Preparation and Comparison of Oral Bioavailability for Different Nano-formulations of Olaparib

• Published in: AAPS PharmSciTech Vol. 20; no. 7; p. 276
• Main Authors: Pathade, Akshay D., Kommineni, Nagavendra, Bulbake, Upendra, Thummar, Mohit M., Samanthula, Gananadhamu, Khan, Wahid
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 06.08.2019
• Subjects: Administration, Oral; Animals; Biochemistry; Biological Availability; Biomedical and Life Sciences; Biomedicine; Biotechnology; Breast Neoplasms; Drug Compounding; Drug Liberation; Humans; Pharmacology/Toxicology; Pharmacy; Phthalazines - administration & dosage; Phthalazines - pharmacokinetics; Phthalazines - therapeutic use; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - therapeutic use; Rats; Research Article; Olaparib; Bioavailability; Nano-formulations; PARP inhibitor
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-019-1468-y

Olaparib (OLA) is a poly ADP ribose polymerase (PARP) inhibitor approved for germline BRCA-mutated (gBRCAm) advanced ovarian cancer and breast cancer. Low oral bioavailability of this drug requires increase in the dose and frequency causing haematological toxicity in the patients. The purpose of this study is to prepare different nano-formulations of OLA lipospheres (LP) by melt dispersion and nano-suspensions (NSP) by solvent evaporation (SE) and wet milling (WM) techniques and compare oral bioavailability of these formulations. Size of the nano-formulations OLA-LP, OLA-NSP SE and OLA-NSP WM were found to be 126.71 ± 4.54, 128.6 ± 2.34 and 531.1 ± 5.34 nm with polydispersity index below 0.3. In vitro release studies were performed by dialysis bag method where the sustained drug release was observed from nano-formulations until 9 h with Higuchi for OLA suspended in 2.5% w / v sodium carboxy methyl cellulose (OLA-SP), OLA-LP and OLA-NSP WM and Peppas for OLA-NSP SE -based drug release kinetics. In vivo pharmacokinetic studies, haematological toxicity and distribution studies were performed on rats. Results showed that there was an improvement in C max , AUC total , t 1/2 and MRT by OLA nano-formulations when compared with OLA-SP. OLA-SP has shown reduction in WBC, platelets and lymphocytes at 12 and 36 h time points; however, no reduction in cell count was observed with OLA nano-formulations. Distribution studies proved FITC nano-formulations were most rapidly absorbed and distributed when compared with FITC-loaded suspension. From the above results, it was concluded that OLA nano-formulations can be an alternative to enhance the oral bioavailability and to reduce the haematological toxicity of OLA.