Aqueous Formulations of Cytotoxic Taxanes with Cyclodextrin

NU 2022-109

INVENTORS

• Brittney Williams
• Matthew Thompson
• Nathan Gianneschi*

SHORT DESCRIPTION

This invention describes aqueous formulations of cytotoxic taxane drugs conjugated to fatty acids, solubilized using cyclodextrin inclusion complexes, providing water-soluble chemotherapy formulations that eliminate the need for toxic organic solvents or albumin pre-complexation while maintaining targeted delivery to cancer cells. See also NU2022-111 and NU2019-135.

BACKGROUND

Prior formulations of fatty acid-derivatized paclitaxel (ODDA-PTX, under NU2022-111) required pre-mixing with human serum albumin (HSA), as ODDA-PTX itself has poor aqueous solubility. Commercial paclitaxel formulations like ABRAXANE™ use nanoparticle albumin technology, while older formulations use CREMOPHOR™ EL solvent systems that cause hypersensitivity reactions requiring premedication. The challenge was to develop an aqueous formulation of ODDA-PTX and related fatty acid-taxane prodrugs that would be sufficiently water-soluble for intravenous administration without requiring albumin pre-complexation.

ABSTRACT

Cytotoxic taxane moieties (like paclitaxel) conjugated to long-chain fatty acid-like hydrophobic moieties are complexed with water-soluble β-cyclodextrins to form aqueous pharmaceutical formulations. The cyclodextrin encapsulates the hydrophobic fatty acid chain in its lipophilic cavity, dramatically increasing aqueous solubility (~500-fold improvement), enabling concentrations >9.5 mM taxane for intravenous administration without organic solvents or albumin. Experiments confirm the fatty acid modification maintains prodrug status, preventing premature drug activation, while retaining the ability of the cyclodextrin complex to bind endogenous HSA. Cytotoxicity studies in cancer cell models and in vivo efficacy studies in xenograft models demonstrate cell killing and tumor regression.

APPLICATIONS

• Simplified clinical cancer chemotherapy formulations enabling direct intravenous administration of aqueous cyclodextrin-complexed ODDA-paclitaxel solutions without requiring albumin pre-mixing, toxic organic solvents, or specialized nanoparticle formulations.
• Pediatric and adolescent cancer treatment where the elimination of excipients from the formulation makes these cyclodextrin-based taxane prodrugs particularly suitable for treating vulnerable patients compared to conventional paclitaxel formulations.
• Targeted therapy for fatty acid transporter-overexpressing cancers where CD36 and related fatty acid uptake proteins are characteristically upregulated.
• Combination chemotherapy protocols and immunotherapy regimens where the aqueous cyclodextrin formulation can be readily co-administered or sequentially dosed, enabling flexible dosing schedules and infusion protocols.

ADVANTAGES

• Dramatically improved aqueous solubility and elimination of problematic excipients, enabling formulations in water or saline, eliminating severe hypersensitivity reactions and simplifying regulatory approval, manufacturing, and clinical administration.
• Preserved prodrug functionality and capacity to bind endogenous albumin, ensuring in vivo tumor targeting via CD36-mediated fatty acid uptake remains intact.
• Superior therapeutic index and reduced toxicity profile - complete tumor regression observed in 5/8 animals at 250 mg/kg weekly dosing for 4 weeks without drug-associated toxicity or significant weight loss (<20%), enabling dose escalation impossible with conventional formulations,
• Versatile pharmaceutical platform and manufacturing simplicity where lyophilized cyclodextrin-ODDA-PTX powder can be readily reconstituted in sterile water or saline at high concentrations (>9.5 mM taxane).

PUBLICATION

Callmann et al. Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin. J Am Chem Soc. 141 (30): 11765-11769 (2019).

IP STATUS

• US patent application US20240092750A1 has been filed.