Paclitaxel and its formulations

Abstract

Paclitaxel (Taxol®) is a promising anti-tumor agent with poor water solubility. It is effective for various cancers especially ovarian and breast cancer. Intravenous administration of a current formulation in a non-aqueous vehicle containing Cremophor EL may cause allergic reactions and precipitation on aqueous dilution. Moreover, the extensive clinical use of this drug is somewhat delayed due to the lack of appropriate delivery vehicles. Due to this there is a need for the development of alternate formulation of paclitaxel having good aqueous solubility and at the same time free of any side effects. Various approaches employed so far include cosolvents, emulsions, micelles, liposomes, microspheres nanoparticles, cyclodextrins, pastes, and implants etc. which are discussed in this paper.

Introduction

Paclitaxel, the first of a new class of microtubule stabilizing agents, has been hailed by National Cancer Institute (NCI) as the most significant advance in chemotherapy of the past 15–20 years. Paclitaxel was not a chance discovery but was the outcome of the investigation of over 12 000 natural compounds for anticancer activity (Appendino, 1993)

Paclitaxel is a diterpenoid pseudoalkaloid (Fig. 1) having molecular formula C₄₇H₅₁NO₁₄, corresponding to molecular weight of 853 Da. For anti-tumor activity it is required that entire taxane molecule (Fig. 2) be present, since the ester and the tetraol formed by a low temperature cleavage of paclitaxel are found to be essentially inactive (Wall and Wani, 1996). Paclitaxel was isolated in early 1960s from the bark of Pacific Yew (Taxus brevifolia; family Taxaceae), one of the geographical varieties of yew (Wani et al., 1971). Paclitaxel was obtained in a pure form in 1969 and its structure was published in 1971, after many complexities due to its low concentration and structure complexities (Wani et al., 1971, Bingham, 1994).

The importance of paclitaxel was not recognized until the late 1970s, since, it is difficult to obtain and also due to its low solubility it has a formulation problem. It was in 1979, that Susan Horwitz discovered that paclitaxel has a unique mechanism of action and interest was further stimulated when impressive activity was demonstrated in NCI tumor screening.

Unlike other microtubule agents, such as Vinca alkaloids, which induce the disassembly of microtubules, paclitaxel promotes the polymerization of tubulin (Schiff et al., 1979, Hamel et al., 1981, Parness and Horwitz, 1981, Schiff and Horwitz, 1981, Rowinsky et al., 1990). The microtubule formed in presence of paclitaxel are extraordinarily stable and dysfunctional, thereby causing the death of the cell by disrupting the normal tubule dynamics required for cell division and vital interphase process. Paclitaxel has neoplastic activity particularly against primary epithelial ovarian carcinoma, breast cancer, colon, head, non-small cell lung cancer, and AIDS related Kaposi's sarcoma (Horwitz, 1992, Spencer and Faulds, 1994, Rowinsky and Donehover, 1995, Alshowaier and Nicholls, 1997). This has led to the approval of the drug in many countries for its use as second line treatment of ovarian and breast cancers. In phase II trials with patients treated previously with high dose chemotherapy, the response rate in advanced and refractory ovarian cancer was 30% (Mcguire et al., 1989). The overall response rate in phase I trials in previously treated patients with metastatic breast cancer was 56% (Holmes et al., 1991). In our present paper, we are going to elaborate on the various formulation aspects of paclitaxel, problems associated with the existing formulation and the promising formulation aspects of paclitaxel.