Development and evaluation of drug delivery system for improving oral absorption of poorly water- soluble olaparib

Abstract

Olaparib (OLA), a poly ADP-ribose polymerase inhibitor (PARP inhibitor), has been known to have therapeutic effects for curing cancers associated with impaired DNA repair capability, especially those with deficiencies in the homologous recombination repair pathway. OLA, a potent cytotoxic anticancer drug, is administrated for the treatment of patients with advanced, recurrent ovarian cancer who have mutations of breast cancer BRCA1 or breast cancer BRCA2. Despite the high therapeutic efficacies of OLA, OLA shows low oral bioavailability due to its low solubility and low permeability, which leads to increased administrated dosage and frequency. The daily dose of Lynparza® tablets is 600 mg, so the patient is obliged to endure the inconvenience of taking 4 tablets containing 150 mg of OLA every day. This high-dose administration reduces patient compliance and triggers undesirable side effects, such as hematological toxicity, nausea, anemia, vomiting and fatigue. Therefore, there is a need for a pharmaceutical formulation that can ultimately improve patient compliance and side effects by increasing the oral absorption of OLA. In this research, we aimed to prepare two solid dosage forms (SMEDDS system and reconstitutable dry emulsion system) containing OLA for improving solubility and to evaluate the obtained formulations in vitro and in vivo. In chapter 1, research on the SMEDDS system was conducted as follows. Through the solubility test of olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. The various physicochemical properties of microemulsion incorporating olaparib were confirmed by investigating the morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and absorption of olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul® MCM 10%, Labrasol® 80% and PEG 400 10%. The fabricated microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that they were maintained well without any problems of physical or chemical stability. The dissolution profiles of olaparib were significantly improved compared to the value of powder. Associated with the high dissolutions of olaparib, the pharmacokinetic parameters were also greatly improved. Taken together with the results mentioned above, the microemulsion could be an effective tool as a formulation for olaparib and other similar drugs. In chapter 2, research on the reconstitutable dry emulsion system (DE) was conducted as follows. A solubility study was conducted to measure OLA solubility in various oils. Based on the obtained results, Capmul® MCM EP/NF was selected as a solubilizer in the DE system. The DE formulation was prepared by spray-drying an o/w emulsion system consisting of Capmul® MCM EP/NF (oil phase) and poloxamer 188 aqueous solution (water phase). Various physicochemical properties of prepared DE, such as droplet size distribution, morphology, physical stability, and chemical stability, were evaluated. In addition, improved dissolution and oral absorption were confirmed through in vitro dissolution experiment and pharmacokinetic study. The prepared DE was well dispersed spherical particles and was stable for 6 months in a long-term storage test. The initial dissolution (at 5 min) of the reconstituted DE system was significantly improved by 5.13 times (at pH 1.2), 4.52 times (at pH 6.8), and 3.63 times (at water), respectively compared to that of OLA powder. The dissolutions at 120 minutes were also higher than those of OLA powder. Consequently, the pharmacokinetic study showed that in the case of oral administration of DE, Cmax and AUCinf were improved by 6.89 times and 2.18 times, respectively, compared to OLA powder. Therefore, the developed DE drug delivery system can be used as one of the useful options to improve the solubility and oral absorption of OLA and can also be applied to other drugs having similar physicochemical properties with OLA.