides testified that the test solutions of the free base substantially more stable thanbis-HCl salt (table 6). Total levels of degrading substances also indicated a similar trend (data not shown). The increase in the level of degrading substances was accompanied by a color change of the solution. Solutions ofbis-HCl salt upon exposure showed a marked darkening, while the solutions of the free base showed very little color change.

Table 6
The formation of sulfoxide in lipid solutions of the free base of ABT-263 and itsbis-HCl salt
Time (weeks)The total sulfoxides, % wt./masses.
Solution aSolution B
The free base
25 mg/ml
bis-HCl salt
25 mg/ml
The free base
100 mg/ml
bis-HCl salt
100 mg/ml
00,050,072,492,24
10,270,793,707,15
20,531,904,1137,52
30,843,44No dataNo data

Example 4: Chemical stability of the free base of ABT-263 in different lipid solutions

Chemical stability of the free base of ABT-263 in solution in various lipid excipients was assessed by conducting a two-week test under stress conditions at 40°C, in the absence of an antioxidant or purging with nitrogen. The results are presented in Table 7.

Concentration (mg/g)
Table 7
The formation of sulfoxide in lipid solutions of the free base of ABT-263
Lipid solventThe total sulfoxides*
% wt./masses.
Source1 week2 weeks
Lipoid S75™ MCT1000,210,330,51
Imwitor 742™25**0,250,200,14
Capmul PG-8™25**0,210,250,19
Tween 80™1000,200,590,84
Crillet 4HP™1000,180,440,64
Plurol Oleique CC497™***/Lipoid S75™ MCT 50:50 vol./about.50**0,312,416,26
Labrafil M 1944 CS™1000,30 5,869,16
Oleic acid (super-purified)1000,040,180,29
Phosal 53 MCT™/ethanol 9:1 vol./about.50n.d.0,140,18
* sulfoxide was analyzed as a % of the peak relative to the peak of ABT-263
** lower concentration was used due to the low solubility of the drug in lipid filler
*** polyricinoleate, available from Gattefosse
n.d. - not detected

From the above studies can be summarized as follows.

Very little or only a slight increase in the formation of sulfoxides visible in the fillers on the basis of phosphatidylcholine, such as Phosal 53 MCT™ or Lipoid S75™ MCT.

Very little or only a slight increase in the formation of sulfoxides visible in Imwitor 742™, Capmul PG-8™ and oleic acid (super-purified quality).

The moderate increase in the formation of sulfoxides visible in Tween 80™. Degradation was slower in those cases, when used Polysorbate 80 with a higher degree of purity (Crillet 4HP™).

Labrafil M 1944 CS™ and Plurol Oleique CC497™, both, were associated with exis�tively degradation of ABT-263. Both of these contain filler oleic acid in its structure, and it is known that unsaturated nature of oleic acid activates the oxidation reaction. This can be a cause of chemical instability of the drug in these fillers.

Example 5: Chemical stability of the free base of ABT-263 in ternary lipid systems of dissolution

Although ABT-263 has proved stable in super-purified oleic acid during the two-week test in stressful conditions of example 4, followed by a test using a multicomponent fillers showed that solutions of drugs containing oleic acid, have a tendency to change color when standing. A comparative study on the chemical stability of the drug during storage was carried out at ambient temperature using a solution of ABT-263 in Imwitor 742™/oleic acid/Tween 80™ (30:40:30 by weight; "IOT-343") and Imwitor 742™/Phosal 53 MCT™/Tween 80™ (40:40:20, by weight; "IPT-442"). IOT-343 filler, in itself, is a colorless, and add this filler of the free base of ABT-263 when 10 wt%. gave the solution only slightly yellowish tint, however, obtained a solution of ABT-263 pointedly darkened during storage. That was the difference in relation to the solution of the free base of ABT-263 �ri 10 wt%. in IPT-442 solution, which had a yellow colored filler in the beginning, however, when storing only slightly darkened. Analysis by HPLC of the two solutions of the drug after storage in ambient conditions for 3 months confirmed that the color change of the solution does correlate with degradation (overall levels of sulfoxides was 1.3% for IOT-343 system and 0.5% for IPT-442 system). Therefore, oleic acid was excluded from lipid excipients to be used for the preparation of the formulation of the composition of a capsule filled with liquid solution of ABT-263.

Further testing under conditions of stress, lipid solutions of the free base using various triple combinations of lipids showed that Labrafil M 1944 CS™ is also associated with significant oxidative degradation of ABT-263. As follows from the results of a three-week test in stressful conditions, are presented in Table 8, the pharmaceutical composition containing Labrafil M 1944 CS™, demonstrated a significant increase in the formation of sulfoxides during storage at 40°C without the presence of an antioxidant or purging with argon. On the other hand, a solution of ABT-263 in Imwitor 742™/Phosal 53 MCT™/Tween 80™ (20:50:30, by mass, "IPT-253") that didn't contain neither oleic acid nor Labrafil M 1944 CS™, showed a significantly higher chemical �stabilnosti in comparison with other subjects of the pharmaceutical compositions namely, Labrafil M 1944 CS™/oleic acid/Tween 80™ (30:40:30 by weight; "LOT-343") and Labrafil M 1944 CS™/Imwitor 742™/Tween 80™ (40:30:30 by weight; "LIT-433"). Therefore, as Labrafil M 1944 CS™ and oleic acid were excluded from the lipid fillers that may be used for the preparation of the formulation of the composition of a capsule filled with liquid solution of ABT-263.

Table 8
The formation of sulfoxides in the ternary lipid solutions of the free base of ABT-263
Triple lipid system dissolutionConcentration (mg/g)The total sulfoxides
% wt./mass.*
Source1
week
2
weeks
3
weeks
LOT-3431002,493,704,11No data
LIT-4331000,213,205,13No data
LIT-4331500,232,283,613,80
IPT-253150n.d.0,260,470,56
* sulfoxide was analyzed as a % of the peak relative to the peak of ABT-263
n.d. - not detected

Example 6: Test of antioxidant for the free base of ABT-263 in lipid systems of dissolution

The effectiveness of various antioxidants in the inhibition of oxidative degradation was evaluated in lipid solutions containing the free base of ABT-263 at 100 mg/g in two different lipid systems of dissolution: (1) Lipoid S75™ MCT and (2) triple lipid system (LIT-433;lookabove). Last deliberately chosen as the system, stimulating significant degradation for a short time, as a filter of antioxidant.The formation of sulfoxide during the two-week testing under stress conditions at 40°C with nitrogen purge is presented in Table 9A.

Table 9A
AntioxidantThe concentration of antioxidantThe total sulfoxides,
% wt./mass.*
In Lipoid S75™ MCTIn LIT-433
Exodus-Noe1 week2 weeksIP-stroke-Noe1 ned-La2 weeks
No0,060,420,680,213,205,13
Ascorbyl-palmitate100% molar**n.d.n.d.n.d.0,311,372,07
BHA100% molar**0,130,260,300,43 2,253,66
BHT100% molar**0,080,170,270,372,073,40
The Na metabisulphite***0,1% (wt./mass.)Cloudy solution0,181,95Of 3.07
Thiosulfate Na ***0,1% (wt./mass.)Cloudy solution0,182,644,31

Diglycerin100% molar**0,080,090,130,330,500,56
α-tocopherol145% molar**0,200,270,500,41 3,999,23
n.d. - not defined (ascorbyl palmitate could not be dissolved at 100% relative molar concentration in the solvent)
* sulfoxide was analyzed as a % of the peak relative to the peak of ABT-263
** molar concentration relative to ABT-263
*** water source a solution of 15% wt./about. get to add an antioxidant.

The free base of ABT-263 degraded at significantly lesser extent in Lipoid S75™ MCT than in LIT-433 system fillers. Diglycerin provided effective inhibition of oxidation of the drug in both systems of the filler. In LIT-433 filler system, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite and sodium thiosulfate inhibited oxidative degradation to some extent when subjects concentrations, and α-tocopherol was ineffective. It is noted that the concentration of sodium metabisulfite and sodium thiosulfate were significantly lower than those that provide molar equivalence relative to ABT-263. Even at low concentrations, the addition of water along with these antioxidants resulted in the formation of a turbid solution. The concentration of ascorbyl palmitate, BHA and BHT were significantly higher conc�tion, usually used for antioxidant purposes.

Example 7: BHA as an antioxidant for the free base of ABT-263 in ternary lipid systems of dissolution

Because of its favourable lipophilic nature and wide use in the lipid system as an antioxidant, the antioxidant efficacy of BHA was tested, at levels above normal for BHA, two additional triple systems of filler, IPT-253 and LIT-433, containing ABT-263 at 150 mg/g. the Test was performed under stress conditions at 40°C without purging with nitrogen. As shown in Table 9B, in both systems, the addition of 0.2% wt./mass. BHA to any inhibition of the formation of sulfoxides. On this basis, concluded that the types of antioxidant, with the ability to capture free radicals, such as BHA and BHT, apparently, cannot be used for the protection of ABT-263 against oxidative degradation in lipid solutions.

Table 9B
The effect of BHA on the formation of sulfoxides in solution of the free base of ABT-263
Triple systemAntioxidantThe total sulfoxides
% wt./masses.
source1 week2
weeks
3
weeks
4
Weeks
IPT-253Non.d.0,260,470,560,67
0,2% wt./mass. BHA0,060,290,490,580,68
LIT-433No0,232,283,613,864,19
0,2% wt./mass. BHA0,242,22It was 3.543,804,19
n.d. - not detected

Example 8: Phospholipid system for dissolution of the free base of ABT-263

Based on the results of the above studies, it was concluded that phosphatidylcholine-contents�ing fillers Phosal 53 MCT™ and Lipoid S75™ MCT provide good chemical stability and solubility of the drug in respect of the free base of ABT-263. However, these pre-mixed fillers are not suitable for use, alone, as filler for capsules filled with liquid solution of ABT-263, or high viscosity (Phosal 53 MCT™) or insufficient solubility of the drug (Lipoid S75™ MCT). Polysorbate 80 can be used to increase the solubility of the drug in the excipient. Fillers such as Capmul PG-8™ or Imwitor 742™, could be used to reduce the viscosity of the lipid solution. Both, has been shown to be chemically compatible with ABT-263. Based on previous experience of use in FDA-approved finished dosage forms, excipient Imwitor 742™ is more preferable in comparison with Capmul PG-8™.

Accordingly, the development of capsules filled with a precursor liquid, the attention has been focused on the fillers, such as Phosal 53 MCT™, Lipoid S75™ MCT, Polysorbate 80 (preferably use a more pure form, such as Crillet 4HP™ and superacidity Tween 80™) and Imwitor 742™.

Two triple systems lipid-based excipient containing either Imwitor 742™/Phosal 53 MCT™/Tween 80™ (abbreviated as "IPT") system, or Imwitor 742™/Lipoid S75™ MCT/ Tween 80™ (short for "IST") of the system with different ratios of excipients were examined in the screening on the composition of the prototype composition. The level� Imwitor 742™ in ternary mixture is limited to not more than 40%, and the level of Polysorbate 80 - no more than 20%. Three-digit suffix after "IPT" or "IST" refers to the respective percentage contents of three ingredients-fillers, in each case omitting the terminating null.

When selecting a precursor compositions of emphasis on the Miscibility of excipients, the solubility of the free base of ABT-263 in the filler, the viscosity of the resulting solution (score estimated by surface tension when released from the pipette) and the ability to samogazirovannoe of drug solution (drug load of 10% wt.), characteristics are summarized in Tables 10 and 11 for IPT and IST systems, respectively. Schematic phase diagram for IPT and IST systems (Fig. 1 and 2) further illustrate the process of selection.

As can be seen from Tables 10 and 11 and phase diagrams shown in Fig. 1 and 2, the IPT system, in General, are much better indicators of such properties as Miscibility fillers, solubility and dispersibility of the drug than the corresponding IST system. IPT-262 and IST-262 (later replaced by IST-172) were chosen as prototype systems of fillers, based on the following reasonable explanation.

Solvent-based phosphatidylcholine (e.g., in the form of Phosal 53 MCT™ or Lipoid S75™ MCT) is required to ensure the chemical �stabilnosti (and bioavailability - see below) the final composition of the capsule. The amount of such solvent is practically unlimited due to their low toxicity and high tolerance to the lecithin used in oral dosage forms.

Polysorbate 80 (especially categories of high purity) is required to facilitate the solubility of the drug in the filler and improve semidisplacement lipid composition. Based on normal daily dose of ABT-263 (for example, 200-250 mg) and the maximum daily dose of Polysorbate 80 (418 mg), it is advisable to limit the level of Polysorbate 80 to not more than 20% in the aggregate for the prototype of the composition at 10% load of the drug. Higher levels of Polysorbate is also unfavorable because of reasons related to chemical stability.

In IPT systems, Imwitor 742™ is required to reduce the viscosity of the final solution of the drug to a level that will enable the machine to carry out the filling of the capsule. In IST system, Imwitor 742™, in addition, be necessary to increase the Miscibility of the system of fillers, since Lipoid S75™ MCT and Polysorbate 80 are not miscible in all proportions. However, the number of Imwitor 742™ is limited to no more than 20% for both prototype systems.

From Table 11 that IST-172, the system demonstrates �lohou Miscibility of fillers. However, it was found that after addition of the free base of ABT-263 full Miscibility of the system is acceptable; thus, IST-172 song has become an acceptable prototype liquid to encapsulate.

Example 9: Selection of antioxidant for solutions on the basis of the phospholipid of the free base of ABT-263

Based on the results initially conducted screening of antioxidant (lookExample 6), were also carried out accelerated studies on the stability of two prototype compositions, using either sodium metabisulfite (NaMTBS), or diglycerin as an antioxidant, together with 0.01% EDTA.

Was evaluated the solubility of pure NaMTBS in IPT-262 and IST-262 solutions containing 10% of the free base of ABT-263 and 0.01% EDTA (in the form of its calcium-dvuhmetrovoy salt). After 5 days of mixing using a rotary mixing device under conditions of ambient temperature, all solutions remained solid particles, when concentrations of particulate NaMTBS of 0.05% wt./mass. (or approximately 2% of the molar concentration relative to ABT-263).

Due to the low solubility NaMTBS lipid alternative way of introducing him into the lipid solution was to add conc�terouanne aqueous feed solution NaMTBS in the lipid solution. For example, received a clear solution when 50 mg/ml solution of the free base in Phosal 53 MCT™/ethanol 9:1 vol./about. added 15% wt./about. the solution NaMTBS to a final concentration of NaMTBS to 9.67 mg/ml (or 100% of the molar concentration relative to ABT-263). However, since the final concentration NaMTBS increased to 150% relative to the molar concentration or more, using 15% wt./about. the original solution, the lipid solution became turbid. Using a stock solution at a concentration greater than 20% also leads to the appearance of turbidity in the solution, indicating that an excess amount of water and NaMTBS can produce a turbid solution.

Example 10: Formation of sulfoxides in the compositions on the basis of a phospholipid-containing antioxidant

The results obtained from a two-week accelerated research on the stability (stress conditions: 40 ° C, with a nitrogen purge), as shown in Table 12, indicate that triglycerin not effective, as well as NaMTBS, in the inhibition of the formation of sulfoxides in both prototype compositions.

However, the study also showed that the water added together with NaMTBS, could adversely affect the chemical stability of the drug solution, and this is how it was found, regardless of the form ABT-263 free base �whether bis-HCl salt), or the system used fillers (lookTable 13; a two-week study at 40°C by blowing nitrogen). For this reason, to avoid turbidity was chosen as the final concentration NaMTBS 0,05% (wt./mass.), and the concentration of the initial solution MTBS should be maintained below about 15% wt./about.

td align="center"> 0.55% of Diglycerin + 0,01% EDTA
Table 12
The formation of sulfoxides in the prototype liquids ABT-263 to encapsulate
The floor-preserverAntioxidantAdd some water, %*The total sulfoxides
% wt./wt.
Exodus-s ' 1 week2 weeks
IST-172No00,060,340,54
IST-1720.05% of NaMTBS + 0,01% EDTA0,320,190,280,22
IST-17200,220,270,55
IPT-262No00,140,410,55
IPT-2620.05% of NaMTBS + 0,01% EDTA0,320,430,310,23
IPT-2620.55% of Diglycerin + 0,01% EDTA00,110,260,42
• water in the form of a % of the composition, introduced 15% wt./about. the original solution NaMTBS

tr>
Table 13
The formation of sulfoxide in lipid solutions of ABT-263: effects NaMTBS and water
The floor-preserverForm of ABT-263The concentration of ABT-263Antioch
sident
water
%
The total sulfoxides
% wt./masses.
PE-91The free base (Form I)50 mg/mlNo00,47
PE-91The free base (Form I)50 mg/mlNo3,000,66
PE-91bis-HCl salt50 mg/mlNo01,90
PE-91bis-HCl salt50 mg/ml0.05% of NaMTBS + 0,01% EDTA0,320,53
PE-91bis-HCl salt50 mg/ml0,1% NaMTBS + 0,01% EDTA0,610,84
PE-91bis-HCl salt50 mg/ml0,2% NaMTBS + 0,01% EDTA1,170,97
IST-172The free base (Form I)100 mg/mlNo00,54
IST-172The free base (Form I)100 mg/ml0.05% of NaMTBS + 0,01% EDTA0,320,22
IST-172The free base (Form I)100 mg/ml0,1% NaMTBS + 0,01% EDTA0,610,22

IST-172The free base (Form I)100 mg/ml0,2% NaMTBS + 0,01% EDTA1,170,58
IPT-262The free base (Form I)100 mg/mlNo00,55
IPT-262The free base (Form I)100 mg/ml 0.05% of NaMTBS + 0,01% EDTA0,320,23
IPT-262The free base (Form I)100 mg/ml0,1% NaMTBS + 0,01% EDTA0,610,37
IPT-262The free base (Form I)100 mg/ml0,2% NaMTBS + 0,01% EDTA1,170,58

Example 11:In vivopharmacokinetic study of capsules filled with a precursor liquid

Two prototype containing 100 mg/g of the free base of ABT-263, the different composition of the final composition of capsules filled with a liquid solution, dosed out the dogs (single dose, non-fasting state) to assess theirinvivopharmacokinetics in comparison with 50 mg/ml oral solutions of the free base of ABT-263 andbis-HCl salt in the system Phosal 53 MCT™/ethanol 9:1 vol./about. with 0.01% EDTA.

Each composition was evaluated in a group of six dogs at a dose of 50 mg/dog. Composition A (IPT-262) and B (IST-262) dosed out the same group of dogs in a consistent manner, and Composition-solutions C and D dosed out a separate group of dogs in a consistent manner. Dogs were subjected to starvation for about�agenie night prior to dosing, however, they were provided with food 30 minutes before dosing. The concentration of parent drug in plasma was determined using the HPLC-MS/MS [combination of high performance liquid chromatography and tandem mass spectrometry] upon completion of each study. The results are presented in Table 14.

The maximum concentration (Cmax) A composition in plasma was slightly lower than the concentration of the composition B, however, the AUC of the composition A was larger than the AUC of the composition B, probably due to slower absorption. Composition B showed more consistent, but shorter Tmax2-3 hours after the dose. The composition is A capsule filled with a liquid solution, gave plasma Cmax, AUC and bioavailability (F), comparable to plasma Cmax, AUC and bioavailability (F) oral solutions (the composition of(C and D). Based on these results, IPT-262 prototype (composition A) was chosen as the composition of the final composition of a capsule filled with liquid, for clinical studies in humans.

Table 14
Comparative pharmacokinetic studies of capsules (A and b) filled with a precursor liquid, and the comparative liquid component�of investments (C and D) on dogs
CompositionWithmax(ág/ml)Tmax
(h)
AUC
(μg.h/ml)
F
(%)
A9,84,798,641,9
B11,02,576,831.8 mm

C11,36,0107,842,5
D11,94,594,137,7

Example 12: Stability during storage of the prototype compositions with and without NaMTBS

Preliminary results on the physical and chemical stability were obtained using two laboratory batch prototype ABT-263-containingcompositions of different composition, intended to be filled in a capsule. The only difference between the two groups was the presence or absence of antioxidant (sodium metabisulphite). The composition �Vuh parties represented in Table 15.

Table 15
The composition of the prototype liquid for capsules used in the study on the stability
ComponentParty 1 (antioxidant)Party 2 (without antioxidant)
mg
per capsule
% wt./
masses.
mg
per capsule
% wt./
masses.
The free base of ABT-26350,010,050,010,0
Sodium metabisulfite0,250,05--
Calcium-dvuhmatchevaya salt EDTA0,0250,0050,0250,005
water*2,480,500,230,05
Phosal 53 MCT™268,3553,67269,8553,97

Mono - and diglycerides of Caprylic/capric acids89,4517,8989,9517,99
Polysorbate 8089,4517,8989,9517,99
Total500,0100,0500,0100,0
* includes water, added together with sodium metabisulphite and calcium-dvuhmetrovoy salt EDTA

For investigation of the chemical stability, the liquid having a composition shown in Table 15, were encapsulated into hard gelatin capsules of size 0 capsules and placed in a blister pack (protective film of polychlorotrifluoroethylene Honeywell Aclar™ UltRx 3000,sealed be opened by clicking the foil). Table 16 presents the data after one month of storage under different conditions. The water content, are presented in Table 1, corresponds according to the analysis, and it is not directly associated with the amount of water added together with NaMTBS and calcium-dvuhmetrovoy salt EDTA, as in Table 15.

Table 16
The results of chemical stability for the prototype capsules with and without antioxidant
PartyStorage conditionsSource1 month
The total sulfoxidesTotal degrading substancesThe water content
(%)*
The total sulfoxidesTotal degrading substancesThe water content
(%)
1 (antioxidant)5°Cn.d.0,03%2,7n.d.0,03%3,1
25°C
60% RH
n.d.0,03% 2,7n.d.0,06%3,6
40°C
75% RH
n.d.0,03%2,7n.d.0,03%4,8

2 (without Antioch of sidhanta)5°C0,08%0,14%3,20,12%0,17%3,3
25°C
60% RH
0,08%0,14%3,20,08%0,11%3,1
40°C
75% RH
0,08%0,14%3,20,29%0,42%3,8
* the initial content of water in the filling solution: 0.4% for batch 1; 0.2% for party 2
n.d. not found

From Table 16 it can be seen that the introduction of the antioxidant sodium metabisulphite�I, significantly inhibited the formation of total sulfoxides during the first month of storage, especially under stressful storage conditions 40°C and 75% relative humidity (RH).

Data on the content of total sulfoxides after storage for up to six months are presented in Table 17. Education total sulfoxides was ingibirovalo for at least 6 months, with the exception of the experiment in a stressful storage conditions, 40°C and 75% relative humidity (RH).

Table 17
The total sulfoxides in the prototype capsules with and without antioxidant
PartyStorage conditionsSource1
month
3
months
6
months
1 (antioxidant)5°Cn.d.n.d.n.d.n.d.
25°C
60% RH
n.d.n.d.n.d. 0,15%
40°C
75% RH
n.d.n.d.no data1,90%
2 (without antioxidant)5°C0,08%0,12%0,11%With 0.13%
25°C
60% RH
0,08%0,08%0,18%0,28%
40°C
75% RH
0,08%0,29%0,91%Of 1.40%
n.d. - not detected

Example 13: Stability during storage of the prototype compositionswith and without antioxidant NaMTBS

The study of stability when stored for nine months spent in the same two laboratory batches described in Example 12, prototype ABT-263-containingcompositions intended for filling into a capsule. And in this experiment the only difference between the two parties was the presence or absence of antioxidant (sodium metabisulphite). The composition of the two batches are presented in Table 15.

For this research�hardware, received the prototype capsule was placed in vessels 3 oz, made of HDPE (high density polyethylene), polypropylene caps with child protection, and the vesselsclosed by means of induction sealing machine. Data on the content of total sulfoxides are presented in Table 18. Education total sulfoxides was ingibirovalo for at least 6 months, with the exception of the experiment in a stressful storage conditions, 40°C and 75% relative humidity (RH).

Table 18
The total sulfoxides in the prototype capsules with and without antioxidant
PartyStorage conditionsSourceMonths 3,8Months
6
Months
9
1 (antioxidant)5°Cn.d.n.d.n.d.n.d.
25°C
60% RH
n.d.n.d.0,08%0,20%
40°C
75% RH
n.d.0,51%1,00%1,74%
2 (without antioxidant)5°C0,08%0,10%0,12%0,16%
25°C
60% RH
0,08%0,18%0,27%0,42%
40°C
75% RH
0,08%0,75%1,45%Of 2.25%
n.d. - not detected

Example 14: pharmacokinetics capsules filled with a precursor liquid, the person in the conditions in vivo

Invivopharmacokinetics of capsules filled with a precursor liquid containing 50 mg ABT-263 (Lot 1, described in Table 15 above), was investigated on the volunteers, people with cancer, in comparison with 25 mg/ml lipid solution of ABT-263bis-HCl salt in the system Phosal 53 MCT™/ethanol 9:1 vol./about. with 0.01% EDTA. To assess nutritional effects, liquid soft-gels was administered to fasting subjects and subjects that received food with a high content of W�RA.

Used the design of a randomized, 3-period crossover study, which was attended by 7 people-patients. Only 6 subjects completed all three periods and were included in the experiment. Each drug was administered at a single dose of 200 mg equivalent of the free base of ABT-263. Plasma samples were collected immediately prior to dosing and through 2, 4, 6, 8, 10, 12, 24, 30 and 48 hours after dosing. The concentration of the parent drug, the free base of ABT-263 in the plasma samples was determined using the HPLC-MS/MS, upon completion of the study. Data (mean 6 of the evaluated patients) is shown in Fig. 3. The calculated pharmacokinetic parameters are presented in Table 19.

Table 19
Pharmacokinetic parameters (mean ± standard deviation; N=6)
Lipid solution (fasting)Capsule with a liquid solution (fasting)Capsule with a liquid solution (which takes food with high fat content)
Withmax(ág/ml)3,30±1,06To 2.74±,68 4,85±1,70
Tmax(h)14,0±8,09,3±2,47,0±2,4
AUC0-48(mg. h/ml)70,2±35,255,0±20,882,5±24,5
AUC0-∞(mg. h/ml)80,7±41,363,7±27,793,2±26,2
T1/2(h)12,8±3,512,8±3,114,7±2,5

1. Pharmaceutical capsule containing a capsule shell comprising encapsulated inside, in an amount of not more than about 500 mg per capsule, liquid solution N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) or its salts bis-hydrochloride at a concentration equivalent of the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263), at least about 40 mg/ml, in essence, enterprise�analina media which comprises as pharmaceutically acceptable excipients: (a) at least one phospholipid, (b) at least one solubilizers agent for at least one phospholipid selected from the group consisting of glycols, glycolide, glycerides and mixtures thereof, (C) at least one surfactant apostolidou nature, and (d) at least one sulfur-containing antioxidant in an amount effective to reduce oxidative degradation of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) storage, where at least one sulfur-containing antioxidant selected from the group consisting of sulfites, bisulfites, metabisulfite thiosulfate and mixtures thereof.

2. Capsule according to claim 1, in which N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) present in free base form.

3. Capsule according to claim 2, in which the above-mentioned fillers are selected and included in amounts effective to maintain in solution, at least about 40 mg of the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cycle�hex-1-ene-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) on the capsule.

4. Capsule according to claim 1, in which the number above the encapsulated liquid solution is from about 300 to about 500 mg per capsule.

5. Capsule according to claim 1, in which at least one phospholipid comprises phosphatidylcholine.

6. Capsule according to claim 1, in which at least one solubilizers agent includes one or more medium chain triglycerides.

7. Capsule according to claim 6, in which at least one solubilizers agent further includes one or more medium chain mono - and/or diglycerides.

8. Capsule according to claim 1 in which at least one surface-active substance apostolidou nature involves one or more of polysorbates.

9. Capsule according to claim 8, in which one or more polysorbates have a peroxide number of less than about 5.

10. Capsule according to claim 1, in which at least one sulfur-containing antioxidant is poorly soluble in lipid and encapsulated liquid solution contains water in an amount up to 1 wt%, sufficient for the introduction of an antioxidant in the form of an aqueous feed solution.

11. Capsule according to claim 10, in which at least one poorly lipid-soluble sulfur-containing antioxidant is present in an amount of from about 0.02% to about 0.2% by weight of the encapsulated liquid solution.

12. Capsule according to claim 10, in which, according to CRA�least one poorly lipid-soluble antioxidant comprises sodium metabisulfite or potassium.

13. Capsule according to claim 10, further comprising at least one pharmaceutically acceptable chelating agent.

14. Capsule according to claim 13, in which at least one chelating agent comprises EDTA or its salt.

15. Capsule according to claim 1, in which the encapsulated liquid solution contains from about 5% to about 20 wt%. the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide, from about 15% to about 60 wt%. of phosphatidylcholine, from about 7% to about 30 wt%. medium chain triglycerides, from about 7% to about 30 wt%. medium chain mono - and diglycerides, from about 7% to about 30% surfactant Polysorbate 80, from about 0.02% to about 0.2 wt%. metabisulphite sodium or potassium, from about 0,003% to about 0.01% EDTA or its salt and from about 0.2% to about 0.8% of water.

16. Capsule according to claim 1, in which the encapsulated liquid solution consists of from about 5% to about 20 wt.%, the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263), �t about 15% to about 60 wt%. of phosphatidylcholine, from about 7% to about 30 wt%. medium chain triglycerides, from about 7% to about 30 wt%. medium chain mono - and diglycerides, from about 7% to about 30% surfactant Polysorbate 80, from about 0.02% to about 0.2 wt%. metabisulphite sodium or potassium, from about 0,003% to about 0.01% EDTA or its salt and from about 0.2% to about 0.8% of water.

17. A method for producing a capsule according to claim 10, including dissolution of the API (active pharmaceutical ingredient), which mainly consists of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) or its salts bis-hydrochloride, at least, the phospholipid and solubilizing agent with obtaining a lipid solution, a mixture of surfactants apostolidou nature with solubilizers agent or lipid solution, dissolution of poorly lipid-soluble sulfur-containing antioxidant in water to obtain aqueous feed solution, mixing the aqueous feed solution with the lipid solution to obtain a liquid solution to be encapsulated and the encapsulating liquid solution in the shell of the capsule.

18. A method according to claim 17, in which the phospholipid and at least part solubilizing agent is supplied in the form of pre�tion of the mixed product.

19. A method according to claim 18, wherein the phospholipid comprises phosphatidylcholine and solubilizers agent, previously mixed with it, includes medium chain triglycerides.

20. A method according to claim 19, wherein the pre-mixed product includes from about 50% to about 7 5% of phosphatidylcholine and from about 15% to about 30% MCTS.

21. A method according to any one of claims. 17-20, in which the API consists mainly of Form I or Form II crystalline free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263).

22. Capsule according to any one of claims. 1-16 for use for the treatment of diseases characterized by dysregulation of apoptosis and/or sverkhekspressiya protevoepilepticescoe protein family Bcl-2, by oral administration to a subject suffering from the disease a therapeutically effective amount of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) within the specified capsule.

23. Capsule according to claim 22 for the above application, where the disease is a tumor.

24. Capsule according to claim 23 d�I the above application, where the neoplasm is selected from the group consisting of malignancies, mesothelioma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or 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 cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, cancer, gastrointestinal (gastric, colorectal and/or duodenal ulcer), chronic lymphocytic leukemia, esophageal cancer, cancer of the small intestine, cancer 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, mechanochemical (liver and/or biliary duct) cancer, 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, lymphoplasma T-cell or β-cell origin, melanoma, multiple myeloma, oral cancer, non-small cell lung cancer, prostate cancer, chalk�kletochnogo lung cancer, cancer of the kidney and/or ureter, vaginal cancer, carcinoma of the renal pelvis, neoplasms 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, gallbladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma or a combination thereof.

25. Capsule according to claim 23 for the above application, where the tumor is lymphoplasma.

26. Capsule according to claim 25 for the above application, where lymphoplasma is nahodkinskuju lymphoma.

27. Capsule according to claim 23 for the above application, where the tumor is a chronic lymphocytic leukemia or acute lymphocytic leukemia.

28. Capsule according to claim 23 for the above application, where from one to some set of the above capsules administered at a dose of from about 50 to about 500 mg of equivalent of the free base Ν-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) per day with an average interval between doses of medication from about 3 hours to about 7 days.

29. Capsule according to claim 28 for the above application�, where from one to some set of the above capsules administered once daily at a dose of from about 200 to about 400 mg of equivalent of the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide(ABT-263) per day.

30. Capsule according to claim 29 for the above application, where the above capsule is a
capsule containing hard gelatin shell capsules of size 0, which includes within itself the encapsulated liquid solution, which contains about 50 mg of the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263), about 150 mg of phosphatidylcholine, about 75 mg medium chain triglycerides, about 90 mg medium chain mono - and diglycerides, about 90 mg surfactant Polysorbate 80, about 0.25 mg of sodium metabisulphite or potassium, about 0.025% EDTA or its salts and about 2.5 mg water.

31. Capsule according to any one of claims. 1-16 for use for maintaining in bloodstream of a subject-person a therapeutically effective plasma concentration of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)--(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzolsulfonat (ABT-263) and/or one or more of its metabolites, by oral administration to a subject one to some set of the above capsules at a dose of from about 50 to about 500 mg of equivalent of the free base of ABT-263 per day, with an average interval between administration of the drug at from about 3 hours to about 7 days.

32. Capsule according to claim 31 for the above application, where supported, the plasma concentration demonstrates, in a stationary state, a maximum of from about 3 to about 8 μg/ml N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263) and at least from about 1 to about 5 μg/ml N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263).

33. Capsule according to claim 28 for the specified application, where the specified capsule is a
capsule containing hard gelatin shell capsules of size 0, which includes within itself the encapsulated liquid solution, which contains about 50 mg of the free base N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-EN-1-yl)methyl)piperazine-1-yl)benzoyl)-4-(((1R)3-(morpholine-4-yl)-1-((phenylsulfanyl)methyl)propyl)-amino)-3-((trifluoromethyl)sulfonyl)benzosulfimide (ABT-263), about 150 mg �of fosfatidilkholina, about 7 5 mg of medium chain triglycerides, about 90 mg medium chain mono - and diglycerides, about 90 mg surfactant Polysorbate 80, about 0.25 mg of sodium metabisulphite or potassium, about 0.025% EDTA or its salts and about 2.5 mg water.



 

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12 cl, 1 dwg, 14 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to compounds of formula (I), wherein R1 and R2 independently represent C6-C10 aryl optionally substituted by -OH, halogen, -OC1-C3 alkyl, -NO2, -CF3 or C1-C3 alkyl, or 5- or 6-merous heteroaryl containing one heteroatom specified in N, S and O; A and M independently represent a methylene group or a single bond; an adjacent aromatic cycle is attached directly to an amide group; the group Y=Z represents together and irregularly oxygen atom (-O-), cis-vinylidene group (-CH=CH-), iminogroup (-N=CH- or -CH=N-) or methylene group with sp2-hybridised carbon atom (=CH-); X irregularly represents methine group (=CH-), cis-vinylidene group (-CH=CH-) or carbon atom (=N-), and W represents hydroxyl group (-OH), C1-C6 alkyl optionally substituted by -SH, 5- or 6-merous heteroaryl containing 1 to 2 nitrogen heteroatoms, or C6-C10 aryl, optionally substituted by -SH, -NH2, and their pharmaceutically acceptable salts.

EFFECT: described are the methods for preparing the compounds, using as a drug for treating cancer and the based pharmaceutical composition.

14 cl, 6 tbl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. What is presented is a completely human monoclonal antibody, which binds insulin-like growth factor-II (IGF-II) and has a cross responsiveness to IGF-I, as well as its antigen-binding fragment. There are disclosed a nucleic acid molecule coding an antibody according to the invention, a vector and a host cell for the expression of the antibody according the invention. There are described a pharmaceutical composition, as well as conjugates for treating and diagnosing malignant tumour, using the antibody according to the invention in preparing the therapeutic agent and a method for determining IGF-II and IGF-I levels in a patient's sample.

EFFECT: present invention can find further application in cancer therapy.

16 cl, 27 ex, 18 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically to a method for producing a mixture of mono- and di-pegylated IL-10, and can be used in medicine. The above method consists in carrying out a reaction of IL-10 protein in the concentration of 1 to 12 mg/ml with activated PEG-linker, wherein the relation of IL-10 and PEG-linker makes 1:1 to 1:7.7 in the presence of 25 to 35 mM of the reducing agent. The appropriate cases may require purifying the produced mixture of IL-10. The invention also refers to a pharmaceutical composition for treating a proliferative condition or disorder, containing a therapeutically effective amount of the mixture of mono- and di-pegylated IL-10 produced as described above, and a pharmaceutically acceptable carrier.

EFFECT: invention enables producing the mixture of mono- and di-pegylated IL-10 accompanied by no side products produced and keeping the protein dimer structure non-destructive.

16 cl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of immunology. Claimed is isolated antibody to ICOS protein of people with increased effector function. Also described are cell and method of obtaining antibody in accordance with claimed invention, pharmaceutical composition, method of treating autoimmune disease or disorder, transplant rejection and malignancy of human T-cells, as well as method of depletion of ICOS-expressing T-cells, method of destroying germ centre structure in secondary lymphoid organ of primates, methods of depleting B-cells of germ centre of secondary lymphoid organ and circulating B-cells, which have undergone class switching, in primates.

EFFECT: invention can be further applied in therapy of diseases, mediated by T-cells.

33 cl, 21 dwg, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to a formulation of a cough medical composition. The formulation of the cough medical composition contains an active substance presented by thermopsis herb powder or a dry extract of thermopsis and sodium hydrocarbonate, as well as an excipient, a granulating agent and a lubricant taken in certain relations (versions).

EFFECT: composition of the cough medical composition possesses improved pharmaceutical (appearance, taste) and technological characteristics (hardness, disintegration).

11 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a storage-stable pharmaceutical composition and a pharmaceutical formulation containing at least one active pharmaceutical ingredient presenting a nitrocatechol derivative, 2,5-dichlor-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, at least one excipients and at least one binding agent, wherein at least one excipient is other than a phosphate derivative, wherein at least one binding ingredient is other than a polyvinylpyrrolidone compound, and wherein the above active pharmaceutical ingredient is present in the granulated form.

EFFECT: compositions and/or formulations according to the invention are stable for a long period of time and show a high stability if stored in the high temperature and moisture environment.

26 cl, 8 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: therapeutic agent contains anastrozole, poly(lactic-co-glycolic acid), polyvinyl alcohol and D-mannitol. The therapeutic agent represents sub-micron particles and can be presented in the form of capsules, granules, powder, as well as a suspension for injections.

EFFECT: using the developed therapeutic agent enables achieving the therapeutic effect with lower therapeutic doses and making the antitumour therapy more comfortable for the patient.

2 cl, 1 tbl, 2 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for producing soft capsule coatings contains corn starch, carrageenan, water and a softening agent in certain proportions.

EFFECT: composition prolongs the shelf life of the soft capsule coatings without usability deterioration.

2 cl, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition with anti-ischemic and antioxidant activity in the form of tablets or capsules, and a method for preparing it. The composition contains 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid in an amount of 40 to 80 wt %, an amino-containing compound and pharmaceutically acceptable excipients. The amino-containing compound is specified in a group of trometamol, methyl glucamine and L-lysine; 1 mole of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid is accounted for 0.05 to 0.25 mole of the above amino-containing compound. The composition also contains lactose, microcrystalline cellulose, calcium stearate and other pharmaceutically acceptable excipients. According to the method for preparing the composition, taking 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid and amino-containing compound in molar ratio 1:0.05 to 1:0.25, pre-mixing, moisturising with a aqueous or alcohol solution of a binding agent, adding pharmaceutically acceptable excipients in such an amount to provide the content of 4-((3-oxo-3-ethoxypropanoyl)amino)benzoic acid from 40 to 80 wt %, granulating the mixture, drying and producing tablets or capsules according to the known technique.

EFFECT: implementing the above application.

6 cl, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics, in particular a pharmaceutical composition in the form of a peroral drug form is described. The composition includes rebamipide as an active ingredient and a pharmaceutically acceptable carrier. Rebamipide is contained in an amount from 0.5 to 50 mg/kg, preferably from 0.6 to 6 mg/kg.

EFFECT: application of the rebamipide-based pharmaceutical composition for the prevention and treatment of arthrosoarthritis.

5 cl, 3 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a composition in the form of a gelatine capsule possessing the antihypertensive action, containing lisinopril dihydrate granules and verapamil hydrochloride tablets in a ratio of 1:5 to 1:20.

EFFECT: invention refers to a method for preparing this composition, consisting in encasing the lisinopril granules and verapamil tablets into the gelatine capsule that provides the ease of preparing the dosage form, and an acceptable profile of the therapeutic substance release.

2 cl, 2 ex, 4 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: coagglomerates of crystalline mannitol and granular starch in the ratio mannitol/starch from 99.5/0.5 to 50/50 have compressibility of 200 N to 450 N, flow time of 3 to 15 s and volume mean diameter D4.3 of particles based on laser granulometry of 60 to 500 mcm. The coagglomerates are intended for producing tablets or solid gelatin capsules for use in pharmaceutics. The method of producing said coagglomerates includes preparing, at 45-65°C, a solution of mannitol and granular starch or a mannitol solution only, where content of solid substance ranges from 25% to 45%, holding said solution at 45-65°C, spray-drying said solution in an MSD-type dryer equipped with a high pressure spray-drying nozzle with recycling of the fine particles at the spray-dryer top and, if necessary, adding dry starch, separating the obtained the coagglomerates of mannitol and of starch. The method can also include granulating the solution of mannitol and starch by spraying in a circular continuous fluidised-bed granulator with a discharge pipe or plug-flow rectangular continuous fluidised-bed granulator.

EFFECT: obtaining coagglomerates with good compressibility and good fluidity.

9 cl, 12 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a dosage form of Clopidogrel presented in the form of a solid gelatine capsule. The dosage form contains Clopidogrel hydrogen sulphate, lactose anhydride, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide and magnesium stearate.

EFFECT: according to the invention, the dosage form of Clopidogrel contains a high amount of the active ingredient; it is prepared without the use of a wet granulation technique, and provides the more accurate dosage of the ingredients and the stability of the substances used.

9 tbl

FIELD: medicine.

SUBSTANCE: immunocorrective agent for the therapy of atherosclerotic diseases containing hawthorn blossom, common St. John's wort herb, as well as calcium stearate and silicone oxide taken in certain proportions.

EFFECT: agent is effective for the therapy of atherosclerotic diseases.

8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to a pharmaceutical composition in the form of the extrudate, containing at least one pharmaceutically active substance in the form of needles, characterised by the fact that the ratio of the particle size of the needle-like active substance to the diameter of strands constitutes at least 1:25.

EFFECT: invention makes it possible to obtain the more homogeneous extrudate.

11 cl, 13 ex, 10 dwg

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