The objective of this study was to formulate once-a-day extended-release (ER) pellet system of imidafenacin (IDN), a recently approved urinary antispasmodic agent with twice-a-day dosing regimen. The sugar sphere pellets were firstly layered with IDN and hypromellose and then coated with Eudragit RS (copolymers of acrylic and methacrylic acid esters), employed as a release modifier, using a fluid-bed coater. Solid-state characterizations using solid-state X-ray diffraction and differential scanning calorimeter indicated that the antispasmodic agent was homogeneously layered onto the pellets in an amorphous state. Drug release from multiple-unit ER system was effectively retarded in proportion to the amount of Eudragit RS in the outer layer, with a high correlation value above 0.86. In a pharmacokinetic evaluation in beagle dogs, the plasma concentration profile of IDN was markedly protracted by ER pellets, exhibiting delayed the time needed to reach the maximum drug concentration and the elimination half-life in plasma, compared to the commercial immediate release form (Uritos® tablet, Kyorin Pharmaceutical Co., Ltd., Japan). Therefore, the novel ER pellets can be a promising tool for oral IDN therapy, providing a once-a-day dosing regimen, and thus, improving patient compliance.
A novel ER system of IDN was successfully fabricated by doubly layering the pellet core; the sugar sphere was firstly layered with the anti-muscarinic agent and coated again with Eudragit RS, employed as a release retardant, in a fluid-bed apparatus. The drug release from the pellets was effectively retarded in proportion to the amount of Eudragit polymer in outer layer, with a high correlation value above 0.86. Consis- tently, the drug concentration in plasma steadily increased (Tmax of 5.0 h) and it gradually decreased with T1/2 of 3.02 h, after administration of the optimized ER pellet system (F2) in beagle dogs. Thus, we expected that the once-a-day ER pellets can be a substitute for the commercial IR tablet, as they offer reduced dose frequency and ensure less fluctuation in plasma drug level in patients with overactive bladder.