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Although the current clinical formulation of paclitaxel (Taxolt) is an important new anti-cancer agent, it has significant side effects, some of which are related to its formulation in Cremophor/ethanol. Paclitaxel is difficult to formulate for i.v. administration because of its poor aqueous solubility. Here, we report the therapeutic effects of 2 liposome formulations of paclitaxel against human ovarian A121 tumor growing as an s.c. xenograft in athymic nude mice. The liposome formulations used were ETL and TTL, which have 1 or 3 lipid components, respectively. TTL was used as a reconstituted lyophilate or as a stable aqueous suspension. ETL was used as a reconstituted lyophilate only. Both pacli-taxel-liposome formulations were much better tolerated than Taxolt after i.v. or i.p. administration. The acute reactions seen after Taxolt administration did not occur when paclitaxel-liposome formulations were administered. All ETL and TTL preparations significantly delayed A121 tumor growth similarly to Taxol at equivalent doses and schedules. Based on pharmacokinetic data, it is possible that paclitaxel rapidly dissociates from ETL or TTL after i.v. administration and distributes in a manner similarly to Taxol. ETL and TTL formulations may be useful clinically not only for eliminating toxic effects of the Cremophor/ethanol vehicle but also for allowing alterations in route and schedule of drug administration. Int. Paclitaxel is a hydrophobic molecule solubilized for clinical use as an anti-neoplastic agent in Cremophore EL (polyethoxylated castor oil) containing 50% dehydrated ethanol, Taxolt (Bristol Myers Squibb, Princeton, NJ). This formulation has shown significant activity against a broad range of human cancers, including refractory human ovarian and breast cancers, non-small-cell lung carcinoma, head and neck carcinoma and melanoma (Huizing et al., 1995; Rowinsky and Donehower, 1995; Rowinsky et al., 1992). However, Cremophor EL, the excipient used in the Taxol formulation , has been shown to cause serious hypersensitivity reactions in humans (Weiss et al., 1990). To reduce the incidence and intensity of hypersensitivity, pre-medication with corticosteroids (dexametha-sone) and anti-histamines is being used. Although the pre-medication regimen has reduced the incidence of serious hypersen-sitivity reactions to less than 5%, milder reactions still occur in approximately 30% of patients (Weiss et al., 1990; Runowicz et al., 1993). Furthermore, it has been shown that Cremophor EL is mainly responsible for the non-linear pharmacokinetic behavior of paclitaxel in mice, and this may also be the case in humans since the plasma Cremophor concentrations at which non-linearity occurs in mice are in the therapeutic range achieved in humans (Sparreboom et al., 1996). Therefore, there is a strong rationale for reformulating taxanes using a safer and better-tolerated vehicle than Cremophor. Since plain liposomes have little toxicity, formulation of pacli-taxel in liposomes may offer advantages over the cremophor-based form...

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The problematic excipients are best explained by the proton accepting capacity of excipient carboxylate groups which have pK(a)'s higher than the pH(max) of the drug salt. Alternative lubricants and disintegrants are suggested and a simple excipient screening process is proposed. Magnesium stearate was the most deleterious excipient for HCl salts due to the formation of the deliquescent salt magnesium chloride.

Amorphous solid dispersions (ASDs) have been increasingly used to maximize human exposures from poorly soluble drug candidates. One well-studied advantage of ASDs is the increased amorphous drug solubility compared to crystalline forms. This provides more rapid dissolution rates. An additional advantage of ASDs is that the dissolution process of the ASD particle may also rapidly transform much of the drug present in the ASD particle to small (<1 μm) amorphous drug nanoparticles which will have fast dissolution rates. This work examines the mechanism by which this nanoparticle formation occurs by studying an ASD consisting of 70-80% copovidone, 20% anacetrapib (a low solubility lipophilic drug), and 0-10% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant). Nanoparticle formation is found to derive from a rapid amorphous drug domain formation within the ASD particle, driven by copovidone dissolution from the particle. The role of surfactant in the ASD particle is to prevent an otherwise rapid, local drug domain aggregation event, which we term "hydrophobic capture". Surfactant thus allows the amorphous drug domains to escape hydrophobic capture and diffuse to bulk solution, where they are reported as nanoparticles. This view of surfactant and nanoparticle formation is compared to the prevailing view in the literature. The work here clarifies the different roles that surfactant might play in increasing nanoparticle yields and extending the useful drug loading ranges in copovidone-based ASDs.