Therapeutic compositions

FIELD: medicine.

SUBSTANCE: there is described oral pharmaceutical composition containing 9,10-dehydroepothilone combined with a pharmaceutically acceptable carrier. According to the second version, the oral pharmaceutical composition contains trans-9,10-degihydroepothilone D and a pharmaceutically acceptable carrier containing hydroxypropyl-β-cyclodextrine, ethanol and propylene glycol. The concentrate for injection contains 9,10-degihydroepothilone D in the pharmaceutically acceptable carrier.

EFFECT: good bioavailability of epothilone D.

21 cl, 4 ex

 

Cross references to related applications

This application claims, in accordance with section 35 of article 119 of the Code of Laws of the United States, on the priority of patent application U.S. serial No. 10/683952, filed October 9, 2003, and PCT application PCT/US03/032055, filed October 9, 2003, each of which in its entirety is incorporated into this description by reference.

The scope of the invention

The present invention is connected with the composition and delivery of therapeutically active substances. More specifically, the present invention relates to compositions and methods of treatment of hyperproliferative diseases, in particular malignant tumors. The invention relates to the field of pharmacology and medicinal chemistry.

Fundamentals of invention

Class polyketides known as epothilone emerged as a potential therapeutic compounds, the action of which resembles that of paclitaxel (Bollag, et al. 1995; Service 1996; Winkler and Axelsen 1996; Bollag 1997; Cowden and Paterson 1997). Interest epothilones and epothilone analogues increased in connection with the observations, according to which epothilone are active against tumors that have acquired resistance to paclitaxel (Harris, et al. 1999a), and also due to their low potential to cause unwanted side effects (Muhlradt and Sasse 1997). Among epothilone is in and epothilone analogues, explored in relation to the effectiveness of their therapeutic actions, say epothilone B1(Oza, et al. 2000) and semi-synthetic analogues epothilone B, BMS-2475502also known as "asiaporn B" (Colevas, et al. 2001; Lee, et al. 2001; McDaid et al. 2002; Yamaguchi, et al. 2002), and BMS-3107053.

Desoxyepothilone B 4, also known as "epothilone D"represents a more derived epothilone, with promising antitumor properties, namely paclitaxel therapeutic efficacy of which has been studied (Su, et al. 1997; Chou, et al. 1998a; Chou, et al. 1998b; Harris, et al. 1999b; Chou, et al. 2001; Danishefsky, et al. 2001b; Martin and Thomas 2001; Danishefsky, et al. 2002). It was shown that this compound has a lower toxicity than epothilone with 12,13-epoxy, such as epothilone B or BMS-247550, mainly due to the absence of highly reactive epoxide fragment

Usually pharmacologists and physicians prefer a therapeutic composition for oral use patients agree more readily and the introduction of which is not associated with difficulties for patients (DeMario and Ratain 1998). Composition, oral activity which has been demonstrated in mice, described for preparations BMS-247550 and BMS-310705 (Lee 2002a; b); however, these compounds are devoid of structural combination of the oxygen of the lactone and olefin detected in E. Athlone D.

In a single message about polyethylene glycol-400: ethanol (10:1) composition epothilone D, oral introduced one mouse at a dose of 50 mg/kg), says about the lack of a significant effect on tumor size (Chou, et al. 1998b). Unfortunately, epothilone D has a low solubility in water; and the present composition epothilone D include an agent that promotes solubilization derivative of castor oil, which is commercially available under the trade name CREMOPHOR® (BASF Aktiengesellschaft), to improve the solubility. Such compositions are suitable only for intravenous administration. Although the present compositions epothilone D and are acceptable for clinical and therapeutic applications, the drug CREMOPHOR® is associated with discomfort and toxicity in patients. Were described compositions epothilone B for intravenous, free of CREMOPHOR® (Van Hoogevest 1999). Therefore, it would be preferable obtaining reinforced composition epothilone D, which does not require the presence of the drug CREMOPHOR®, and even more preferably, such a composition would be presented in a form for oral administration.

SUMMARY of INVENTION

In one aspect of the present invention associated with obtaining pharmaceutical compositions for the treatment of hyperproliferative disease is s, usually - though not necessarily - in a mammal, preferably humans. In one of the embodiments of the present invention relates to a pharmaceutical composition comprising epothilone and a pharmaceutically acceptable carrier, the embodiment which will be described in detail hereinafter. Epothilone provided in a therapeutically effective concentration, and the pharmaceutical composition is effective to deliver a therapeutically effective amount epothilone by oral administration.

In specific embodiments, pharmaceutical compositions provided by the present invention, such pharmaceutical composition according to the invention includes at least one cyclodextrin, and in more specific embodiments the specified cyclodextrin is hydroxyalkyl-β-cyclodextrin, and in still more specific embodiment - hydroxypropyl-β-cyclodextrin. In other embodiments of the present invention, the cyclodextrin is sulfoalkylation, and in more specific embodiments, sulfoalkylation is sulfopropyl-β-cyclodextrin.

In other embodiments of the present invention epothilone and cyclodextrin presented in lyophilized form, which in some embodiments is a "residue" of the lyophilisate.

In another waples the Institute, the compounds and compositions according to the invention are used in combination with other therapeutic agents or procedures. In particular embodiments, the other therapeutic agents include other antiproliferative agents, agents that enhance antiproliferative activity antiproliferative compounds (for example, inhibitors of Hsp90), and agents that weaken the adverse effects of antiproliferative agent.

In another aspect according to the invention offers the pharmaceutical composition used for treatment of malignant tumors. In particular embodiments compositions containing epothilone, used for the treatment of malignant tumors that are sensitive to epothilones.

In other embodiments of the proposed pharmaceutical composition used for treatment of non-malignant diseases characterized by hyperproliferative activity of cells (e.g., psoriasis, restenosis, multiple sclerosis, rheumatoid arthritis, atherosclerosis, and so on).

In another aspect of the present invention offers a pharmaceutical composition effective to provide a therapeutically effective dosage levels epothilone for a patient in need of such treatment. In particular embodiments the composition is effective in providing dose level PR is approximately between 0.1 mg/m 2and about 200 mg/m2.

DETAILED description of the INVENTION

In one aspect of the present invention offers pharmaceutical compositions (also referred to here simply as "songs") for the treatment of hyperproliferative diseases, usually - but not necessarily - in a mammal, preferably humans. In one of the embodiments of the present invention features a pharmaceutical composition comprising epothilone and a pharmaceutically acceptable carrier, specific embodiments of which will be described in more detail hereinafter. Epothilone offered in a therapeutically effective concentration, and the pharmaceutical composition is effective to deliver a therapeutically effective amount epothilone through the mouth. In certain embodiments the pharmaceutical compositions are available in a physical form suitable for oral administration, for example, in the form of soft gel capsules.

Here, the term "epothilone" is used to refer to any epothilone, such as not limited, however, the above - epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, 4-desmethylation D, asiaporn B, 21-aminopurin B, 9,10-dehydroemetine D, 9,10-degidro 26 trifter-epothilone D, 11-hydroxyapatite D, 19-axisoperation D, 10,11-dehydroemetine D, 19-oxazolyl-10,11-dehydr epothilone D, 9,10-dehydroemetine B, 9,10-dehydroemetine D, 26 trifter-9,10-dehydroemetine B or D, as well as their analogues and derivatives. Epothilone used in the pharmaceutical compositions according to the invention, can thus be any epothilone, and more specifically any epothilone having useful therapeutic properties (Hoefle, et al. 1993; Nicolaou, et al. 1998; Reichenbach, et al. 1998; Danishefsky, et al. 1999a; Danishefsky, et al. 1999b; Hoefle, et al. 1999; Nicolaou, et al. 1999a; Nicolaou, et al. 1999b; Vite, et al. 1999a; Vite, et al. 1999b; Vite, et al. 1999d; c; Hoefle, et al. 2000a; Hoefle, et al. 2000b; Danishefsky, et al. 2001a; Danishefsky, et al. 2001b; Santi, et al. 2001; Avery 2002; Danishefsky, et al. 2002; Nicolaou, et al. 2002a; Nicolaou, et al. 2002b; Wessjohann and Scheid 2002; White, et al. 2002). Such epothilone can be obtained using any combination of the complete chemical synthesis, partial chemical synthesis or methods of hemobiotech, as well as materials known to experts in the field of organic chemistry, medicinal chemistry and biotechnology (Hoefle, et al. 1993; Hoefle and Kiffe 1997; Hofle and Kiffe 1997; Schinzer, et al. 1997; 1998; Hofle and Sefkow 1998; Mulzer and Mantoulidis 1998; Nicolaou, et al. 1998; Reichenbach, et al. 1998; Schinzer, et al. 1998; Wessjohann and Gabriel 1998; Wessjohann and Kalesse 1998; Altmann et al. 1999; Danishefsky, et al. 1999a; Danishefsky, et al. 1999b; Hoefle, et al. 1999; Hofmann, et al. 1999; Kim and Borzilleri 1999; Kim and Johnson 1999; Klar, et al. 1999a; b; Mulzer and Mantoulidis 1999; Nicolaou, et al. 1999a; Nicolaou, et al. 1999b; Schupp, et al. 1999; Vite, et al. 1999a; Vite, et al. 1999b; Vite, et al. 1999d; c; Beyer and Mueller 2000; Borzilleri, et al. 2000; Buchmann, et al. 2000; Cabral 2000; Georg, et al. 2000; Gustafsson and Betlach 2000; Hoefle, et al. 2000a; Hoefle, et al. 2000b; Hofle, et a. 2000; Julien, et al. 2000; Kim and Johnson 2000; Li, et al. 2000; Mulzer, et al. 2000; Arslanian, et al. 2001; Danishefsky, et al. 2001a; Danishefsky, et al. 2001b; Kim and Johnson 2001; Klar, et al. 2001; Kumar, et al. 2001; Lee 2001; Li, et al. 2001); (Mulzer and Martin 2001; Santi, et al. 2001; Strohhaecker 2001; Vite, et al. 2001; Avery 2002; Danishefsky, et al. 2002; Dimarco, et al. 2002; Hoefle and Glaser, 2002; Julien, et al. 2002; Khosla and Pfeifer 2002; Koch and Oiseleur 2002; Kuesters and Unternaehrer 2002; Li, et al. 2002; Nicolaou, et al. 2002a; Nicolaou, et al. 2002b; Santi, et al. 2002a; Santi, et al. 2002b; Santi, et al. 2002c; Smith, et al. 2002; Wessjohann and Scheid 2002; Wessjohann, et al. 2002; White, et al. 2002). Specific examples epothilones having useful therapeutic properties include, but are not limited, however, listed, epothilone A, epothilone B, epothilone C, epothilone D, 4-desmethylation D, asiaporn B, 21-aminopurin B, 9,10-dehydroemetine D, 9,10-degidro-26-cryptographie D, 11-hydroxyapatite D, 19-axisoperation D, 10,11-dehydroemetine D, 19-oxazolyl-10,11-dehydroemetine D, 9,10-dehydroemetine B, 9,10-dehydroemetine D, as well as their analogues and derivatives.

In more specific embodiments proposed in the present invention the pharmaceutical compositions pharmaceutical compositions according to the invention include at least one cyclodextrin. Used herein, the term "cyclodextrin" refers to the value covering both native cyclodextrins (e.g., α-, β-, γ-cyclodextrins and the like)and derivatives of native cyclodextrins, such as hydroxyalkyl the bathrooms cyclodextrins (e.g., gidroksietilirovanny and hydroxypropylamino cyclodextrins), sulfoalkylation cyclodextrins (e.g., sulforaphane and sulfobetaine cyclodextrins), and other chemical derivatives of cyclodextrins. In particular embodiments, the cyclodextrin is hydroxyalkyl-β-cyclodextrin, and in still more specific embodiment - hydroxypropyl-β-cyclodextrin. Even more specific embodiments in which the carrier comprises hydroxypropyl-β-cyclodextrin, includes cases when the hydroxypropyl-β-cyclodextrin has a degree of substitution comprising at least about 4.6%, and more specifically the degree of substitution, which is at least approximately 6.5%. More specific embodiments of the pharmaceutical compositions according to the invention are those in which the carrier comprises hydroxypropyl-β-cyclodextrin having a degree of substitution, which is approximately 4.6% and about 6.5%. In other embodiments of the present invention, the cyclodextrin is sulfopropyl-β-cyclodextrin.

In one of the embodiments epothilone used in the pharmaceutical compositions is epothilone D. In a more specific embodiment of the pharmaceutical composition according to the invention contains epothilone D and hydroxyalkyl-β-qi is lodenstein, and in still more specific embodiment - hydroxypropyl-β-cyclodextrin. In even more specific embodiments pharmaceutical compositions containing epothilone D and hydroxypropyl-β-cyclodextrin specified hydroxypropyl-β-cyclodextrin has a degree of substitution of approximately component of at least 4.6%, and more specifically the degree of substitution of approximately component of at least 6.5 percent. More specific embodiments of the pharmaceutical compositions according to the invention are those in which epothilone is epothilone D, and the carrier includes hydroxypropyl-β-cyclodextrin having a degree of substitution, which is approximately 4.6% and about 6.5%. Among the pharmaceutical compositions according to the invention, which includes epothilone D and hydroxypropyl-β-cyclodextrin, more specific embodiments include compositions in which epothilone D and hydroxypropyl-β-cyclodextrin is combined in a weight ratio of approximately 10 mg epothilone D and approximately 0.4 g hydroxypropyl-β-cyclodextrin.

In other embodiments of the present invention epothilone and cyclodextrin presented in lyophilized form, which in some embodiments is a "residue" of the lyophilisate. Such embodiments can be obtained with the aid of the translated materials and technologies, which are well known to the specialists in the field of pharmacy (Gennaro 2000). In one of specific embodiments epothilone and hydroxyalkyl-β-cyclodextrin unite in water-ethanol solution, which is then subjected to lyophilization. More specific embodiments include those in which epothilone D and hydroxpropyl-β-cyclodextrin unite in water-ethanol solution, which is then subjected to lyophilization. In even more specific embodiments, about 10 mg epothilone D and about 0.4 g hydroxpropyl-β-cyclodextrin unite in 60%solution of a tert-butanol - water, which is then subjected to lyophilization. In even more specific embodiments, about 10 mg epothilone D and about 0.4 g hydroxpropyl-β-cyclodextrin unite in 60%solution of a tert-butanol - water, which further lyophilizer, getting a "sludge".

Unexpectedly discovered that the above lyophilizate proposed in the present invention possess a very acceptable solubility in pharmaceutically applicable carrier, in particular in pharmaceutically applicable carrier, which are considered more appropriate media than the media containing the drug CREMAPHOR®. Thus, in another aspect, the present invention offers applicable pharmaceutical composition, the content is the following epothilone and hydroxyalkyl-β-cyclodextrin, as described above, in a pharmaceutically acceptable carrier that is free from any substantial amount of the drug CREMAPHOR®. A more specific embodiment of the present invention include pharmaceutical compositions resulting from the recovery of freeze-dried as described above, using a mixture comprising water, ethanol and at least one glycol. In the present description, the term "glycol" refers to the fact that the substance includes such molecules as propylene glycol, propylene glycol-400, polyoxyethylene-sorbitan-monooleate (commercially available under the trade name TWEEN 80) and related oxygendemand hydrocarbons. Of course, it is understood that the glycols of different chain length and different molecular weights (e.g., polyethylene glycol-1000, other TWEEN-compounds) are also included in the scope of this definition. For therapeutic purposes, water used for recovery of the mixture is a water purity, which corresponds to one of the solutions for injection.

In some embodiments, the mixture used to restore the freeze-dried, includes water, ethanol and polyoxyethylene-sorbitan-monooleate (TWEEN 80). In more specific embodiments of this mixture includes at least about 10% water (% volume/volume), more particularly by at least about 40% water (% volume/volume), and even more preferably at least about 60% water (% volume/volume). In some embodiments, the mixture used to restore the freeze-dried, comprises approximately 60% water and about 70% water (% volume/volume), more specifically from about 60% water and up to about 65% water (% volume/volume), and in a particular embodiment, approximately 62.5% of water (% volume/volume).

In some embodiments the mixture used to restore the lyophilisate containing water in the above-described concentrations, this mixture is optionally include TWEEN 80 at a concentration of approximately 25% (% volume/volume) and about 10% (% volume/volume), more specifically between approximately 20% (% volume/volume) and about 15% (% volume/volume). In one of specific embodiments of TWEEN 80 provided at a concentration of approximately component of 15% (% volume/volume).

In some embodiments described above mixture used to restore the freeze-dried, includes water and TWEEN 80 in the above-described concentrations, balanced blend of ethanol. Examples of relevant regenerating mixtures include water/ethanol/TWEEN 80 concentration (% volume/volume) of order 10/65/25, 20/55/25, 40/35/25, 62,5/12,5/25, 60/20/20 and 60/25/15. In another embodiment healing mixture is a mixture of propylene glycol/ethanol/water in a ratio of 40/10/50 (% volume/volume).

The above restore mixtures are suitable for use is any lyophilisate, formed using any of the combinations epothilone (epothilone) and hydroxyalkyl-β-cyclodextrin or sulfoalkyl-β-cyclodextrin, as described above. More specific embodiments include compositions obtained in the recovery of lyophilisate comprising epothilone D. Still more specific embodiments include compositions that result from the recovery of freeze-dried, in which epothilone is epothilone D, and hydroxyalkyl-β-cyclodextrin is a hydroxypropyl-β-cyclodextrin. Still more specific embodiments include compositions that result from the recovery of freeze-dried, in which epothilone is epothilone D, and sulfoalkyl-β-cyclodextrin is sulfolobus-β-cyclodextrin.

Some embodiments according to the invention include compositions, resulting in the recovery of freeze-dried, formed approximately 10 mg epothilone D and about 0.4 g of hydroxypropyl-β-cyclodextrin, which is mixed with 60% solution in tert-butanol - water and reducing the mixture, which includes a combination of water/ethanol/TWEEN 80 (% volume/volume) in a ratio of about 10/65/25, 20/55/25, 40/35/25, 62,5/12,5/25, 60/20/20 or 60/25/15. More specific embodiment is connected with the composition, receiving the I in the recovery of freeze-dried, educated about 10 mg epothilone D and about 0.4 g of hydroxypropyl-β-cyclodextrin mixed with 60% solution in tert-butanol - water and reducing the mixture comprising a combination of water/ethanol/TWEEN 80 (% volume/volume) in a ratio of about 62,5/12,5/25, 60/20/20 or 60/25/15. Yet more specific embodiment is a composition resulting from the recovery of freeze-dried, formed approximately 10 mg epothilone D and about 0.4 g of hydroxypropyl-β-cyclodextrin mixed with 60% solution in tert-butanol - water and reducing the mixture comprising a combination of water/ethanol/TWEEN 80 (% volume/volume) in a ratio of about 62,5/12,5/25.

In another embodiment of the present invention epothilone used in the pharmaceutical compositions is a 9,10-dehydroemetine D. In a more specific embodiment of the present invention the pharmaceutical composition comprises 9,10-dehydroemetine D and hydroxyalkyl-β-cyclodextrin, and in a more specific embodiment - hydroxypropyl-β-cyclodextrin. In more specific embodiments of the present invention pharmaceutical compositions include 9,10-dehydroemetine D and hydroxypropyl-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin has a degree of substitution of at least component of approximately 4.6%, and more spiral is but the degree of substitution, at least component of approximately 6.5%. Another specific embodiment of the pharmaceutical compositions according to the invention are those compositions in which epothilone represents a 9,10-dehydroemetine D, and the carrier includes hydroxypropyl-β-cyclodextrin having a degree of substitution, which is approximately 4.6% and about 6.5%.

In other embodiments of the present invention epothilone offered as a concentrate for injection, comprising epothilone dissolved in a pharmaceutically acceptable carrier, and concentrate for injection is diluted immediately prior to introduction. In particular embodiments of the present invention, the pharmaceutically acceptable carrier is used for concentrate for injection, including alcohol, for example ethanol. In additional specific embodiments of the present invention, the pharmaceutically acceptable carrier used to obtain the concentrate for injection, includes alcohol together with a glycol, such as propylene glycol. In specific embodiments the concentrate for injection includes 9,10-dehydroemetine D, dissolved in a concentration of between approximately 0.1 mg/ml and about 50 mg/ml in a pharmaceutically acceptable carrier comprising ethanol and propylene glycol. In a more specific voploscheni the x concentrate for injection includes 9,10-dehydroemetine D, dissolved in a concentration of between approximately 0.1 mg/ml and about 50 mg/ml in a pharmaceutically acceptable carrier, comprising about 50-90% (vol/vol) ethanol, and about 10-50% (volume/volume) of propylene glycol. In more specific embodiments the concentrate for injection includes 9,10-dehydroemetine D, dissolved in a concentration of between approximately 0.1 mg/ml and about 50 mg/ml in a pharmaceutically acceptable carrier, comprising approximately 70% (volume/volume) of ethanol and approximately 30% (volume/volume) of propylene glycol. In even more specific embodiments the concentrate for injection includes 9,10-dehydroemetine D, dissolved in a concentration of between about 1 mg/ml and about 50 mg/ml in a pharmaceutically acceptable carrier, comprising approximately 70% (volume/volume) of ethanol and approximately 30% (volume/volume) of propylene glycol. In a more specific embodiment the concentrate for injection consists of 9,10-dehydroemetine D, dissolved at a concentration of approximately 5 mg/ml in a pharmaceutically acceptable carrier, consisting of approximately 70% (vol/vol) ethanol, and about 30% (volume/volume) of propylene glycol.

The above concentrate for injection before the introduction diluted in appropriate solvents. In certain embodiments of the present invented the I such solvents include one or more cyclodextrins, selected from the above list and dissolved in water for injection. In particular embodiments of the present invention, such a solvent includes hydroxyalkyl-β-cyclodextrin dissolved in water for injection. In more specific embodiments of the present invention, such a solvent includes hydroxypropyl-β-cyclodextrin dissolved in water for injection at a concentration of approximately 10 mg/ml to about 1000 mg/ml In even more specific embodiments of the present invention, the solvent comprises hydroxypropyl-β-cyclodextrin dissolved in water for injection at a concentration of approximately 50 mg/ml and about 500 mg/ml In even more specific embodiments of the present invention, the solvent comprises hydroxypropyl-β-cyclodextrin dissolved in water for injection at a concentration of from about 50 mg/ml and about 250 mg/ml In even more specific embodiments of the present invention, the solvent comprises hydroxypropyl-β-cyclodextrin dissolved in water for injection at a concentration of approximately component of 133 mg/ml In certain embodiments of the present invention the concentrate for injection is dissolved in a solvent, producing approximately 2-fold (volume/volume) and about 20-fold (volume/volume) rubbable the Oia in the solvent. In specific embodiments of the present invention produce approximately 5-fold (volume/volume) to about 15-fold (vol/vol) dilution of the concentrate for injection in a solvent. In even more specific embodiments of the present invention the concentrate for injection diluted in the solvent is about 10-fold (volume/volume).

Thus, in certain embodiments according to the invention proposed pharmaceutical composition comprising epothilone dissolved in a pharmaceutically acceptable carrier, where the carrier comprises an alcohol, a glycol and a cyclodextrin. In specific embodiments of the proposed invention the pharmaceutical composition comprising 9,10-dehydroemetine dissolved in a pharmaceutically acceptable carrier, where the carrier comprises an alcohol, a glycol and a cyclodextrin. In more specific embodiments in the invention proposed pharmaceutical composition comprising 9,10-dehydroemetine dissolved in a pharmaceutically acceptable carrier, where the carrier comprises ethanol, propylene glycol and hydroxypropyl-β-cyclodextrin. In even more specific embodiments in the invention proposed pharmaceutical composition consisting of 9,10-dehydroemetine dissolved in a pharmaceutically acceptable carrier, where the carrier in the core the main consists of ethanol, propylene glycol and hydroxypropyl-β-cyclodextrin. In even more specific embodiments in the invention proposed pharmaceutical composition consisting of about 0.5 mg/ml 9,10-dehydroemetine dissolved in a pharmaceutically acceptable carrier, where the carrier mainly consists of approximately 7% of ethanol, about 3% propylene glycol and about 12% (volume/volume) hydroxypropyl-β-cyclodextrin in water for injection.

Not wishing to be bound by any particular theory, the inventors would like to note, however, that the efficiency of the combination of hydroxypropyl-β-cyclodextrine freeze-dried in one of reducing water mixtures described above for the formation of therapeutically effective compositions comparable with the formation of a complex between hydroxyalkyl-β-cyclodextrin and epothilones in lyophilisate and more preferably with the inclusion complex (adduct) between hydroxyalkyl-β-cyclodextrin and epothilones in the lyophilisate. Thus, in some embodiments of the present invention includes complexes epothilone D-hydroxypropyl-β-cyclodextrin, and more specifically the inclusion complexes epothilone D-hydroxypropyl-β-cyclodextrin. The above complexes and inclusion complexes can be prepared or in the form of a lyophilisate, and/or in the form of vosstanovlenie the solution.

Therapeutic use of the compositions according to the invention

Described herein compositions are effective for delivery of a therapeutically effective amount epothilone to ensure mediated epothilones of the disease, i.e. disease introduction epothilone the patient such as a mammal, and more preferably to human, causing a beneficial effect. Thus, the present invention also includes methods of treatment mediated by epothilones diseases. Examples of indirect epothilones diseases include, but are not limited to, hyperproliferative diseases, such as malignant tumors, including malignant tumors of the head and neck which include tumors of the head, neck, nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx (podporucznik), salivary glands and paraganglioma; malignant tumor of the liver and biliary tree, particularly hepatocellular carcinoma; malignant tumor of the intestine, in particular cancer of the colon and rectum; ovarian cancer; small cell and non-small cell lung cancer; breast cancer, sarcomas, such as fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, leiomyosarcoma, neurofibro the sarcoma, osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft tissue sarcoma; neoplasma Central nervous system, in particular malignant brain tumors; lymphoma, such as Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, associated with mucosal lymphoma lymphoid tissue lymphoma cells of the cerebral cortex, both lymphoma B-cell, Burkitt's lymphoma and both anaplastic lymphoma T-cells. Clinically, the application of the methods and compositions described here (in cases where they are applicable) will lead to a decrease in the size or number of malignant tumors and/or to reduce the associated symptoms. In relation to the pathology of the application of the methods and compositions described here will lead to the emergence associated with abnormal response, such as inhibition of proliferation of malignant cells, reducing the size of a malignant neoplasm or tumor, prevention of further metastasis and inhibition of tumor angiogenesis.

The methods and compositions according to the invention can be used in combination therapy. In other words, compounds and compositions according to the invention can be introduced simultaneously, before or after one or more other therapeutics is their or medical procedures. If there is a specific combination of treatments and therapeutic techniques in the combined mode, it is necessary to consider the comparability of the different types of treatment and/or therapeutic techniques with therapeutic effect, which seek to achieve. Thus, the compositions described herein can be combined with other treatments such as surgical treatment and/or radiation. Described herein compositions can also be used in combination with other oncolytic agents such as 5-fluorouracil or 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-citizen (which is sold under the trade name XELODAV (Roche). Illustrative examples of other anti-cancer agents include, but are not limited, however, by them, (i) alkylating drugs such as mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide; (ii) antimetabolites, such as methotrexate; (iii) agents, stabilizing microtubules, such as vinblastine, paclitaxel, docetaxel, and discodermolide; (iv) inhibitors of angiogenesis; and (v) cytotoxic antibiotics such as doxorubicin (adriamycin), bleomycin, and mitomycin. Illustrative examples of other anti-cancer treatments include (i) surgery; (ii) radiotherapy; and (iii) photodynamic therapy.

In another embodiment of the compounds and compositions according subramaniyapuram in combination with an agent or procedure, reducing potential side effects such as diarrhea, nausea and vomiting that may be caused by compounds or compositions according to the invention. Diarrhea can be treated with antidiarrheal agents, such as opioids (eg, codeine, Diphenoxylate, Difenoxin and loperamide (loeramide), bismuth, subsalicylate and octreotide. Effects of nausea and vomiting can be removed antiemetic means, such as dexamethasone, metoclopramide, diphenylhydramine, diazepam, ondansetron, prochlorperazine, tietilperazin and dronabinol.

In another aspect according to the invention the composition according to the invention are used to treat non-cancer diseases characterized by cellular hyperproliferation. Illustrative examples of such diseases include, but are not limited to, atrophic gastritis, inflammatory hemolytic anemia, graft rejection, inflammatory neutropenia, bullous pemphigoid, gluten enteropathy (celiac disease), demyelinizing neuropathy, dermatomyositis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), multiple sclerosis, myocarditis, myositis, nasal polyps, chronic sinusitis, common bladderwort, primary glomerulonephritis, psoriasis, postoperative adhesions, stenosis or restenosis, inflammation of the sclera, scleral the RMU, eczema (including atopic dermatitis, irritant dermatitis, allergic dermatitis), periodontal disease (i.e. periodontitis), polycystic kidney disease and diabetes type I. Other examples include vasculitis (e.g., giant cell arteritis diagnostics (temporal arteritis diagnostics, Takayasu (syndrome), Takayasu's), Nowotny polyarteritis, allergic anghit and Wegener (syndrome Cerca-Strauss), syndrome overlay inflammation of many vessels, allergic (hypersensitive) vasculitis (morbus Shenleyn's disease), serum sickness, vasculitis caused by the drug, infectious vasculitis, neoplastic vasculitis, vasculitis associated with connective tissue diseases, vasculitis associated with congenital deficiencies of the complement system, Wegener's granulomatosis, a disease Kawasaki, vasculitis of the Central nervous system, Buerger's disease (thromboangiitis obliterans) and systemic sclerosis); diseases of the gastrointestinal tract (e.g., pancreatitis, Crohn's disease, ulcerative colitis, ulcerative proctitis, primary sclerosing Holandia, benign obstruction of any nature, including idiopathic (for example, blockage of the bile ducts, esophagus, duodenum, small intestine, or rectum); respiratory disease (e.g. asthma, hypercholesterol the initial pneumonitis, asbestosis, silicosis and other forms of pneumoconiosis, chronic bronchitis and chronic obstructive disease of the Airways); diseases of the nasolacrimal duct (for example, blockage of all kinds, including idiopathic); and diseases Evstafieva pipes (for example, blockage of all kinds, including idiopathic).

The method of treatment of such diseases includes introduction to a subject suffering from such diseases, a therapeutically effective amount of the compounds according to the invention. If necessary, the method can be played back repeatedly. The methods according to the invention described in more detail below, with reference to three illustrative non-cancer diseases.

In one embodiments of the compounds according to the invention are used to treat psoriasis, a condition characterized by cellular hyperproliferative activity of keratinocytes that grow on the skin, forming a protuberance in the form of scaly lesions. The method includes introducing to a subject suffering from psoriasis, a therapeutically effective amount of the compounds according to the invention. If necessary, the method can be replayed or for repair of lesions, or to reduce the number of affected areas or extent of injury. Clinically, the application of the method will decrease once the development or the number of skin lesions, reduction of skin symptoms (pain, burning and bleeding skin) and/or to reduce associated symptoms (e.g., redness, fever and swelling of the joints, diarrhoea, pain in the abdomen). In relation to the pathology of the application of the method will cause one of the following reactions: inhibition of proliferation of keratinocytes, reduce inflammation of the skin (reflected, for example, on attractively and growth factors, presentation of antigens, the formation of the products of reactive oxygen species and matrix metalloproteinases) and inhibition of angiogenesis in the skin.

In another aspect, compounds according to the invention is used to treat multiple sclerosis, a condition characterized by progressive demyelination in the brain. Although the exact mechanisms involved in the loss of myelin, has not yet been clarified, but it is known that there is an increase in proliferation of astrocytes and their accumulation in areas of myelin destruction. In these areas there is microforaminotomy activity and increased proteolytic activity, which is at least partially responsible for the degradation of the myelin sheath. The method includes the introduction of a therapeutically effective amount of the compounds according to the invention to a subject suffering from multiple sclerosis. In case of necessity, with whom persons may be reproduced, reused, or for inhibition of proliferation of astrocytes, and/or reduce the severity of the loss of motor function, and/or for preventing or reducing chronic progression of the disease. Clinically, the application of the method will lead to the reduction of visual symptoms (loss of vision, diplopia), the reduction of gait disorders (weakness, axial instability, loss of sensation, spasticity, hyperreflexia, loss of physical dexterity), a decrease in dysfunction of the upper extremities (weakness, spasticity, sensory loss), reduction of bladder dysfunction (urgent urination, incontinence, hesitancy, incomplete emptying), depression, emotional lability, and slowing the deterioration of cognitive functions. In relation to the pathology of the application of the method will lead to a reduction of one or more of such events as the loss of myelin, the destruction of the blood-brain barrier, allocatedata infiltration of mononuclear cells, immunological abnormalities, the formation of the glial scar and proliferation of astrocytes, the production of metalloproteinases and slow conduction.

In another aspect, the compositions according to the invention is used to treat rheumatoid arthritis, chronic relapsing Multisystem inflammatory disease that is characterized by the fact that sometimes results is it to destruction and ankylosis of affected joints. Rheumatoid arthritis is characterized by a significant thickening of the synovial membrane, which forms the villous protrusions penetrating into the joint space, a multi-layer sheath of synoviocytes (proliferation synoviocytes), infiltration of the synovial membranes of white blood cells (macrophages, lymphocytes, plasma cells and lymphoid follicles; the so-called "inflammatory synovitis") and deposition of fibrin, necrotic cells within the synovium. Tissue, formed as a result of this process, called pannus, and ultimately the pannus grows, filling the space of the joint. The formation of pannus accompanied by the development of an extensive network of newly formed blood vessels during angiogenesis, which is a common phenomenon when synovitis. The release of digestive enzymes (matrix metalloproteinases (e.g., collagenase, stromelysin)) and other mediators of inflammation (e.g., peroxide, superoxide, lysosomal enzymes and products of arachidonic acid metabolism) from the cells of the pannus tissue leads to progressive destruction process of cartilage tissue. Pannus invasive articular cartilage that leads to erosion and fragmentation of the cartilage. Ultimately, there is erosion of the subchondral bone with fibrous, ankylo the om and in the end the ankylosis of the bones involved in the joint.

In another aspect, the compositions according to the invention used for the treatment of atherosclerosis and/or restenosis, particularly in patients who have limited mobility of joints can be treated with endovascular stent. Atherosclerosis is a chronic vascular lesions, in which some of the normal cells vascular smooth muscle (vascular smooth muscle cells, "VSMC") in the arterial wall, which are usually in control of vascular tone, regulating blood flow, change their nature, developing a behavior similar to those of the "recoveredby cells. Such VSMC become abnormally proliferating secretion of substances (growth factors, enzymes, tissue degradation and other proteins)that allow them to envirovet, giving you the ability to penetrate into the interior of blood vessels, blocking blood flow and creating the conditions under which the vessel becomes abnormally prone to a full blockade under the action of local thrombus formed in the vessel. Restenosis, recurrent stenosis or blockage of an artery after corrective procedures, is an accelerated form of atherosclerosis. Alternatively, the compositions according to the invention can be used to provide covering stent layer comprising a therapeutically effective amount epothilone, to establish the stent in the patient with the court of a patient, suffering from atherosclerosis. Methods of coating the stent connection described, for example, in U.S. patent No. 6156373 and 6120847. Clinically the use according to the invention will lead to the manifestation of one or more of the following effects: (i) the increase in arterial blood flow; (ii) decrease the severity of clinical signs of disease; (iii) to reduce the frequency of restenosis; or (iv) prevention/attenuation of chronic progression of atherosclerosis. In relation to the pathology of the application according to the invention will lead to at least one of the following effects at the site of stent implantation: (i) reduction of the inflammatory response, (ii) inhibition of secretion by cells VSMC matrix metalloproteinases; (iii) inhibition of accumulation of cells vascular smooth muscle; and (iv) inhibition dedifferentiated phenotype of VSMC cells.

The levels and the introduction of dosages

In one of the embodiments of the compositions according to the invention effective to ensure levels of dosages epothilone, in particular epothilone D, or epothilone selected from the group consisting of epothilone A, epothilone B, epothilone C, 4-desmethylation D, asiaoceania B, 21-aminonaphthalene B, 9,10-dehydroemetine D, 9,10-degidro 26 trifter-epothilone D, 11-hydroxyapatite D, 19-oxazolidinone D, 10,11-dehydroemetine D, 19-oxazolyl-10,11-dehydroemetine D, 9,10-dehydroabietyl is on B, 9,10-dehydroemetine D, 26 trifter-9,10-dehydroemetine D and 26 trifter-9,10-dehydroemetine B drug in the form of input to a subject suffering from a malignant tumor or cancer disease, characterized by cell proliferation, approximately from 0.1 mg/m2and approximately 200 mg/m2and can be introduced in the form of a bolus (using any suitable route of administration, including oral or intravenous) or as a continuous infusion (e.g., one-hour, three-hour, six-hour, 24-hour, 48-hour or 72-hour) weekly, biweekly, or on demand, every three weeks. It should be understood, however, that the selection of specific levels of dosage for a given patient will depend on many different factors. Such factors include the activity is specifically used for the connection; the age of the patient, the weight of his body, General health, gender, and subjective preferences in diet, time and route of administration, and rate of excretion of drugs; whether combined treatment with medicines; and the degree of severity of the condition to be treated.

In another embodiment, the dosage levels of approximately 10 mg/m2and approximately 150 mg/m2preferably from about 10 the g/m 2and approximately 75 mg/m2and more preferably from about 15 mg/m2and approximately 50 mg/m2in three weeks time, as needed and depending upon tolerability. In another embodiment, the dosage levels are from about 1 mg and about 150 mg/m2preferably from approximately 10 mg/m2and approximately 75 mg/m2and more preferably from about 25 mg/m2and approximately 50 mg/m2in two weeks time, as needed and depending upon tolerability. In another embodiment, the dosage levels of approximately 1 mg/m2and approximately 100 mg/m2preferably from about 5 mg/m2and approximately 50 mg/m2and more preferably from approximately 10 mg/m2and approximately 25 mg/m2once a week , if necessary and depending upon tolerability. In another embodiment, the dosage levels are from about 0.1 mg/m2and approximately 25 mg/m2preferably from about 0.5 mg/m2and approximately 15 mg/m2and more preferably from about 1 mg/m2and approximately 10 mg/m2daily, as needed and depending upon tolerability.

In another embodiment of the levels of the dosage amount is from about 0.1 mg/m 2and approximately 50 mg/m2preferably from about 0.1 mg/m2and approximately 25 mg/m2and more preferably from about 0.5 mg/m2and approximately 25 mg/m2every three weeks, as needed and depending upon tolerability.

In order to ensure that acceptable levels of toxicity has not been exceeded, monitored for side effects, including peripheral neuropathy, which may as such be manifest as feelings of numbness in the lower extremities, dizziness and others. Monitoring should be conducted after a certain period of time after injection (infusion); usually, the lower the dose, the longer the interval between the introduction and monitoring. For example, if the dose level from 9 to 60 mg/m2infusion monitoring usually start to spend on the 5th day and continue until the 15th day; however, at higher doses, such as from 90 to 120 mg/m2monitoring should begin on the day after the infusion. Other side effects may include nausea and vomiting, fatigue, rash, alopecia, and changes in key indicators of the vital functions, such as orthostatic hypotension. Should be monitored and mielosupression, although usually mielosupression under the action of this drug is about money not watching. Myelosuppression as such can manifest as anemia, neutropenia, thrombocytopenia and other things.

Pharmacokinetics, generally favorable. Pharmacokinetics is dose-dependent, and the curve of the dependence of concentration on time of launch, AUC, at dosages of from 9 to 150 mg/m2has a linear character. The half-life of epothilone D had an average value of about 9.6 ± 2.2 hours, and distribution volume (Vz) is 172 ± 74 l, which indicates a good level of penetration of drugs. This average is slightly higher than the same parameters of paclitaxel, which are 140 ± 70 L. These pharmacokinetic parameters are not changed when the second infusion compared with the first infusion.

Efficacy of medicinal product can be subjected to monitoring by conducting a quantitative assessment of the formation of bundles of microtubules in interphase cells. This is considered an acceptable indicator of the effectiveness of agents, stabilizing microtubules, such as paclitaxel or epothilone. The formation of bundles of microtubules can be easily measured by immunofluorescence assay method or by the method of Western blotting. Usually with this definition the patient selected whole blood and to assess the formation of bundles of microtubules from it produce mononuclear cells (PBMC). Significant values which is of bundles of microtubules receive at such low doses, as 18 mg/m2and with the dose increasing this value increases. At 120 mg/m2almost all of microtubules formed in the beams.

EXAMPLES

The following examples, to help professionals in this field, illustrate certain aspects of the present invention to facilitate its implementation. These examples are in no way intended to limit the scope covered by the present invention.

EXAMPLE 1

The formation of lyophilisate epothilone D-hydroxypropyl-β-cyclodextrin

A combination of ten milligrams ("mg") epothilone D and 0.4 grams ("g") hydroxypropyl-β-cyclodextrin ("HPβCD) was dissolved in 60% solution of tert-butanol in water to obtain 1 milliliter ("ml") solution. Received a second solution containing ten mg epothilone D and ten mg of mannitol dissolved in 60% solution of tert-butanol in water. Also received a third solution containing ten mg epothilone D and ten mg of mannitol dissolved in 60% solution of tert-butanol in water. Solutions of compositions containing ten mg/ml epothilone D, was poured into a 8-ml glass vials for lyophilization.

Each of the three solutions liofilizirovanny using commercially available apparatus for freeze-drying, with excellent education lyophilic sediment. Freeze precipitate containing hydroxypropyl-β-cyclodextrin, seemed to be the more solid and less smooth, than the other two sediment.

EXAMPLE 2

The recovery of freeze-dried epothilone D-hydroxypropyl-β-cyclodextrin and solubility in normal saline

The solubility of liofilizatow, obtained as described in section 0, was determined in various regenerating solvents at ambient temperatures (i.e. at temperatures between approximately 20°and approximately 25°C). Approximately one mg epothilone D was placed in a glass tube. In test tubes was doing a serial dilution of regenerating solution, getting the solutions of about 100 microliters ("μl"), 900 ml and 9.0 ml. After each addition of the reducing solution, the resulting solution was intensively stirred for thirty seconds. By dissolving the lyophilisate was determined solubility upon dilution with normal saline solution.

Only those lyophilizate, which were obtained using hydroxypropyl-β-cyclodextrin, as it turned out, have satisfactory solubility (i.e. solubility, approximately more than one mg/ml). The results obtained when using different reducing solvents shown in the table. ("Wfl" means water, "PG" means propylene glycol,"EtOH" means ethanol, and "PEG400" means polyethylene glycol-400. The symbol "D" indicates races is varenie; and the letter "P" means the precipitation.)

Regenerating Solvent (% volume/volume)Solubility,S(mg/ml)Solubility after dilution with normal saline 1:10/1:20/1:100
WfI/EtOH/Tween-80
10/65/251 ≤ S < 10D//
20/55/251 ≤ S < 10D//
40/35/251 ≤ S < 10D//
62,5/12,5/251 ≤ S < 10D//
60/20/202 ≤ S < 10D/D/
60/25/15S ≥ 10D/D/D
60/35/5S ≥ 10P//
PG/EtOH/Wfl
40/10/50 0,1 ≤ S < 1,0D//

The best results were obtained using a three-component solvent system: WfI/EtOH/Tween-80 = 60/25/15 (% volume/volume), which was 100-fold diluted in normal saline solution, not watching this sedimentation. Compositions in which the amount of Tween-80 was more than approximately 20% by volume or less than approximately 10% by volume, had a less than satisfactory properties solubility.

EXAMPLE 3

Oral activity epothilone D

Three test groups, each of which consisted of five rats were injected either intravenously dose epothilone D (10 mg/kg)or oral dose epothilone D 20 mg/kg or oral dose epothilone D 40 mg/kg blood Samples were collected from rats after a 24-hour period after administration of the dosage. Absolute bioavailability when ingested doses of 20 mg/kg and 40 mg/kg have been changed accordingly in the range of 7-10% and 10-20%. The half-life was 8 hours for groups of intravenous and 5.6-6 hours for groups of oral administration. As expected, the value of Cmaxturned out to be much higher, and the clearance is faster when intravenous dosages.

In a similar study, three dog breed Beagle was intravenously injected a single dose of 2 mg/kg aptilo the and D, and then, at intervals of one week, after the probe was administered oral dose of 2 mg/kg and 4 mg/kg epothilone D in the same medium, which when administered intravenously (30% propylene glycol, 20% Chremophor® and 50% ethanol), diluted 1:10. Blood samples were collected before dose, at the end of infusione dose or immediately after administration of the oral dose and 48 hours after administration of the oral dose. Monitored hematological and chemical parameters of the blood, so that before the introduction of the next dosage to make sure that the animals have enough time to recover (recover). In dogs, which was intravenously injected epothilone D, manifested a notable hypersensitivity reactions, however, oral administration tolerated them very well.

Obtained from dog plasma samples was studied using LC/MS/MS analysis, ratified in the region from 2 ng/ml to 500 ng/ml, and the obtained data were analyzed using version 4.1.1 computer program Kinetica (InnaPhase Corporation, Philadelphia, PA). Pharmacokinetic parameters were calculated using decompartmentalizing analysis and simulated using dvukhkomponentnoi extravascular model. The calculated AUC for oral doses, comprising 2 mg/kg and 4 mg/kg, was 9,856 ± 3,879 ng*h/ml and 15,486 ± 8,060 ng*h/ml, respectively, and biotester oral administration was > 50%. The mean half-life after oral administration was 9,13 hours, while the half-life after oral administration of 4 mg/kg was slightly higher (10,9 hours instead of 6.4 hours - time-life is obtained at a dose of 2 mg/kg). The average clearance when administered orally was 0,27 l/h/kg, Vss= 2.57 m l/kg, and MRT = 9,81 hours. Indicators clearance, Vss, MRT time and half-life were basically the same, what was observed with intravenous drugs.

The data obtained showed that epothilone D has good bioavailability when administered orally, suggesting that oral administration in patients with malignancy or patients suffering from other hyperproliferative conditions or diseases, is quite feasible.

EXAMPLE 4

Composition 9,10-dehydroemetine D

Concentrate for injection was obtained by dissolvingTRANS-9,10-dehydroemetine D at a concentration of 5 mg/ml in 70% (vol/vol) ethanol and 30% (volume/volume) propylene glycol. Concentrate for injection (2 ml ± 0.2 ml) was transferred into a sterile 5-ml glass serum vials type I (neck 22 mm), closed 20-millimeter coated with Teflon lids and the lid was sealed by crimping the caps on top of the white lacquered IU alicebraga clamp. In the process of filling the bottles with a concentrate for injection to displace the air used sterile dry nitrogen.

Diluted drug was prepared by dissolving hydroxypropyl-β-cyclodextrin at a concentration of 133 mg/ml in water for injection. The solvent (18 ml) was aseptically poured into 20-ml glass serum vials type I (neck 22 mm), closed 20-millimeter coated with Teflon lids and the lid was sealed by crimping the caps on top of the white lacquered metal clip.

Parenteral dosage formTRANS-9,10-dehydroemetine D was obtained by taking 2 ml concentrate for injection and adding them into the vial containing 18 ml of solvent. The resulting solution containing 0.5 mg/mlTRANS-9,10-dehydroemetine D, gently stirred. Received parenteral dosage form can optionally be dissolved in a physiological solution (0.9% NaCl, W/V)to obtain solutions for injection that contains theTRANS-9,10-dehydroemetine D in smaller concentrations. Typically, these breeding range from about 0.05 mg/ml and about 0.1 mg/ml, however, these limits may be revised, depending on the specific therapeutic needs.

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1. Pharmaceutical composition for oral administration comprising 9,10-dehydroemetine together the pharmaceutically acceptable carrier, in which 9,10-dehydroemetine presented in a therapeutically acceptable concentration for administration to a patient.

2. The pharmaceutical composition according to claim 1, in which 9,10-dehydroemetine represents a 9,10-degidro-12,13 - desoxyepothilone.

3. The pharmaceutical composition according to claim 1, in which 9,10-dehydroemetine represents a 9,10-dehydroemetine D.

4. The pharmaceutical composition according to claim 1, in which 9,10-dehydroemetine is a TRANS-9,10-dehydroemetine D.

5. The pharmaceutical composition according to claim 1, which includes at least one cyclodextrin.

6. The pharmaceutical composition according to claim 5, in which the cyclodextrin is selected from the group consisting of β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfopropyl-β-cyclodextrin.

7. The pharmaceutical composition according to claim 6, in which the cyclodextrin is a hydroxypropyl-β-cyclodextrin.

8. The pharmaceutical composition according to claim 5, which additionally comprises a glycol.

9. The pharmaceutical composition of claim 8, in which the glycol is a glycol.

10. The pharmaceutical composition according to claim 5, which additionally comprises ethanol.

11. The pharmaceutical composition of claim 8 which additionally includes ethanol.

12. The pharmaceutical composition according to claim 1, in which the pharmaceutically acceptable carries the l includes cyclodextrin, ethanol, propylene glycol.

13. Pharmaceutical composition for oral administration comprising TRANS-9,10-dehydroemetine D in a pharmaceutically acceptable carrier, where the pharmaceutically acceptable carrier comprises hydroxypropyl-β-cyclodextrin, ethanol and propylene glycol.

14. The pharmaceutical composition according to item 13, in which the pharmaceutically acceptable carrier comprises hydroxypropyl-β-cyclodextrin in the amount of approximately between 5% volume/volume and about 20% volume/volume ethanol in the amount of approximately between 5% volume/volume and about 20% volume/volume and the propylene glycol in the amount of approximately between 1% volume/volume and approximately 10% volume/volume.

15. The pharmaceutical composition according to item 13, in which the pharmaceutically acceptable carrier comprises hydroxypropyl-β-cyclodextrin in an amount of about 12% volume/volume ethanol in the amount of approximately 7% volume/volume and the propylene glycol in the amount of approximately 3% volume/volume.

16. The pharmaceutical composition according to item 13, in which the pharmaceutically acceptable carrier consists mainly of hydroxypropyl-β-cyclodextrin in an amount of about 12% volume/volume ethanol in the amount sostavlyajushie is approximately 7% volume/volume, and propylene glycol in the amount of approximately 3% volume/volume in water.

17. Concentrate for injection, including 9,10-dehydroemetine D in a pharmaceutically acceptable carrier, and 9,10-dehydroemetine D presents in therapeutically acceptable concentration for dilution of the concentrate for injection and the introduction of the patient.

18. Concentrate for injection 17, in which the pharmaceutically acceptable carrier comprises ethanol and propylene glycol.

19. Concentrate for injection 17, in which the pharmaceutically acceptable carrier comprises ethanol in an amount of about between 50% volume/volume and about 90% volume/volume, together with propylene glycol in the amount of approximately between 10% volume/volume and about 50% volume/volume.

20. Concentrate for injection according to claim 19, in which the pharmaceutically acceptable carrier comprises ethanol in an amount of about 70% volume/volume and the propylene glycol in the amount of approximately 30% volume/volume.

21. Concentrate for injection 17, in which 9,10-dehydroemetine D represents TRANS-9,10-dehydroemetine D.



 

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SUBSTANCE: prevention of carcinogenic action of diethyl nitrosamine in experimental animals is ensured by introduction of kaskorutol dosed 0.4 g/kg within 9 months as an anticarcinogen, while diethyl nitrosamine is introduced in a dose 100 mg/l 5 days after introduction of kaskorutol within 4 months.

EFFECT: reduced carcinogenic action of diethyl nitrosamine due to inhibition of blastomogenic process, lowered level of lipid peroxidation, improved activity of antioxidant enzymes.

2 tbl, 8 dwg, 1 ex

FIELD: pharmacy.

SUBSTANCE: antineoplastic preparation which coordination compound on the magnesium gluconate base wherein the ligands are chosen from the group consisting of γ-aminobutyric acid (GABA), 3-hydroxy-GABA, ethylendiaminotetraacetic acid and ethylenglycoltetraacetic acid or binary salt chosen from the group consisting of magnesium butyrogluconate, oxymagnesium butyrogluconate, magnesium glucarate-gluconate, calcium butyrogluconate, calcium oxybutyrogluconate, calcium glucarate-gluconate and their combinations.

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4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to oncology, and concerns development of a medicinal agent for angiogenesis control. It is ensured by application of sphingosine-1-phosphate receptor agonist representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3 diol, or its hydrochloride, or phosphate. The present invention also can include these substances combined with chemotherapeutic agents.

EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

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9 cl, 7 dwg

FIELD: medicine.

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EFFECT: invention provides angiogenesis regulation including inhibition of uncontrolled neoangiogenesis, particularly in solid tumour therapy.

9 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, and can be used in therapy of epidermoid skin cancer without metastases in regional lymph nodes. Said therapy is ensured by close-focus roentgenotherapy of total focal dose 6000 R. The irradiation course is followed with over- and subfascial introduction of Klein solution in tumour projection in a dose 20 ml. Then tumour-associated fascia is removed by endoscopic or surgical technique at the distance at least 1 cm from the irradiation zone.

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2 ex

FIELD: chemistry.

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EFFECT: high-yield end product.

26 cl, 5 tbl, 50 ex

FIELD: chemistry.

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EFFECT: new compound is characterised with useful biological activity.

2 tbl, 1 ex

FIELD: chemistry.

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EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

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EFFECT: new bengamide derivatives are characterised with useful biological properties.

15 cl, 7 tbl, 18 ex

FIELD: medicine; pharmacology.

SUBSTANCE: lyophilised preparation forms and solutions CCI-779 are available for production of lyophilised preparation forms CCI-779. The specified solutions consist of CCI-779 and solvent chosen from dimethylsulfoxide, acetonitrile, ethanol, isopropanol, tert-butyl alcohol and their mixtures. Besides, methods of lyophilised preparation forms CCI-779 preparation and restoration are offered.

EFFECT: improved storage stability and preservation of initial activity.

21 cl, 10 ex

FIELD: medicine; pharmacology.

SUBSTANCE: sterile aripiprazole compound for injections with controllable elution in the form of sterile suspension provides aripiprazole release after an injection within at least one week, including: (a) aripiprazole which has the average size of particles approximately from 1 to 10 micron, (b) aripiprazole carrier, and (c) water for injections, and the specified structure for injections contains aripiprazole in amount from approximately 1% to 40% wt in relation to the total amount of the specified sterile compound for injections.

EFFECT: increase of adaptable ability of patients and decrease in frequency of relapses at schizophrenia treatment.

27 cl, 2 tbl, 3 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: offered is method of blood substitute production and related installation for method implementation. Method of blood substitute production includes production of deoxygenated haemoglobin, its polymerisation and purification. Production of deoxygenated haemoglobin includes haemolysis of water addition to erythrocytic mass, stroma separation, non-heme protein precipitation and removal from produced haemoglobin solution. Polymerisation includes processing of produced deoxygenated haemoglobin with modified glutaric aldehyde and restoration with sodium borane, with purification including ultra filtration. Deoxygenated haemoglobin is produced using leukocyte-free erythrocytic mixture. Non-heme proteins are precipitated by concentrated sodium chloride solution added to haemoglobin solution. Removal of non-heme proteins is followed with ultra filtration concentration of haemoglobin solution. Haemoglobin is produced in polymeric disposable containers, while deoxygenation and polymerisation are carried out in gas vortex reactor with nitrogen atmosphere within 1-6 hours each. Diafiltration purification is performed in polymeric disposable containers on shutoff dampers to produce end product molecular weight within 100 kDa to 450 kDa. Method allows for simplified production of polyhaemoglobin with lowered cost and higher outcome. Related installation for method implementation includes series haemoglobin production area, haemoglobin polymerisation reactor and end-product purification system. Haemoglobin production area contains series haemolysis tank with filtration manifold for stroma separation, non-heme protein precipitation tank with filtration manifold for removal of precipitated non-heme proteins. End product purification system contains ultra filtration tanks and units with shutoff dampers. All tanks within haemoglobin production area are polymeric disposable containers. Non-heme protein precipitation tank is connected to the tank for concentrated solution of sodium chloride. Polymerisation reactor is designed as gas vortex unit. End product purification system tanks are polymeric disposable containers. Haemoglobin production area, haemoglobin polymerisation reactor and end product purification system, as well as all tanks and units are interconnected by means of sterile rapid-action coupling.

EFFECT: allows for reduced material consumption of installation with higher productivity, sterile conditions of technological process.

6 cl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns chemical pharmaceutical industry, particularly pharmaceutical administration forms with delayed liberation, containing at least one active peptide. The invention also concerns method for obtaining such forms, a kit containing liophilised peptide and water non-organic salt or acetate solution, and application of water non-organic salt or acetate solution in obtaining a pharmaceutical administration form sustaining continuous peptide liberation for a prolonged time.

EFFECT: prolonged liberation of active peptide due to the depot effect.

42 cl, 7 ex, 4 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: injection dosage form for acute stroke treatment includes noopeot in therapeutically effective amount as reactant, and as adjuvants, at least one selected from group including lactose, saccharose, polyvinyl alcohol, polyvinylpyrrolidone, sorbite, mannitol, glycine, aqueous solutions, fatty oils, ethyl oleate, glycerine, ethyl alcohol, propylene glycol, polyethylene oxide 400, benzyl benzoate, benzyl alcohol and other adjuvants allowed for medical application. Injection dosage form meets all requirements of State Pharmacopeia, XI edition. Medical product Noopept (N-phenyl acetyl-L- prolyl glycine ethyl ether) as injection dosage form provides high nootropic and neuroprotective activity applied to models of extensive ischemic stroke and hemorrhagic stroke.

EFFECT: stabile storage ability and high bioavailability.

8 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention concerns pharmaceutical composition resulted from sublimation drying in vacuum, containing oxalyplatine as an active component and pharmaceutically acceptable carrier containing as a carrier at least one alcoholic sugar of not-animal origin, thus mass ratio of oxalyplatine to alcoholic sugar of not-animal origin makes 1:3 to 1:7.

EFFECT: invention provides decreased risk of virus infection, especially animal cancellous encephalopathy agent.

5 cl, 4 ex, 2 tbl

FIELD: pharmaceuticals.

SUBSTANCE: claimed method includes step of dissolution of AB-type block-copolymer, comprising hydrophilic polymer structure unit representing polyethylene oxide derivatives and hydrophobic polyamino acid structure fragment representing polyasparaginic acid together with drug (doxorubicine or salt thereof) in mixed solvent containing water and low boiled water miscible organic solvent followed by concentration of obtained solution.

EFFECT: new block-copolymer-drug composite.

4 cl, 2 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a method for preparing a liquid antitumor composition containing derivative of camptothecin. Derivative is prepared by binding compound of the formula (I): with polysaccharide having carboxyl groups through amino acid or peptide, and pH value of composition is brought about to 5-8 using a buffer. As a buffer method involves using one or more compounds chosen from group consisting of citric acid, alkaline metal citrate, acetic acid, alkaline metal acetate and alkaline metal dihydrophosphate that provides the excellent stability of composition at storage being not only as a lyophilizate but as a solution also.

EFFECT: improved and valuable pharmaceutical properties of preparation.

17 cl, 6 tbl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a novel stable ready formulation of pharmaceutical composition containing VIII factor and can be used in treatment of hemophilia. Invention relates to a solid pharmaceutical composition prepared by lyophilization of an amino acid-free solution and comprising the following components: (a) VIII factor in the concentration 50-10000 IU/ml for human VIII factor or human recombinant VIII factor, or 50-10000 U/ml for swine VIII factor or swine recombinant VIII factor; (b) surfactant in the concentration above critical micellar concentration up to 1% (vol./vol.); (c) calcium chloride; (d) sucrose; (e) sodium chloride; (f) trisodium citrate, and (g) amino acids-free buffer in the concentration 1-50 mM with pH 6-8 before lyophilization and after dissolving in water for injection. Also, invention relates to a liquid pharmaceutical composition prepared after dissolving indicated stable solid pharmaceutical composition in sterile water optionally containing sodium chloride. Invention provides preparing a stable ready formulation of pharmaceutical composition of VIII factor wherein albumin is replaced with other stabilizing agents.

EFFECT: improved and valuable properties of pharmaceutical composition.

25 cl, 3 tbl, 3 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises N-(chloro-4-morpholin-4-yl)-phenyl-N'-hydroxyimidoformamide and β-cyclodextrin sulfobutyl ester or its salt. Invention provides stability of a drug in storage, heating and light effect and shows practice in using also.

EFFECT: improved and valuable properties of pharmaceutical composition.

3 cl, 3 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, medicine and cosmetology, and concerns an agent for liver pathologies, as well as for improved skin colour and structure, lassitude relief, higher immune protection function, intensified sexual function. The composition contains Laennec, a solution containing ammonium glycyrrhizinate, glycine, L cysteine, 20% dextrose solution ("ничифарген"), vitamin B1, B2, B6, B12, C solutions, physiologic saline. Another version of the composition contains Laennec, 20% dextrose solution, vitamin B1, B2, B6, B12, C solutions, physiologic saline. The compositions are intravenously droplet introduced while providing complex action practically without by-effects.

EFFECT: composition effectiveness is ensured with synergetic action of all the components.

2 cl, 9 ex

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