SPiP and QbD oriented optimized nanocubosomes for ameliorated absorption of tolterodine tartrate: In vitro and in vivo evaluations

The study explored HSPiP and QbD-(quality by design) enabled optimized cubosomes for sustained drug release, improved permeation, and enhanced oral bioavailability. OCUB1 (the optimized product) was characterized for size, zeta potential (ZP), thermal analysis, and surface roughness. In vitro drug release and hemolysis studies were carried out using a dialysis membrane and rat erythrocytes (4 % suspension), respectively. An ex vivo non-everted intestinal permeation study (180 min) compared permeation potential between DS (suspension) and OCUB1. In vivo pharmacokinetic (PK) study investigated PK parameters in rats whereas hematological and biochemical assays ensured the safety of OCUB1. HSPiP predicted glyceryl monooleate (GMO), poloxamer-188, and polyvinyl alcohol (PVA) as optimal excipients based on minimum RED (relative energy difference) values while QbD identified OCUB1 as the most optimized formulation with desirable attributes such as low size (169 nm), high ZP (-29.2 mV), low polydispersity index (0.23), and maximum entrapment efficiency (85.3 %). Thermal analysis confirmed solubilization of TOTA in OCUB1, and atomic force microscopy (AFM) technique confirmed its cubical shape. OCUB1 showed extended drug release (98.1 % over 48 h) and sustained ex vivo permeation (J ss = 6.69 μg/cm2/min, steady state flux) across rat intestine as compared to DS (J ss = 9.172 μg/cm2/min). In vivo PK parameters exhibited significant improvement, with 3.2-fold increase in Cmax as compared to the DS. In vitro hemolysis, along with biochemical and hematological assays, ensured the safety of OCUB1 for oral delivery. Conclusively, OCUB1 presents a promised alternative to conventional capsule, offering reduced side effects and enhanced patient compliance.