Oral pharmaceutical compositions containing taxanes and methods of treatment employing the same

Description of the invention

The invention relates to an oral taxane-containing composition and its use.

Many valuable pharmacologically active compounds cannot be administered orally to human patients because of their premature or inconsistent systemic absorption from the gastrointestinal tract. Generally, for this reason, such pharmaceuticals are administered by intravenous routes requiring the intervention of a physician or other healthcare professional, entailing considerable discomfort and potential local trauma to the patient and, for certain intravenous infusions, even requiring administration in a hospital setting with surgical access.

One important category of cytotoxic agents that are not normally bioavailable when administered orally to humans are taxanes, which include paclitaxel (paclitaxel), its derivatives and analogs. Paclitaxel (paclitaxel) (now marketed as TAXOL® by the Bristol-Meyers Squibb Cancer Division) is a natural diterpene product separated from the yew tree (Taxus brevifolia). It is a member of the taxane family of terpenes. It was first isolated by Wani and colleagues in 1971 (J. Am. Chem. Soc. 93: 2325, 1971), who characterized its structure by chemical and crystallographic methods. One of the mechanisms of its activity is related to the ability of paclitaxel (paclitaxel) to bind tubulin, as a result of which cancer cell growth is inhibited. 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: 10435-10441 (1981).

Paclitaxel (paclitaxel) is approved for clinical use in the United States for the treatment of refractory ovarian cancer (Markman et al., Yale Journal of Biology and Medicine, 64: 583, 1991; McGuire et al., Ann. Intern. Med., 111: 273, 1989) ). It is effective in the chemotherapy of several types of cancer including breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991) and has also been approved for the treatment of breast cancer. He is a potential candidate for the treatment of skin cancers (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46), lung cancer, and head and neck cancers (Forastire et al., Sem. Oncol., 20:56, 1990). The compound also shows potential for treatment of renal cystic disease (Woo et al., Nature, 368; 750, 1994) and malaria.

Paclitaxel (paclitaxel) is only slightly soluble in water and this has created considerable problems in the development of suitable injectable and infusion formulations useful in anti-cancer chemotherapy. Certain paclitaxel (paclitaxel) formulations for intravenous infusion have been developed using CREMOPHOR EL ™ (polyethoxylated castor oil) as the drug carrier due to the lack of water solubility of paclitaxel (paclitaxel). For example, paclitaxel (paclitaxel) used in clinical trials under the aegis of the NCI was formulated in 50% CREMOPHOR EL ™ and 50% dehydrated alcohol. However, CREMOPHOR EL ™, when administered intravenously as such, is toxic and causes vasodilation, strenuous respiration, lethargy, hypotension and death in dogs. It is also believed to be at least partially responsible for the allergic-type reactions seen with paclitaxel (paclitaxel) administration, although there is evidence that paclitaxel (paclitaxel) can induce acute reactions by itself, even in the absence of Cremophor.

In the search for an increase in the solubility of paclitaxel (paclitaxel) and the development of more clinically safe formulations, the research aimed at the synthesis of paclitaxel (paclitaxel) analogues in which the 2 'and / or 7 positions were introduced groups increasing the water solubility. These efforts have provided pro-drug compounds that are more water-soluble than the parent compound and that exhibit cytotoxic properties when activated. One important group of such prodrugs includes 2'-onium salts of paclitaxel (paclitaxel) and docetaxel (docetaxel), especially 2'-methylpyridinium (2'-MPM) mesylate salts.

Paclitaxel (paclitaxel) is very poorly absorbed after oral administration (less than 1%); see Eiseman et al., Second NCI Workshop on Taxol and Taxus (September 1992); Suffness et al., In Taxol Science and Applications (CRC Press 1995). Eiseman and colleagues show that paclitaxel (paclitaxel) has 0% oral bioavailability, and Suffness and colleagues report that oral dosing of paclitaxel (paclitaxel) does not seem possible as no evidence of anticancer activity has been found after oral administration up to 160 mg / kg / day. For this reason, paclitaxel has not previously been administered orally to human patients and certainly not in the treatment of paclitaxel (paclitaxel) responsive diseases.

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Docetaxel (docetaxel) (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl-paclitaxel) is commercially available as TAXOTERE® (Rhone-Poulenc-Rorer SA) parenterally administered in the treatment of breast cancer. To date, there are no reports in the literature on the oral absorption of docetaxel (docetaxel) in animals or patients.

It has been speculated whether in some cases the poor or no oral bioavailability of a drug such as paclitaxel is due to the activity of the multidrug membrane-bound P-glycoprotein which functions as an energy-dependent transport or efflux pump to reduce intracellular drug accumulation by displacing xenobiotics from the cell. Such a P-glycoprotein has been identified in normal endothelial secretory tissues such as the bile lining, the brush border of the proximal renal tubules and the luminal surface of the intestine, and the vascular endothelial cells of the blood brain, placenta and testes barrier lining.

The efflux pump is believed to prevent certain pharmaceutical compounds from moving through the mucosal cells of the small intestine and thereby being absorbed into the systemic circulation. Several known non-cytotoxic P-glycoprotein inhibiting pharmacological agents have been shown to include, but are not limited to, cyclosporin A (also known as cyclosporin), verapamil, tamoxifen, quinidine, and phenothiazines. Much of this research has been directed to achieving greater accumulation of intravenously administered cytotoxic drugs in cancer cells. Indeed, clinical trials were performed to investigate the effects of cyclosporin on the pharmacokinetics and toxicity of paclitaxel (paclitaxel) (Fisher et al., Proc. Am. Soc. Clin. Oncol., 13: 143, 1994); doxorubicin (Bartlett et al. J. Clin. Oncol. 12: 835-842, 1994); and etoposide (Lum et al. J. Clin. Oncol. 10: 1635-42,1992), all of which are anti-cancer agents known to be subject to multidrug resistance (MDR). These studies showed that patients receiving intravenous cyclosporine just before or in combination with anti-cancer drugs had higher blood levels of these drugs, possibly due to decreased clearance, and showed the expected toxicity at substantially lower dose levels. These conclusions would indicate that co-administration of cyclosporin abolishes the MDR (multi-drug resistance) effect of P-glycoprotein, allowing for greater intracellular accumulation of therapeutic agents. For a general discussion of the pharmacological implications of the clinical use of P-glycoprotein inhibitors, see Lum et al., Drug Resist. Clin. He c. Hemat., 9: 319-336 (1995); Schinkel et al., Eur. J. Cancer, 31A: 1295-1298 (1995).

In the above-described studies of the use of cyclosporin to increase blood levels of pharmaceuticals, active anticancer agents and cyclosporin were administered intravenously. There is no suggestion in these publications that cyclosporin should be administered orally to substantially increase the bioavailability of orally administered anti-cancer drugs and other pharmaceutical agents that are as such poorly absorbed from the gut without producing highly toxic side effects. None of these published studies have provided any pattern for implementing effective oral administration to humans of drugs with poor bioavailability such as paclitaxel (paclitaxel), e.g. indicating appropriate dose ranges and timing for specific target drugs and bioavailability enhancers are most useful for oral enhancement. absorption of each target drug or class of drugs.

In PCT published patent application WO 95/20980 (published August 10, 1995), Benet et al. Disclose a proprietary method of increasing the bioavailability of orally administered hydrophobic pharmaceutical compounds. The method includes orally administering such compounds to a patient concurrently with a biamplifier comprising an enzyme cytochrome P450 3A inhibitor or a P-glycoprotein mediated membrane transport inhibitor. In general, however, Benet et al. Do not provide means of identifying which bioavailability enhancers will improve the availability of specific "target pharmaceutical compounds, nor indicate specific dosage amounts, regimens, or conditions for administering the enhancing or target agents." Indeed, although the Benet and colleagues report lists dozens of potential enhancers (P450 3A inhibitors) and target drugs (P450 3A substrates), the only combination of enhancer and target that has been proven by any experimental evidence is ketoconazole as an enhancer and cyclosporin A in the report. as a target drug.

Disclosing the general characteristics of compounds that can be used as bio-enhancers by reducing the transport activity of P-glycoprotein, Benet et al. Indicated that these are hydrophobic compounds that generally, but not necessarily, include two coplanar aromatic rings, a positively charged nitrogen group, or carbonyl, that is, it is the class that

PL 196 267 B1 comprises a huge number of compounds, most of which would not provide the desired absorption-enhancing activity for specific target agents. In addition, the classes or targets disclosed by Benet and colleagues include the vast majority of pharmaceuticals compiled in the Physician's Desk Reference. These inclusion criteria are of no value to practitioners seeking safe, practical, and effective means of orally administering specific pharmaceutical agents.

In general, Benet and colleagues do not provide guidelines by which medical and pharmaceutical professionals can identify appropriate bioamplifier / target drug combinations or design specific regimens and regimens that would make therapeutically effective target agents orally administered to human patients. Also, Benet et al. Do not suggest any guidelines regarding the possibility of oral administration to humans of paclitaxel (paclitaxel) and other taxanes with therapeutic efficacy and acceptable toxicity.

In published PCT application WO 97/15269, which corresponds to U.S. Patent Application Serial No. 08/733 142 (the predecessor of the present application), and which is normally assigned to this application, it is disclosed that various therapeutically effective pharmaceutical "target agents that exhibit poor oral the bioavailability can be made bioavailable, ensuring therapeutic blood levels of the active agent, by oral co-administration of certain bioavailability enhancers. Preferred examples of such target agents disclosed in WO 97/15269 include cyclosporins, e.g. cyclosporins A, D and G. Preferred examples of the target agents include the taxane class of anti-cancer agents, especially paclitaxel (paclitaxel). Treatment regimes and dose amounts for co-administration are also disclosed for the target agents and the corrective agents. All the disclosures of published patent application WO 97/15269 are hereby incorporated by reference.

However, neither the widely recognized application WO 97/15269 nor any of the prior art disclosures describes classes of oral formulations or compositions containing an active target, e.g. paclitaxel (paclitaxel) together with a TPGS containing vitamin E carrier that is particularly suited for co-administration with an oral bioavailability enhancer to obtain therapeutic blood levels of target agents heretofore considered unsuitable for oral administration.

International application WO 99/12570 discloses compositions with increased bioavailability containing e.g. paclitaxel and a medium containing Cremophor or polyethoxylated sorbitan monooleates, but the compositions described below are not disclosed.

WO 99/06024 discloses pharmaceutical compositions containing an oily phase composed of specific mono- and diglycerides. These compositions may contain taxanes as active substances. For example, a composition containing mono- and dioleates and Cremophor is disclosed, but the compositions of the present invention are not disclosed in any way.

The present invention relates to oral pharmaceutical compositions containing taxane anticancer agents, e.g. significant blood levels of the active drug.

The compositions of the invention include a vehicle comprising a carrier in which the taxane agent is dissolved or dispersed. The vehicle may also contain a viscosity-reducing solubiliser which makes the vehicle more fluid at body temperature or at least reduces the melting point of the vehicle below body temperature, and may also provide increased solubility of the taxane.

The carrier used in the novel compositions is preferably a nonionic surfactant or emulsifier having a hydrophilic-lipophilic balance (HLB) value of at least about 10. The viscosity-reducing solubiliser is selected from, for example, organic solvents suitable for oral administration, 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 novel 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 medium contains at least 30%

It is based on the weight of carrier and about 0-70% solubiliser, and may also contain conventional pharmaceutical additives and excipients such as flavoring and perfuming agents and the like.

The oral pharmaceutical compositions of the invention contain at least two components: an active agent containing a taxane, preferably the anti-cancer agent paclitaxel (paclitaxel) or docetaxel (docetaxel), and a therapeutically inactive vehicle containing a pharmaceutically acceptable carrier for the taxane.

In order to prepare orally administrable compositions that are liquid or at least liquid at body temperature (about 37 ° C), which is generally required for oral bioavailability, in some cases it is required to add an additional ingredient to the vehicle: a viscosity-lowering solubiliser, which reduces the viscosity and increases the flowability of the vehicle at body temperature and may also increase, compared with the carrier alone, the amount of active agent that can be dissolved or dispersed in the vehicle.

The invention relates to a pharmaceutical composition for oral administration to mammals, comprising a taxane as the active ingredient and a vehicle containing at least 30% by weight of a taxane carrier, characterized in that the vehicle for the taxane contained in the vehicle comprises vitamin E TPGS, and the vehicle further comprises a solubiliser of the selected type. from the group consisting of:

a1) ethanol and propylene glycol, a2) ethanol and lower molecular weight PEG polyethylene glycol, a3) ethanol in an amount of 10-50% by weight based on the weight of the vehicle, the composition being in the form of an oral hard or soft gelatin capsule, a4 ) propylene glycol, a5) a lower molecular weight PEG polyethylene glycol selected from the group consisting of PEG 200 polyethylene glycol and PEG 400, the solubilizing agent is present in an amount of 10-50% by weight with respect to the weight of the base, a6) N-methyl-2-pyrrolidone, a7) glycerin esters or propylene glycol esters of caprylic and capric acids, a8) polyethylene glycol esters of acids caprylic and capric, a9) saturated coconut and palm fatty acids, a10) saturated polyglycolized glycerides.

Preferably the solubiliser comprises ethanol and propylene glycol.

Preferably the solubiliser is present in an amount of 50 to 70% by weight based on the weight of the base.

Preferably the composition is in a liquid dosage form.

Preferably, the solubiliser comprises ethanol and a lower molecular weight PEG polyethylene glycol.

Preferably the lower molecular weight PEG polyethylene glycol comprises PEG 200 or PEG 400 polyethylene glycol, more preferably the lower molecular weight PEG polyethylene glycol comprises PEG 400 polyethylene glycol.

Preferably, the vehicle comprises about 10-50% by weight of the solubiliser.

Preferably the composition is in the form of an oral hard or soft gelatin capsule.

Preferably the solubiliser comprises ethanol in an amount of 10-50% by weight based on the weight of the support.

Preferably, the solubiliser comprises propylene glycol.

Preferably propylene glycol is present in an amount of up to 70 wt.% Based on the weight of the base, more preferably propylene glycol is present in an amount of 10 to 50 wt.% Based on the weight of the base.

Preferably, the solubiliser additionally comprises ethanol.

Preferably the solubiliser is present in an amount of 50-70% by weight based on the weight of the base.

Preferably the composition is a solution or a suspension.

Preferably the composition is in a liquid oral dosage form.

Preferably, the solubiliser comprises a lower molecular weight PEG polyethylene glycol selected from the group consisting of PEG 200 polyethylene glycol and PEG 400, wherein the solubiliser is present in an amount of 10-50% by weight based on the weight of the substrate.

Preferably the composition is a solution or a suspension.

PL 196 267 B1

Preferably, the solubiliser additionally comprises ethanol.

Preferably the lower molecular weight PEG polyethylene glycol is PEG 400 polyethylene glycol.

Preferably the composition is in the form of an oral hard or soft gelatin capsule.

Preferably, the solubiliser comprises saturated polyglycolized glycerides.

Preferably the saturated polyglycolized glycerides contain C8-C18 fatty acid glycerides.

Preferably, the solubiliser additionally comprises ethanol.

Preferably the solubiliser comprises N-methyl-2-pyrrolidone, glycerin esters or propylene glycol esters of caprylic and capric acids, polyethylene glycol esters of caprylic and capric acids, saturated coconut and palm fatty acids or saturated polyglycolized glycerides.

Preferably the solubiliser is present in an amount of 10-50% by weight based on the weight of the base.

Preferably the medium comprises 30-90 wt% Vitamin E TPGS.

Preferably, the taxane is dissolved or dispersed in the vehicle.

Preferably, the taxane is present in the vehicle at a concentration of 2-500 mg / ml or mg / g.

Preferably the concentration of the taxane in the vehicle is 2-50 mg / ml or mg / g.

Preferably the composition additionally comprises pharmaceutical excipients, diluents, sweetening, flavoring or coloring agents.

Preferably the composition additionally comprises sweetening, flavoring or coloring agents.

₂

Preferably the composition is in an oral dosage form which contains 20-1000 mg / m2² of the taxane based on the body surface area of ​​the mammal, and more preferably the oral dosage form contains 50-200 mg / m2² of the taxane per body surface area of ​​the mammal.

Preferably the composition is in the form of an oral dosage form which contains 0.5-30 mg / kg of taxane based on the body weight of the mammal.

Preferably the oral dosage form comprises 2-6 mg / kg taxane based on the body weight of the mammal.

Preferably, the taxane is paclitaxel or docetaxel.

The invention also relates to the use of a composition as defined above in the manufacture of an oral medicament for the treatment of taxane responsive conditions in a mammal.

Preferably the medicament used further comprises an effective bioavailability enhancer amount of an oral bioavailability enhancer to be administered with the composition.

Preferably, the effective amount of the bioavailability enhancer is 0.1-20 mg / kg based on the weight of the mammal.

Preferably the bioavailability enhancer is cyclosporin, more preferably the cyclosporin is cyclosporin A.

Preferably the cyclosporin is selected from the group consisting of: cyclosporins A to Z, (Me-I1e-4) -cyclosporin, dihydro-cyclosporin A, dihydro-cyclosporin C and acetyl-cyclosporin A.

Preferably the cyclosporin is selected from the group consisting of: cyclosporin A, cyclosporin C, cyclosporin D, cyclosporin F, dihydro-cyclosporin A, dihydro-cyclosporin C and acetyl-cyclosporin A.

The disease states include cancers, tumors, malignancies, uncontrolled tissue growth or secondary cell growth following tissue damage, renal cystic disease, and malaria.

The disease state is cancer selected from the group consisting of hepatocellular carcinoma, hepatic metastases, cancers of the gastrointestinal tract, pancreatic, prostate and lung cancer, and Kaposi's sarcoma.

Preferably, the composition and the bioavailability enhancer are presented in separate oral dosage forms.

The novel compositions may contain more than one taxane as active ingredient and more than one carrier and / or solubiliser as inactive vehicle ingredients. The medium comprises at least 30% by weight of a carrier, preferably 30-90% by weight. Carriers for use in the invention are nonionic surfactants or emulsifiers having HLB values ​​of at least about 10. Such nonionic surfactants or emulsifiers have been found to be not only compatible carriers for lipophilic taxa (which are poorly soluble in water) but also to aid absorption of the active ingredient from the gastrointestinal tract into the bloodstream.

PL 196 267 B1

Such carriers include, for example, Vitamin E TPGS (da-tocopheryl polyethylene glycol 1000 succinate, Eastman Chemical Co., Kingsport, TN); saturated polyglycolized glycerides such as the products GELUCIRE ™ and LABRASOL ™ (Gattefosse Corp., Westwood, NJ) which include C8-C18 fatty acid glycerides; CREMOPHOR ™ EL or RH40 modified castor oils (BASF, Mt. Olive, NJ); MYRJ ™ polyoxyethylated stearic ester (ICI Americas, Charlotte, NC); TWEEN ™ (ICI Americas) and CRILLET ™ (Croda Inc., Parsippany, NJ) polyoxyethylated sorbitol esters; BRIJ ™ polyoxyethylated fatty ethers (ICI Americas); CROVOL ™ modified (polyethylene glycol) glycerides of almond and corn oil (Croda Inc.); EMSORB ™ sorbitan diisostearin esters (Henkel Corp., Ambler, PA); SOLUTOL ™ polyoxyethylated hydroxystearates (BASF); and β-cyclodextrin. The carriers used in these compositions have HLB values ​​of about 10 or greater.

Preferred viscosity-lowering solubilizers include, for example, PHARMASOLVE ™ (N-methyl-2-pyrrolidone, International Specialty Products, Wayne, NJ); MIGLYOL ™ glycerin esters or propylene glycol esters of caprylic and capric acids (H ^ s AG, Marl, Germany); polyoxyethylated hydroxystearates (e.g. SOLUTOL ™ HS 15); TWEEN ™ polyoxyethylated sorbitol esters; SOFTIGEN ™ polyethylene glycol esters of caprylic and capric acids (H ^ s AG, Marł, Germany); modified castor oils (such as CREMOPHOR ™ EL or RH 40); vegetable oils such as olive oil, polyoxyethylated fatty ethers or modified castor oils; some saturated polyglycolized glycerides (such as LABROSOL ™); citrate esters such as tributyl citrate, triethyl citrate and acetyl triethyl citrate; propylene glycol, alone or in combination with PHARMASOLVE ™; ethanol; water; and lower molecular weight polyethylene glycols such as PEG 200 and 400.

It should be noted that some materials identified as carriers have been found to be effective solubilizers, either alone or in combination with other tackifiers, for some other carriers. In general, any solvent in which paclitaxel (paclitaxel) or other taxanes are at least moderately soluble at body temperature or when gently heated can be used as solubilizers in the vehicle of the new compositions.

Preferred solubilizers are those in which at least 25 mg / ml of paclitaxel (paclitaxel) or other taxane can be dissolved at about 20-25 ° C.

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

The compositions of the invention can be prepared by any conventional method known to those skilled in the pharmaceutical art for the preparation of liquid formulations or other liquid oral formulations containing surfactants and lipophilic active substances. Since most of the preferred carriers are very viscous at room temperature, and in some cases maintain a relatively high viscosity, even with the addition of a smaller proportion of the solubiliser, it is generally preferred to mix the used carriers and solubilizers in preparing new compositions, adding of the taxane active ingredient, and warming the resulting mixture with agitation, for example, to about 40 ° C. This method makes it possible to obtain clear solutions. Some solubilizers, especially PHARMASOLVE ™, however, lower the viscosity of the carrier and increase the solubility of the taxane to such an extent that a composition can be obtained by mixing at room temperature without heating.

It is desirable that the viscosity of the finished composition be no greater than 40,000 cps at body temperature (approximately 37 ° C).

Oral compositions of the present invention may be in the form of proper solutions, emulsions or even suspensions, but solutions of the taxane active ingredient in a carrier or carrier / solubiliser system are preferred.

The compositions of the invention can be used in the manufacture of a medicament for the treatment of human patients afflicted with cancers, tumors, Kaposi's sarcoma, malignancy, uncontrolled tissue growth or cell proliferation secondary to tissue damage and any other taxane responsive disease conditions such as paclitaxel (paclitaxel) or docetaxel. (docetak8

Sel), and / or prodrugs and derivatives of the foregoing, treatment with new orally administered pharmaceutical compositions. Among the types of cancer that can be treated particularly effectively with oral paclitaxel (paclitaxel), docetaxel (docetaxel), other taxanes and their pro-drugs and derivatives are hepatocellular carcinoma and liver metastases, cancers of the digestive system, pancreas, prostate and lungs , and Kaposi's sarcoma. Examples of non-cancerous disease states that can be effectively treated with these orally administered active agents of the present invention are tissue uncontrolled or cellular hyperplasia secondary to tissue damage, renal cystic disease, inflammatory diseases (e.g., arthritis), and malaria, including parasites. malaria resistant to chloroquine and pyrimethamine (Pouvelle et al., J. Cin. Invest., 44: 413-417, 1994).

Although some of the oral pharmaceutical compositions of the invention may provide therapeutic blood levels of the taxane active ingredient when administered alone, it is preferred to use oral compositions containing the target agent for treating mammalian patients (particularly human patients) suffering from taxane responsive conditions. taxane with the concomitant administration of at least one dose of an oral bioavailability enhancer.

A preferred embodiment of the use of the invention for the manufacture of a medicament for oral administration to humans of paclitaxel (paclitaxel) and other taxanes comprises the use of an agent to improve oral absorption or bioavailability simultaneously with or just before, or both simultaneously with and just prior to, oral administration to increase the rate of absorption of the intact target agent. into the bloodstream.

Orally administered enhancers that can be used in the preferred embodiment of the invention are, without limitation, the following:

Cyclosporins including cyclosporin A to Z, but especially cyclosporin A (cyclosporin), cyclosporin F, cyclosporin D, dihydrocyclosporin A, dihydrocyclosporin C, acetylcyclosporin A, PSC-833, SDZ-NIM 811¹ (both from Sandoz Pharmaceutical Corp.). The structures of cyclosporins AZ are disclosed below in Table 1.

¹SDZ-NIM 811 is (Me-11e-4) -cyclosporin, an antiviral, non-immunosuppressive cyclosporine.

Table 1a 1. Cyclosporins AZ

<td>Cyclo- dispute</td><td colspan="11">Amino acids</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td><td> 11</td><td> 12</td>

<td>Cy</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td><td> 11</td>

<td>CyA</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyB</td><td>Mebmt</td><td>Ala</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyC</td><td>Mebmt</td><td>Thr</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>Cyd</td><td>Mebmt</td><td>Val</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyE</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>Dig</td><td>Deoxy- Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyG</td><td>Mebmt</td><td>Nva</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyH</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>D-Mev</td>

<td>Cyl</td><td>Mebmt</td><td>Val</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>Leu</td><td>MeVal</td>

<td>Tick</td><td>Deoxy- Mebmt</td><td>Val</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyL</td><td>Bmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyM</td><td>Mebmt</td><td>Nva</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>TIN</td><td>Mebmt</td><td>Nva</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>Leu</td><td>MeVal</td>

<td>CyO</td><td>MeLeu</td><td>Nva</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyP</td><td>Bmt</td><td>Thr</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

PL 196 267 B1 cont. table 1

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td><td> 11</td><td> 12</td>

<td>CyQ</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>Val</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyR</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>Leu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>Leu</td><td>MeVal</td>

<td>CyS</td><td>Mebmt</td><td>Thr</td><td>Sar</td><td>Val</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D- Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>Cit</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyU</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>Leu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyV</td><td>Mebmt</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyW</td><td>Mebmt</td><td>Thr</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>Val</td>

<td>CyX</td><td>Mebmt</td><td>Nva</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>Leu</td><td>Ala</td><td>D-Ala</td><td>Leu</td><td>MeLeu</td><td>MeVal</td>

<td>CyY</td><td>Mebmt</td><td>Nva</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>Leu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

<td>CyZ</td><td>Acid MeAmino octyl</td><td>Abu</td><td>Sar</td><td>MeLeu</td><td>Val</td><td>MeLeu</td><td>Ala</td><td>D-Ala</td><td>MeLeu</td><td>MeLeu</td><td>MeVal</td>

Cyclosporins are a group of non-polar, cyclic oligopeptides (some of which have immunosuppressive activity) produced by the genus Topycladium, including, for example, Topycladium inflatum Gams (formerly Trichoderma polysporum), Topycladium terricola and other imperfect fungi. The major component cyclosporin A (cyclosporin or CsA) has been identified along with several other minor metabolites, for example cyclosporin B through Z, some of which exhibit substantially lower immunosuppressive activity than cyclosporin A. Several synthetic and semi-synthetic analogues have also been obtained. See generally, Jegorov et al., Phytochemistry, 38: 403-407 (1995). The present invention includes natural, semi-synthetic and synthetic analogs of cyclosporins.

Cyclosporins are neutral, lipophilic, cyclic undecapeptides with molecular weights of about 1200. They are used intravenously or orally as immunosuppressants, primarily in organ transplantation and certain other conditions. Cyclosporins, especially cyclosporin (cyclosporin A), are known inhibitors of P-glycoprotein efflux pump and other transport pumps, as well as certain P450-degrading enzymes, but effective treatment regimens using this property have not yet been developed clinically, to the point of clinical and commercial feasibility or approval. regulations.

The dose range of the corrective agent to be co-administered with the target is about 0.1 to about 20 mg / kg of patient body weight. "Co-administration of the corrective agent includes administration substantially simultaneously with the target agent (or less than 0.5 hours before, less than 0.5 hours after, or total), from about 0.5 to about 72 hours. prior to administration of the target agent, or both, i.e. with one or more doses of the same or different corrective agents, administered at least 0.5 hours. before and one dose administered substantially simultaneously with (or in conjunction with or immediately before or after) the target compound. Additionally, "co-administration includes the administration of more than one dose of the target compound within 72 hours after the dose of the enhancing agent, in other words, the enhancement agent (s) need not be re-administered before or during each administration of the target, but may be administered discontinuously during the course of treatment.

The dose range of orally administered taxane targets will vary from compound to compound based on its therapeutic index, the requirements of the condition being treated, the condition of the subject being treated, and so on. The method of the invention allows the administration of paclitaxel (paclitaxel) and other taxanes orally in the range of about 20 mg / m2.² up to about 1000 mg / m²(based on patient body surface area) or approximately 0.5-30 mg / kg (based on patient weight) as single or divided (2-3) daily doses, and maintaining human plasma paclitaxel (paclitaxel) levels within the range 50-500 ng / ml for an extended period of time (e.g., 8-12 hours) after each oral dose. These levels are at least comparable to those achieved with paclitaxel (paclitaxel) treatment in 96 hour intravenous infusion therapy with paclitaxel (paclitaxel) (which causes the patient great discomfort, discomfort, loss of quality duration, infectious potential, etc.).

PL 196 267 B1

Moreover, such plasma levels of paclitaxel (paclitaxel) are more than sufficient to provide the desired pharmacological activities of the target drug, e.g. inhibition of tubulin destruction (which occurs at levels of about 0.1 μM, or about 85 ng / ml) and inhibition of protein isoprenylation (which occurs at levels about 0.03 μM, or about 25 ng / ml), which are directly related to its action anti-cancer by inhibition of oncogenic functions, and other signal transducing proteins that play a key role in regulating cell growth.

The two or more corrective agents and / or two or more different taxane targeting agents may be administered together, alternatively or discontinuously.

As demonstrated above, oral paclitaxel (paclitaxel) administered alone (e.g. in the form of a solid dose or even in a liquid vehicle not containing a vehicle to enhance oral absorption) shows a bioavailability close to zero. A pharmaceutical composition containing paclitaxel (paclitaxel) or other taxanes for the purposes of the present invention to be considered orally bioavailable must meet the following criteria: if the composition is orally administered to a treated mammalian subject (e.g. laboratory rat or human patient), that is, ingested by the treated subject, one hour after administration of an effective oral dose of an orally bioavailable enhancer, the amount of active substance absorbed into the bloodstream is at least 15% of the amount absorbed, if the same dose of paclitaxel ( paclitaxel) is administered to an intravenously treated subject in a standard intravenous vehicle, for example CREMOPHOR ™ EL / ethanol vehicle. The relative percent absorption is determined by comparing the corresponding AUC (area under the curie) values ​​of the blood taxane levels against the time curve generated after oral administration and the corresponding curve generated after intravenous administration.

A preferred bioavailability enhancer for use in experimentally determining whether a particular oral composition meets the 15% intravenous absorption criterion is cyclosporin A, for example a single oral dose of 5 mg / kg of CsA.

The novel pharmaceutical compositions can be administered in any known pharmaceutical dosage form. For example, the compositions may be encapsulated in a soft or hard gelatin capsule, or they may be administered in the form of a liquid preparation. Each dosage form can include, in addition to the essential ingredients of the composition (at least one carrier or one component with taxane activity, and in some cases at least one solubiliser), conventional pharmaceutical excipients, diluents, sweeteners, flavoring agents, coloring agents, and any other co-formulants usually contained in dosage forms intended for oral administration (see e.g. Remington's Pharmaceutical Sciences, 17th edition, 1985).

The exact amounts of each of the target drugs contained in the oral dosage form will vary depending on the age, weight, disease, and condition of the patient. For example, paclitaxel (paclitaxel) or other taxane dosage forms may contain sufficient amounts of the target agent to provide a daily dose of about 20-1000 mg / m2.² (based on the body surface area of ​​the mammalian subject or patient) or about 0.5-30 mg / kg (based on the body weight of the mammalian subject or patient) as single or divided (2-3) daily doses. Preferred dosage amounts are about 50-200 mg / m2² or about 2-6 mg / kg.

Dosing regimens in a method of treatment, for example, treatment of paclitaxel (paclitaxel) responsive diseases with oral dosage forms of paclitaxel (paclitaxel) co-administered with improvement agents, may be analogously adjusted taking into account the patient characteristics and the condition of the disease. Preferred dosing regimens for the administration of paclitaxel (paclitaxel) are (a) administering daily to a patient in need thereof 1-3 equally divided doses providing about 20-1000 mg / m2² (based on body surface area), and preferably about 50-200 mg / m2², with said daily administration being continued for 1-4 consecutive days every 2-3 weeks, or (b) administration for one day each week. The previous regimen is comparable to the 96-hour infusion of paclitaxel (paclitaxel) every 2-3 weeks, which some consider the preferred intravenous regimen.

Oral administration of taxanes can actually reduce the toxic side effects in many cases compared to current intravenous therapy. Instead of producing a sudden and rapid high blood concentration level, as is usually the case with an intravenous infusion, absorption of the active agent through the gut wall (assisted by improvers) ensures a more gradual appearance in the blood and the persistent, stable maintenance of these blood levels within the ideal or close to ideal range over a long period of time.

PL 196 267 B1

The pharmaceutical compositions can be administered in a two-part drug system. For example, there are certain carriers within the scope of the present invention that use in vehicles is desirable for certain taxane agents because of their ability to dissolve the taxane and aid in its oral absorption, but the carrier may be chemically or physically incompatible with the desired additional ingredients such as flavoring or coloring agents. In such cases, the active ingredient may be administered to the patient as the first part of the drug in a relatively small amount of any suitable liquid dissolution medium (such as water, CREMOPHOR ™, or ethanol) that may be sweetened, flavored, or colored if it is desired to mask the unpleasant taste of the vehicle and making it more tasty. Following administration of the active ingredient, a second portion of the drug may be administered: a larger volume of fluid, for example 1 to 8 ounces volume (30-240 ml), containing at least one carrier or carrier / solubiliser system. It has been found that administering a second "chasing formulation a short time after the taxane active" can delay the precipitation of the taxane that might otherwise occur upon ingestion into the gastric fluid, and aid oral absorption to an extent comparable to that observed when the taxane is mixed with vehicle and administered concurrently.

Illustrative examples of chaser formulations that can be used in the two-part oral taxane drug include:

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

b) 2-25% vitamin E TPGS 2-25% PHARMASOLVE ™ + water as needed;

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

The oral compositions of the invention may contain not only one or more taxane actives but also one or more bioavailability enhancing agents in a combined dose form. Such a combination dosage form, for example, may contain from about 0.1 to about 20 mg / kg (based on average patient weight) of one or more cyclosporins A, D, C, F and G dihydro-CsA, dihydro-CsC and acetyl-CsA including about 20 to about 1000 mg / m 2² (based on average patient weight), and preferably about 50-200 mg / m2² paclitaxel (paclitaxel), docetaxel (docetaxel), other taxanes or paclitaxel derivatives (paclitaxel) or docetaxel (docetaxel).

The compositions of the present invention provide many advantages over the previous intravenous compositions containing paclitaxel (paclitaxel) or other taxanes and the previous intravenous administration regimens. In addition to causing reduced toxicity, patient convenience and comfort, ease of administration and cost reduction previously discussed, the present invention enables the administration of potent taxane anti-cancer agents to patients with a greatly reduced likelihood of allergic hypersensitivity reactions that are common when administered intravenously. Therefore, the need for premedication with H-1 and H-2 blockers plus steroids can be eliminated.

The present invention also enables the administration of taxanes, e.g. paclitaxel (paclitaxel) in comparatively infrequent daily doses (e.g. around twice / day) and on a regimen which would otherwise not be possible or practicable by intravenous route. The use of an agent that improves bioavailability (e.g. cyclosporin A) supports the oral absorption of paclitaxel (paclitaxel) for the first dose and if the second dose of paclitaxel (paclitaxel) is to be administered later in the day, additional cyclosporin A may not even be needed. In this way, paclitaxel (paclitaxel) could be administered discontinuously as a single dose according to a fixed schedule (weekly, biweekly, etc.) or continuously over consecutive days (e.g. 4 days) every 2-4 weeks with the aim of maintaining levels in the area of ​​a safe and effective 'window.

The following examples illustrate various aspects of the invention. These examples are not intended to limit the invention in any way, nor are they intended to represent specific actives, carriers, solubilizers, improvers, dose ranges, testing procedures, or other parameters that must be used solely for the purpose of practicing the invention.

Example 1

Animal classification model

Groups of three male rats each were fasted for 16-18 hours immediately prior to administration of the radiolabelled ³H paclitaxel (paclitaxel). Each group of animals received one oral dose of cyclosporin A (5 mg / kg) just prior to their administration of an experimental oral formulation of paclitaxel (paclitaxel). One hour after the administration of cyclosporin, each group received approximately 9 mg / kg of paclitaxel (paclitaxel) orally in the form of a composition of the invention. Each group received a different oral formulation.

PL 196 267 B1

Blood samples were collected from each animal at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after dosing with paclitaxel (paclitaxel). Blood samples were burned and their total radioactivity was determined.

₃

The levels of total radioactivity in the blood (corresponding to the concentration in the blood ³H-paclitaxel (paclitaxel)) is plotted against the time elapsed after dosing. Data for each group of rats are summarized as AUC, Cmax and Tmax.

Absorption percentage ³H-paclitaxel (paclitaxel) for each group of animals was calculated by comparing the mean AUC of the group to the corresponding mean AUC of the standard group of intravenously administered rats. ³H-paclitaxel (paclitaxel) (9 mg / kg) in the form of PAXENE ™ (Baker Norton Pharmaceuticals, Miami, Florida) which contains CREMOPHOR ™ EL, ethanol and citric acid.

Table 2 lists all combinations of carriers and carriers / solubilizers that were compiled into oral compositions containing paclitaxel (paclitaxel) according to the present invention, which were tested in rats according to the above procedure, and which achieved an absorption percentage in experimental animals of 15% or greater compared to with intravenously administered paclitaxel (paclitaxel).

Table 1a 2. Combinations of carriers and carriers / solubilizers that achieved greater than 15% percent paclitaxel (paclitaxel) absorption values.

<td>Carriers</td><td colspan="7">Solubilizers</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td>

<td>TPGS</td><td>Pharma- solve</td><td>Glycol propylene</td><td>Mygliole</td><td>Softigen</td><td>PEG 200 and 400</td><td>Glycol propylene / Pharmasolve</td><td>PEG 200 and 400 / Pharmasolve</td>

<td>Gelucire 44/14</td><td>Pharma- solve</td><td>Mygliole</td><td>Oil olive green / Brij 97</td><td>Oil olive/ Cremophor RH 40</td><td>Oil olive/ TPGS</td><td>Cremophor EL</td><td>Cremophor RH 40</td>

<td>Gelucire 44/14</td><td>Labrasol</td><td>TPGS / Solutol HS 15</td><td>Tween 80</td><td>PEG 40</td><td></td><td></td><td></td>

<td>Gelucire 50/13</td><td>Tween 80</td><td>PEG 400</td><td>Cremophor EL</td><td></td><td></td><td></td><td></td>

<td>Cremophor EL</td><td>Pharma- solve</td><td>Esters citrate</td><td>Ethanol/ water</td><td>Ethanol</td><td></td><td></td><td></td>

<td>Cremophor RH 40</td><td>Ethanol/ water</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Myrj 49</td><td>Pharma- solve</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Myrj 52</td><td>Pharma- solve</td><td>Glycol propylene</td><td></td><td></td><td></td><td></td><td></td>

<td>Myrj 53</td><td>Pharma- solve</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Tween 40 *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Tween 60 *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Tween 80 *</td><td>Ethanol</td><td>Esters citrate</td><td>Oil olive</td><td>PEG 400</td><td>water</td><td></td><td></td>

<td>Crillet 6 *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Emsorb 2726</td><td>Pharma- solve</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Solutol HS 15 *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

PL 196 267 B1 cont. table 2

<td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td>

<td>Brij 76</td><td>Pharma- solve</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Brij 78</td><td>Pharma- solve</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Brij 98</td><td>Pharma- solve</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Crovol A-40 *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Crovol H-40 *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>β-cyclo- dextrin</td><td>Water</td><td></td><td></td><td></td><td></td><td></td><td></td>

* Has been shown to act as both a solubiliser and carrier

Note: All vehicles listed above can dissolve more than 25 mg / ml paclitaxel (paclitaxel) at 37 ° C.

Example 2

Fatty acid esters of polyoxyethylated sorbitol as carriers

Table 3 lists carrier formulations containing certain fatty acid esters of (polyoxyethylated) POE sorbitol as carriers for oral paclitaxel (paclitaxel), alone or in combination with a solubiliser. In formulations where more than one component is present in the vehicle, the respective weight ratios of the components are given. Each of these formulations was tested in the animal model described in Example 1 and found to give percent oral paclitaxel (paclitaxel) absorption higher (in some cases much higher) than approximately 15% of a comparable intravenous dose of paclitaxel (paclitaxel). The table shows the total dose of paclitaxel incorporated into each vehicle as actually administered to the experimental animals, the concentration of paclitaxel (paclitaxel) in the composition, the HLB value of the vehicle, the mean AUC value of the formulation group of rats and the percent absorption of paclitaxel (paclitaxel) compared to intravenous administered rats.

Table 3. Results of the absorption of polyoxyethylated sorbitan fatty acid esters as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>HLB</td><td>AUC pg.equ xh / ml</td><td>% ABS</td>

<td>POE 20 sorbitan monolaurate (Tween 20)</td><td> 10,2</td><td> 18</td><td> 16,7</td><td> 17,2</td><td> 54,6</td>

<td>POE 20 Sorbitan Monopalmitate (Tweed 40)</td><td> 10,2</td><td> 18</td><td> 15,6</td><td> 17,6</td><td> 55,9</td>

<td>POE sorbitan monostearate (Tween 60)</td><td> 8,9</td><td> 25</td><td> 14,9</td><td> 17,1</td><td> 62,3</td>

<td>POE 20 sorbitan tristearate (Tween 65)</td><td> 9,4</td><td> 25</td><td> 10,5</td><td> 6,15</td><td> 21,1</td>

<td>POE 20 sorbitan monooleate (Tween 80}</td><td> 9,0</td><td> 18</td><td> 15,0</td><td> 11,4</td><td> 40,9</td>

<td>POE 20 Sorbitan Monoisostearate (Crillet 6)</td><td> 9,3</td><td> 20</td><td> 14,9</td><td> 13,6</td><td> 47,5</td>

<td>POE 40 sorbitan diisostearate / Pharmosolve (3: 1) [Emsorb 2726]</td><td> 10,2</td><td> 25</td><td> 15,0*</td><td> 7,76</td><td> 24,6</td>

* Percentage of absorption relative to AUC of intravenous paclitaxel (paclitaxel) (same for Tables 4-11).

Example 3

POE alkyl ethers as carriers

Table 4 relates to the carrier formulations containing POE alkyl ethers as carriers. The data shown corresponds to the data described in the previous example referring to Table 3.

PL 196 267 B1

Table 4. Results of the absorption of polyoxyethylated (POE) alkyl ethers as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>HLB</td><td>AUC μg.equ xhh / ml</td><td>% ABS</td>

<td>POE 10 sterile ether / Pharmasolve (3: 1) [Brij 76]</td><td> 10,2</td><td> 18</td><td> 12,4*</td><td> 9,54</td><td> 30,3</td>

<td>POE 20 sterile ether / Pharmasolve (3: 1) [Brij 78]</td><td> 9,5</td><td> 18</td><td> 15,6</td><td> 11,4</td><td> 38,7</td>

<td>POE 20 Oleyl Ether / Pharmasolve (3: 1) [Brij 98]</td><td> 9,6</td><td> 25</td><td> 15,3*</td><td> 5,89</td><td> 20,9</td>

* This is not the actual HLB of the mixture. Numbers represent the HLB values ​​of pure surfactants.

Example 4

POE stearates as carriers

Table 5 relates to carrier formulations containing POE stearates as carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

Table 5. Results of the absorption of polyoxyethylated (POE) stearates as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>HLB</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>POE 20 sterile ether / Pharmasolve (3: 1) [Myrj 49]</td><td> 9,2</td><td> 25</td><td> 15,0*</td><td> 10,3</td><td> 36,4</td>

<td>POE 40 sterile ether / Pharmasolve (3: 1) [Myrj 52]</td><td> 9,4</td><td> 18</td><td> 16,9*</td><td> 16,2</td><td> 57,3</td>

<td>POE 50 sterile ether / Pharmasolve (3: 1) [Myrj 53]</td><td> 10,0</td><td> 25</td><td> 17,9*</td><td> 7,01</td><td> 22,3</td>

* This is not the actual HLB of the mixture. Numbers represent the HLB values ​​of pure surfactants.

Example 5

Ethoxylated modified triglycerides as carriers

Table 6 relates to carrier formulations containing ethoxylated modified triglycerides as carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

Table 6. Results of the absorption of ethoxylated modified triglycerides as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>HLB</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>PEG-20 almond glycerides (Crovol A-40)</td><td> 9,5</td><td> 20</td><td> 10</td><td> 8,06</td><td> 27,6</td>

<td>PEG-20 corn glycerides (Crovol M-40)</td><td> 9,6</td><td> 20</td><td> 10</td><td> 7,46</td><td> 25,3</td>

Example 6

POE 660 hydroxystearates as carriers

Table 7 relates to carrier formulations containing POE 660 hydroxystearates as carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

PL 196 267 B1

Table 7. Polyoxyethylated (POE) Absorption Results

660 hydroxystearate as a carrier

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>HLB</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>POE 660 hydroxystearate (Solutol HS 15)</td><td> 9,1</td><td> 25</td><td> 14</td><td> 10,8</td><td> 38,4</td>

<td>Gelucire 44/14 + Solutol HS + TPGS (2: 1: 1)</td><td> 9,3</td><td> 25</td><td> 14</td><td> 6,54</td><td> 22,8</td>

Example 7

Saturated polyglycolized glycerides as carriers

Table 8 relates to carrier formulations containing saturated polyglycolized glycerides as carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

Table 8. Results of absorption of saturated polyglycolized glycerides as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>Gelucire 44/14 + PEG 400 (6: 1)</td><td> 10,3</td><td> 25</td><td> 11,9</td><td> 37,4</td>

<td>Gelucire 44/14 + Labrasol (6: 1)</td><td> 9,3</td><td> 25</td><td> 12,1</td><td> 42,1</td>

<td>Gelucire 44/14 + Mygliol 810 (6: 1)</td><td> 8,7</td><td> 25</td><td> 4,75</td><td> 17,6</td>

<td>Gelucire 44/14 + Mygliol 818 (6: 1)</td><td> 10,3</td><td> 25</td><td> 8,45</td><td> 26,6</td>

<td>Gelucire 44/14 + Mygliol 840 (6: 1)</td><td> 9,5</td><td> 25</td><td> 6,48</td><td> 22,0</td>

<td>Gelucire 44/14 + Cremophor RH 40 (6: 1)</td><td> 9,5</td><td> 25</td><td> 10,7</td><td> 36, 6</td>

<td>Gelucire 44/14 + Cremophor EL (6: 1)</td><td> 9,8</td><td> 25</td><td> 11,5</td><td> 38,1</td>

<td>Gelucire 44/14 + Solutol HS + TPGS (2: 1: 1)</td><td> 9,3</td><td> 25</td><td> 6,54</td><td> 22,8</td>

<td>Gelucire 44/14 + olive oil + Tween 80 (2: 1: 1)</td><td> 9,6</td><td> 20</td><td> 11,9</td><td> 39,9</td>

<td>Gelucire 44/14 + olive oil + TPGS (2: 1: 1)</td><td> 9,6</td><td> 20</td><td> 9,83</td><td> 33,2</td>

<td>Gelucire 44/14 + olive oil + POE oleyl (2: 1: 1)</td><td> 9,6</td><td> 20</td><td> 9,07</td><td> 30,6</td>

<td>Gelucire 44/14 + olive oil + Cremophor RH 40 (2: 1: 1)</td><td> 9,1</td><td> 20</td><td> 7,73</td><td> 27,5</td>

<td>Gelucire 44/14 H + Tween 80 (6: 1)</td><td> 9,7</td><td> 25</td><td> 10,05</td><td> 33,5</td>

<td>Gelucire 50/13 + Tween 80 (5: 2)</td><td> 9,4</td><td> 25</td><td> 8,21</td><td> 28,4</td>

<td>Gelucire 50/13 + PED 400 (6: 1)</td><td> 9,3</td><td> 25</td><td> 6,46</td><td> 22,5</td>

<td>Gelucire 50/13 + Cremophore EL (6: 1)</td><td> 9,1</td><td> 25</td><td> 8,11</td><td> 28,9</td>

Labrasol: Saturated polyglycolized C8-C10 glycerides (HLB = 14)

Mygliols: Neutral oils (coconut and palm saturated fatty acids) mainly C8-C10 fatty acids

Cremophor EL: Polyoxyl 35 Castor Oil (HLB 12-14)

Cremophor RH 40: Polyoxyl Hydrogenated Castor Oil (HLB 14-16)

Example 8

Vitamin E TPGS systems as carriers

Table 9 relates to carrier formulations containing TPGS vitamin E systems as carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

PL 196 267 B1

Table 9. Results of the absorption of TPGS systems as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>TPGS + Pharmasolve (1.5: 1)</td><td> 8,2</td><td> 25</td><td> 8,93</td><td> 35,2</td>

<td>TPGS + Pharmasolve (1: 1)</td><td> 9,5</td><td> 25</td><td> 8,72</td><td> 29,8</td>

<td>TPGS + Pharmasolve (2: 1)</td><td> 9,1</td><td> 25</td><td> 8,83</td><td> 31,4</td>

<td>TPGS + Propylene glycol (1: 1)</td><td> 8,5</td><td> 20</td><td> 9,65</td><td> 36,9</td>

<td>TPGS + Pharmasolve + PEG 200 (2: 1: 1)</td><td> 9,0</td><td> 25</td><td> 8,31</td><td> 29,8</td>

<td>TPGS + Pharmasolve + PEG 400 (2: 1: 1)</td><td> 8,2</td><td> 25</td><td> 6,62</td><td> 26,3</td>

<td>TPGS + Pharmasolve + PG (2: 1: 1)</td><td> 8,9</td><td> 25</td><td> 8,07</td><td> 29,3</td>

<td>TPGS + Mygliol 810 (1: 1)</td><td> 9,1</td><td> 25</td><td> 5,65</td><td> 20,0</td>

<td>TPGS + Softigen 767 (1: 1)</td><td> 10,2</td><td> 25</td><td> 8,66</td><td> 27,5</td>

<td>TPGS + PEG 200 (1: 1)</td><td> 8,3</td><td> 25</td><td> 7,75</td><td> 30,4</td>

<td>TPGS + PEG 400 (1: 1)</td><td> 9,6</td><td> 25</td><td> 7,32</td><td> 24,6</td>

Softigen 767: PEG-6-caprylic / capric glycerides

Example 9

POE and hydrogenated castor oil derivatives as carriers

Table 10 relates to carrier formulations containing POE and hydrogenated castor oil derivatives as carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

Table 10. Results of the absorption of polyoxyethylated castor oil derivatives (Cremophor) as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>Intravenous Paxone</td><td> 10,0</td><td> 6</td><td> 11,15</td><td> 37,2</td>

<td>Cremophor EL + ethanol + water (1: 1: 8)</td><td> 9,2</td><td> 1,3</td><td> 6,07</td><td> 21,5</td>

<td>Intravenous Paxone + water (1: 1)</td><td> 8,9</td><td> 3</td><td> 8,70</td><td> 31,8</td>

<td>Intravenous Paxone + water (1: 5)</td><td> 9,1</td><td> 1</td><td> 10,76</td><td> 38,5</td>

<td>Cremophor EL + Pharmasolve (1: 1)</td><td> 8,6</td><td> 20</td><td> 6,74</td><td> 25,3</td>

<td>Cremophor EL + TBC (1: 1)</td><td> 9,0</td><td> 20</td><td> 9,35</td><td> 31,9</td>

<td>Cremophor EL + Gelucire 44/14 (1: 6)</td><td> 9,8</td><td> 25</td><td> 11,5</td><td> 38,1</td>

<td>Cremophor EL + Gelucire 50/13 (1: 6)</td><td> 9,1</td><td> 25</td><td> 8,11</td><td> 28,9</td>

<td>Cremophor RH 40 + ethanol + water (1: 1: 2)</td><td> 9,0</td><td> 3</td><td> 7,14</td><td> 25,7</td>

<td>Cremophor RH 60 + Gelucire 44/14 (1: 6)</td><td> 9,5</td><td> 25</td><td> 10,7</td><td> 36,6</td>

<td>Cremophor RH 40 + Gelucire 44/14 + olive oil (1: 2: 1)</td><td> 9,1</td><td> 20</td><td> 7,73</td><td> 27,5</td>

Example 10

Polysorbate 80 carriers

Table 11 relates to carrier formulations containing polysorbate 80 as at least one of the carriers. The data shown corresponds to the data described in Example 2 with reference to Table 3.

PL 196 267 B1

Table 11. Absorption results for Polysorbate 80 (Tween 80) systems as carriers

<td>Formulations</td><td>Dose [mg / kg]</td><td>Concentration [mg / kg]</td><td>AUC μg.equ xh / ml</td><td>% ABS</td>

<td>Polysorbate 80</td><td> 9,0</td><td> 18</td><td> 11,4</td><td> 40, 9</td>

<td>Polysorbate 80 + ethanol + water (1: 1: 8)</td><td> 8,0</td><td> 1,2</td><td> 7,92</td><td> 31,2</td>

<td>Polysorbate 80 + ethanol (3: 1)</td><td> 8,9</td><td> 18</td><td> 9,97</td><td> 36,3</td>

<td>Polysorbate 80 + water (3: 1)</td><td> 8,2</td><td> 18</td><td> 7,15</td><td> 28,3</td>

<td>Polysorbate 80 + TBC (1: 1)</td><td> 9,5</td><td> 20</td><td> 9,12</td><td> 31,2</td>

<td>Polysorbate 80 + ATEC (1: 1)</td><td> 9,1</td><td> 20</td><td> 8,50</td><td> 30,3</td>

<td>Polysorbate 80 + olive oil (3: 1)</td><td> 9,0</td><td> 20</td><td> 13,3</td><td> 43,7</td>

<td>Polysorbate 80 + PEG 400 (1: 1)</td><td> 9,7</td><td> 20</td><td> 9,41</td><td> 31,5</td>

<td>Polysorbate 80 + Gelucire 44/14 + olive oil (1: 2: 1)</td><td> 9,6</td><td> 20</td><td> 11,9</td><td> 39,9</td>

<td>Polysorbate 80 + Gelucire 44/14 (1: 6)</td><td> 9,7</td><td> 25</td><td> 10,05</td><td> 33,5</td>

TBC = Tributyl Citrate (Citrate Ester)

ATEC = Acetyl triethyl citrate (citrate ester)

In this way, it is shown that compositions and methods are provided that implement the various objects of the present invention and that are well suited to meet practical application conditions.