RU2236226C2 - Oral pharmaceutical compositions comprising taxanes and methods for treatment using thereof - Google Patents

Abstract

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions for oral administration in mammals that comprise taxane or taxane derivative (for example, paclitaxel or docetaxel) as an active component and carrying an agent comprising at least 30% of vehicle by mass for taxane wherein indicated vehicle has value HLB at least about 10. Composition can comprise also up to 0-70% of co-solvent reducing viscosity index. Compositions can be components of usual oral pharmaceutical dosed formulations or to exist in the form of bicomponent medicinal agent wherein the first part represents taxane in solubilizing carrying agent and the second part represents a vehicle for taxane in order to promote to oral absorption. Also, invention describes methods for treatment of pathological states that sensitive to taxanes effect and comprising new compositions wherein compositions can be administrated alone or in combination with oral agent enhancing bioavailability. Composition provides the enhanced bioavailability of taxanes and therapeutic level of blood taxanes content.

EFFECT: improved methods for treatment, valuable pharmaceutical properties of compositions.

115 cl, 11 tbl, 10 ex

Description

BACKGROUND OF THE INVENTION

1. Field of invention

The invention relates to compositions for oral administration of paclitaxel and related taxanes to patients and methods of treatment using such compositions.

2. Description of prior knowledge

Many valuable pharmacologically active compounds cannot be effectively administered to patients by the oral route because of their prior or incompatible absorption from the gastrointestinal tract. Therefore, such pharmaceuticals are administered predominantly intravenously by a doctor or other medical professional, which entails noticeable discomfort and possible local injury to the patient, and even requires administration in a hospital with surgical intervention in the case of some iv. infusion.

2325, 1971), которые охарактеризовали его структуру химическими методами и методом рентгеновской кристаллографии. Один из механизмов его активности имеет отношение к способности паклитаксела связывать тубулин, подавляя таким образом рост клеток злокачественной опухоли. Schiff et al., Proc. Natl. Acad. Sci. USA,

1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J.Biol.Chem.,

10435-10441 (1981).One of the important classes of cytotoxic agents that are usually bioavailable when administered orally to humans are taxanes, which include paclitaxel, its derivatives and analogues. Paclitaxel (currently sold by the Bristol-Meyers Squibb Oncology Division under the name TAXOL®; TAXOL) is a naturally occurring diterpene product isolated from Pacific yew (Taxus brevifolia). He is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. (J. Am. Chem. Soc.,

2325, 1971), which characterized its structure by chemical methods and X-ray crystallography. One of the mechanisms of its activity is related to the ability of paclitaxel to bind tubulin, thus inhibiting the growth of cancer cells. Schiff et al., Proc. Natl. Acad. Sci. USA

1561-1565 (1980); Schiff et al., Nature, 277: 665-667 (1979); Kumar, J. Biol. Chem.,

10435-10441 (1981).

583, 1991; McGuire et al., Ann. Intern. Med.,

273, 1989). Он является эффективным при химиотерапии некоторых типов новообразований, включая таковые молочной железы (Holmes et al., J. Nat. Cancer Inst.,

1797, 1991), а также принят для лечения рака молочной железы. Он является потенциальным кандидатом для лечения новообразований кожи (Einzig et al., Proc. Am. Soc. Clin. Oncol.,

46), рака легких и карцином головы и шеи (Forastire et al., Sem. Oncol.,

56, 1990). Данное соединение также обладает возможным потенциалом в лечении поликистоза почек (Woo et al., Nature, 368:750, 1994) и малярии.Paclitaxel is accepted for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine,

583, 1991; McGuire et al., Ann. Intern. Med.,

273, 1989). It is effective in the chemotherapy of certain types of neoplasms, including those of the mammary gland (Holmes et al., J. Nat. Cancer Inst.,

1797, 1991), and also adopted for the treatment of breast cancer. He is a potential candidate for the treatment of skin neoplasms (Einzig et al., Proc. Am. Soc. Clin. Oncol.,

46), lung cancer and carcinomas of the head and neck (Forastire et al., Sem. Oncol.,

56, 1990). This compound also has potential in the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750, 1994) and malaria.

Paclitaxel is only slightly soluble in water, and this creates significant problems in the development of suitable injection and infusion compositions useful for anticancer chemotherapy. Some paclitaxel formulations have been developed for iv. infusion using CREMOPHOR EL ™ (polyethoxylated castor oil) as a drug carrier due to the insolubility of paclitaxel in water. For example, paclitaxel, used in a clinical trial under the auspices of the NCI, was part of a composition based on 50% CREMOPHOR EL ™ and 50% dehydrated ethyl alcohol. However, CREMOPHOR EL ™ when administered intravenously is toxic in itself and causes vasodilation, shortness of breath, lethargy, hypotension and death in dogs. It is also suggested that it is at least partially responsible for allergic reactions observed during the administration of paclitaxel, although there is some evidence that paclitaxel alone can provoke acute reactions even in the absence of Cremophor.

In attempts to increase the solubility of paclitaxel and to develop safer clinical compositions, the studies focused on the synthesis of paclitaxel analogues in which the 2 'and / or 7 positions are replaced by groups that can increase the solubility in water. Such attempts led to the production of prodrug compounds, which are more soluble in water than the parent compound, and which upon activation exhibit cytotoxic properties. One important group of such prodrugs includes 2'-salts of paclitaxel and docetaxel, in particular, salts of 2'-methylpyridinium mesylate (2'-MRM).

When administered orally, paclitaxel is very poorly absorbed (less than 1%); see Eiseman et al., Second NCI Workshop on Taxol and Taxus (Sept. 1992); Suffness et al., In Taxol Science and Application (CRC Press 1995). Eiseman et al. indicate that paclitaxel when administered orally has a bioavailability of 0%, a Suffness et al. report that oral dosing of paclitaxel seems impossible, since oral administration of antitumor activity has not been proven at doses up to 160 mg / kg / day. For this reason, according to the prior art in the art, paclitaxel was not administered to patients orally, and, of course, was not used in this way in the course of treatment of diseases treatable with paclitaxel.

Docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-N-deacetylpaclitaxel) became commercially available under the name TAXOTERE® (TAXOTHER; Rhone-Poulenc-Rorer S.A.) in a parenteral form for the treatment of breast cancer. To date, no references have been made to the oral absorption of docetaxel in animals or patients in the scientific literature.

It is suggested that in some cases, the poor or absent bioavailability of a drug, such as paclitaxel, after oral administration is the result of the activity of a multi-drug transporter, a membrane-bound P-glycoprotein, which functions as a non-volatile transporter or leak pump to reduce intracellular drug accumulation by displacing xenobiotics from the cell . This P-glycoprotein has been identified in normal tissues of the secretory endothelium, such as the biliary lining, the ciliary edge of the proximal tubule in the kidney and the surface of the intestinal lumen, and in the vascular endothelial cells that form the blood-brain barrier, placental and testicular barriers.

143, 1994); доксорубицина (Bartlett et al., J. Clin. Oncol.,

835-842, 1994) и этопозида (Lum et al., J. Clin. Oncol.,

1635-42, 1992), причем все из них являются противораковыми средствами, известными как зависимые от мультилекарственной резистентности (MDR). Данные испытания показали, что пациенты, получавшие циклоспорин внутривенно перед или одновременно с противораковыми лекарственными средствами, обладали более высоким содержанием данных лекарственных средств в крови, преимущественно за счет сниженного клиренса организма, и проявляли ожидаемую токсичность при существенно более низких уровнях дозы. Эти результаты указывают на то, что сопутствующее введение циклоспорина подавляло MDR-действие Р-гликопротеина, приводя к большему внутриклеточному накоплению терапевтических средств. Для общей дискуссии по фармакологическим применениям ингибиторов Р-гликопротеина для клинического использования см. Lum et al., Drug Resist. Clin. Onc. Hemat.,

319-336 (1995); Schinkel et al., Eur. J. Cancer,

1295-1298 (1995).It is believed that the P-glycoprotein leakage pump prevents the penetration of certain pharmaceutical compounds through the mucous cells of the small intestine and, therefore, from absorption into the systemic circulation. It has been shown that a number of non-cytotoxic pharmacological agents are inhibited by P-glycoprotein, including, among others, cyclosporin A (also known as cyclosporin), verapamil, tamoxifen, quinidine and phenothiazines. Many of these studies are aimed at achieving greater accumulation of intravenously administered cytotoxic drugs inside tumor cells. In fact, clinical trials have been conducted to study the effects of cyclosporin on the pharmacokinetics and toxicity of paclitaxel (Fischer et al.,. Proc. An. Soc. Clin. Oncol.,

143, 1994); doxorubicin (Bartlett et al., J. Clin. Oncol.,

835-842, 1994) and etoposide (Lum et al., J. Clin. Oncol.,

1635-42, 1992), all of which are anticancer drugs known as multidrug resistance (MDR). The test data showed that patients who received cyclosporin intravenously before or simultaneously with anti-cancer drugs had a higher content of these drugs in the blood, mainly due to reduced body clearance, and showed the expected toxicity at significantly lower dose levels. These results indicate that concomitant administration of cyclosporin suppressed the MDR effect of P-glycoprotein, leading to greater intracellular accumulation of therapeutic agents. For a general discussion on the pharmacological uses of P-glycoprotein inhibitors for clinical use, see Lum et al., Drug Resist. Clin. Onc. Hemat.,

319-336 (1995); Schinkel et al., Eur. J. Cancer,

1295-1298 (1995).

In the studies described above regarding the use of cyclosporine to increase pharmaceutical levels in the blood, active antitumor agents and cyclosporin were administered intravenously. In these publications, it was not suggested that cyclosporine could be administered orally to significantly increase the bioavailability of orally administered anticancer drugs and other pharmaceuticals, which themselves are poorly absorbed in the intestine without causing highly toxic side effects. None of the published studies provides any rules for the use of effective oral administration to people of drugs with reduced bioavailability, such as paclitaxel, for example, an indication of the corresponding dose limits and time schedule for the administration of specific target drugs, and bioavailability enhancers, which are most suitable for improving the oral absorption of each target drug or class of drugs.

In PCT published application WO 95/20980 (published August 10, 1995) Benet et al. describe a method aimed at increasing the bioavailability of orally administered hydrophobic pharmaceutical compounds. This method involves the oral administration to patients of such compounds simultaneously with a bioenhancer, including an inhibitor of the cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein-mediated membrane transporter. However, Benet et al. essentially did not provide means to determine which particular bioavailability enhancing agent would improve the availability of specific “target” pharmaceutical compounds, nor did they provide specific dose values, regimens, and regulations for administering the enhancing or target agent. In fact, although Benet et al. many potential enhancers (P450 3A inhibitors) and target drugs (P450 3A substrates) are listed, the only combination of the amplifier and the target agent, confirmed in the application by any experimental evidence, is ketoconazole as an amplifier and cyclosporin A as the target drug.

When describing the main characteristics of compounds that can be used as bio-enhancers that lower the activity of the P-glycoprotein transporter, Benet et al. note that they are hydrophobic compounds that basically, but not necessarily, contain two aromatic rings lying in the same plane, a positively charged nitrogen group or carbonyl group - a class that includes a huge number of compounds, most of which will not have the required enhancing absorption activity in the case of a specific target funds. Moreover, the target drug classes described by Benet et al. Include a large number of pharmaceuticals listed in the Physician ^, s Desk Reference. These inclusion criteria are not meaningful for medical practitioners who need safe, practical, and effective methods of oral administration of specific pharmaceuticals.

In general, Benet et al. they do not provide guidelines that medical and pharmaceutical specialists can follow to determine suitable bio-enhancer / target drug combinations or to draw up specific regimens and treatment regimens that will make target drugs therapeutically effective when administered orally to patients. Benet et al. nor do they provide anything regarding the possible oral administration of paclitaxel and other taxanes to humans in the presence of therapeutic efficacy and acceptable toxicity.

PCT published application WO 97/15269, which corresponds to U.S. Patent Application Serial No. 08/733142 (preceding this application) and which is in common ownership with the present application, discloses that various therapeutically effective pharmaceutical “target agents” exhibiting low oral bioavailability, can become bioavailable with therapeutic levels of the active agent in the blood by co-administration of specific bioavailability enhancing agents. Preferred examples of such target agents described in WO 97/15269 include cyclosporins, for example, cyclosporin A, D and G. Preferred examples of target agents include a taxane class of anti-neoplastic agents, in particular paclitaxel. Also described are therapeutic schedules and dose rates for co-administration of target agents and enhancers. All disclosures of published application WO 97/15269 are incorporated herein by reference.

Neither WO 97/15269 general tenancy application, nor any prior art messages in this area describe classes of oral formulations or compositions containing an active target agent, for example, paclitaxel, which are mainly adapted for co-administration with an oral bioavailability agent with the goal is to achieve therapeutic levels of the target drug in the blood, which was previously considered impossible with oral administration.

SUMMARY OF THE INVENTION

The present invention relates to oral pharmaceutical compositions containing taxane antitumor agents, for example, paclitaxel or docetaxel, which, when administered to a mammal, preferably together with an oral bioavailability agent, provide significant absorption of the taxane agent from the gastrointestinal tract into the bloodstream to achieve therapeutically significant levels active drug content.

The compositions of the invention include a carrier agent, which comprises a carrier in which the taxane agent is dissolved or dispersed. The carrier means may also include a viscosity-reducing cosolvent, which renders the carrier agent more fluid at body temperature or at least decreases the melting point of the carrier agent below body temperature, and may also provide increased solubility of the taxane.

The carrier used in the new compositions is preferably a non-ionic surfactant or emulsifier characterized by a hydrophilic lipophilic balance coefficient (HLB) of at least about 10. A viscosity reducing co-solvent is selected, for example, from organic solvents suitable for oral administration the introduction of vegetable oils, hydrogenated or polyoxyethylated castor oil, citrate esters and saturated polyglycolized glycerides. Certain saturated polyglycolized glycerides may also serve as carriers in the compositions of the invention.

The new pharmaceutical compositions contain about 2-500 mg / ml or mg / g taxane and preferably about 2-50 mg / ml or mg / g taxane. The therapeutically inactive carrier means comprises at least 30% by weight of the carrier and about 0-70% of a co-solvent and may also contain conventional pharmaceutical additives and excipients, such as flavoring and coloring agents and the like.

Another aspect of the invention relates to methods for treating mammals suffering from diseases subject to taxanes by administering to such patients the oral pharmaceutical compositions of the invention, preferably by co-administration of a bioavailability enhancing agent.

DETAILED DESCRIPTION OF THE INVENTION

The oral pharmaceutical compositions of the invention contain at least two components: an active agent comprising a taxane, preferably an antitumor agent paclitaxel or docetaxel, and a therapeutically inactive carrier agent comprising a pharmaceutically acceptable carrier for said taxane.

In order to obtain compositions for oral administration, which are liquid or at least in fluid form at a body temperature (approximately 37 ° C), which is mainly required for oral bioavailability, in some cases it is necessary to add an additional component to the carrier: a viscosity-reducing cosolvent, which reduces the viscosity and increases the fluidity of the carrier at body temperature, and can also increase the amount of active agent that can be dissolved or dispersed but in the carrier facility, as compared with using a single carrier.

New compositions may include more than one taxane as an active ingredient and more than one carrier and / or cosolvent as inactive carrier components. The carrier means comprises at least 30% by weight of the carrier, preferably 30-90% by weight. Preferred carriers for use according to the invention are non-ionic surfactants or emulsifiers characterized by HLB values of at least about 10. Such non-ionic surfactants or emulsifiers have been found to be not only compatible carriers for lipophilic taxanes (which are only slightly soluble) in water), but also contribute to the absorption of the active ingredient from the gastrointestinal tract into the bloodstream.

Preferred carriers for use according to the invention include, for example, Vitamin E TPGS (d-α-tocopheryl polyethylene glycol succinate 1000; Eastman Chemical Company Co., Kingsport, TN); saturated polyglycolized glycerides, such as GELUCIRE ™ and LABRASOL ™ products (Gattefosse Corp., Westwood, NJ), which include C ₈ -C ₁₈ fatty acid glycerides; CREMOPHOR ™ EL or RH40 modified castor oils (BASF, Mt Olive, NJ); MYRJ ™ polyoxyethylated stearate ester (ICI Americas) and TWEEN ™ polyoxyethylated sorbitan esters (ICI Americas) and CRILLET ™ (Croda Inc., Parsipanny, NJ); BRIJ ™ polyoxyethylene fatty ethers (ICI Americas); modified (polyethylene glycol) glycerides of almond and corn oils CROVOL ™ (Croda Inc.); EMSORB ™ diisostearate sorbitan esters (Henkel Corp., Ambler, PA); SOLUTOL ™ polyoxyethylene hydroxystearates (BASF); and β-cyclodextrin. Only such members of these surfactant families that are characterized by HLB values of about 10 or higher can be used as carriers in the present compositions.

Preferred viscosity reducing cosolvents include, for example, PHARMASOLVE ™ (N-methyl-2-pyrrolidone, International Specialty Products, Wayne, NJ); MIGLYOL ™ glycerol or propylene glycol esters of caprylic and capric acids (Huels AG, Marl, Germany); polyoxyethylated hydroxystearates (e.g. SOLUTOL ™ HS 15); TWEEN ™ polyoxyethylene sorbitan esters; caprylic and capric acid polyethylene glycol esters (Huels AG); modified castor oils (such as CREMOPHOR ™ EL or RH 40); vegetable oils, such as olive oil, polyoxyethylated fatty ethers or modified castor oils, certain saturated polyglycolized glycerides (such as LABRASOL ™); citrate esters such as tributyl citrate, triethyl citrate and acetyl triethyl citrate; propylene glycol, alone or in combination with PHARMASOLVE ™; ethanol; water; and low molecular weight polyethylene glycols like PEG 200 and 400.

The carrier means contains about 0-70% by weight of a co-solvent, and preferably about 10-50% by weight.

It should be noted that some of the materials established as carriers exhibit the property of being effective cosolvents either by themselves or in combination with other viscosity reducing agents for certain other carriers. In general, any solvent in which paclitaxel or other taxanes is at least moderately soluble at body temperature or by gentle heating can be used as a co-solvent in the carrier of the new compositions. Preferred cosolvents are those in which at least 25 mg / ml paclitaxel or another taxane can be dissolved at about 20-25 ° C.

The concentration of the active taxane ingredient or ingredients in the composition may vary depending on the solubility of the active agent in the carrier (s) or the carrier (s) / co-solvent (s) system and the desired total dose of taxane to be administered orally to the patient. The concentration of taxane may range from about 2 to about 500 mg / ml or mg / g in a carrier, and preferably from about 2 to about 50 mg / ml or mg / g.

The compositions of the invention can be prepared in the usual manner known to those skilled in the pharmaceutical art for the preparation of liquid or other flowable oral formulations containing surfactant carriers and lipophilic active ingredients. Since most preferred carriers at room temperature are very viscous and in some cases retain a relatively high viscosity even after adding a co-solvent in a small ratio, when preparing new compositions, it is generally preferable to mix the carriers and cosolvents used, add the taxane active ingredient and heat the resulting mixture as a result, the mixture, for example, to about 40 ° C. This method provides pure solutions. However, some cosolvents, in particular PHARMASOLVE ™, reduce the viscosity of the carrier and increase the solubility of the taxane to such an extent that the composition can be prepared by stirring at room temperature without heating.

It is desirable that the viscosity of the final composition does not exceed 40,000 centipoise at body temperature (approximately 37 ° C).

Oral compositions of the invention may exist in the form of true solutions, emulsions or even suspensions, but solutions of the active taxane ingredient in a carrier or carrier / cosolvent system are preferred.

413-417, 1994).The present invention also encompasses methods of treating people suffering from malignant tumors, tumors, Kalosha’s sarcoma, malignant neoplasms, uncontrolled tissue or cell proliferations secondary to tissue damage, and any other pathological conditions that are susceptible to taxanes, such as paclitaxel and docetaxel and / or prodrugs and derivatives of the above compounds, new pharmaceutical compositions for oral administration. Among the types of carcinomas that can be treated orally with paclitaxel, docetaxel, other taxanes and their prodrugs and derivatives are particularly effective, are hepatocellular carcinoma and hepatic metastases, cancers of the gastrointestinal tract, pancreas, prostate and lung and Kaposi's sarcoma. Examples of non-malignant pathological conditions that can be effectively treated with these active agents administered orally according to the present invention are uncontrolled tissue or cell proliferations secondary to tissue damage, polycystic kidney disease, inflammatory diseases (e.g. arthritis), and malaria, including malaria infection parasites resistant to chloroquine and pyrimethamine (Pouvelle et al., J. Cin. Invest.,

413-417, 1994).

Although some of the oral pharmaceutical compositions of the invention may provide therapeutic levels of the taxane active ingredient in the blood with only their administration, the preferred method of the invention for treating mammals (in particular humans) suffering from pathological conditions susceptible to taxanes is the administration of oral compositions containing a taxane target agent, simultaneously with the introduction of at least one dose of a bioavailability enhancing agent.

A preferred embodiment of the method of the invention for oral administration to humans of paclitaxel, its derivatives, analogs and prodrugs and other taxanes includes oral administration to a human of an oral absorption or bioavailability enhancing agent, simultaneously with or previously, or both simultaneously and before oral administration to increase absorption intact target funds in the bloodstream.

Enhancers for oral administration that can be used in carrying out the preferred embodiment of the invention include the following non-limiting examples:

Cyclosporins, including cyclosporins A to Z, but especially cyclosporin A (cyclosporin), cyclosporin F, cyclosporin D, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSS-833, SDZ-NIM 811 ¹ (both from Sandoz Pharmaceutical Corp). The structures of cyclosporins AZ are described in table 1.

¹ SDZ-NIM 811 is (Me-Ile-4) -cyclosporin, an antiviral, non-immunosuppressive cyclosporin.

403-407 (1995). Настоящее изобретение охватывает природные, полусинтетические и синтетические аналоги циклоспоринов.Cyclosporins are a group of nonpolar cyclic oligopeptides (some of which are immunosuppressive) produced by organisms of the genus Topycladium, including, for example, Topycladium inflatum Gams (formerly called Trichoderma polysporum), Topycladium terricola and other types of imperfect fungi. The main component, cyclosporin A (cyclosporin or CsA) was identified along with some other minor metabolites, for example, cyclosporins B to Z, some of which exhibit significantly less immunosuppressive activity than cyclosporin A. Many synthetic and semisynthetic analogs were also obtained. In general, see Jegorov et al., Phytochemistry,

403-407 (1995). The present invention encompasses natural, semi-synthetic and synthetic analogues of cyclosporins.

Cyclosporins are neutral, lipophilic, cyclic undecapeptides with a molecular weight of approximately 1200. They are used intravenously or orally as immunosuppressants, primarily in organ transplantation and some other conditions. Cyclosporins, in particular cyclosporin (cyclosporin A), are known inhibitors of the P-glycoprotein leakage pump and other conveyor pumps, as well as some P450 degradation enzymes, but so far no effective regulations for the clinical use of this property have been brought to the level of clinical and commercial implementation or approval by regulatory authorities.

The dosage of the enhancing agent to be co-administered with the target agent of the invention is from about 0.1 to about 20 mg / kg of the patient’s body weight. “Co-administration” of an enhancing agent includes: essentially simultaneously administering with the target agent (or in less than 0.5 hours, in less than 0.5 hours, or together); administration in advance, from about 0.5 to about 72 hours, prior to administration of the target agent; or both, that is, one or more doses of the same or different reinforcing agents, which give at least 0.5 hours before, and one dose, administered essentially simultaneously (or together, or immediately before or after) with the target agent. In addition, “coadministration” encompasses the administration of more than one dose of the target agent over a period of 72 hours after the dose of the enhancing agent, in other words, the enhancing agent (s) need not be reintroduced before or with each administration of the target agent, but it may administered intermittently during the course of treatment.

The dosage of orally administered taxane-based target agents will vary from compound to compound, depending on their therapeutic index, requirements for treatment conditions, subject's condition, and so on. The method according to the invention makes it possible to orally administer paclitaxel and other taxanes ranging from about 20 mg / m ² to about 1000 mg / m ² (based on the patient’s body surface area) or from about 0.5-30 mg / kg (based on patient’s body weight) in the form of one or divided (2-3) daily doses, and maintain the content of paclitaxel in human plasma in the range of 50-500 ng / ml for a long period of time (for example, 8-12 hours) after each oral dose . These levels are at least comparable to those obtained at 96-hour iv. paclitaxel infusion therapy (which causes the patient great inconvenience, discomfort, loss of full time, risk of infections, etc.). Moreover, such plasma concentrations of paclitaxel are more than sufficient to provide the required pharmacological activity of the target drug, for example, inhibition of tubulin breakdown (which occurs at levels of approximately 0.1 μM, or approximately 85 ng / ml) and inhibition protein isoprenylation (which occurs at levels of approximately 0.03 μM, or approximately 25 ng / ml), which are directly related to its antitumor effects through inhibition of tions oncogenes and other signal transduction proteins that play a pivotal role in cell growth regulation.

Two or more enhancing agents and / or two or more different taxane target agents may be administered together, alternatively or intermittently in all of the various aspects of the method of the invention.

As noted above, one paclitaxel administered orally (for example, in solid dosage form or in a liquid carrier which does not contain an oral absorption carrier) exhibits a bioavailability close to zero. In order to be considered an oral bioavailable pharmaceutical composition containing paclitaxel or other taxanes for the purposes of the present invention, the composition must meet the following criteria: when the composition is administered orally to a mammal (e.g., a laboratory rat or patient), i.e., is absorbed by the subject one hour after administration effective oral dose of an oral bioavailability enhancing agent; the amount of active ingredient that enters the bloodstream is at least 15% of the amount Released to the bloodstream in the case of administration to a subject of the same dose of paclitaxel intravenously in a standard carrier vehicle for intravenous administration, e.g., in the carrier means CREMOPHOR ™ EL / ethanol. A close percentage of absorption is obtained by comparing the corresponding values of the AUC (area under the curve) of the curve of the level of taxane in the blood depending on the time built after oral administration and the corresponding curve built after intravenous administration.

A bioavailability enhancing agent preferred for use when performing an experimental determination of whether a given oral composition meets the criterion of 15% w / w. The intake is cyclosporin A, for example, in a single oral dose of CsA equal to 5 mg / kg.

New pharmaceutical compositions may be administered in any known pharmaceutical dosage forms. For example, the compositions may be encapsulated in soft or hard gelatin capsules and may be administered in the form of a liquid preparation. Each dosage form, in addition to the essential components of the composition (at least one carrier and one taxane active ingredient, and in some cases at least one co-solvent), may include conventional pharmaceutical excipients, diluents, sweeteners, flavors, colorants, and any other inert ingredients typically included in the composition of dosage forms intended for oral administration (see, for example, Remington's Pharmaceutical Sciences, 17 ^th Ed., 1985).

The exact amounts of each of the target drugs included in the oral dosage forms will vary depending on the age, weight, disease and condition of the patient. For example, dosage forms of paclitaxel or another taxane may contain sufficient amounts of the target agent to provide a daily dose of about 20-1000 mg / m ² (based on the surface area of the patient or mammal) or about 0.5-30 mg / kg (from calculation based on the body weight of the patient or mammal) in the form of one or divided (2-3) daily doses. Preferred dosage amounts are about 50-200 mg / m ² or about 2-6 mg / kg.

The dosage schedule for the treatment method of the present invention, for example, the treatment of diseases amenable to paclitaxel, with oral dosage forms of paclitaxel, administered together with enhancing agents, can also be established taking into account the characteristics of the patient and the condition of the disease. Preferred dosage regimens for administering paclitaxel orally are: (a) daily administration to a patient, if necessary, of 1-3 equally divided doses of about 20-1000 mg / m ² (based on body surface area) and preferably about 50-200 mg / m ² , despite the fact that the described daily administration continues for 1-4 consecutive days every 2-3 weeks, or (b) administration for one day of each week. The previous schedule is comparable with the 96-hour infusion of paclitaxel every 2–3 weeks, which is considered to be some of the most preferred intravenous / intravenous regimens. treatment.

Oral administration of taxanes of the present invention can significantly reduce toxic side effects in many cases, compared with currently used iv. therapy. Compared with the sudden and rapid occurrence of high concentrations in the blood, which usually happens in the case of iv. infusion, absorption of the active agent through the intestinal wall (which is facilitated by an enhancing agent) provides a more gradual achievement of a given level in the blood and stable, stationary maintenance of such a level in an ideal or close to it limit for a long period of time.

In a further embodiment of the present invention, the oral compositions of the invention can be administered in a two-component drug system. So, for example, it may be certain carriers that are within the scope of the present invention, which it is desirable to use in carrier vehicles for certain taxane agents because of their ability to solubilize the taxane and its oral absorption, but the carrier may be chemically or physically incompatible with the required additional ingredients such as flavors and colorants. In such cases, the active ingredient may be administered to the patient as a first part of the drug in a relatively small volume of any suitable liquid solubilizing carrier vehicle (such as water, CREMOPHOR ™ or ethanol) that may be sweetened, aromatic or colored as needed to mask the unpleasant taste of the carrier and make it more enjoyable. The introduction of the active ingredient may be followed by the introduction of the second part of the drug: a larger volume of liquid, for example, from 1 to 8 ounces (30-240 ml), containing at least one carrier or carrier / cosolvent system according to the invention. It was found that the introduction of a second, “haunting” composition shortly after the taxane active ingredient can delay the precipitation of taxane, which could otherwise occur after it enters the gastric juice, and promote oral absorption at a level comparable to that observed when the taxane is mixed with the carrier and introduced simultaneously with it.

Illustrative examples of “haunting” compositions that can be used in a two-component oral taxane drug include:

a) 2-20% (by weight) of vitamin E TPGS + water as needed;

b) 2-25% Vitamin E TPGS + 2 - 25% PHARMSOLVE ™ + water as needed;

c) 2-20% Vitamin E TPGS + 2 - 25% propylene glycol + water as needed.

In accordance with another aspect of the invention, the oral compositions of the invention may contain not only one or more taxane active ingredients, but also one or more bioavailability agents in a combined dosage form. For example, such a combined dosage form may contain from about 0.1 to about 20 mg / kg (based on average patient body weight) of one or more cyclosporins A, D, C, F and G, dihydro-CsA, dihydro-CsC and acetyl-CsA together from about 20 to about 1000 mg / m ² (based on the average surface area of the patient’s body), and preferably about 50-200 mg / m ^{2 of} paclitaxel, docetaxel, other taxane or derivatives of paclitaxel or docetaxel.

The compositions and methods of the present invention provide many advantages compared with the previous intravenous compositions containing paclitaxel and other taxanes and the intravenous modes of administration preceding in this field. In addition to the issues of reduced toxicity, patient convenience and comfort, ease of administration and reduced cost, which were discussed above, the invention makes it possible to administer to patients potent taxane antitumor agents with a greatly reduced likelihood of developing allergic hypersensitivity reactions that are common with iv. administered. Thus, there may be no need for premedication modes of N-1 and N-2 blockers and steroids.

The present invention also makes it possible to administer taxanes, for example paclitaxel, at relatively infrequent daily doses (for example, approximately twice a day) and according to regulations that, on the other hand, could not be possible or practiced with the intravenous route of administration. The use of a bioavailability enhancer (e.g., cyclosporin A) promotes the oral absorption of paclitaxel in the first dose, and if a second dose of paclitaxel is to be administered later that day, additional use of cyclosporin A may even be unnecessary. Thus, paclitaxel can be administered intermittently in a single dose according to a fixed schedule (weekly, once every two weeks, etc.) or continuously for a period of consecutive days (for example, 4 days) every 2-4 weeks in order to maintain levels of its content within a safe and effective “window”.

The following examples illustrate various aspects of the invention. However, these examples in no way limit the invention or the listing of specific active ingredients, carriers, joint solubilizers, enhancers, dosage values, test procedures or other parameters that should be used solely for carrying out the invention.

EXAMPLE 1

Animal Screening Model

Groups of three male rats each did not receive food for 16-18 hours before a dose of radioactively labeled ³ H paclitaxel was administered. Each group of animals received one oral dose of cyclosporin A (5 mg / kg) before a dose of the experimental oral composition of paclitaxel was administered. One hour after the dose of cyclosporine was administered, each group received approximately 9 mg / kg paclitaxel orally in the form of a composition of the invention. Each of the groups received a different oral composition.

Blood samples were taken from each animal 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after the dose of paclitaxel.

Blood samples were burned and their total radioactivity was measured.

Using the levels of total blood radioactivity (corresponding to blood concentrations of ³ H-paclitaxel), we plotted their dependence on time after the dose was administered. Data for each group of rats were compiled as AUC, C _max and T _max .

The percent absorption of ³ H-paclitaxel for each group of animals was calculated by comparing the average PPC in each group with the corresponding average PPC of the control group of rats, which were administered ³ H-paclitaxel (9 mg / kg) intravenously in the form of PAXENE ™ (Baker Norton Pharmaceuticals, Miami, PL), which includes CREMOPHOR ™ EL, ethanol and citric acid.

Table 2 lists all carriers and carrier / cosolvent combinations that were formulated in paclitaxel-containing oral compositions of the invention, were tested in rats according to the procedure described above, and, as shown, provided experimental animals with a percent absorption rate of 15% or higher by compared with paclitaxel iv.

EXAMPLE 2

Polyoxyethylated (POE) sorbitan fatty acid esters as carriers

Table 3 lists the carrier formulations comprising certain POE sorbitan fatty acid esters as carriers for oral paclitaxel as such or in combination with a co-solvent. For compositions where more than one component is present in the carrier, the mass ratios of the components are given. Each of these formulations was tested on the animal models described in Example 1, and it was found that the percentage of absorption of paclitaxel after oral administration was higher (in some cases much higher) than 15% of the absorption of an intravenous approximately comparable dose of paclitaxel. Table 3 shows the total dose of paclitaxel included in each carrier, as really introduced by the experimental animals, the concentration of paclitaxel in the composition, the HLB value of the carrier, the average value of the AUC for the group of rats receiving the composition and the percentage of absorption of paclitaxel compared to rats receiving in. /in. introduction.

EXAMPLE 3

POE alkyl ethers as carriers

Table 4 relates to carrier compositions containing POE alkyl ethers as carriers. The indicated data is the data described in the previous example in accordance with table 3.

EXAMPLE 4

POE stearates as carriers

Table 5 relates to carrier compositions containing stearates as POE carriers. These data are the data described in example 2 in accordance with table 3.

EXAMPLE 5

Ethoxylated Modified Triglycerides as Carriers

Table 6 relates to carrier compositions containing ethoxylated modified triglycerides as carriers. These data are the data described in example 2 in accordance with table 3.

EXAMPLE 6

POE 660 hydroxystearates as carriers

Table 7 relates to carrier compositions containing POE 660 hydroxystearates as carriers. These data are the data described in example 2 in accordance with table 3.

EXAMPLE 7

Saturated polyglycosylated triglycerides as carriers

Table 8 relates to carrier compositions containing saturated polyglycosylated triglycerides as carriers. These data are the data described in example 2 in accordance with table 3.

EXAMPLE 8

TPGS Vitamin E Systems as Carriers

Table 9 relates to carrier formulations containing TPGS as vitamin E carriers. These data are the data described in example 2 in accordance with table 3.

EXAMPLE 9

POE and hydrogenated derivatives of castor casel as carriers

Table 10 relates to carrier compositions containing POE and hydrogenated castor oil derivatives as carriers. These data are the data described in example 2 in accordance with table 3.

EXAMPLE 10

Polysorbate-based media 80

Table 11 relates to carrier compositions containing polysorbate 80 and at least one carrier.

These data are the data described in example 2 in accordance with table 3.

Thus, it is shown that the provided compositions and methods achieve various objectives of the invention and are well adapted to meet the conditions of practical use.

Since embodiments of the above invention are possible, and since various changes may be made in the above embodiments, it should be obvious that all the issues discussed should be interpreted as illustrative, but not in the sense of limitation.

Something new that is claimed and requires patent protection is described in the following claims.

Claims (115)

1. A pharmaceutical composition for oral administration to a mammal, comprising a) a taxane or taxane derivative as an active ingredient; b) a carrier agent comprising at least 30% by weight of a taxane carrier, said carrier having an HLB value of at least about 10, and the carrier agent further comprises about 0-70% by weight of a co-solvent that reduces the viscosity of the carrier agent. 2. The composition according to claim 1, where the specified carrier includes at least one non-ionic surfactant or emulsifier. 3. The composition of claim 2, wherein said surfactant or emulsifier is selected from the group consisting of Vitamin E TPGS, saturated polyglycosylated glycerides, modified castor oils, polyoxyethylated esters of stearate, polyoxyethylated sorbitan ester, polyoxyethylated fatty ethers, modified glycerides almond and corn oils, sorbitan esters of diisostearate, polyoxyethylated hydroxystearates and β-cyclodextrin. 4. The composition of claim 3, wherein said saturated polyglycosylated glycerides include C ₈ -C ₁₈ fatty acid glycerides. 5. The composition according to claim 3, where these modified castor oils are polyoxyethylene or hydrogenated castor oils. 6. The composition according to claim 3, where the polyoxyethylene fatty ethers are stearyl or oleyl ethers. 7. The composition according to claim 3, where these modified glycerides of almond and corn oils include polyethylene glycol glycerides of almond or corn oils. 8. The composition according to claim 1, where the carrier means contains approximately 30-90% by weight of the carrier. 9. The composition according to claim 1, where the taxane is dissolved or dispersed in the carrier. 10. The composition according to claim 1, where the concentration of taxane in the carrier is approximately 2-500 mg / ml or mg / g 11. The composition according to claim 1, where the concentration of taxane in the carrier is approximately 2-50 mg / ml or mg / g 12. The composition according to claim 1, where in the co-solvent is capable of dissolving at least about 25 mg / ml taxane at about 20-25 ° C. 13. The composition according to claim 1, where the carrier means contains approximately 10-50% by weight of a co-solvent. 14. The composition according to claim 1, where the co-solvent is selected from the group consisting of N-methyl-2-pyrrolidone, glycerol or propylene glycol esters of caprylic and capric acids, polyoxyethylated hydroxystearates, polyoxyethylene sorbitan esters, polyethylene glycol ethers of caprylic and capric acid, oils, vegetable oils such as olive oil, saturated polyglycosylated glycerides, esters of citrate, propylene glycol, ethanol, water and low molecular weight polyethylene glycols aces. 15. The composition of claim 14, wherein said modified castor oils are polyoxyethylene or hydrogenated castor oils. 16. The composition of claim 14, wherein said vegetable oils include olive oil. 17. The composition of claim 14, wherein said saturated polyglycosylated glycerides include C ₈ -C ₁₈ fatty acid glycerides. 18. The composition of claim 14, wherein said citrate esters include tributyl citrate, triethyl citrate or acetyl triethyl citrate. 19. The composition of claim 14, wherein said low molecular weight polyethylene glycols include PEG 200 or PEG 400. 20. The composition according to claim 3, where the carrier includes vitamin E TPGS. 21. The composition according to claim 4, where the carrier includes saturated polyglycosylated glycerides of C ₈ -C ₁₈ fatty acids. 22. The composition according to 17, where the co-solvent includes saturated polyglycosylated glycerides of C ₈ -C ₁₈ fatty acids. 23. The composition according to claim 3, where the carrier includes polyoxyethylene esters of stearate. 24. The composition of claim 14, wherein the co-solvent comprises N-methyl-2-pyrrolidone. 25. The composition of claim 14, wherein the cosolvent comprises ethanol. 26. The composition according to claim 1, which, when taken by a mammal orally one hour after taking an effective oral dose of an oral bioavailability enhancing agent, allows the taxane active ingredient from the gastrointestinal tract of the mammal to be absorbed into the bloodstream to a level of at least 15 % of the absorption level obtained when the same amount of taxane active ingredient is administered to a mammal by intravenous injection in a pharmaceutically acceptable intravenous carrier redstve. 27. The composition according to p, where the specified means of increasing bioavailability is a cyclosporine. 28. The composition of claim 27, wherein said cyclosporin is cyclosporin A. 29. The composition according to claim 1, where the specified taxane is paclitaxel or docetaxel. 30. The composition according to clause 29, where the specified taxane is paclitaxel. 31. An oral pharmaceutical dosage form comprising the pharmaceutical composition of claim 1. 32. The dosage form according to p, which includes a liquid preparation. 33. The dosage form of claim 31, wherein the pharmaceutical composition is encapsulated in a soft or hard gelatin capsule. 34. The dosage form according to p, which further includes pharmaceutical excipients, diluents, sweeteners, flavorings or colorings. 35. The dosage form of claim 31, wherein the taxane is paclitaxel or docetaxel. 36. The dosage form of claim 35, wherein the taxane is paclitaxel. 37. The dosage form according to p, which contains approximately 20-1000 mg / m ² taxane, based on the surface area of the body of a mammal. 38. The dosage form according to clause 37, which contains approximately 50-200 mg / m ² taxane, based on the surface area of the body of a mammal. 39. The dosage form according to p, which contains approximately 0.5-30 mg / kg taxane, based on the weight of the mammal. 40. The dosage form of claim 39, which contains approximately 2-6 mg / kg taxane, based on the weight of the mammal. 41. A two-component drug for oral administration to a mammal, wherein the first part of said drug comprises a taxane or taxane derivative as an active ingredient in a solubilizing carrier for said taxane, and the second part of said drug comprises at least 30% by weight of a taxane carrier said carrier being characterized by an HLB value of at least about 10. 42. The two-component drug of claim 41, wherein at least about 25 mg / ml taxane is able to dissolve in the solubilizing carrier vehicle at about 20-25 ° C. 43. The two-component drug according to paragraph 41, where the solubilizing carrier agent includes water, ethanol or polyoxyethylated or hydrogenated castor oil. 44. The two-component drug according to paragraph 41, where the solubilizing carrier agent includes sweeteners, flavors or colorants. 45. The two-component drug according to paragraph 41, where the solubilizing carrier product contains approximately 2-500 mg / ml or mg / g taxane. 46. The two-component drug according to item 45, where the solubilizing carrier agent contains approximately 2-50 mg / ml or mg / g taxane. 47. The two-component drug according to paragraph 41, where the carrier includes at least one non-ionic surfactant or emulsifier. 48. The two-component drug according to clause 47, where the carrier includes at least one non-ionic surfactant or emulsifier selected from the group consisting of vitamin E TPGS, saturated polyglycosylated glycerides, modified castor oils, polyoxyethylated esters of stearate, polyoxyethylated sorbitan complex esters, polyoxyethylated fatty ethers, modified glycerides of almond and corn oils, sorbitan esters of diisostearate, polyoxyethylated droksistearatov and β-cyclodextrin. 49. The two-component drug according to paragraph 41, where the second part of the drug includes approximately 30-240 ml of liquid. 50. The two-component drug according to paragraph 41, where the taxane is paclitaxel or docetaxel. 51. The two-component drug of claim 50, wherein the taxane is paclitaxel. 52. A method for treating a mammal suffering from a pathological condition susceptible to taxanes, comprising orally administering to a subject a pharmaceutical composition comprising a) a taxane or taxane derivative as an active ingredient; b) a carrier agent comprising at least 30% by weight of a taxane carrier, said carrier having an HLB value of at least about 10, and the carrier agent further comprises about 0-70% by weight of a co-solvent that reduces the viscosity of the carrier. 53. The method according to paragraph 52, where the specified carrier includes at least one non-ionic surfactant or emulsifier. 54. The method of claim 53, wherein the carrier comprises at least one non-ionic surfactant or emulsifier selected from the group consisting of Vitamin E TPGS, saturated polyglycosylated glycerides, modified castor oils, polyoxyethylated stearate esters, polyoxyethylated sorbitan esters, polyoxyethylated fatty ethers, modified almond and corn oil glycerides, sorbitan diisostearate esters, polyoxyethylated hydroxystearates and β-cyclodextrin a. 55. The method according to item 54, where these saturated polyglycosylated glycerides include glycerides of C ₈ -C ₁₈ fatty acids. 56. The method of claim 54, wherein said modified castor oils are polyoxyethylene or hydrogenated castor oils. 57. The method according to clause 54, where the polyoxyethylene fatty ethers are stearyl or oleyl ethers. 58. The method according to item 54, where these modified glycerides of almond and corn oils include polyethylene glycol glycerides of almond or corn oils. 59. The method according to paragraph 52, where the carrier means contains approximately 30-90% by weight of the carrier. 60. The method according to paragraph 52, where the taxane is dissolved or dispersed in a carrier. 61. The method according to paragraph 52, where the concentration of taxane in the carrier is approximately 2-500 mg / ml or mg / g 62. The method of claim 61, wherein the concentration of taxane in the carrier is about 2-50 mg / ml or mg / g. 63. The method according to paragraph 52, where in the co-solvent is capable of dissolving at least about 25 mg / ml taxane at about 20-25 ° C. 64. The method according to paragraph 52, where the carrier means contains approximately 10-50% by weight of a co-solvent. 65. The method according to paragraph 52, where the co-solvent is selected from the group consisting of N-methyl-2-pyrrolidone, glycerol or propylene glycol esters of caprylic and capric acids, polyoxyethylated hydroxystearates, polyoxyethylated sorbitan esters, polyethylene glycol ethers of caprylic and caprices oils, vegetable oils such as olive oil, saturated polyglycosylated glycerides, esters of citrate, propylene glycol, ethanol, water and low molecular weight polyethylene glycols s. 66. The method of claim 65, wherein said modified castor oils are polyoxyethylene or hydrogenated castor oils. 67. The method of claim 65, wherein said vegetable oils include olive oil. 68. The method of claim 65, wherein said saturated polyglycosylated glycerides include C ₈ -C ₁₈ fatty acid glycerides. 69. The method of claim 65, wherein said citrate esters include tributyl citrate, triethyl citrate or acetyl triethyl citrate. 70. The method of claim 65, wherein said low molecular weight polyethylene glycols include PEG 200 or PEG 400. 71. The method of claim 54, wherein the carrier comprises Vitamin E TPGS. 72. The method of claim 55, wherein the carrier comprises saturated polyglycosylated C ₈ -C ₁₈ fatty acid glycerides. 73. The method according to p, where the co-solvent includes saturated polyglycosylated glycerides of C ₈ -C ₁₈ fatty acids. 74. The method of claim 54, wherein the carrier comprises polyoxyethylated stearate esters. 75. The method according to p, where the co-solvent includes N-methyl-2-pyrrolidone. 76. The method according to item 65, where the co-solvent includes ethanol. 77. The method according to paragraph 52, where the composition, being taken orally by the mammal one hour after receiving an effective oral dose of an oral bioavailability enhancing agent, allows the taxane active ingredient from the gastrointestinal tract of the mammal to be absorbed into the bloodstream to a concentration level of at least at least 15% of the absorption level obtained when the same amount of taxane active ingredient is administered to a mammal by intravenous injection in a pharmaceutically acceptable intravenous carrier carrier. 78. The method according to p, where the specified means of increasing bioavailability is cyclosporine. 79. The method of claim 78, wherein said cyclosporin is cyclosporin A. 80. The method of claim 52, wherein said taxane is paclitaxel or docetaxel. 81. The method of claim 80, wherein said taxane is paclitaxel. 82. The method of claim 52, wherein said pharmaceutical composition is administered to a subject in an oral pharmaceutical dosage form. 83. The method of claim 82, wherein the dosage form comprises a liquid preparation. 84. The method of claim 82, wherein the pharmaceutical composition is encapsulated in a soft or hard gelatin capsule. 85. The method of claim 82, wherein the dosage form further comprises pharmaceutical excipients, diluents, sweeteners, flavorings, or colorings. 86. The method of claim 82, wherein the taxane is paclitaxel or docetaxel. 87. The method of claim 86, wherein the taxane is paclitaxel. 88. The method according to paragraph 82, where the dosage form contains approximately 20-1000 mg / m ² taxane, based on the surface area of the body of a mammal. 89. The method according to p, where the dosage form contains approximately 50-200 mg / m ² taxane, based on the surface area of the body of a mammal. 90. The method of claim 82, wherein the dosage form contains about 0.5-30 mg / kg taxane, based on the weight of the mammal. 91. The method of claim 90, wherein the dosage form contains about 2-6 mg / kg taxane, based on the weight of the mammal. 92. A method of treating a mammal suffering from a pathological condition susceptible to exposure to taxanes, comprising orally administering to the subject a two-component drug, the first part of said drug comprising a taxane or taxane derivative as an active ingredient in a solubilizing carrier for said taxane, and the second part of said the medicament comprises at least 30% by weight of a taxane carrier, said carrier being characterized HLB value of at least about 10. 93. The method according to paragraph 92, where in a solubilizing carrier agent is capable of dissolving at least about 25 mg / ml taxane at about 20-25 ° C. 94. The method of claim 92, wherein the solubilizing carrier agent comprises water, ethanol, or polyoxyethylated or hydrogenated castor oil. 95. The method according to p, where the solubilizing carrier means includes sweeteners, flavors or colorants. 96. The method of claim 92, wherein the solubilizing carrier agent comprises about 2-500 mg / ml or mg / g taxane. 97. The method of claim 92, wherein the solubilizing carrier agent comprises about 2-50 mg / ml or mg / g taxane. 98. The method of claim 92, wherein the carrier comprises at least one non-ionic surfactant or emulsifier. 99. The method of claim 92, wherein the carrier comprises at least one nonionic surfactant or emulsifier selected from the group consisting of Vitamin E TPGS, saturated polyglycosylated glycerides, modified castor oils, polyoxyethylated stearate esters, polyoxyethylated sorbitan esters, polyoxyethylated fatty ethers, modified almond and corn oil glycerides, sorbitan diisostearate esters, polyoxyethylated hydroxystearates and β-cyclodextrin a. 100. The method according to paragraph 92, where the second part of the composition comprises approximately 30-240 ml of liquid. 101. The method according to paragraph 92, where the taxon is paclitaxel or docetaxel. 102. The method of claim 101, wherein the taxane is paclitaxel. 103. The method of claim 52, further comprising co-administering to the subject an effective bioavailability enhancing amount of an oral bioavailability agent. 104. The method according to p, where the specified effective amount of enhancing agent is approximately 0.1-20 mg / kg, based on the weight of the mammal. 105. The method according to p. 103, where the enhancing agent is administered either a) approximately 0.5-72 hours before the introduction of taxane, or b) less than 0.5 hours before the introduction of taxane, together with the introduction of taxane, or less than 0.5 h after administration of taxane, or c) approximately 0.5-72 hours before and less than 0.5 h before administration of taxane, together with administration of taxane, or less than 0.5 h after administration taxana. 106. The method of claim 105, wherein said enhancing agent is administered one hour before the administration of the taxane-containing pharmaceutical composition. 107. The method according to p, where the enhancing agent is selected from the group consisting of cyclosporin from A to Z, (Me-Ilé-4) -cyclosporin, dihydrocyclosporin A, dihydrocyclosporin C and acetylcyclosporin A. 108. The method of claim 107, wherein the enhancer is selected from the group consisting of cyclosporin A, cyclosporin C, cyclosporin D, cyclosporin F, dihydrocyclosporin A, dihydrocyclosporin C, and acetylcyclosporin A. 109. The method of claim 108, wherein the enhancing agent is cyclosporin A. 110. The method according to paragraph 52 or 103, wherein said pathological condition is selected from the group consisting of malignant tumors, tumors, malignant neoplasms, uncontrolled tissue or cell proliferation secondary to tissue damage, polycystic kidney disease and malaria. 111. The method of claim 110, wherein said disease is a malignant tumor selected from the group consisting of hepatocellular carcinoma, hepatic metastases, cancers of the gastrointestinal tract, pancreas, prostate and lung, and Kaposi’s sarcoma. 112. The method of claim 103, wherein the taxon and enhancing agent are administered together in a combined oral dosage form. 113. The method of claim 103, wherein the taxane is paclitaxel or docetaxel. 114. The method according to p, where the taxane is paclitaxel. 115. The method according to PP.52, 82, 92 or 103, where the mammal is a human.