Porous paclitaxel matrices and methods of manufacture thereof

Abstract

Paclitaxel is provided in a porous matrix form, which allows the drug to be formulated without Cremophor and administered as a bolus. The paclitaxel matrices preferably are made using a process that includes (i) dissolving paclitaxel in a volatile solvent to form a paclitaxel solution, (ii) combining at least one pore forming agent with the paclitaxel solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of paclitaxel. The pore forming agent can be either a volatile liquid that is immiscible with the paclitaxel solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. In a preferred embodiment, microparticles of the porous paclitaxel matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

Description

[0001]This invention claims priority U.S. Ser. No. 60 / 186,310 filed Mar. 2, 2000, and is a continuation to PCT / US00 / 14578 filed May 25, 2000, which claims priority to U.S. Ser. No. 60 / 136,323 filed May 27, 1999, and U.S. Ser. No. 60 / 158,659 filed Oct. 8, 1999.BACKGROUND OF THE INVENTION[0002]This invention generally relates to formulations of paclitaxel and more particularly to methods of making formulations of paclitaxel.[0003]Paclitaxel is a natural product which has been shown to possess cytotoxic and antitumor activity. Indeed, paclitaxel may be among the most active single agent for ovarian and breast cancers. This compound is found in small concentrations in the Taxus brevifolia species such as the Pacific yew tree among other Taxus species. While having an unambiguous reputation of tremendous therapeutic potential, paclitaxel as a therapeutic agent has some patient related drawbacks. These stem, in part, from its extremely low solubility in water, which makes it difficult to ...

AI Technical Summary

Benefits of technology

[0010]The porous matrices that contain the paclitaxel are preferably made using a process that includes (i) dissolving a paclitaxel in a volatile solvent to form a paclitaxel solution, (ii) combining at least one pore forming agent with the paclitaxel solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the dry porous matrix of paclitaxel. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the paclitaxel. The pore forming agent can be either a volatile liquid that is immiscible with the paclitaxel solvent or a volatile solid compound, preferably a volatile salt. If the pore forming agent is a liquid, the agent is emulsified with the paclitaxel solution. If the pore forming agent is a solid, the agent is (i) dissolved in the paclitaxel solution, (ii) dissolved in a solvent that is not miscible in the paclitaxel solvent and then emulsified with the paclitaxel solution, or (iii) suspended as solid particulates in the paclitaxel solution. Optionally, hydrophilic excipients, wetting agents, and / or tonicity agents may be added to the paclitaxel solvent, the pore forming agent solvent, or both. The solution, emulsion, or suspension of the pore forming agent in the paclitaxel solution is then processed to remove the paclitaxel solvent and the pore forming agent, as well as any pore forming agent solvent. In a preferred embodiment, spray drying, optionally followed by lyophilization, fluid bed drying, or vacuum drying, is used to remove the solvents and the pore forming agent.

[0011]An advantage of the formulations is that they can be administered as a bolus, when the paclitaxel normally must be infused to avoid toxicity and to avoid precipitation of the drug. By avoiding precipitation of paclitaxel in vivo, the formulations can also be administered intrarterially, intravenously, locally, intracranially, intrathecally, or directly into a tumor. An additional advantage is the formulations can be administered in reduced volumes.

[0012]In one embodiment, the matrix further includes a pegylated excipient with the paclitaxel. The pegylated excipient shields the paclitaxel from macrophage uptake, which prolong its half-life or enhance bioavailability of the paclitaxel.

Problems solved by technology

While having an unambiguous reputation of tremendous therapeutic potential, paclitaxel as a therapeutic agent has some patient related drawbacks.

These stem, in part, from its extremely low solubility in water, which makes it difficult to provide in suitable dosage form.

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