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

Abstract

Pharmaceutical compositions for oral administration to mammalian subjects comprise a taxane or taxane derivative (e.g., paclitaxel or docetaxel) as active ingredient and a vehicle comprising at least 30% by weight of a carrier for the taxane, said carrier having an HLB value of at least about 10. The compositions may also comprise 0-70% of a viscosity-reducing co-solubilizer. The compositions may be incorporated into conventional oral pharmaceutical dosage forms, or can be in the form of a two-part medicament wherein the first part includes the taxane in a solubilizing vehicle and the second part comprises a carrier for the taxane to promote oral absorption. Methods of treatment of taxane-responsive disease conditions employing the novel compositions are also disclosed, whereby the compositions can be administered alone or in association with an oral bioavailability enhancing agent.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of co-pending application Ser. No. 09 / 055,818, which is a continuation-in-part of co-pending application Ser. No. 08 / 863,513, abandoned, which is a continuation-in-part of application Ser. No. 08 / 733,142, filed Oct. 16, 1996, now U.S. Pat. No. 6,245,805, which is a continuation-in-part of application Ser. No. 08 / 608,776, filed Feb. 29, 1996, now U.S. Pat. No. 5,968,972, which claims the priority of provisional application Ser. No. 60 / 007,071, filed Oct. 26, 1995.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The invention relates to compositions for orally administering paclitaxel and related taxanes to human patients, and methods of treatment employing such compositions. [0004] 2. Description of the Prior Art [0005] Many valuable pharmacologically active compounds cannot be effectively administered by the oral route to human patients because of poor or inconsistent systemic absorp...

AI Technical Summary

Benefits of technology

"The present invention is about oral pharmaceutical compositions that contain taxane antitumor agents, such as paclitaxel or docetaxel, which can be absorbed from the gastrointestinal tract into the bloodstream to provide therapeutically significant blood levels of the active drug. The compositions include a vehicle in which the taxane agent is dissolved or dispersed, and a viscosity-reducing co-solubilizer that makes the vehicle more flowable at body temperature and increases the solubility of the taxane agent. The compositions also contain a carrier, which is a non-ionic surface active agent or emusifier with a hydrophilic-lipophilic balance value of at least 10. The therapeutically inactive vehicle comprises at least 30% by weight of carrier and 0-70% of co-solubilizer, and may also contain conventional pharmaceutical additives and excipients such as flavoring and coloring agents. The invention also pertains to methods of treatment of mammalian patients suffering from taxane-responsive disease conditions by the administration of the oral pharmaceutical compositions in accordance with the invention, preferably with co-administration of an oral bioavailability enhancing agent."

Problems solved by technology

Many valuable pharmacologically active compounds cannot be effectively administered by the oral route to human patients because of poor or inconsistent systemic absorption from the gastrointestinal tract.

These pharmaceutical agents are, therefore, generally administered via intravenous routes, requiring intervention by a physician or other health care professional, entailing considerable discomfort and potential local trauma to the patient and even requiring administration in a hospital setting with surgical access in the case of certain IV infusions.

Paclitaxel is only slightly soluble in water and this has created significant problems in developing suitable injectable and infusion formulations useful for anticancer chemotherapy.

CREMOPHOR EL™ however, when administered intravenously, is itself toxic and produces vasodilation, labored breathing, lethargy, hypotension and death in dogs.

For this reason, paclitaxel has not been administered orally to human patients in the prior art, and certainly not in the course of treating paclitaxel-responsive diseases.

It has been speculated that, in some cases, the poor or non-existent bioavailability of a drug such as paclitaxel after oral administration is a result of the activity of a multidrug transporter, a membrane-bound P-glycoprotein, which functions as an energy-dependent transport or efflux pump to decrease intracellular accumulation of drug by extruding xenobiotics from the cell.

These trials showed that patients receiving intravenous cyclosporine prior to or together with the anti-cancer drugs had higher blood levels of those drugs, presumably through reduced body clearance, and exhibited the expected toxicity at substantially lower dosage levels.

Benet et al., however, provide virtually no means for identifying which bioavailability enhancing agents will improve the availability of specific “target” pharmaceutical compounds, nor do they indicate specific dosage amounts, schedules or regimens for administration of the enhancing or target agents.

These inclusion criteria are of no value to medical practitioners seeking safe, practical and effective methods of orally administering specific pharmaceutical agents.

In general, Benet et al. provides no teaching that could be followed by persons skilled in the medical and pharmaceutical arts to identify suitable bioenhancer / target drug combinations or to design specific treatment regimens and schedules which would render the target agents therapeutically effective upon oral administration to human patients.

Neither commonly owned application WO 97 / 15269 nor any prior art disclosure, however, describes classes of oral formulations or compositions containing the active target agent, e.g., paclitaxel, which are particularly adapted for co-administration with an oral bioavailability enhancing agent to yield therapeutic blood levels of target agents heretofore considered unsuitable for oral administration.