Abstract
Regarding compliance and minimization of side effects of nilotinib therapy, there is a medical need to have a gastroretentive drug delivery system (GRDDS) to enhance the oral bioavailability that is able to administer an optimal dose in a quaque die (QD) or daily manner. In this study, the influence on a swelling and floating (sf) GRDDS composed of a polymeric excipient (HPMC 90SH 100K, HEC 250HHX, or PEO 7000K) and Kollidon® SR was examined. Results demonstrated that PEO 7000K/Kollidon SR (P/K) at a 7/3 ratio was determined to be a basic GRDDS formulation with optimal swelling and floating abilities. MCC PH102 or HPCsssl,SFP was further added at a 50% content to this basic formulation to increase the tablet hardness and release all of the drug within 24 h. Also, the caplet form and capsule form containing the same formulation demonstrated higher hardness for the former and enhanced floating ability for the latter. A pharmacokinetic study on rabbits with pH values in stomach and intestine similar to human confirmed that the enhanced oral bioavailability ranged from 2.65–8.39-fold with respect to Tasigna, a commercially available form of nilotinib. In conclusion, the multiple of enhancement of the oral bioavailability of nilotinib with sfGRDDS could offer a pharmacokinetic profile with therapeutic effectiveness for the QD administration of a reasonable dose of nilotinib, thereby increasing compliance and minimizing side effects.
Highlights
Nilotinib with the brand name of Tasigna was approved by the United States (US) Food and Drug Administration (FDA) for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML)
Hydrophilic polymers that possess gelling properties in water are widely used in formulating swellable gastroretentive drug delivery system (GRDDS) with sustained-release characteristics
Our study compared the influence on the swelling and floating caused by water absorption with hydrophilic polymeric excipients including hydroxypropyl methylcellulose (HPMC) 90SH 100K, hydroxyethyl cellulose (HEC) 250HHX, and PEO7000K in the presence of various amounts of Kollidon® SR
Summary
Nilotinib with the brand name of Tasigna was approved by the United States (US) Food and Drug Administration (FDA) for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML). With once-daily administration, steady-state nilotinib exposure was linear in the dose range of 50–200 mg/day and was dose-dependent, with less than dose-proportional increases in systemic exposure at dose levels of >400 mg/day, possibly because of limited solubility in gastric acid or saturation of its uptake. Upon twice-daily administration, there was no relevant increase in exposure to nilotinib when the dose was increased from 400 to 600 mg/day [2]. This might have been due to the maximal solubility in gastric acid being achieved in this dose range. At a dose of 800 mg/day, exposure to nilotinib following 400 mg twice daily was about 35% higher than after 800 mg given once daily, while the increase in exposure to nilotinib between the first dose and steady state was approximately two-fold for once-daily dosing and 3.8-fold for twice-daily dosing, both possibly because of the total solubility in gastric acid with two divided doses being higher than that for a single dose, leading to enhanced bioavailability [2,3]
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