Method, medicinal formulation and sets for enhancing oral biological availability of pharmaceutical agents

FIELD: medicine, oncology, pharmacology, pharmacy.

SUBSTANCE: invention relates to methods and medicinal formulations used in antitumor treatment and enhancing oral biological availability of taxanes. Method involves administration of taxane in combination with agent enhancing biological availability of taxane in oral administration in subject wherein concentrations of taxane attain levels of therapeutic activity in subject. Ketoconazol representing inhibitor of cytochrome P-450 is used as agent enhancing oral biological availability of taxane. Invention provides enhancing bioavailability of taxane in its oral administration in subject in subtherapeutic doses that results to decreasing toxicity of treatment.

EFFECT: improved and valuable medicinal properties of drug.

33 cl, 42 dwg, 10 tbl, 12 ex

 

Cross-reference to related applications

This application is an application with a partial continuation of concurrently pending application No. 08/608776, filed February 29, 1996, which claims priority to provisional application No. 60/007071, filed October 26, 1995

Link to documents that reveal the essence of the invention

This application includes material that lies in the document, revealing the essence of the invention No. 377063, filed June 23, 1995; No. 386504, filed December 11, 1995; No. 391109, filed February 7, 1996, and No. 391228, filed February 7, 1996.

Background of invention

1. The technical field to which the invention relates.

The present invention relates to methods, compositions and kits for improving the bioavailability of pharmaceutical agents that are poorly absorbed from the gastrointestinal tract, as well as to methods of treating patients by oral administration of these agents. In one of its aspects the present invention relates to the use of cyclosporine in order to enhance the bioavailability of paclitaxel and related taxan.

2. Description of the prior

Many valuable pharmacologically active compounds cannot effectively be administered orally because of their lack of systemic absorption from the gastro-intestinal tract is. So all of these pharmaceutical agents are usually injected intravenously or intramuscularly, which requires the intervention of a doctor or medical personnel, and causing the patient considerable discomfort, and entails the potential for local injury, and even the possible placement of a patient in the hospital for surgical intervention in the event of some intravenous infusion.

An assumption was made that in some cases insufficient bioavailability of drugs after oral administration is the result of activity associated with the membrane P-glycoprotein, which is the carrier of many drug compounds and which carries out energy-dependent transport or acts as a suction pump to reduce the intracellular accumulation of drugs by removal of xenobiotics from cells. The specified P-glycoprotein was identitarian in normal tissues secretory endothelium, such as biliary pavement, brush border of renal proximal tubules and luminaries surface of the small intestine and vascular endothelial cells lining the blood-brain barrier, placenta, and testes.

Suppose that P-glycoprotein that acts as a suction pump, prevents the passage of the pharmacy is practical connections through the mucosal cells of the small intestine and thereby the absorption of these compounds in the systemic circulation. It has been shown that some known nezatocheny pharmaceutical agents inhibit P-glycoprotein, including cicloprofen (also known as cyclosporine, verapamil, tamoxifen, quinidine, phenothiazines, and the like, Many of these studies were aimed at achieving greater accumulation of cytotoxic compounds inside tumor cells. Really, have conducted clinical trials in order to study the action of cyclosporine on the pharmacokinetics and toxicity of paclitaxel (Fisher et al., Proc. Am. Soc. Clin. Oncol., 13, 143, 1994); doxorubicin (Bartlett et al., J. Clin. Onc. 12, 835-842, 1994); and etoposide (Lum et al., J.Clin. Onc. 10, 1635-42, 1992), which are anti-cancer agents and to which, as you know, patients produced the MDR (resistance to many drugs) (MDR). These trials showed that patients who intravenously was administered cyclosporine together with anticancer drugs or prior to their introduction, had high levels of these medicines in the blood, which is probably caused by reduced excretion of drugs from the body; and these drugs were found in the expected toxic effects at much lower doses. The results obtained indicate that the introduction of cyclosporine with drugs inhibit MDR-action is of P-glycoprotein, encourage greater accumulation of therapeutic agents inside cells. A General discussion of the pharmacological aspects of the clinical use of inhibitors of P-glycoprotein can be found in the works of Lum et al., Drug Resist. Clin. One. Hemat., 9, 319-336 (1995); Schinkel et al., Eur.J.Cancer, 31A: 1295-1298 (1995).

In the above studies regarding the use of cyclosporine for increasing levels of pharmaceutical agents in the blood, in relation to which the patient produces P-glycoproteinoses resistance, these active agents and cyclosporine were administered intravenously. In these publications have not made any assumptions about what the cyclosporine or other compounds, which are believed capable of inhibiting P-glycoprotein "suction pump"could be administered orally in order to significantly enhance the bioavailability of orally injected anticancer funds and other pharmaceutical agents that are poorly absorbed from the intestines into the bloodstream, but at the same time so that they were not produced side effects with a high level of toxicity. Indeed, in the above review 1995 Lum and others have shown that the joint intravenous MDR inhibitors and chemotherapeutic agents, which produced the MDR (MDR), increases the level of what she toxicity and exacerbation of serious side effects in the patient. Schinkel, etc. briefly mention the fact that the cells of the mucous membrane of the small intestine are enriched and MDRI P-glycoproteins, and this may affect the bioavailability of drugs, having as a substrate of P-glycoprotein, however, these authors did not state any assumptions or did not imply that oral administration of MDR-suppressing agents can increase the oral bioavailability of drugs with poor bioavailability. In addition, as Lum and others, Schinkel and others warn that inhibitors of P-glycoprotein can dramatically increase the toxicity during chemotherapy, and therefore they must be applied with great caution.

In earlier publications Schinkel and others have shown that the absorption ivermectin, oral injected mice homozygous for disruption of the gene MDR-1, was higher than in normal mice, suggesting that P-glycoprotein plays an important role in reducing the bioavailability of this agent (Cell, 77, 491-502, 1994). In addition, this study also showed that the penetration of vinblastine in various tissues from mutant mice was higher.

While none of the published studies are not described conditions for the exercise of effective oral administration otnositelnogo absorbable drugs, so, for example, is not specified anywhere appropriate intervals doses and schemes specific target drugs and agents that enhance their bioavailability, as well as never specify what MDR-inhibiting agents are most suitable for the stimulation of each absorption from oral input of medicines or of a particular class of drugs.

Disclosed earlier ways of increasing intestinal absorption of drugs introduced thus far, only parenteral, were focused mainly on the use of agents that increase the permeability and solubility, as stimulating agents or joint use of inhibitors of P-glycoprotein by intraluminal perfusion in the small intestine or by intravenous injection, as described, for example, Leu and others in Cancer Chemother. Pharmacol., 35: 432-436, 1995 (perfusion or i.v infusion. quinidine inhibits the output from the bloodstream into the cavity of the gastrointestinal tract). However, all these methods have several disadvantages. For example, agents that increase the solubility and permeability, are often unsuitable or ineffective for oral administration in the required doses and can adversely affect the pharmacological activity of the target drugs. Parenteral introduction the man inhibitors of P-glycoprotein in therapeutic (or close to certiticates) doses can cause serious clinical complications. For example, in the case of intravenous quinidine can cause arrhythmia, vasodilation, gastrointestinal disorders, etc.

In the published (10 August 1995) the PCT-application WO 95/20980, Benet, etc. disclose a method of increasing bioavailability of oral input hydrophobic pharmaceutical compounds. This method is oral administration to the patient of these compounds together with biosilica containing inhibitor of the enzyme cytochrome P450 3A or inhibitor of P-glycoproteinoses membrane transport. However, in essence, Benet and others do not disclose the method for the identification of the most appropriate agents that increase the bioavailability of specific "target" pharmaceutical compounds, and do not indicate specific doses or schemes use augmentative or targeted agents. Indeed, although the application Benet listed many potential agents that enhance bioavailability (P450 3A inhibitors), and targeted drug substrates for P450 3A), but in this application are described only experimentally proven combination of ketoconazole used as a reinforcing agent, and cyclosporine And used as the target of the drug.

When describing the main characteristics of compounds that can be used is the quality of the agents, increasing bioavailability due to the inhibition of the transport activity of P-glycoprotein, Benet and others have shown that these compounds are hydrophobic and contain, but not necessarily, two coplanar aromatic rings, positively charged nitrogen group or a carbonyl group; and this class of compounds covers a huge number of compounds, most of which are not able to provide the desired increased absorption specifically used to target agents. In addition, classes of targeted agents disclosed Benet and others, include the vast majority of pharmaceutical agents that are listed in the Physicians Desk References. These inclusion criteria do not represent value for practitioners seeking to find a safe, easy to use and effective methods of oral administration of a particular pharmaceutical agents.

Another disadvantage Benet and the other is the criterion used to estimate the increase bioavailability of poorly absorbed drugs after oral administration. Benet and others have shown that any agent, which inhibits P-glycoprotein, present in the intestine in this concentration and reducing transport through the membrane is mediated by P-glycoprotein Rhodamine 123 in membrane vesicles brush the edges or in the region of glycoproteinoses cells by 10% or more can be considered as the agent, increasing bioavailability for a given concentration, and can be used for practical implementation of their inventions. However, the increase in absorption from the intestine is almost not absorbed under normal conditions medicinal agent 10% is insufficient to make this agent is therapeutically valuable for any purpose. Indeed, according to the regulations of the Federal control over the quality of the food and drug administration, two pharmaceutical preparation containing the same active ingredient but different in terms of its biological availability -20%/+25%, are still biologically equivalent because for most drugs the difference in concentration of the active ingredient in the blood at -20%/+25% is not clinically significant. Approved Drug Products with Therapeutics Equivalence Evaluation (Dept. of HHS, 14th ed. 1994). If, in accordance with FDA regulations, two pharmaceutical drug are considered to be biologically equivalent, physicians and pharmacists consider these two pharmaceutical drug used interchangeably.

Generally speaking, Benet and others do not give specific instructions about what considerations should guide professionals physicians and pharmacists to identify suitable combinations of bio is elites/target drugs or to develop specific schemes or methods of treatment, that would allow to achieve the desired therapeutic effect after oral administration of the target agent.

Thus, the need to develop safe and also effective way to increase system availability introduced oral drug, which hitherto was administered only parenterally because of their insufficient or inadequate absorption when administered orally, is still relevant, because this method has not yet been described in previous papers.

Brief description of the invention

It has been unexpectedly discovered and experimentally confirmed that some agents, obviously inhibit the transport activity of P-glycoprotein, especially cyclosporine, can be used to significantly improve oral bioavailability of poorly digestible or even unassimilated pharmaceutical agents, for example, anticancer drugs such as paclitaxel (formerly known as Taxol), its analogs and derivatives, and etoposide.

In one of its aspects the present invention relates to a method of increasing the bioavailability upon oral administration of pharmaceutical agents that are poorly or not at all absorbed from the gastro-intestinal tract or intestines, where the specified process is carried out is here prior and/or contemporaneous oral administration of one or a combination of agents, known that they are effective inhibitors of P-glycoprotein, which acts as a pump-carrier medicines. In the case of the preliminary injection of the agent or agents that increase the bioavailability of drugs, should be introduced in sufficient quantities and shortly before the introduction of this drug (target drug" or "trust agent") so that by the time of introduction of the target agent in the place of its absorption remained a sufficient amount of an agent that increases the bioavailability, and thus ensured the effective inhibition of the activity of P-glycoprotein or other vectors of multiple drug compounds.

In its second aspect the present invention relates to compositions and dosage forms for oral administration of pharmaceutical agents, which were hitherto used only for parenteral injection. In its third aspect the present invention relates to the introduction of such oral dosage forms or their combinations to patients for the treatment of diseases susceptible of active agents contained in these oral forms.

The present invention also relates to pharmaceutical kits comprising one or more of peroralnyh dosage forms, containing the target agent, and one or more oral dosage forms containing a reinforcing agent.

Brief description of drawings

Figure 1 is a graph illustrating the levels of paclitaxel in serum samples taken over a period of 6-8 hours from three groups of rats, where one group was injected intravenously only paclitaxel, the second group was injected paclitaxel only orally; and the third group oral was administered paclitaxel and cyclosporin a (hereinafter referred to as cyclosporine or CsA); and the dose of cyclosporine was administered before and immediately after injection of the dose of paclitaxel.

Figure 2 is a graph illustrating the comparative levels of paclitaxel in serum taken from two of the three groups of rats, described in Figure 1, namely the group that oral was administered only one paclitaxel, and from group to which oral was administered paclitaxel with prior or concurrent oral dose of cyclosporine.

Figure 3 is a graph illustrating the level of paclitaxel in plasma samples taken over a period of 24 hours from two groups of rats, where one group (A) oral was administered cyclosporine for one hour before oral administration of a combination of cyclosporine and paclitaxel, and the second group (R) oral introduced one ciclosporin one hour before oral administration of paclitaxel.

4 is a graph illustrating the levels Pak is Taxila in plasma samples taken from two groups of rats, where one group (G) was administered paclitaxel IV over 3 hours after administration of the oral dose of cyclosporine, while the second group (H) was administered only paclitaxel IV.

5 is a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from three groups of rats over a period of 24 hours, where one group (group a) was administered only radioactive labeled paclitaxel IV, the second group (Group b) was administered orally only radioactively labeled paclitaxel, and the third group (Group C) was administered orally radioactively labeled paclitaxel together with oral doses of cyclosporine, which was administered 1 hour before and immediately after administration of the dose of paclitaxel.

6 is a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from the individual rats Group (described for Figure 5).

7 is a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from the individual rats Group (defined above in the description of Figure 5).

Figa is a graph illustrating the levels of total radioactivity and unchanged paclitaxel, registered in samples of whole blood, taken over a period of 24 hours from a group of 10 rats that were orally introduced radioactively labeled paclitaxel (9 mg/kg) and oral dose of cyclosporine (5 m is/kg), entered 2 hours before and immediately after injection of the dose of paclitaxel.

FIGU is a graph illustrating the levels of total radioactivity and metabolites of paclitaxel 1, 2 and 3, registered in samples of whole blood taken from a group of 10 rats (defined above for Figa) for a period of time of 24 hours.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours from the three groups of rats, where one group oral was administered 10 mg/kg of verapamil as a reinforcing agent, the second group oral was administered progesterone as a reinforcing agent, and the third group oral was administered dipyridamole as a reinforcing agent; and each of these groups were administered an oral dose of the same reinforcing agent within one hour after administration of the oral dose of radioactively labeled paclitaxel.

Fig.9 is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the first group defined above for Fig (which was administered 10 mg/kg of verapamil oral); in rats group that oral was administered only one radioactively labeled paclitaxel, and in rats of group oral was administered cyclosporine for one hour and immediately after injection oral dose of radioact the EIT labeled paclitaxel.

Figure 10 is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the second group defined above for Fig (which is administered orally progesterone), the group of rats which were administered orally one paclitaxel, and the group of rats that orally was administered cyclosporine for 1 hour before injection, and then immediately after injection of radioactively labeled paclitaxel.

11 is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the third group defined above for Fig (which oral was administered dipyridamole); the group of rats that orally was administered only one paclitaxel; and the group of rats that orally was administered cyclosporine for 1 hour before injection, and then immediately after the introduction of oral radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours from the three groups of rats, where one group oral was administered 100 mg/kg of verapamil (As shown in Fig, rats given the high dose of verapamil did not survive more than about 8 hours) as a reinforcing agent, the second group was injected oral megestrol acetate (MEGACE brandRBristol-Myers Squibb Oncology) as the reinforcing agent, and the third group oral was administered ketoconazole as a reinforcing agent; and each group was administered the same oral dose of the same reinforcing agent within one hour after administration of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the first group defined above for Fig (which oral was administered 100 mg/kg of verapamil); in rats group that oral was administered only one radioactively labeled paclitaxel; in rats group that oral was administered cyclosporine for one hour prior to injection, and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the second group defined above for Fig (which oral introduced magistralata); in rats group that oral was administered only one radioactively labeled paclitaxel; in rats group that oral was administered cyclosporine for one hour prior to injection, and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole the blood, taken over a period of 24 hours in rats of the third group defined above for Fig (which oral was administered ketoconazole); in rats group that oral was administered only one radioactively labeled paclitaxel; in rats group that oral was administered cyclosporine for one hour prior to injection, and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the first group defined for Fig (which was administered 10 mg/kg of verapamil); rats of the first group defined above for Fig (which was administered 100 mg/kg of verapamil); in rats group that oral was administered only one radioactively labeled paclitaxel; in rats group that oral was administered cyclosporine for one hour prior to injection and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of 24 hours in rats of the second group defined above for Fig (which oral was administered progesterone); rats of the second group defined above for Fig (which oral introduced magistralata); in rats group that oral was administered only one radioactively labeled paclitax is l; rats of group oral was administered cyclosporine for one hour prior to injection, and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

Figa is a graph illustrating a comparison of the curve dose-response relationships, built for a group of rats that orally was administered cyclosporine for one hour prior to injection, and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel, with a wry dose dependence, built for a group of rats that orally administered ketoconazole one hour before the injection, and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

On FIGU shows a comparison of AUC0-24defined for the same two groups of rats.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of time 24 hours from three groups of rats, where one group was injected intravenously (IV) only radioactively labeled etoposide; the second group oral introduced only radioactively labeled etoposide; and the third group oral was administered radioactively labeled etoposide in combination with oral doses of cyclosporine, which was administered before and immediately after a dose of etoposide, and in this graph, the ordinate axis deferred equivalents to etoposide (mlnd) from 0 to 1 in whole blood.

Fig - a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from three groups of rats defined above for Fig; where the ordinate axis deferred equivalents radioactively labeled etoposide (mlnd) from 0 to 0.2 in whole blood.

Fig is a graph illustrating the percent (%) average cumulative dose of radioactivity, registered in faeces and urine taken from three groups of rats over a period of 168 hours, where one group was injected intravenously only radioactively labeled paclitaxel; the second group oral introduced only radioactively labeled paclitaxel; and the third group oral was administered radioactively labeled paclitaxel in combination with oral doses of cyclosporine before or immediately after the administration of paclitaxel.

Fig - histogram showing mean values (mlnd) equivalents of paclitaxel registered blood and plasma from three groups of rats defined for Fig through 168 hours (7 days) after the administration of paclitaxel.

Fig - histogram showing mean values (mlnd) equivalents of placitella, registered in various tissues (liver, kidney, testes and bone) for those groups of rats defined above for Fig through 168 hours (7 days) after the administration of paclitaxel.

Fig - histogram showing mean values (mlnd) equivale the comrade of paclitaxel, registered in various tissues (muscle, pancreas, bones, lungs and seminal vesicles), derived from rats of the three groups defined above for Fig through 168 hours (7 days) after the administration of paclitaxel.

Fig - histogram showing mean values (mlnd) equivalents of paclitaxel, registered in various tissues (brain, heart, gastrointestinal tract, spleen, and prostate gland) rats from the three groups defined above for Fig through 168 hours (7 days) after the administration of paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of time 24 hours from three groups of rats, where one group oral was administered cyclosporine D for an hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; the second group oral was administered cyclosporine G for one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; and the third group was administered cyclosporine And one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of time 24 hours from three groups of rats, where one group oral was administered ketoconazole for about the in the hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; the second group oral introduced a combined dose of cyclosporine and ketoconazole for one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; and the third group was administered cyclosporine a for one hour and immediately after the introduction of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of time 24 hours from three groups of rats, where one group oral was administered captopril two hours before and immediately after administration of the oral dose of radioactively labeled paclitaxel; the second group was administered cyclosporine And one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; and the third group oral introduced only one radioactively labeled paclitaxel.

Fig illustrates the profile of radioactivity in HPLC-extract plasma from rats of the Groups defined above for Figure 5.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood, taken over a period of time 24 hours from four groups of rats, where one group oral was administered 10 mg/kg cyclosporine D one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; the second group oral was administered 10 mg/kg cyclosporine F for one chatto and immediately after the introduction of the oral dose of radioactively labeled paclitaxel; the third group was administered 5 mg/kg cyclosporine D one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel; and the fourth group was administered 5 mg/kg cyclosporine F for one hour before and immediately after administration of the oral dose of radioactively labeled paclitaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from three groups of rats over a period of time 24 hours, where one group (group a) was intravenously injected only radioactively labeled docetaxel (Taxotere"); the second group (Group b) oral introduced only radioactively labeled docetaxel; and the third group (Group C) oral was administered radioactively labeled docetaxel in combination with oral doses of cyclosporine, administered 1 hour before and immediately after administration of the dose of docetaxel; and in this graph, the ordinate axis deferred averages (MLD) equivalents of docetaxel.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from three groups of rats defined above for Fig; and in this graph, the ordinate axis deferred averages (Junior doctor) equivalents of docetaxel from 0 to 2.0.

Fig is a graph illustrating the levels of radioactivity, registered in samples of whole blood taken from three groups of rats p is the period of time 24 hours, where one group (group a) was intravenously injected only one radioactively labelled paclitaxel; the second group (Group b) oral introduced only one radioactively labeled paclitaxel; and the third group (Group C) oral was administered radioactively labeled paclitaxel in combination with oral doses of CSP, administered before and immediately after administration of the dose of paclitaxel.

Fig is a graph illustrating the levels unchanged radioactively labeled paclitaxel in samples of whole blood taken from three groups of rats defined above for Fig through 1-24 hours after a dose.

Fig is a graph illustrating the levels unchanged radioactively labeled paclitaxel in samples of whole blood, taken over 0-12 hours after administration of the dose in rats of Group As defined above for Fig, and rats of the fourth group (Group D), which was injected intravenously radioactively labeled paclitaxel in combination with oral doses of cyclosporine, administered 1 hour before and immediately after administration of the dose of paclitaxel; and in this graph, the ordinate axis deferred MLD of paclitaxel from 0 to 30.

Fig is a graph illustrating the levels unchanged radioactively labeled paclitaxel in samples of whole blood, taken through 1-12 hours after administration of the dose in rats of Group As defined above for Fig, and in rats of Group D defined above for Fig, when the eat in this graph, the ordinate axis deferred MLD of paclitaxel from 0,000 to 5,000.

Fig-41 schematically illustrate the method of extraction and the distribution of radioactivity, registered in the composite (homogenate) from various organs of rats of Groups a and C, respectively, as defined above for Fig.

Fig is a graph illustrating the levels of paclitaxel, registered in the plasma samples taken after a certain period of time the group of ten rats on the third and on the fourth day of the experiment, where these rats twice a day was administered orally (5 mg/kg cyclosporine, and then, after 1 hour, has introduced a combination of the same oral dose of cyclosporine + oral dose (3 mg/kg) paclitaxel.

Detailed description of the invention

In General terms, the present invention relates to improved oral absorption and bioavailability of the pharmacologically active agents after oral administration, particularly agents that are poorly absorbed or not absorbed from the gastrointestinal tract or bowel. In its preferred embodiment, the present invention relates to the method of increasing the oral bioavailability of anticancer agents, in particular paclitaxel (currently known under the trademark TAXOL® Bristol-Myers Squibb Oncology Division) and its derivatives; other taxan; palpitations the CSOs analogue of paclitaxel, docetaxel (N-desbenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol), produced under the trademark TAXOTERE®, Rhone-Poulenc Rorer S.A.; and etoposide; (b) dosage forms and kits for oral administration of anticancer agents and other drugs, which were hitherto was administered only parenterally; and (C) to methods of treating patients suffering from cancer, with the use of these oral forms or their combinations.

The terms "oral bioavailability" and "bioavailability by oral administration", as used in the present description, refer to system availability (i.e., levels in blood/plasma) of this number of medicines, oral introduced to the patient.

Paclitaxel is a natural diterpenoid product isolated from the Pacific (korotkolistnaya) yew (Taxus brevifolia). He is a member of tecknologi family of terpenes. First paclitaxel was isolated in 1971 Wani and others (J. Am. Chem. Soc., 93: 2325, 1971), who described its structure by chemical methods and by x-ray crystallography. One of the mechanisms of activity of paclitaxel is its ability to bind tubulin and thus to the inhibition of growth of cancer cells. Schiff et al., Proc. Natl. Acad. Sci. USA, 77: 1561-1565 (1980); Schiff et al., Nature 277: 665-667 (1979); Kumar, J. Biol. Chem., 256: 1435-10441 (1981).

Paclitaxel was approved in the US for clinical use in the treatment of untreatable cancer of the ovary (Markman et al., Yale Journal of Biology amd Medicine, 64: 583, 1991; McGuire et al., Ann. Intern. Mod., 111; 273, 1989). Paclitaxel is effective for chemotherapy of certain types of cancer, including breast cancer (Holmes et al., J. Nat. Cancer Inst., 83; 1797, 1991), and was also approved for treating breast cancer. He is a potential candidate to obtain the drug, which can be used to treat skin tumors (Einzig et al., Proc. Am. Soc. Clim Oncol., 20, 46), and carcinoma of the head and neck (Forastire et al., Sem. Oncol., 20: 56, 1990). This connection can also be used to treat polycystic kidney disease (Woo et al., Nature, 368; 750, 1994), lung cancer and malaria.

Paclitaxel has only a very small solubility in water, which creates big problems in the development of appropriate drugs for injection and infusion, used in cancer chemotherapy. Some drugs paclitaxel intravenous infusions were developed using CREMOPHOR EL™ (polyethoxysiloxane castor oil) as a carrier of drugs as paclitaxel is almost insoluble in water. So, for example, paclitaxel, used in clinical trials under the protection of the NCl was made in the form of drug in 50% CREMOPHOR EL™ and 50% digidratirovannogo alcohol is. However, CREMOPHOR EL™when it is administered intravenously, is toxic and causes vasodilation, dyspnea, lethargy, hypotension, and death in dogs. I believe that CREMOPHOR EL™ is responsible for allergic reactions of the type observed in the introduction of paclitaxel.

In order to improve the solubility of paclitaxel and development of safer clinical drug studies have been conducted aimed at the synthesis of analogues of paclitaxel, where 2 - and/or 7-position derivatization groups, which should enhance the solubility. These studies have led to proletarienne compounds which have greater solubility in water than the parent compound, and which detect the cytotoxic properties after activation. One of the important groups such proletarienne compounds are 2'-onieva salt of paclitaxel and docetaxel, in particular salt nelfinavir 2'-methylpyridine (2'-MPM).

Paclitaxel is very poorly absorbed when administered orally (less than 1%) (see Eiseman et al., Second NCI Workshop on Taxol and Taxus (Sept. 1992); Suffness et al., in Taxol Science and Applications (CRC Press 1995). Eiseman and others have shown that the bioavailability of paclitaxel after oral administration is 0%, a Suffness and others have reported that oral administration of paclitaxel, in all probability, is inefficient because at the dose of 160 mg/kg/day it is not barribal notable antitumor activity. In addition, was not developed an effective method of oral administration of paclitaxel (i.e., a method that improves the bioavailability of paclitaxel when administered orally) or other taxan or analogues of paclitaxel, such as docetaxel, which have antitumor activity. Proceeding from this to date paclitaxel has not been used for oral administration to man and therefore was not used properly for the treatment of diseases susceptible to paclitaxel.

Doxetaxel made by the industry in the form of parenteral drug under the trademark TAXOTERE® and is used to treat breast cancer. To date in the scientific literature does not met any links or instructions on oral absorption of docetaxel in animals or humans.

Etoposide is a semisynthetic derivative podofillotoksina and is used for the treatment of certain neoplastic diseases, in particular cancer of the genital organs (for example, cancer of the testicles (testicular cancer)and small cell lung cancer (Loehrer. Sem. One., 19, No. 6, supp. 14, rr. 48-52, 1992). Oral etoposide is manufactured by the industry (in the form of capsules VEPESID®Bristol-Myers Squibb Oncology), but this drug does not possess good oral assorbimento (the average value of peroral the Noah bioavailability of etoposide capsules is approximately 50%).

Cyclosporine are a group of nonpolar cyclic oligopeptides (some of which have immunosuppressive activity)produced by microorganisms of the genus Topycladium, including, for example, Topycladium inflatum Gams (formerly Trichoderma polysporum). Topycladium terricola and other fungi. Was identified the main representative of this group of compounds, cyclosporin a (cyclosporine or CsA), together with several of his smaller metabolites, such as cyclosporine-Z, some of which find significantly less immunosuppressive activity than cyclosporine A. was also obtained a number of synthetic and semi-synthetic analogues. In General, see Jegorov and others, Phytochemistry, 38: 403-407 (1995). The present invention encompasses natural, semi-synthetic and synthetic analogs of cyclosporin.

Cyclosporine are neutral, lipophilic, cyclic undecapeptide with molecular masses, which account for about 1200. They are typically used intravenously or orally as immunosuppressants, mainly in organ transplantation and certain other conditions. Cyclosporine, especially cyclosporin a (cyclosporine)are known inhibitors of P - glycoprotein, which acts as a suction pump, as well as some digestive enzymes P450, but up to the present time and was not developed an effective scheme for clinical application of this property of cyclosporine, such that it was feasible and appropriate from a clinical and from a commercial point of view, or that it gave the opportunity to carry out control tests.

From a mechanistic point of view oral introduced cyclosporine able to inhibit P-glycoprotein pump in the upper small intestine, which is the area where most absorption of the drug. Intravenous drug at high degree of metabolism, such as cyclosporine, obviously not able to remain intact in the region of the intestine, which is usually absorbed drugs. After parenteral cyclosporine is extracted by the liver and enters the bile ducts and bowel distally located with respect to the specified area of optimal absorption. One of the surprising discoveries of the present invention is that the immunosuppression observed when using some of cyclosporine, is not necessarily a prerequisite for improving oral bioavailability of therapeutic agents. So, for example, cyclosporin F increases oral bioavailability of paclitaxel, even without, as reported in the literature, immunosuppressive activity. Cm. Stewart et al., Transplantation Proceedings 20: (Supp. 3) 989-992 (1988); Granelli-Piperno et al. Transplantation 46: 53-60S (1988).

Ketoconazole is a widely used fungicide imidazolone derivative, which is also, to some extent, is used for the treatment of carcinoma of the prostate. It was shown that ketoconazole, in accordance with one of its properties, is able to suppress vysokorazvynenych carcinoma cells human KB (Siegsmund et al., J.Urology, 151; 485-491, 1994) and, in addition, it may also inhibit the action of enzymes catalyzing the metabolism of drug compounds, for example of enzymes such as cytochrome P450.

It was found that many of the pharmaceutical agents that have bad profiles of oral absorption, can be successfully administered orally and discover sufficient systemic absorption and therapeutic activity, provided that oral administration will be accompanied by oral administration of a certain dose of cyclosporine or other agents known that they inhibit drug MDR, multi-drug transport activity of P-glycoprotein intracellular pump, and some reinforcing agents whose ability to inhibit P - glycoprotein transport have yet to be determined. Another unexpected discovery of the present invention is that when the same sa the s conditions oral administration leads to a more favorable pharmacokinetic profile, to better penetration into tissue and to a higher volume of distribution of targeted therapeutic agent.

In studies using animals, it was found that some agents immunosuppressive drug polyresistance, such as cyclosporine and ketoconazole, when orally administered immediately after and/or before the introduction of drugs such as paclitaxel and etoposide, increase the absorption of these medicines from the gut to the unexpectedly high level, which allows to achieve the appropriate therapeutic conditions. However, it remains unclear whether we can explain the results obtained by the suppression of the P-glycoprotein pump.

Another possible explanation for the observed increased bioavailability of paclitaxel and etoposide is the fact that between cyclosporine and paclitaxel may be an interaction at the level of the enzymes catalyzing the metabolism of drug compounds. It is known that both of these agent are subjected to a high degree of metabolism under the influence of cytochrome P-450 (e.g., P450 3A), which is concentrated in the liver and in the small intestine. It is assumed that cyclosporine, which was introduced first, can inhibit these enzymes to paclitaxel, which is nonpolar and lipophile the second connection, could be absorbed. In the absence of such local inhibition of paclitaxel undergoes metabolism with the formation of more polar metabolites, which should not pass through the cells of the mucosa. The inability to demonstrate the pharmacokinetic interaction between cyclosporine and paclitaxel in the case of the introduction of cyclosporine 3 hours before intravenous administration of paclitaxel, suggests that the above interaction is the cavity of the intestine. However, even this theoretical rationale cannot explain the sudden opening of the authors of the present invention lies in the fact that some inhibitors of P-glycoprotein (e.g., cyclosporine and ketoconazole) contribute to improving the oral bioavailability of specific targeting of drugs to a sufficiently high level, whereas other agents which are known, are also active inhibitors of P-glycoprotein, find an insignificant activity as amplifiers oral absorption for the same target medicines.

In accordance with theory of inhibition of intestinal metabolism of the target agent should not lead or should lead to a slight increase in the level of the target agent in the total blood flow when it is within Ivanna introduction. In addition, since the main effect of agent that increases oral absorption may be a local effect in the cavity of the intestine, to achieve the desired effect should be effective subtherapeutic dose. This consideration is very important if we take into account that in the case of use as a reinforcing agent cyclosporine with strong immunosuppressive activity, administration of high doses of this agent may create problems associated with its toxicity. Therefore, the detection by the authors of the present invention the fact that cyclosporine, not having immunosuppressive activity, such as cyclosporin F, can also act as oral amplifiers absorption is of great clinical value.

It is important to note that although we have a hypothesis about the mechanisms of action underlying the present invention, however, in reality, we are not aware of the mechanisms explaining discussed above unexpectedly discovered facts, but this does not prevent the practical use of the present invention by any specialist.

The method of the present invention, aimed at improving oral bioavailability of targeted therapeutic agent with a low oral absorption under normal conditions (i.e. its cf is dnaa a bioavailability of 50% or less), provides for oral administration to a mammal (human or animal) agent that increases oral absorption or bioavailability of the target agent simultaneously with the introduction of the target agent, either prior to its introduction, or simultaneously with introduction and before the oral administration of this targeted agent in order to increase the number and duration of absorption of intact target agent into the bloodstream.

Such oral input amplifying absorption agents that can be used for the purposes of the present invention, but are not limited to, are the following connections:

- cyclosporine, including cyclosporine A-Z, especially cyclosporin a (ciclosporin, cyclosporin F, cyclosporin D, dihydrocyclopenta And, dihydrocyclopenta, acetylserotonin A, PSC-833, assuming your-NIM 8112(Assuming your-NIM 811 - (Me-11e-4)cyclosporine, antiviral cyclosporine, non-immunosuppressant) (both are manufactured by the pharmaceutical Corporation Sandoz Pharmaceutical Corp), and related oligopeptides produced by microorganisms of the genus Topycladium. Patterns of cyclosporine And described below in Table 1;

- fungicides - ketoconazole;

- drugs acting on the cardiovascular system - MS-209 (from BASF), amiodarone, nifedipine, reserpine, quinidine, nicardipine, ethacrynic acid, propafenone, reserpine, amiloride;

- natural products against migraine - ergot alkaloids;

- antibiotics - cefoperazon, tetracycline, chloroquine, fosfomicin;

- antiparasitic remedies - ivermectin;

inhibitors policecourtneu resistance - VX-710 and VX-853 (Vertex Pharmaceuticals Incorporated);

- tyrosine kinase inhibitors - genistein and related isoflavones, quercetin;

inhibitors of protein kinase C - calphostin;

- inducers of apoptosis - ceramide;

agents with activity against receptors of endorphins - morphine, other representatives of the compounds of class morphines, other opiates and opiate antagonists, including (but not limited to) alogan, naltrexone, nalmefene.

To the class of oral input target therapeutic agents, oral absorption which increases with the introduction of reinforcing agents include, but are not limited to, the following connections:

- paclitaxel and other taxanes, docetaxel, their derivatives and prodrugs, in particular 2 - MRM-salt and other 2'-methylpyridinium salt;

other chemotherapeutic agents that have low or highly unstable oral bioavailability, including etoposide, camptothecin, CPT-11 (Pharmacia and decision Upjohn), topotecan (SmithKline Beecham), doxorubicin, vincristine, daunorubicin, mitoxantrone and colchicine, all of these agents, obviously, is exposed near the Union of the P-glycoprotein pump;

- other drugs that have been shown to be affected by the action of P-glycoprotein, but which can be orally absorbed in the presence of an inhibitor of P - glycoprotein in the intestine, such as ganciclovir, postamat, camptothecin and derivatives camptothecin.

Table 1
Cyclosporine A-Z
CyclosporineAmino acids
Cy-1234567891011
CyAMebmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyBMebmtAlaSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyCMebmtThrSarMeLeuValMeLeuAlaD-Ala MeLeuMeLeuMeVal
CyDMebmtValSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyEMebmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuVal
CyFDesoxy-MebmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyGMebmtNvaSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyHMebmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuD-Mev
CyIMebmtValSarMeLeuValMeLeuAlaD-AlaMeLeuLeuMeVal
CyKDesoxy-Mebmt ValSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyLBmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyMMebmtNvaSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyNMebmtNvaSarMeLeuValMeLeuAlaD-AlaMeLeuLeuMeVal
CyOMebmtNvaSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyPBmtThrSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyQMebmtAbuSarValValMeLeuAla D-AlaMeLeuMeLeuMeVal
CyRMebmtAbuSarMeLeuValLeuAlaD-AlaMeLeuLeuMeVal
CySMebmtThrSarValValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyTMebmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuLeuMeVal
CyUMebmtAbuSarMeLeuValLeuAlaD-AlaMeLeuMeLeuMeVal
CyVMebmtAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal
CyWMebmtThrSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuVal
CyXMebmt NvaSarMeLeuValMeLeuAlaD-AlaLeuMeLeuMeVal
CyYMebmtNvaSarMeLeuValLeuAlaD-AlaMeLeuMeLeuMeVal
CyZMeAmino octylacidAbuSarMeLeuValMeLeuAlaD-AlaMeLeuMeLeuMeVal

In accordance with the present invention, the interval of the dose-enhancing agent, added together with the target agent is from about 0.1 to about 15 mg/kg weight of the patient. The term "co-administration" reinforcing agent is meant, primarily, the simultaneous introduction with the target agent (or less than half an hour before the introduction of, or less than half an hour after the introduction of the target agent, or together with the introduction of the target agent), the introduction of about 0.5 to 24 hours before the introduction of the target agent or a combination of both the injection mode, i.e. one or several doses of the same or various reinforcing agents can be introduced, at least 0.5 hour before the introduction of the target agent and one dose can be introduced simultaneously the Enen with the introduction of targeted agent (either together with the target agent, either directly after its introduction). In addition, the term "co-administration" refers to the introduction of more than one dose of the target agent within 24 hours after administration of the dose-enhancing agent, in other words, the reinforcing agent (agents) do not have to be re-entered before the introduction of or simultaneously with the introduction of the target agent, it can also be given periodically during treatment.

The range of doses for oral administration of the target agent may vary for each specific used medicines depending on its therapeutic index, and depending on the mode required for the treatment of this disease, the patient's condition and the like, the Method of the present invention allows to enter paclitaxel orally in doses, comprising from about 20 mg/m2to about 1000 mg/m2(in the calculation of the surface area of the patient's body) or estimated from 2 to 30 mg/kg (calculated on the weight of the patient's body) as a single dose or fractional doses (2-3) a day and maintain the levels of paclitaxel in plasma in the range from 50 to 500 ng/ml for an extended period of time (e.g., 8-12 hours) after administration of each oral dose. These levels are at least comparable to the levels that are achieved with 96-hour intravenous infusion taxo is a (which is causing the patient significant discomfort, discomfort, disorientation in time, possible infection, and the like). Moreover, these levels of paclitaxel in plasma are more than sufficient to achieve the desired pharmacological effects target medicinal agent, such as inhibition of the degradation of tubulin (which occurs at levels of about 0.1 μm, or about 85 ng/ml) and inhibition of isoprenaline protein (which occurs at levels of about 0.03 micrometers, or about 25 ng/ml), which are directly related to their antitumor effects by inhibiting oncogenic functions, and other signal-traducerea proteins, which play a critical role in the regulation of cell growth.

In some cases it is preferable to enter the patient is higher, the shock, the initial dose target agent to achieve peak levels of this agent in the blood followed by the introduction of lower maintenance doses.

Two or more different reinforcing agent and/or two or more different target agent can be introduced together, sequentially or intermittently in all the various aspects of the method of the present invention.

The present invention also relates to a method for treating mammals suffering from cancer, tumors, Kaposi sarcoma, malignant diseases, uncontrolled proliferation of tissues or cells in arachnoi against tissue damage and any other pathological conditions, susceptible to the effects of paclitaxel, taxan, docetaxel, etoposide, their prodrugs and derivatives, paclitaxel 2'-MPM, and docetaxel 2' -MPM by oral administration dosage forms containing one or more of these agents. Among all types of carcinomas particularly effective treatment with oral paclitaxel, docetaxel, other taxan and their prodrugs and derivatives amenable to hepatocellular carcinoma and liver metastases, and cancer of the gastrointestinal tract, pancreas and lungs. Examples of non-malignant diseases, which can be subjected to effective treatment by oral administration of the above active agents in accordance with the present invention, are uncontrolled secondary to tissue damage proliferation of tissues or cells; polycystic kidney disease; malaria, including parasitic chloroquine - and pyrimethamine-resistant malaria (Pouvelle et al., J. Clin. Invest., 44: 413-417, 1994).

In accordance with the present invention antitumor agents, which previously could only be introduced parenterally, can now be administered orally with a bioavailability that is sufficient to provide pharmacologically active concentrations of drugs in blood, which is particularly effective for the treatment of the ia patients, with primary tumors and metastases. Thanks to prior and/or contemporaneous to the introduction of MDR inhibitors or other amplifiers biological digestibility of these active ingredients can penetrate the intestinal wall and quickly get into the portal circulation, thereby providing higher initial local concentration of chemotherapeutic agents in the liver (much higher local concentration than is typically achieved in therapy by intravenous infusion)than in the General bloodstream or in most other organs for 7 days. In addition, it should be noted that higher levels of paclitaxel in the liver after oral administration may not be reflected in the increase in its levels in plasma due to the effect of its primary high-pass in the liver. Thanks to selectively produced high concentrations of anticancer agents in the blood of the method of the present invention is particularly suitable for the treatment of liver cancer (e.g., hepatocellular carcinoma and metastases in the liver), cancers of the gastrointestinal tract (for example, cancer of the colon and rectum) and lung cancer.

Similarly after oral administration in accordance with the present invention, in the gastrointestinal tract, pancreas and lung were detected (after EN is Lisa tissue distribution) higher levels (compared to levels in the General circulation and in most other organs) of paclitaxel for 24 hours after the injection. Due to this fact, oral administration of paclitaxel can be very effective in the treatment of cancer of the gastrointestinal tract, pancreas and lungs.

Especially unexpected and noteworthy are Fig-24. In some cases, the present invention relates to a method for achieving a comparable and sometimes higher local concentrations of paclitaxel in the tissues when administered orally than intravenously. This corresponds to a higher volume of distribution of therapeutic agent. In addition, it was shown that oral administration of reinforcing agent prior to and immediately after the introduction of the target agent (in the case of cyclosporine and paclitaxel, see Fig) leads to the production of even higher than when administered intravenously, the concentration of the target agent in the urine. Therefore, such a joint oral administration of the reinforcing agent and the destination agent must be effective in the case of treatment of patients suffering from tumors or metastases urinary tract.

According to the present invention in addition to higher than previously achieved, the local concentration of active ingredients in the liver, the distribution in the plasma and tissues active targeted agents, administered orally together with the reinforcing agents in accordance with the crust is Asim invention, unexpectedly turned out to be the same as the distribution observed when administered intravenously. A series of experiments conducted using experimental animals have shown that stable levels of paclitaxel in plasma are reached on the third day after oral administration together with the CsA. These stable levels of the target agent is comparable to the levels obtained with 96-hour infusion of paclitaxel. Patients with deficit taxane suffering from breast cancer with metastases and treated by continuous 96-hour infusion every three weeks, was observed in 27%of the reaction rate (Seidiaan et al., J.Clin.Oncol., 14; 1877, 1996). It is assumed that similar results can be achieved using the methods of the present invention, which do not cause side effects commonly observed with long-term intravenous infusion, such as discomfort and anxiety, as well as the risk of infectious contamination.

In addition, and very importantly, when administered orally, carried out in accordance with the present invention, the concentration of paclitaxel and above other anti-tumor agents in the blood on the phase of elimination of approximately analogous to the corresponding concentrations observed when administered intravenously, and these high effective therapeutic level and can be maintained for 8-12 hours after each injection. An increase in the excretion of drugs from urine after oral administration in the presence of CsA not only confirms the increased oral absorption of paclitaxel, but also delivers more drugs in urinary ways to treat cancer.

Oral dosage forms of the target agents, bioavailability increases joint introduction of reinforcing agents, can be made in the form of pharmaceutical preparations such as tablets, capsules, granules, gel microcapsules, tablets, liquids (for example, solutions, suspensions or elixirs, lozenges, and any other oral dosage forms commonly used in pharmaceutical practice. Liquid preparations may contain, for example, paclitaxel or other taxon in the filler comprising CREMOPHOR EL or other polyethoxysiloxane castor oil, alcohol and/or polyoxyethylene servicemanual (for example, TWEEN® 80, ICI Americas,Inc.). Each dosage form comprises an effective amount of the target agent (for example, an effective antitumor or antineoplastic amount of antitumor or antineoplastic agent and a pharmaceutically inert ingredients, such as standard eccipienti, carriers, fillers, binders, is integrityusa agents, solvents, solubilizing agents, sweetening agents, colorants and any other inactive ingredients that are commonly used in the manufacture of pharmaceutical dosage forms for oral administration. Many of these dosage forms and oral media listed above in the list of inactive ingredients described in Remington's Pharmaceutical 17th edition (1985). Each dosage form also contains a pharmacologically effective amount, for example, an effective antineoplastic or antitumor amount of one of the target drugs.

The exact number of each of the target drug in the dosage form varies depending on age, weight, disease and health status of the patient. For example, drugs paclitaxel may contain quantities of paclitaxel enough to get a daily dose of about 20-1000 mg/m2(based on the body surface of the patient) or about 2-30 mg/kg (calculated on the weight of the patient's body) as a single dose or fractional (2-3) doses. Oral drugs etoposide may contain the number etoposide enough to get a daily dose of about 20-200 mg/m2(based on the average body surface of the patient) as a single daily dose or fractional (2-3) doses.

®containing 50 mg (each) etoposide.

When selecting a treatment regimen for each individual patient, which you want to enter the oral dosage forms of the present invention containing the target drug, you must take into account an increased bioavailability of the drug, due to the simultaneous and/or by pretreatment of the reinforcing agents. For example, although the manufacturer's recommended dose capsules VEPESID®for the treatment of small cell lung cancer, twice the intravenous dose (rounded up to 50 mg), however, increased bioavailability of etoposide, provide pre-and/or simultaneous introduction of reinforcing agents, such as cyclosporine, can significantly reduce the dose oral etoposide and achieve the same effective levels of the drug in the blood resulting in longer and stability actions, and without increasing (and sometimes even with the reduction of toxic side effects. Oral rst is the situation, you can avoid high peak levels of the drug in the blood, as these peak levels are responsible for some of the toxic side effects. On the basis of the obtained experimental data (see Fig and 19 and Table 6), indicating that the oral absorption of etoposide in the presence of cyclosporine is almost full (about 96%), oral daily dose of etoposide for the treatment of testicular cancer should be about 50-100 mg/m2and for the treatment of small cell lung cancer, the dose should be about 35-50 mg/m2in the calculation of the body surface of the patient.

The scheme of administration of drugs for treatment of diseases of the methods of the present invention, for example, in the treatment of paclitaxeleluting diseases by oral administration of paclitaxel together with the introduction of the reinforcing agents may be appropriately adjusted according to the physiological characteristics of the patient and severity of the disease. The preferred scheme using oral drug paclitaxel provides for (a) daily administration to a patient in need of such introduction, 1-3 equal divided doses, providing a daily dose of about 20-1000 mg/m (based on the body surface of the patient), and this daily administration continues within 1-4 days following each other every 2-3 weeks, or (b) enter the tion in one day every week. The first scheme application is similar to using a 96-hour infusion of paclitaxel every 2-3 weeks, which to some extent is considered as a preferable scheme of intravenous. The preferred scheme of oral administration of etoposide joint introduction-enhancing agents provides for daily administration to a patient in need of such introduction, 1-3 equal divided doses, providing a daily dose of 50-100 mg/m2(based on the body surface of the patient) for treatment of patients suffering from cancer of the testicles; the daily dose of about 35-50 mg/m2for the treatment of patients suffering from small cell lung cancer, and in each case such daily administration continues for 5-21 days with an interval of about 2-3 weeks between each treatment.

In accordance with the present invention, oral administration of potent chemotherapeutic agents can, in many cases, actually reduce toxic side effects commonly seen with intravenous therapy. Unlike intravenous infusion, which quickly produced high levels of the active agent in the blood, upon absorption of the active agent through the wall of the intestine is stimulated and reinforcing agents) there is a gradual increase Konz is traci active agent in the blood to a stationary level, which is maintained at this value or the value close to the ideal interval during a long period of time.

In accordance with another of its aspects the present invention relates to a combined oral dosage forms that contain a fixed amount of at least one reinforcing agent and at least one target agent. For example, these dosage forms can be manufactured in the form of tablets, capsules, microcapsules, gel capsules, pills, liquids, tablets and any other standard oral dosage forms containing as active ingredient an effective amount of an agent that increases oral bioavailability of anticancer or antineoplastic agent, antitumor agent, and suitable inactive ingredients. One such combination product contains from about 0.1 to about 15 mg/kg of one or more cyclosporin A, D, C, F and G, dihydro CsA, dihydro CsC and acetyl CsA, together with about 20-1000 mg/m2(based on the average body surface of the patient) of paclitaxel, docetaxel, other taxan or derivative of paclitaxel or docetaxel, such as paclitaxel 2'-MPM or docetaxel 2' -MPM. Other suitable dosage form contains from about 0.1 to about 15 mg/to the cyclosporine or cyclosporine D or F in combination with about 20-200 mg/m 2etoposide.

Introduction of joint reinforcing agents with targeted drugs not only stimulates the oral bioavailability of these agents, but also allow their use in the treatment of tumors localized in areas of highly protected MDP, for example, in the testes and brain. Thus, in another aspect the present invention relates to a method for delivery of anticancer agents to the site of localization of the tumor, protected MDP, where the method involves introduction of joint reinforcing agents and antitumor agents, which allows for the treatment of brain tumors, such as many forms of glioblastomas.

In another aspect the present invention relates to a method for delivery of an active metabolite of paclitaxel to the disease site in a therapeutic quantity necessary for the treatment of diseases susceptible to paclitaxel. Identified major in vivo metabolites of paclitaxel, and in particular, the following gidroksilirovanii metabolites of paclitaxel, and:

A: R1=H, R2=OH; R1=OH, R2=OH; R1=OH, R2=OH (Paclitaxel: R1=H, R2=H).

In some in vitro tests, it was found that the metabolite In, you specified the e (referred to in the literature as well as metabolite M4), has a higher therapeutic index (the ratio of the toxic concentration to the level of effective concentration)than paclitaxel, for some tumor cell lines of human rights. The present invention provides the ability to deliver high amounts of metabolite and other active metabolites of paclitaxel to the location of tumors due to the fact that after oral administration all entered paclitaxel enters the liver and is subjected there to metabolism via hepatic microsomes, resulting in the total flow enters the greater the amount of each metabolite than that achieved by intravenous injection.

In another aspect the present invention relates to kits for treating mammals suffering from disorders susceptible to the effects of any pharmacologically active target agents, oral absorption and bioavailability of which increases under the influence of reinforcing agents. These kits include one or more oral dosage forms, at least one reinforcing agent, and one or more oral dosage forms at least one target agent or one or more dosage forms containing both agent.

For example, the kit of the present invention may contain the substance of one or more of such dosage forms, as tablets, capsules, microcapsules, gel capsule, or liquid preparations containing cyclosporin or ketoconazole; and one or more of such dosage forms as tablets, capsules, micro-capsules, gel capsules or liquid preparations containing paclitaxel or etoposide doses, intervals described above. These sets can be used in hospitals, clinics, physician offices or in-home patients to facilitate the introduction of augmentative and targeted agents. These kits should also contain the insert statement indicating doses for joint introduction augmentative and targeted agents.

These kits can also include combinations of the various reinforcing agents and/or combinations of targeted agents. For example, the kit may include, respectively, the oral pharmaceutical form containing cyclosporine and ketoconazole as reinforcing agents, and only one paclitaxel as the target agent, or a combination of paclitaxel with another anticancer agent. In this case, the second target agent should be (like paclitaxel) drug, which also has poor oral bioavailability, but which, when combined with the introduction reinforcing agents can reach therapeutically effective levels in the blood after his pen is real introduction. The target agent may be present together with the reinforcing agent in the same dosage form or it may be present in separate dosage forms.

The following examples illustrate various aspects of the present invention and demonstrate an unexpected and significant increase in oral absorption of the target agents. These examples in no way limit the present invention and do not pretend to describe any specific augmentative or targeted agents, spacing doses, procedures, tests or other parameters that should be used exclusively for the practice of the present invention.

EXAMPLE 1

Eighteen (18) healthy rats Spraque Dawley, weighing 225-275 grams each, at around the age of 6-8 weeks were randomly divided into three groups of 6 animals each. The first group of six rats were administered intravenous paclitaxel at a dose of 9 mg/kg, the Second group received a single oral dose of paclitaxel, equal to 9 mg/kg And the third group received a single oral dose of cyclosporine, equal to 5 mg/kg, and within one hour of this group were administered an oral dose of cyclosporine 5 mg/kg of paclitaxel in the 9 mg/kg

Blood samples were taken from the tail vein of each rat at 0.5; 1; 2; 3; 4 and 6 hours after administration of the dose of paclitaxel. The intravenously treated rats of the first group took the stage niteline the blood sample through 8 hours after administration of the dose of paclitaxel. Each blood sample was centrifuged, and the separated serum. Then for each time interval received one representative sample by combining the six samples per group. All samples were analyzed on an unmodified paclitaxel using LC/MS with a lower limit of quantitation of 50 PG/ml

The research results are graphically illustrated in figures 1 and 2. Figure 1 shows comparative graphs for all three groups of rats, and figure 2 shows the graphs only for the second and third groups that oral was administered paclitaxel. From these graphs we can see that in the absence of cyclosporine bioavailability of paclitaxel in serum is less than 1%, however, with the introduction of rats (the third group) cyclosporine for one hour prior to the introduction of a combined dose of cyclosporine/paclitaxel bioavailability of paclitaxel increases to 6-7%.

The following Table 2 presents the data to determine the values of area under the curve (AUC)calculated for the three groups of rats. These data show that the values of AUC0-6the hours for the third group received cyclosporine and paclitaxel, almost 8 times higher than the AUC values for the second group of rats received only one oral paclitaxel.

td align="center" namest="c0" nameend="c2"> The absolute bioavailability of paclitaxel
Table 2
AUC0-CASIV (ng·h/ml)AUC0-CASRO (ng·h/ml)The absolute value of F
9230*800,9%
* the value of the AUC, which does not include the data from the 1-hour sample
** F=[AUCPO/AUCIV]x100
The interaction of paclitaxel with cyclosporine
AUC0-CASRO (ng·h/ml)AUC0-CASRO cyclosporine (ng·h/ml)The relative importance of F***
80629786
*** f=[AUCPO cyclosporine/AUCPO]x100

EXAMPLE 2

Forty (40) healthy rats Spraque Dawley having the same data as the rats used in the experiment described in Example 1, were randomly divided into four groups of ten rats each, labeled A, F, G and H. The following Table 3 illustrates the processing of each test group rats and specify the time intervals for each dose.

Table 3
GroupThe number of ratsTime (hours)Processing the Dose (mg/kg)Route of administration
And100cyclosporine5oral
1

1
paclitaxel cyclosporine9

5
oral oral
F100cyclosporine5oral
1paclitaxel9oral
G100cyclosporine5
3paclitaxel9intravenous
H100paclitaxel9intravenous

Blood samples were taken from the tail vein of each rat through 0,25; 0,5; 1; 2; 3; 4; 5; 6; 8; 12 and 24 hours after administration of paclitaxel. After appropriate processing of samples and receipt of the consolidated sample for each group of plasma from each sample was analyzed on an unmodified paclitaxel.

The results of this analysis are graphically illustrated in figure 3 and 4. Figure 3 shows for comparison the two curves of concentration is from time to Group a, which have introduced pre-dose cyclosporine, and after one hour - a combined dose of paclitaxel-cyclosporine, and for Group F, which was introduced pre-dose cyclosporine, and then after 1 hour only oral dose of paclitaxel. Figure 4 shows the comparison between the results obtained for Groups G and H, both of which were administered by intravenous paclitaxel and G, in addition, three hours before the administration of paclitaxel were administered an oral dose of cyclosporine. As shown in figure 4, these two groups were found mainly identical levels of paclitaxel in plasma in the same time intervals.

Table 4 shows the AUC values for all four groups of rats that participated in this experiment. As can be seen from the Table, the values of AUC for Groups G and H, in the main, identical, and AUC values for a Group of 25-30% exceed the values for Group F, which testifies to the effectiveness of pretreatment with cyclosporine, and then the joint introduction of cyclosporine with paclitaxel.

Table 4
Bioavailability of paclitaxel in plasma
ProcessingAUC0-tF (%)
Intravenous (IV) (Group H)24280
IV + oral CsAa(Group G)2413799,4
Oral + CsA* (Group F)10974,5
Oral + CsA** (group a)1393the 5.7
a)3 hours before the administration of paclitaxel
*)pre-treatment of CsA for 1 hour before administration of paclitaxel
**)pre-treatment of CsA (one hour) and the simultaneous introduction of CsA and paclitaxel

EXAMPLE 3

Eighteen (18) healthy rats Spraque Dawley having the same physical data as the rats used in the experiment described in Example 1, were randomly divided into three groups of six rats in each Group a, b and C. group a intravenously (IV) injected radioactively labeled paclitaxel; Group oral introduced3N-labeled paclitaxel; and Group C was administered oral dose of cyclosporine, and then, after one hour, was administered combination oral dose of cyclosporine and oral dose of radioactively labeled paclitaxel.

Blood samples were taken from the tail vein of each rat through the intervals specified in Example 2. These samples were preserved in the form of whole blood. In addition, through 2-24 hours after the dose of paclitaxel, each rat was sampled mo is I. Blood samples and urine were analyzed for radioactivity.

Figure 5 shows the comparative levels of paclitaxel in samples of whole blood, taken from Groups a, b and C. comparing the levels of paclitaxel for individual members of the Group and is illustrated in 6 and 1, respectively.

In this experiment, oral absorption of radioactivity (expressed in equivalents of paclitaxel) in whole blood in the absence of cyclosporine (Group b) was about 10%, and the introduction of cyclosporine (Group C), it was about 40%. The absorption of radioactivity was determined by measuring the AUC after intravenous and oral administration of radioactively labeled paclitaxel. Formally bioavailability of paclitaxel were not measured in this experiment, because for this purpose it is necessary to conduct analysis of unchanged drug for each time period. Although for a single time parameter was conducted by standard HPLC-analysis of the radioactivity extracted from the plasma, which showed that at least 32% of the radioactivity present in the plasma accounted for unmodified paclitaxel. Profile of radioactivity HPLC extract plasma for animal Groups, detect, mainly one peak (which is paclitaxel), shown in Fig. AUC, CmaxTmaxand other data obtained in the same experiment, presented in Table 5.

Table 5
Full radioactivity to paclitaxel in blood/urine and in % of the radioactivity extracted
The parameter RKIV (B)PO (B)PO+CsA** (C)
AUC0-24(μg EQ * h/ml)32,83,212,1
Withmax(µg EQ/ml)not ODA.0,210,82
Tmax(h)-25
% dose in urine (4-24 h)2,21,98,3
% of paclitaxel*not ODA.7,8***32***
* % of paclitaxel from the extracted radioactivity (RA) 4-hour sample.
** CsA entered 1 hour before and simultaneously with paclitaxel.
*** these values are the lowest estimates, the resulting procedures are incomplete extracti is.
Table 5A
The full absorption of radioactivity after oral administration3N-paclitaxel with cyclosporine without cyclosporine (CsA) in rats (n=10)
The parameters RKPaclitaxel intravenousPaclitaxel oralPaclitaxel oral + cyclosporine
AUC0-24h(µg EQ. h/ml)23,81,48,1
AUC0(µg EQ. h/ml)27,44,515,0
F(%) based on AUC0-24h5,934,0
F(%) based on AUC016,454,7
The dose of paclitaxel = 9 mg/kg
CsA (5 mg/kg) was administered 1 hour before the administration of paclitaxel and concurrent with paclitaxel.
F=AUCoral/AUCintravenous.
Table 5B
Pharmacological parameters of paclitaxel after peroral the th introduction CsA/without CsA in rats (n=10)
The parameters RKIV doseRO-doseRO+CsA
AUC0-24h(μg h/ml)20,430,3144,27
AUC0-(ug. h/ml)21,020,3495,41
F (%)1,725,7
Cl (ml/HR/kg)429440430
V (ml/kg)423650295958
t1/2 (hour)6,8(r2=0,95)8,1(r2=0,78)9,6(r2=0,96)
Cl=F*dose/AUC
Dose=9 mg/kg
F=AUCoral/AUCintravenous

For rats treated as described in Example 3 was determined by AUC for total radioactivity. On the basis of the relationship AUCp.o./AUCi.v. for time intervals up to infinity oral absorption in the presence of cyclosporine increased to 54.7% compared to 16.4%absorption in otsutstvie cyclosporine (table 5A). Using similar analyses for unmodified paclitaxel in the blood, it was found that the bioavailability of paclitaxel is 25.7% in the presence of cyclosporine and 1.7% in the absence of cyclosporine (table 5B). The excretion of drugs from the body appeared to be surprisingly similar for all three groups. The volume of distribution of paclitaxel in the group which was administered cyclosporine and oral paclitaxel, about 50% higher than the corresponding volume in the group, which was administered paclitaxel intravenously.

In the experiments described in the following Examples 4-5 were used rats Spraque Dawley with the same physical characteristics as the rats in the experiment of Example 1, and these rats were divided into three groups of three rats (male) in each. For 12-14 hours prior to the doses of all the rats were kept on a starvation diet. After a period of fasting rats, which must be entered reinforcing agents, were first introduced these agents, and then, after 1 hour, they were injected radioactively labeled (3N)-paclitaxel (9 mg/kg) and a dose-enhancing agent. Rats, which should not be entered reinforcing agents, after fasting was injected radioactively labeled paclitaxel.

Each animal took a blood sample through 0,5; 1; 2; 3; 4; 5; 6; 7; 8; 12 and 24 hours after administration of the dose of paclitaxel. Mo is I took over 4-24 hours after a dose. Then, for each rat was determined full radioactivity in the blood and urine and calculated average values for each group.

EXAMPLE 4

Three groups of rats were administered 10 mg/kg of verapamil oral, 5 mg/kg of oral progesterone and 10 mg/kg of dipyrimidine oral as reinforcing agents, and these reinforcing agents were introduced first separately, and then, after 1 hour, together with oral dose of paclitaxel. Comparison of the curves of concentration in whole blood from time to time (the equivalent concentration against time), built for all three groups, shown in Fig. The data presented illustrate almost similar (roughly) the results that were obtained with the use of verapamil and dipyridamole as reinforcing agents, whereas data bioavailability obtained with the use of progesterone showed significantly lower values.

Figure 9 presents for comparison the curves of the concentration of paclitaxel from time built for a group of rats which were administered verapamil (10 mg/kg) as a reinforcing agent for a group of animals with the previous experiment, which was orally introduced one paclitaxel (9 mg/kg), and for another group of animals, which was orally introduced cyclosporine (5 mg/kg) first 1 hour before, and then immediately p is after the introduction of the oral dose of paclitaxel (9 mg/kg). The group that received cyclosporine, found significantly higher levels of paclitaxel in the blood than other groups, during almost the whole 24-hour period.

Figure 10 and 11 is illustrated a side by side comparison with Figure 9, except that instead of the values for the group which was administered verapamil (Figure 9), compared to values for the group, which was administered progesterone (Figure 10), and for the group, which was administered dipyridamole (11).

EXAMPLE 5

Three groups of rats were injected respectively 100 mg/kg of verapamil oral, 5 mg/kg registeroutput oral and 50 mg/kg of ketoconazole oral as reinforcing agents, and these reinforcing agents are introduced separately, and then, after 1 hour, they were introduced together with oral dose of radioactively labeled paclitaxel. Graphical comparison of the curves of the time dependence of the concentration of paclitaxel in whole blood (measured as the dependence of the equivalent concentration against time), built for all three groups, shown in Fig. The data presented illustrate almost similar (roughly) the results obtained with the use of verapamil and registeroutput as reinforcing agents, whereas data bioavailability obtained with the use of ketoconazole, showed significantly higher values for the first 1 hours.

On Fig illustrates a graphical comparison of the curve of the concentration of radioactivity from time obtained for the group of rats which were administered verapamil (100 mg/kg) as a reinforcing agent, with curves, obtained in the previous experiment for a group of rats that orally was administered one paclitaxel (9 mg/kg), and for the group of rats that orally was administered cyclosporine (5 mg/kg) 1 hour before and then immediately after the introduction of the oral dose of radioactively labeled paclitaxel (9 mg/kg).

On Fig and 15 is illustrated a parallel graphical comparison with Fig, but for teams that have introduced registeralarm (Fig) and ketoconazole (Fig) instead of the group, which was administered verapamil (Fig).

On Fig illustrates a graphical comparison of the dependence of the concentration of radioactivity from time to time, for certain groups of rats, which were administered 10 mg/kg of verapamil (as described in Example 4), and for a group of rats who were administered 100 mg/kg of verapamil (as described in Example 5).

On Fig illustrates a graphical comparison of the dependence of the concentration of radioactivity from time to time, for certain groups of rats, which were administered 5 mg/kg of progesterone, as described in Example 4, and for a group of rats who were administered 5 mg/kg registeroutput as described in Example 5.

On Fig and 17 also shows the W the most profiles, depicted on Fig-15, for study groups, which were introduced only one radioactively labeled paclitaxel and oral radioactively labeled paclitaxel immediately after injection and 1 hour after administration of 5 mg/kg cyclosporine.

Studies have been conducted data dose-response relationships for cyclosporine. Increasing the dose to 10 mg/kg and 20 mg/kg for the introduction of cyclosporine in 1 hour and simultaneously with the introduction of paclitaxel led to oral absorption of radioactivity to about 45%. This result differs from the result obtained for ketoconazole where doses up to 50 mg/kg, which were introduced for 1 hour before and simultaneously with paclitaxel did not lead to further increase oral absorption of radioactivity (see Figa and 17B).

Average pharmacokinetic parameters for the studied groups of animals discussed in Examples 4 and 5, are presented in Table 6 (the Experiment of Example 4 shown in Table 6 as the Protocol NP951202, and the experiment of Example 5 is designated as the Protocol NP960101.).

The data obtained in the experiments of Examples 4 and 5 and are presented in Table 6 and Fig-17B, a clear indication of the effectiveness of cyclosporine as an agent for enhancing oral bioavailability of the active agent and its advantage compared to verapamil, progesterone or magistraltelekom as when the izkuyu, and at high doses, especially in the first 12 hours after administration of the dose of paclitaxel. These data also indicate that ketoconazole, although it is not as effective as cyclosporine, but also has a remarkable activity, stimulating oral absorption of paclitaxel.

Table 6
Average pharmacokinetic parameters for NP951202 and NP960101
The research ProtocolProcessingDose/route of administration (mg/kg)AUC0-24(ug·EQ. h/ml)F %T1/2 (hour)Withmax(µg EQ/ml)
1234567
NP951001
only paclitaxel9/IV32,0420,1537
only paclitaxel9/RO3,24the 10.118,860,21
cyclosporine5/RO(C)
12,0237,514,510,82
NP951202
verapamil10/RHO(V)
9/RO(P) 10/RHO(V)6,3419,824,40,78
progesterone5/O(Pro)
9/RO(P) 5/PO(Pro)3,7811,820,00,26
dipyridamole10/RHO(D)
9/RO(P) 10/RHO(D)6,1819,326,60,46
NP960101
verapamil (animals100/RO(V)
died)9/RO(P) 100/RO(V)NANANA0,44
megesterol zitat 5/RO(M),
9/RO(P) 5/RO(M)5,1916,223,10,44
ketoconazole50/RHO(K)
9/RO(P) 50/RHO(K)8,0325,19,230,69

EXAMPLE 6

Three groups of rats, three rats-males each, held on the starvation diet for 16-18 hours prior to the introduction of doses. At the end of the fasting period, one group of rats were administered oral dose (5 mg/kg) of cyclosporine. Then, after 1 hour, this group is administered orally 5 mg/kg of cyclosporine and 1 mg/kg radioactively labelled3N-etoposide. The other two groups, after fasting was introduced only 1 mg/kg3N-etoposide intravenous, 1 mg/kg3N-oral etoposide, respectively. Procedures for the sampling of blood and urine and determination of total radioactivity was carried out as described in Examples 4 and 5, except that in rats, which were injected etoposide intravenously, and blood samples were taken after 0,033 and 0.25 hours. The results of the experiment are presented in Table 7.

On Fig and 19 graphically polluter is arranged according to the average concentration of etoposide in whole blood from time defined for the three study groups. On Fig y-axis deferred equivalent concentrations of etoposide from 0 to 0.2 (ppm), and Fig y-axis deferred equivalents etoposide from 0 to 0.2 (MLD to illustrate the differences between values obtained for the considered three groups.

The data presented in Table 7 and Fig and 19, showed that cyclosporine is an effective agent that increases oral bioavailability of etoposide, especially in the first 12 hours after administration of the doses.

td align="center"> 1,04
Table 7
Average pharmacokinetic parameters for NP960102
The research ProtocolProcessingDose/route of administration (mg/kg)AUC0-24(ug·EQ. h/ml)F %T1/2 (hour)Withmax(µg EQ/ml)
NP960102
Grp Aonly etoposide1/IV1,0826,52,16
Grp Bonly etoposide1/RO0,6156,519,10,03
Grp CCsA, etoposide + CsA5/RO(C)

1/RHO(R) 5/RO(C)
96,318,10,12

EXAMPLE 7

In another series of experiments, three groups of rats (three rats-males in each group) were kept on starvation diet for 16-18 hours prior to the introduction of doses. After a time of fasting, one group of rats were administered oral dose of ketoconazole (2 mg/kg). Then, after 1 hour, the group oral was administered 2 mg/kg of ketoconazole and 1 mg/kg radioactively labelled3N-etoposide. Two other groups were treated similarly, except that after fasting, these groups orally was administered 10 and 50 mg/kg of ketoconazole, respectively, before and immediately after the introduction of3N-etoposide. Procedures for the sampling of blood and urine and detection of radioactivity were carried out as described in Examples 4 and 5. The data obtained are presented in Table 7A. Thus, in contrast to the actions of cyclosporine, which almost doubles the oral absorption of radioactive paclitaxel, ketoconazole, entered into a wide range of doses, did not show the ability to improve oral absorption of etoposide compared with the data obtained in the case of the introduction of a single etoposide.

Table 7A
NP960501 F %
Grp AEtoposide + Ketoconazole1/SW(2/Keto)0,5450,390,026147,8
Grp BEtoposide + Ketoconazole1/EO(10/Keto)0,6963,95to 0.03224-91,5
Grp CEtoposide + Ketoconazole1/SW(50/Keto)0,6458,91to 0.060438,1

EXAMPLE 7A

Studies have been conducted balance excretion of paclitaxel in rats. Three groups of rats, 4-5 of male rats each, were kept on a starvation diet for 12-14 hours prior to the introduction of doses. After a time of fasting, one group of rats were administered oral dose (5 mg/kg) of cyclosporine. Then, after 1 hour, the group oral was administered 5 mg/kg cyclosporine and 9 mg/kg radioactively labeled paclitaxel. The other two groups were administered after fasting only 9 mg/kg radioactively labeled paclitaxel intravenously and 9 mg/kg radioactively labeled paclitaxel oral.

Urine and faeces were taken from each animal at the following intervals: after 0-2, 2-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96, 96-120, 120-144, and 144-168 hours after administration of the dose. Tissue samples were taken after 168 h the owls after a dose. Determination of total radioactivity was carried out as described in Examples 4 and 5.

In Fig. 20 illustrates a graphical comparison of the average cumulative percentage of the dose of paclitaxel detected in faeces and urine of test animals within a 168-hour period of time. The group of rats which were administered cyclosporine before and together with oral paclitaxel was found significantly lower percentage of the dose in faeces than the other two groups, and a significantly higher percentage of the dose in the urine than the other two groups, which suggests that animals treated with cyclosporine, a significantly larger number of oral paclitaxel was diffundiruet through the intestinal wall and fell into the General bloodstream. In addition, the fact that the percentage of the dose in urine was significantly higher in rats treated with oral cyclosporine and paclitaxel than in rats, which was intravenously injected paclitaxel suggests that the joint oral administration facilitates the passage of the higher concentrations of radioactivity through the urinary path.

On Fig-2.4 presents a histogram illustrating the mean values (MLD) of paclitaxel obtained for a number of tissue taken from rats of three groups, where group a is animal, which was intravenously injected paclitaxel. Group pre what is animal which oral was administered paclitaxel, and the Group represents animals that were administered cyclosporine. The obtained graphs showed that the levels of paclitaxel, registered in various tissues taken from mice Groups, roughly comparable to the levels of paclitaxel observed in rats of Group a, which was intravenously injected paclitaxel, except the liver, where the level of paclitaxel treated with cyclosporine group at two times the rate of the paclitaxel group, which was administered paclitaxel intravenously. The levels of paclitaxel detected in tissues of rats of Group b (which is administered orally only one paclitaxel)were very low, and in most cases significantly less than half the levels observed in any other group.

The data obtained in this experiment are presented in Tables 8 and 9.

Table 8
The study of the balance excretion of paclitaxel in rats
Radioactivity in urine, faeces and tissues, expressed as % of the dose (mean values)
SampleGroup aGroupGroup
Urine9,1606,66018,350
The faeces79,66084,41061,250
Cloth1,7100,6001,430
Only90,53091,67081,030
Table 9
The study of the balance excretion of paclitaxel in rats
Residual radioactivity in tissues, expressed in ppm (average)
SampleGroup aGroupGroup
The brain0,1010,0290,096
Heart0,0850,0250,088
Light0,1430,0300,136
Liver0,2370,0740,566
Kidney0,180to 0.0320,119
Muscles0,0790,0250,080
Gastrointestinal tract0,0830,0210,055
Testicles0,3460,0370,217
Pancreas0,0780,0180,080
Pozvonochnyh the 0,1430,0530,099
Bones0,0350,0070,034
Spleen0,1010,0240,083
The prostate glandof 0.0810,0220,090
Seminal vesicles0,1210,0240,094
Blood0,1120,0340,106
Plasma0,1260,0380,124

EXAMPLE 8

It was also conducted another study of the distribution of paclitaxel in rat tissues. Two groups of rats (10 rats-males in each group) were kept on starvation diet for 12-14 hours prior to the introduction of doses. When after a time of fasting, one group of rats were administered oral dose (5 mg/kg) of cyclosporine. Then, after 1 hour, the group oral was administered 5 mg/kg cyclosporine and 9 mg/kg radioactively labeled paclitaxel. Another group after fasting was injected intravenously only 9 mg/kg radioactively labeled paclitaxel.

Tissue samples were taken 24 hours after the dose. Determination of total radioactivity was determined as described in Examples 4 and 5.

In Table 9A presents values (MLD) radioactivity emitted by paclitaxel and ZAR is registered in various tissues, taken from the rats of the two studied groups. One group consisted of animals that intravenously injected paclitaxel, and the second group consisted of animals that were injected paclitaxel together with cyclosporine, administered 1 hour before and immediately after administration of paclitaxel. The levels of paclitaxel detected in various tissues taken from treated with cyclosporine rats were roughly comparable to the level of paclitaxel observed in rats, which paclitaxel was injected, with the exception of the spleen, pancreas and gastrointestinal tract, where the levels of paclitaxel treated with cyclosporine group of about two times the levels of paclitaxel for the group, which was administered paclitaxel intravenously.

In Table 9B illustrates the comparison of unmodified concentrations of paclitaxel in various organs for the group, which was intravenously injected only one paclitaxel, and for the group, which was administered oral paclitaxel in combination with cyclosporine. In the lungs and the gastrointestinal tract after oral administration was found to have higher concentrations of unchanged paclitaxel than after intravenous administration.

td align="left"> 0,370
Table 9A
Radioactivity equivalents (MLD) pacl is Taxila in tissues for Groups C and A (average)
ClothOral dose CsAIntravenous doseRadioactivity
The brain0,2670,2840,94
Heart1,1610,5762,02
Light2,0761,2301,69
Liver4,3283,6851,17
Kidney2,3251,2591,85
Muscles0,9510,6391,49
Gastrointestinal tract11,2825,6731,99
Testicles0,4350,8040,54
Pancreas1,9990,9112,19
The spine1,0430,8581,22
Bones1,0570,6121,73
Spleen3,0891,1802,62
The prostate gland2,2121,6601,33
Seminal vesicles1,8912,6930,70
Blood0,3730,4010,93
Plasma0,3471,07

Table 9B
Extraction of radioactivity from various tissues
GroupCloth3N (MLD) in tissue%3N analyzed by HPLCLevel (ppm) of paclitaxel in tissue%3N identified as paclitaxel
Nutriv.Liver3,775,9of 1.3436,2
Light1,379,50,8263,1
VC.-symptoms such. tractof 5.478,11,5528,7
Peroral. With CsALiver4,575,50,9320,7
Light2,3for 91.31,4261,7
VC.-symptoms such. tract10,691,45,1748,8
1,0 ppm peakLiver1,0102,70,7777,0

EXAMPLE 9

Repeating the procedure described in Examples 4 and 5, except that the REM groups of rats (three rats-males each) oral introduced respectively dose (5 mg/kg cyclosporine D, cyclosporine G and cyclosporine A; moreover, these doses were introduced separately, and then immediately after 1 hour after administration of the oral dose (9 mg/kg) radioactively labeled paclitaxel. In Fig. 25 illustrates a graphical comparison of the dependences of the concentration of radioactivity in whole blood from time defined for all three groups. Although all three of cyclosporine showed significant activity in promoting oral absorption of paclitaxel, but the greatest activity, enhancing the bioavailability of paclitaxel, discovered cyclosporine D, from which all three subjects cyclosporin has the lowest immunodepressants activity (Jeffery, Clin. Biochem., 24: 15-21 (1991)).

EXAMPLE 10

Conducted a series of experiments in which repeated the procedures described in Examples 4 and 5, and in which groups of three rats each males, oral introduced 5-10 mg/kg of different cyclosporine separately, and then, after 1 hour after administration of the oral dose (8 mg/kg) radioactively labeled paclitaxel. Table 10 illustrates the comparison of AUC and % absorbance values obtained in these experiments, each of which is identified by Protocol number, prefixed with "NP".

Table 10
AUC and % absor the tion for different cyclosporine
ProtocolCyclosporineDose (mg/kg)AUC0-24(ug•EQ. h/ml)% absorption
NP960507And2×513,9142,1
960503And2×1010,1733,6
960503And2×2014,6348,3
NP960507Acetyl And2×58,3925,4
9605072×5is 11.3934,5
960507E2×55,9618,0
960507N2×56,0018,1
960507U2×55,0215,2
NP960103D2×515,9248,2
960103G2×513,2240,0
NP960704 D2×1014,23to 43.1
960704F2×1011,9936,3
NP960605F2×58,9927,2
960605Dihydro A2×58,525,7
NP960801Leu42×57,3824,6
960801Dihydro2×5to 13.0945,1

EXAMPLE 11

Repeating the procedure described in Examples 4 and 5, except that three groups of rats consisting of three rats each males, oral was administered 5 mg/kg cyclosporine a, 50 mg/kg of ketoconazole and 5 mg/kg cyclosporine A+50 mg/kg of ketoconazole; all doses were administered separately, and then after 1 hour after administration of the oral dose (9 mg/kg) radioactively labeled paclitaxel. A graphical comparison of the obtained results are illustrated in Fig. The group that received the combination of ketoconazole and cyclosporine A, unexpectedly discovered for nearly 24-hour time period that significantly higher levels of radioactivity than the group that received the only one of these reinforcing agents.

EXAMPLE 12

Repeating the procedure described in Examples 4 and 5, except that three groups of rats (three rats-males each) oral introduced respectively at 100 mg/kg of captopril separately and in two hours after administration of the oral dose (9 mg/kg) radioactively labeled paclitaxel; 5 mg/kg cyclosporine separately and within one hour after administration of the oral dose (9 mg/kg) radioactively labeled paclitaxel; and 9 mg/kg radioactively labeled paclitaxel. A graphical comparison of the obtained results are illustrated in Fig.

The above experiments revealed a previously unknown and unexpected facts that are of great importance for the clinical treatment of many diseases, including certain types of cancer:

1. Some inhibitors of MDR (P-glycoprotein), as well as other agents that are not known as MDR inhibitors can be administered orally in order to effectively improve the oral bioavailability of active medicinal agents, which still was administered only parenterally, as after oral administration they could not reach therapeutic levels in the blood.

2. Joint introduction-enhancing agents of the present invention together with the target drugs with poor oral bioavailability, allows DOS is iGATE stably supported levels of the target drug in the blood, comparable to the levels obtained when therapy by intravenous infusion, but without their initial sharp increase, and therefore with a lower risk of toxic side effects.

3. Joint oral administration of reinforcing agents and targeted pharmaceutical agents, compared with intravenous administration, increases the concentration of the target agent in the liver, lungs and gastrointestinal tract, which makes this new method of introduction is particularly effective for the treatment of tumors and metastases in the liver.

4. Oral administration of reinforcing agent prior to the introduction of combined oral doses reinforcing agent and the target agent helps to increase the bioavailability of the target drugs to a much higher degree than just joint introduction augmentative and targeted agents without prior introduction of a reinforcing agent. This introduction allows to achieve therapeutic levels of the target medicinal agent in the plasma.

5. Cyclosporine, especially cyclosporin A, D, and F are more effective agents for increasing the bioavailability of anticancer agents than the MDR inhibitors like verapamil and progesterone. Ketoconazole has a remarkable activity aimed at improving oral is biologicheskii availability of the medicinal product, but less than cyclosporine.

In General terms we can say that various aspects of the present invention for the first time allows to perform oral administration dosage forms commonly used pharmaceutical agents, particularly anti-cancer drugs such as paclitaxel and related taxanes and etoposide, which previously could effectively be administered only by intravenous infusion. The use of such oral dosage forms in clinical cancer therapy provides patient comfort, convenience and security, and also helps save funds spent on treatment of patients, hospitals, government and private health insurers.

In addition, this description of the present invention is relevant information regarding the selection of the target and reinforcing agents, as well as time, schemes and doses of their introduction. This information, the methods and compositions of the present invention allow a physician-clinicians to maintain a stable therapeutic levels of drugs that require a narrow range of concentrations in order to avoid unnecessary and often harmful peaks and dips in the levels of concentrations in the blood. In addition, the increased volume of distribution of paclitaxel in the presence of cyclosporine allows PR is dologite, there must be a large number of drugs with antitumor activity.

In addition policecourtneu resistance due to P-glycoprotein, encoded by the genome of MDP1, there is another gene, which was recently installed, is the phenotype policecourtneu resistance in some laboratory systems: the gene encoding a protein associated with policecourtneu resistance, MRP (see, for example, Zaman et al., Proc.NatI. Acad. Sci. USA, 91: 8822-8826,: 1994).

About this new gene and its protein product, membrane-associated 190 kDa-glycoprotein, little is known. Although both genes MRP and MDR1 encode membrane glycoproteins, which may act as carriers of many medicinal agents, but their features and differences, which are probably caused by the substrates and the prognostic value of these two genes. For example, the expression of MRP, but not MDR1 gene, is a good indicator of poor clinical prognosis for patients with neuroblastoma. The proposed MRP-associated proteins is that they serve as a suction pump for conjugates of glutathione S. Thus, molecules that undergo conjugation with glutathione, should be susceptible to the effects of MRP-associated system.

Oral biological available is to be pharmacologically active agents (or the impact of these agents on tumor), which produces resistance under the action of MRP - associated proteins can be increased through joint oral administration of inhibitors of MRP. The preferred implementation of such a method of increasing bioavailability of drugs provides for oral administration of one or more inhibitors of MRP to oral joint introduction of one or more inhibitors of MRP and one or more target agents, which is produced by the MRP-mediated resistance.

Examples of target agents of this type include, but are not limited to) vinylchloride (e.g., vincristine, anthracyclines, epidophyllotoxin (e.g., etoposide) and various taxanes. Examples of MRP inhibitors, which may increase the oral bioavailability of target agents include, but are not limited to, cyclosporine, ketoconazole, and experimental drug VX-710 and vx-853 (Vertex Pharmaceuticals, Inc., Cambridge, MA). The structure of VX-710 and VX-853, and other related compounds disclosed in U.S. patent No. 5192773.

Another method of increasing the oral bioavailability of pharmaceutical agents, which is produced by the MRP-mediated resistance, provides for co-administration with these agents glutathione, or connections, to the verge form conjugated with glutathione products, impeding the functioning of the MRP system and increases the absorption of the target agent from the gut, or increase the systemic impact of targeted agents under MRP-mediated transport.

Another system that is able to carry pallacanestro resistance is the so-called protein associated with resistance in the lungs (LRP)since it was first identified in multidrug-resistant cell lines of lung cancer. This protein is the main structural protein of the so-called vaulted apparatus and represents a widespread cytoplasmic ribonucleoprotein particle, which was given to man from myxomycetes. Inhibition of this system may also positively affect the bioavailability of some agents. The greatest expression of LRP was detected in the epithelial cells with secretory and excretory functions, as well as in cells exposed to constant exposure of xenobiotics, such as cell lines the bronchi and small intestine (Scheffer et al., Nature Medicine, 1: 578-582, 1955). Therefore, this system can also serve as a target in the method of increasing the bioavailability of drugs.

Thus, as indicated above, the methods, compositions and kits used for the purposes of the present invention, can be soo is appropriate manner adapted according to the conditions of practical use.

It should be noted that the above-described variants of the present invention are only illustrative and not restrictive, and therefore it can be made various changes, not beyond being and scope of the invention.

Everything is new and, preferably, protected by the patent, as claimed in the following claims.

1. The method of increasing the bioavailability upon oral administration to a subject taxane, including oral co-administration to a subject taxane and agent, enhancing bioavailability, the agent enhancing bioavailability is ketoconazole, and Texan reaches therapeutic levels of activity of the specified entity.

2. The method according to claim 1, characterized in that taxon selected from the group consisting of paclitaxel, docetaxel and their derivatives and prodrugs.

3. The method according to claim 1, characterized in that the ketoconazole is administered essentially simultaneously with the introduction of texana, before the introduction of taxane or before the introduction of taxane, and simultaneously with the introduction of texana.

4. The method according to claim 1, characterized in that taxon and ketoconazole are entered together in the form of combined oral dosage forms.

5. The method according to claim 1 or 3, characterized in that taxonom is paclitaxel.

6. The method according to claim 5, wherein paclitaxel, wodis is divided daily dose.

7. The method according to claim 1 or 3, characterized in that taxonom is docetaxel.

8. The method according to claim 1, characterized in that taxon, ketoconazole, or both, each is entered in a dosage form selected from the group consisting of tablets and capsules.

9. The method of treatment of a subject suffering from a condition susceptible to taxane, including joint oral administration to a subject taxane and agent, enhancing bioavailability, the agent enhancing bioavailability is ketoconazole, and Texan reaches therapeutic levels of activity of the specified entity.

10. The method according to claim 9, characterized in that taxon selected from the group consisting of paclitaxel, docetaxel and their derivatives and prodrugs.

11. The method according to claim 9, characterized in that the ketoconazole is administered essentially simultaneously with the introduction of texana, before the introduction of taxane or before the introduction of taxane, and simultaneously with the introduction of texana.

12. The method according to claim 9, wherein the subject is human.

13. The method according to claim 9, characterized in that taxon and ketoconazole are entered in separate oral dosage forms.

14. The method according to claim 9, characterized in that taxon and ketoconazole are entered together in the form of combined oral dosage forms.

15. The method according to claim 9 or 11, characterized in that taxonom is paclitaxel is.

16. The method according to item 15, wherein the paclitaxel is introduced in the form of a divided daily dose.

17. The method according to claim 9 or 11, characterized in that taxonom is docetaxel.

18. The method according to claim 10, characterized in that taxon, ketoconazole, or both, each is entered in a dosage form selected from the group consisting of tablets and capsules.

19. The method according to claim 9, wherein the condition is a tumor or malignancy.

20. The method according to claim 19, characterized in that taxonom is paclitaxel.

21. The method according to claim 20, wherein paclitaxel is administered in divided daily doses.

22. The method according to claim 19, characterized in that taxonom is docetaxel.

23. The method according to any of p, 19 and 20, wherein the subject is human.

24. Oral pharmaceutical dosage form for chemotherapy, including Texan and the agent for enhancing the bioavailability of the agent, enhancing bioavailability, is ketoconazole, and Texan reaches therapeutic levels of activity specified subject, when specified oral dosage form is administered to the subject.

25. Dosage form according to paragraph 24, wherein taxon selected from the group consisting of paclitaxel, docetaxel and their derivatives and prodrugs.

26. Dosage form according to paragraph 24, Otley is audacia fact, that taxonom is paclitaxel.

27. Dosage form according to paragraph 24, wherein taxonom is docetaxel.

28. Dosage form according to paragraph 24, characterized in that it is a tablet or capsule.

29. Set for chemotherapy comprising oral dosage form containing an agent that increase the bioavailability of the agent, enhancing bioavailability, is ketoconazole, an oral dosage form, containing taxon, or combined oral dosage form, containing the agent, enhancing bioavailability, which is ketoconazole, and Texan, and oral joint introduction taxane and agent, enhancing bioavailability, achieved levels of therapeutic activity taxane.

30. Set on clause 29, characterized in that it further includes a liner containing printed information on dosing with the joint introduction of ketoconazole and taxane.

31. Set on clause 29, characterized in that it includes a combined dosage form.

32. Set on clause 29, wherein taxonom is paclitaxel.

33. Set on clause 29, wherein taxonom is docetaxel.



 

Same patents:

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to hemin-peptide of general formula I , wherein R1 is ArgTrpHisArgLeuLysGlu(OMe)OH; R2 is -OH; Y is Cl; Me is Fe, or pharmaceutically acceptable salts thereof having virulicidal and anti-viral activity, including activity against herpes virus and HIV, and capability for destroying of λ fag, herpes and HIV DNA. Hemin-peptide fragment also is disclosed.

EFFECT: new anti-viral agent.

2 cl, 5 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to derivatives of 2-aminonicotine amide of the formula (I): , to methods of their synthesis and a pharmaceutical composition based on thereof inhibiting activity of receptor tyrosine kinase vessel endothelial growth factor (VEGF) and to corresponding method for inhibition of activity of VEGF-receptor tyrosine kinase. It is suggested that this activity will allow offering the curative effect in proliferative diseases associated with angiogenesis, in particular, in treatment of tumors, retinopathy or age degeneration of yellow (corneal) spot.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 42 ex

FIELD: medicine, ophthalmology, ophthalmooncology.

SUBSTANCE: one should intravenously inject a photosensitizer photosens at 0.1-1.0 mg/kg patient's body weight. In about 48-72 h since the moment of photosens injection it is important to detect the presence of preparation's therapeutic dosage in the tumor. For this purpose one should specify the coefficient of contrast degree between the tumor and healthy adjacent tissues. Planning of photodynamic therapy should be fulfilled individually by orienting to concrete values of the coefficient of contrast degree in a concrete patient. At the value of coefficient of contrast degree being ≥4, but under 10 it is necessary to irradiate with low single dosages (ranged 80-150 mW/sq. cm) by increasing the number of seances conducted (up to 10). At the value of the above-mentioned coefficient being ≥10.0 irradiation should be carried out once or during 2-3 seances at high single radiation dosages (ranged 150-800 mW/sq. cm). The innovation enables to optimize therapy in patients with intraocular tumors.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to using dicarboxylic acids of the general formula (2): R-CONH-OH (2) wherein R means -HO-HNCO, -HO-NHCOCH-(OH)CH(OH), -HOOC-CH2CH2, -HO-OCCH=CH as inhibitors of metastasis and agents enhancing chemotherapeutic activity of antitumor preparations. Also, invention relates to a method for enhancing effectiveness of cytostatics in carrying out cytostatic chemotherapy of tumors. Method is carried out by using cytostatics in combination with derivatives of dicarboxylic acids of the formula (2). Also, invention relates to a method for inhibition of metastasizing process. Method is carried out by effect of the known cytostatics and derivatives of dicarboxylic acid of the formula (2) on tumor. Proposed substances provide enhancing antitumor and anti-metastatic activity of known cytostatics based on using derivatives of dicarboxylic acids.

EFFECT: valuable medicinal properties of agents and preparations, enhanced effectiveness of metastasizing inhibition.

4 cl, 4 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: method involves impregnating sterile gauze napkins with Tactivin solution, in the amount of 100 mcg per each napkin, and imposing it on mammary gland. Then, variable magnetic field treatment is applied. When applying the procedure one day and one hour prior to operation the napkins are arranged on both sides with respect to nodular formation, 3 cm far from it. When carrying out the procedure at the third day after operation, napkins are placed directly onto zone under operation.

EFFECT: reduced risk of complications in postoperative period.

FIELD: medicine.

SUBSTANCE: method involves concurrently giving Cyclopheron and Licopid under immunogram control at traditional doses and courses. Thus, if even one of parameters of immunogram, carried out in 2 months after treatment, does not reach normative limits, additional Licopid administration is applied under traditional preventive scheme.

EFFECT: enhanced effectiveness of immunocorrective and immononormalizing treatment; reduced risk of complications.

FIELD: medicine, pharmaceutical agents.

SUBSTANCE: disclosed is indolylacetic acid and sodium, potassium and lithium salts thereof having immunomodulatory (based on leukocyte levels in patient blood suffering from viral infection or after cytoctatic chemotherapy), anti-inflammation (based on normalizing of erythrocyte sedimentation rate and after ascyte treatment) and anti-tumor properties (in patient suffering from lymphoma and carcinoma). Said salts are produced by treatment of indolylacetic acid with solution of NaOH, or KOH, or LiOH, addition of heated distilled water in obtained solution, keeping at the same temperature to produce bright solution, followed by cooling and drying.

EFFECT: preparation with increased effectiveness, having no allergic action and other site effects.

3 cl, 5 ex

FIELD: medicine, pharmaceutical agents.

SUBSTANCE: disclosed is A-naphthylacetic acid and sodium, potassium and lithium salts thereof having immunomodulatory (based on leukocyte levels in patient blood suffering from viral infection), anti-inflammation (based on normalizing of erythrocyte sedimentation rate and monocytes in patient blood) and anti-tumor properties (in patient suffering from lymphomatoid granulomatosis and carcinoma of lung). Said salts are produced by treatment of A-naphthylacetic acid with solution of NaOH, or KOH, or LiOH, addition of heated distilled water in obtained solution, keeping at the same temperature to produce bright solution, followed by cooling and drying.

EFFECT: preparation with increased effectiveness, having no allergic action and other site effects.

3 cl, 5 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with methods and compositions for targeted supply of circulation -overlapping solid-phase thrombocytes-binding preparations for treating vascularized tumor or hyperplastic tissue. The solid-phase preparation covered except polystyrene with thrombocytes-binding preparation, such as Willebrand's factor, should be purposefully directed towards vascular net-target in vivo, where it binds and activates thrombocytes which, in their turn, bind and activate other thrombocytes. Variant of composition for inducing thrombogenesis in vivo and containing a solid-phase thrombocytes-binding preparation, except polystyrene, could be consisted of the first binding component and the second binding component, where the first binding component has got binding area for binding a solid-phase preparation with a ligand-receptor complex, and not with a ligand or receptor separately, as for the second binding component it has got binding area for thrombocytes. The innovation provides rapid formation of a dense thrombus that leads to overlapping the circulation in the desired area due to thrombocytic fixation towards the surface of a solid-phase preparation along with increasing its sizes and developing a multi-layer structure of activated thrombocytes as a dense matrix.

EFFECT: higher efficiency.

29 cl, 12 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a compound of the formula (I): wherein X means alkylene group; Y means -CO-, -CS- or -SO2-group; Z represents a simple bond or -NR5-group; R1 represents unsubstituted phenyl or phenyl substituted with halogen atom. (C1-C20)-alkyl group; R2 is chosen from -alkyl, -alkyl-O-alkyl; R3 and R4 represent alkyl; R5 represents hydrogen atom or (C1-C10)-alkyl group; Also, invention describes intermediate compounds - derivatives of imidazopyridine-4-amine, 2-phenoxypyridine and 4-phenoxypyridine. Proposed compounds and pharmaceutical compositions are able to stimulate biosynthesis of different cytokines and can be used in treatment of viral and tumor diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

32 cl, 1 tbl, 9 ex

FIELD: medicine, cardiology.

SUBSTANCE: the present innovation deals with preparing patients to operation on coronary angioplasty and stenting coronary arteries. So, before surgical interference at the background of applying aspirin, thienopyridines, heparin, it is necessary to inject additionally intravenously dalargin by drops in 100 ml physiological solution at the arte of about 5-7 mcg/kg/h at daily dosage being 25-30 mcg/kg and 200 ml rheopolyglucin solution. Subsequent introduction of dalargin of rheopolyglucin should be fulfilled once daily for 4-5 d after operation. The innovation enables to increase the level of cardioprotection and decrease the level of thrombogenesis due to multi-component action, antioxidant one, among them, also, the method in question is of high antinociceptive action due to decreasing the activation of hypothalamo-hypophyseo-adrenal system.

EFFECT: higher accuracy and efficiency of prophylaxis.

2 ex

FIELD: medicine.

SUBSTANCE: method involves applying IAG-laser treatment to exudates fixation region. Then, drug mixture is additionally introduced into lymphatic orbit region. The mixture has Lidocaine 20-40 mg, Dalargin 1-2 mg, Mexidol 50-100 mg, Lidase 16-32 units, Hemase 3000-5000 IU. The drug mixture is introduced into the lymphatic orbit region daily by carrying out pterygopalatine block on the same side with the injured eye with 3-5 blocks in a course.

EFFECT: accelerated postoperative rehabilitation; accelerated exudates destruction; arrested inflammatory process with drug mixture.

3 cl

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an anti-coagulating, anti-thrombocytic, anti-thrombosis, fibrin-depolymerizing and fibrinolytic agent containing heptapeptide selank of the formula: Thr-Lys-Pro-Arg-Pro-Gly-Pro. The claimed agent possesses high activity and effectiveness as compared with the known agents.

EFFECT: enhanced medicinal properties of agent.

2 tbl, 3 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an anti-thrombosis, anti-coagulating, fibrin-depolymerizing and fibrinolytic agent containing the known peptide semax of the formula: Met-Glu-His-Phe-Pro-Gly-Pro. The claimed agent possesses high activity and effectiveness as compared with the known agents.

EFFECT: enhanced medicinal properties of agent.

1 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an anti-thrombosis, anti-coagulating, fibrin-depolymerizing and fibrinolytic agent for intranasal administration containing semax. The claimed agent possesses high activity and effectiveness as compared with the known agents.

EFFECT: enhanced medicinal properties of agent.

1 tbl, 1 ex

FIELD: medicine, stomatology.

SUBSTANCE: one should lance purulent focus, drain it followed by total and local antiphlogistic, immunotropic therapy. As an immunotropic preparation one should apply Deltaran to introduce intranasally per 2 drops into each nasal meatus according to the following scheme: once just before surgical interference, on the 1st d after operation this preparation should be introduced 6 times, and during the next 3 d per 3 times daily. The innovation enables to shorten terms of therapy and patient's staying at the hospital, decreases traumatism and the chance for transmitting infection, also, it is very simple and convenient in usage.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, chemistry of peptides, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an anti-thrombosis, anticoagulant, fibrin-depolymerizing and fibrinolytic agent comprising peptide of the formula: Pro-Arg-Pro-Gly-Pro. The claimed agent possesses high activity and effectiveness as compared with the known agents.

EFFECT: enhanced and valuable medicinal properties of peptide.

1 tbl, 3 ex

FIELD: medicine, peptides, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an agent possessing anti-thrombosis, anti-coagulant, fibrin-depolymerization and fibrinolytic activities and comprising the known peptide semax of the formula: Met-Glu-His-Phe-Pro-Gly-Pro. The claimed agent possesses high activity and effectiveness as compared the known agents.

EFFECT: enhanced and valuable medicinal properties of agent.

1 tbl, 1 ex

FIELD: medicine, peptides, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to an agent possessing anti-coagulant, fibrin-depolymerization, anti-thrombosis and fibrinolytic activities and comprising peptide of the formula: Lys-Pro-Arg-Pro-Gly-Pro. The claimed agent possesses high activity and effectiveness as compared the known agents.

EFFECT: enhanced medicinal effectiveness of peptide.

1 tbl, 3 ex

FIELD: medicine, hepatology, immunology.

SUBSTANCE: invention proposes using an opioid peptide DSLET of the formula: Tyr-D-Ser-Gly-Phe-Leu-Thr used for stimulation of reparative regeneration of liver and correction of immune reactivity under conditions of toxic hepatopathy. Opioid peptide DSLET is administrated by parenteral route (intaperitoneally) in the dose 50 mcg/kg of body mass in 0.1 ml of physiologically solution in course for 10 doses with break for 24 h between injections to experimental animal (rat) with toxic hepatopathy. The advantage of invention involves the possibility for using this peptide in toxic hepatopathy. Invention can be used for stimulation of regeneration of hepatocytes and correction of immune reactivity in experimental toxic hepatopathy.

EFFECT: valuable medicinal properties of agent.

2 tbl, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a composition used in solubilization of paclitaxel. The composition comprises the following components, wt.-%: monoolein, 40-89.99 (or 40-64.7 as variants); oil, 10-59.99 (or 25-49.7 as variants), and paclitaxel, 0.3-4 (or 0.01-10 as variants), and to a method for preparing such composition. Paclitaxel-containing compositions don't comprise potentially toxic surface-active substances, show stability for prolonged time and possess high mucoadhesive capacity and high bioavailability.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

22 cl, 5 tbl, 3 dwg, 19 ex

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