Sustained intravesical drug delivery using thermosensitive hydrogel.
OBJECTIVE
Direct instillation of drug solutions into the bladder through a urethral catheter (i.e., intravesical therapy) evades systemic adverse effects of drugs used for bladder diseases. However, conventional vehicles for these drugs fail to extend duration of drug exposure in the bladder beyond the first voiding of urine postinstillation. The current study seeks to overcome the aforementioned inherent limitation of intravesical drug administration by using thermosensitive hydrogel as a matrix for sustained intravesical drug delivery.


METHODS
Under halothane anesthesia, normal adult female Sprague-Dawley rats were catheterized with PE-50 tubing to instill either 0.02% w/v solution of fluorescein isothiocyanate (FITC) or the same amount of FITC in a 30% w/v dispersion of thermosensitive [Poly(ethylene glycol)-Poly[lactic acid-co-glycolic acid]-Poly(ethylene glycol)) (PEG-PLGA-PEG) polymer in a 0.1 M phosphate buffer. After instillations, rats were kept in metabolic cages for urine collection. Fluorescence emanating from FITC was measured in the urine at various time points up to 24 h after instillation. A rat model of cyclophosphamide-induced cystitis was chosen for the efficacy study using misoprostol as a model drug entrapped in the thermosensitive hydrogel in place of FITC. Efficacy of hydrogel containing misoprostol was compared against rat groups instilled with saline, hydrogel, and misoprostol independently.


RESULTS
Prolonged drug exposure to the bladder afforded by hydrogel was evident from the time course of FITC elimination in the urine and by the green fluorescence of FITC seen at the bladder surface when isolated 24 h after instillation. Rats instilled with free FITC voided almost all of the fluorescence in the urine within the first 8 h, whereas rats instilled with hydrogel encapsulated FITC showed sustained release up to 24 h after instillation. Using a cyclophosphamide-induced cystitis model, rats instilled with misoprostol, a synthetic PGE1 analog, showed significantly reduced frequency of urine voiding (p < 0.05) as compared to the rats instilled with saline. Histological examination of the urothelium showed near normal morphology in rats instilled with misoprostol in hydrogel, whereas extensive tissue damage was observed in rats instilled with saline.


CONCLUSIONS
Our study showed that PEG-PLGA-PEG polymer could be used as a viable sustained drug delivery system for intravesical therapy of diseases of the bladder such as cystitis using misoprostol.
Tyagi
Pradeep
P
Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Li
Zhenhua
Z
Chancellor
Michael
M
De Groat
William C
WC
Yoshimura
Naoki
N
Huang
Leaf
L
D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006207:Half-Life; D020100:Hydrogels; D007267:Injections; D016595:Misoprostol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D011500:Protein Synthesis Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013696:Temperature; D001743:Urinary Bladder / Q000473:pathology; D014549:Urinary Incontinence / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology
D003692:Delayed-Action Preparations; D005456:Fluorescent Dyes; D020100:Hydrogels; D011500:Protein Synthesis Inhibitors; D016595:Misoprostol; D003520:Cyclophosphamide; D016650:Fluorescein-5-isothiocyanate