The Development Of Floating Hydrogel Drug Delivery System For Intravesical Instillation

lntravesical drug administration is commonly performed by instilling chemical drugs to bladder using a urethral catheter. It provides high drug concentration in bladder and simultaneously reduces systemic exposure. However, the chemical drug is usually kept inside bladder less than 2 hours and is eliminated due to the first voiding of urine. The efficacy of intravesical instillation is a large extent determined by the drug residence time in bladder. Therefore, a controlled delivery system for intravesical instillation is necessary.A recent study was to use thermo-sensitive hydrogels as drug depots on the bladder wall. Due to the adhesion, hydrogels could attach to the bladder wall even after the urine voiding. Thus, the drug residence time in bladder was significantly extended. Nevertheless, due to the high viscosity of hydrogel, one serious problem is urinary obstruction. Gels adhering to the bladder may block the urinary tract, such as internal urethral orifice and ureteric orifice with narrow opening. As hydrogels attach to the bladder wall, another problem may be serious bladder irritation symptoms. Therefore, despite that the hydrogel has many advantages in intravesical drug delivery, its application is limited due to these two shortcomings.To overcome the critical defects arising from the hydrogel, a floating hydrogel delivery system was designed in our study. The floating hydrogel was made of thermo-sensitive polymer (Poloxamer 407) and NH4HCO3, which was liquid at low temperature while forming hydrogel at high temperature. Meanwhile, at high temperature, NH4HCO3 decomposed to produce CO2 bubbles, which helped hydrogel float in bladder without urinary obstruction.The mixture containing 45% P407 and 6% NH4HCO3 was selected as the optimal formulation. The vitro study showed that, at 37℃, the mixture formed hydrogel and produced many bubbles which could be observed by B ultrasound, the antitumor drug Doxorubicin was released in a controlled manner. In vivo study, after the mixture was instilled into rabbit bladder, it formed hydrogel and floated in the bladder. The bladder stimuli was reduced and antitumor drugs could be released continuously in the bladder. Our results showed that this floating hydrogel may be an optimal carrier for Dox (Doxorubicin) to prolong the drug residence time in bladder. Our study suggested that the floating hydrogel was a feasible intravesical drug delivery system and may have application prospects in intravesical therapy for bladder cancer.