The marine ecosystem is more and more acknowledged as a source of potential anticancer agents. After the identification of a potential substance several hurdles have to be overcome before a marine candidate can enter the clinic. Amongst these are the establishment of a method which ensures sufficient supply and, which is the focus of this review, the development of a clinically useful pharmaceutical formulation. General issues with respect to the pharmaceutical development of marine anticancer agents will be discussed, which will be illustrated by highlighting aspects of the pharmaceutical development and clinical use of some representative compounds.

Kahalalide F is a novel antitumor agent isolated from the marine mollusk Elysia rufescens; it has shown highly selective in vitro activity against androgen-independent prostate tumors. The purpose of this study was to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. Solubility and stability of kahalalide F were studied as a function of polysorbate 80 (0.1%-0.5% w/v) and citric acid monohydrate (15-15 mM) concentrations using an experimental design approach. Stabilities of kahalalide F lyophilized products containing crystalline (mannitol) or amorphous (sucrose) bulking agents were studied at +5 degrees C and +30 degrees C +/- 60% relative humidity (RH) in the dark. Lyophilized products were characterized by infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Recovery studies after reconstitution of kahalalide F lyophilized product and further dilution in infusion fluid were carried out to select an optimal reconstitution vehicle. It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a hulking agent were more stable compared to the products containing mannitol. The glass transition temperature of the sucrose-based product was determined to be + 46 degrees C. The amorphous state of the product was confirmed by IR analysis. A solution composed of Cremophor EL, ethanol, and water for injection (5%/5%/90% v/v/v CEW, kept kahalalide F in solution after reconstitution andfurther dilution with 0.9% w/v sodium chloride (normal saline) to 1.5 microg/m. A stable lyophilized formulation was presented containing 100 microg of kahalalide F, 100 mg sucrose, 2.1 mg citric acid monohydrate, and 2mg polysorbate 80 to be reconstituted with a vehicle composed of 5%/5%/90% v/v/v CEW and to be diluted further using normal saline.

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Kahalalide F is a novel marine-derived antitumor agent isolated from the marine mollusk Elysia rufescens, an organism living in the seas near Hawaii. The compound has shown highly selective in vitro activity against prostate tumors and phase I trials in patients with androgen independent prostate tumors incorporating a daily times five and weekly schedule have been initiated. Kahalalide F is pharmaceutically formulated as a lyophilized product containing 150 microg active substance per dosage unit. Prior to i.v. administration it is reconstituted with a solution composed of Cremophor EL, ethanol absolute and Water for Injection (CEW, 5/5/90% v/v/v) with further dilution in 0.9% w/v sodium chloride for infusion. The aim of this study was to investigate the compatibility and stability of kahalalide F with different infusion systems prior to the start of clinical trials with the compound. Due to the presence of Cremophor EL in the infusion solution, leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride infusion containers (PVC, Add-a-Flex) was found. Loss of kahalalide F as a consequence of sorption to contact surfaces was shown with an infusion container composed of low density polyethylene (LD-PE, Miniflac). We conclude that kahalalide F must be administered in a 3-h infusion in concentrations of 0.5 microg/mL to 14.7 microg/mL using an administration set consisting of a glass container and a low-extrables, DEHP-free extension set. Kahalalide F 150 microg/vial powder for infusion reconstituted with 5/5/90% v/v/v CEW is stable in the original container for at least 24 h at room temperature (+20-25 degrees C) and ambient light conditions. Infusion solutions stored in glass infusion containers at either room temperature (+20-25 degrees C, in the dark) or refrigerated conditions (+2-8 degrees C, in the dark) are stable for at least 5 days after preparation.

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