Formulation Development of Anti-Cancer Drugs

Abstract

Formulation issues, including stability, solubility and bioavailability, have been identified as key concerns in anti-cancer drug development. The challenges in pharmaceutical formulation often arise from the different physicochemical attributes of a molecule and the need to deliver the compound to a desired site. The major problems of small molecule drug formulation development are poor water solubility and off target toxicity. In chapter 2 of this dissertation, a prostate specific membrane antigen (PSMA) targeted micelle was made to deliver a PI3K inhibitor, TGX-221, for prostate cancer treatment. The in vitro cell culture based study indicated that the targeted micelle significantly improved cellular uptake by PSMA positive cells. The in vivo animal efficacy study showed that the targeted micelle significantly reduced tumor size and progression in a xenograft model. Ridaforolimus, a non-prodrug rapamycin analog, has entered clinical trials for cancer treatment. Formulations of ridaforolimus being evaluated in the clinical trials include intravenous infusion and oral administration. The intravenous bolus formulation of this drug is very limited due to poor water solubility (ca. 200 µg/mL). In chapter 3, we showed that a new formulation of ridaforolimus using DSPE-PEG2000 micelle as a carrier greatly improved the drug solubility, increasing it 40 times. In addition, the pharmacokinetic properties examined in rats showed that this formulation significantly increased drug retention in the plasma. In chapter 4, a hyaluronic acid-rapamycin conjugate was synthesized and characterized. The disposition and efficacy of the drug conjugate were studied and demonstrated that the hyaluronic acid drug conjugate could be used for treating localized CD44 positive cancer. In chapter 5, a doxorubicin prodrug was developed for enhancing oral bioavailability. Doxorubicin was chemically conjugated with quercetin, a flavonoid, via a glycine linker. Quercetin is a P-glycoprotein inhibitor; thus, it prevents doxorubicin efflux by this mechanism. The oral bioavailability of DOX was significantly improved in rats through this prodrug strategy. In the last chapter, an HPLC method was developed for the separation of active compounds from degraded alternol, which could be used for alternol manufacturing and stability studies.