Category: Formulation and Quality
Purpose: Overactive bladder (OAB) is defined as a symptomatic syndrome characterized by urinary urgency and the symptoms are similar to lower urinary tract symptoms, accompanied by frequent urination and nocturia. OAB has a significant negative effect on the quality of life (QOL) of those affected. For the clinical treatment of OAB, muscarinic receptor antagonists (antimuscarinic agents) have been widely used. Solifenacin is one of the antimuscarinic agents, and is marketed as tablets and orally disintegrating tablets. Only oral dosage forms of solifenacin are currently available, and they are not ideal for patients who have difficulty swallowing. In addition, owing to the symptoms of OAB, some patients dislike consuming water when taking drugs. Transdermal drug delivery offers several advantages over oral routes. Transdermal formulations, such as creams and tapes, can be administered without water, which address the problems associated with oral dosage forms. The formulations allow the drug to be absorbed slowly into the blood over a long period of time, which further reduces side effects and frequency of administration as compared to oral formulations. Therefore, the aim of this study was to develop cream and tape formulations of solifenacin, and evaluate the transdermal permeation and absorption of the drug from the two formulations in vitro and in vivo, respectively.
Methods: In the preparation of cream formulation, solifenacin succinate was dissolved in purified water, and the mixture was added to the hydrophilic (white petrolatum 25% and stearyl alcohol 20%) cream. Then, aqueous sodium hydroxide was added to the cream. The content of solifenacin succinate in formulation was 0.5, 1, 3, 5, 7, 10 and 15%. In the preparation of the tape formulation, solifenacin succinate was mixed with propylene glycol, diisopropanolamine, triethyl citrate, and EUDRAGIT® E100, and then they were dissolved in a solvent containing a mixture of acetonitrile, ethanol and isopropanol. The dissolved solvent was poured onto a polyethylene film, and dried for 20 min to obtain solifenacin tapes, in which the contents of solifenacin succinate were 2, 5, 10, 15, and 20 %.
In vitro skin permeation of each formulation was evaluated using Franz-type diffusion cells. We applied each formulation (2, 5 and 10 mg/cm2 for the cream formulations; 2.5, 5 and 10 mg/cm2 for the tape formulations) to the ear skin of a pig and placed it on the receptor cell and the donor chamber was clamped in place. The cell was filled with the receptor solution (phosphate-buffered saline, pH 7.4) maintained at 37 °C. Then, 1 mL of sample was collected from the receptor solution at 2, 4, 6, 8, 10, and 24 h, and the concentrations of solifenacin in the samples were measured by HPLC. The apparent in vitro steady-state permeation flux (J) was calculated. In in vivo pharmacokinetic studies, the creams (5%, 2 and, 10 mg/cm2) and tapes (15%, 2 and, 5 mg/cm2) were applied to the dorsal section (4 × 5 cm area) of rats. Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hr, and the plasma concentrations of solifenacin were measured using LC-MS/MS.
Results: The in vitro skin permeation of cream and tape formulations with different contents of solifenacin was evaluated. The J values for the cream formulations increased with an increase in solifenacin content in the formulations up to 3% (1.40±0.55 µg/cm2/hr), but did not increase for cream formulations at higher contents (Figure 1a). For the tape formulations, the J value increased at the highest content (20%) of solifenacin (8.61±1.69 µg/cm2/hr, Figure 1b). In the evaluation of the amount applied in the skin permeation study, the J value for both cream and tape formulations increased with an increase in the amount applied (up to 10 mg/cm2). In the in vivo pharmacokinetic study, maximum plasma concentrations of solifenacin were noted at 24 hr after application of both formulations to the skin of rats, and then slowly decreased. The area under the concentration vs curve from 0 to 24 hr (AUC0-24) in the cream formulations was 40.7 ± 17.1 and 173 ± 63 hr･ng/mL at 2 and 10 mg/cm2, respectively. The AUC0-24 at 2.5 and 5 mg/cm2 for the tape formulations was 18.2 ± 5.6 and 68.5 ± 23.3 hr･ng/mL, respectively. The AUC0-24 after the oral administration of solifenacin (30 mg/kg) was 69.8 ± 15.5 hr･ng/mL, which was equivalent to and lower than for the higher dose of cream tape formulations.
Conclusion: In this study, we prepared transdermal formulations of solifenacin. Significant in vitro permeability and in vivo absorption of solifenacin from the transdermal formulations were observed, which can achieve the sufficient plasma concentration when applied for clinical use. Thus, the formulations could provide new options for OAB treatment.
Shinya Uchida– Associate professor, University of Shizuoka, Shizuoka, Shizuoka, Japan
Mitsunobu Yoshida– Shizuoka, Shizuoka, Japan
Jyunko Imoto– Shizuoka, Shizuoka, Japan
Yasuharu Kashiwagura– Assistant professor, University of Shizuoka, Shizuoka, Shizuoka, Japan
Shimako Tanaka– Assistant professor, University of Shizuoka, Shizuoka, Shizuoka, Japan
Rakan Matsui– Shizuoka, Shizuoka, Japan
Noriyuki Namiki– Professor, University of Shizuoka, Shizuoka, Shizuoka, Japan