Purpose: Oxybutynin is a commonly used drug that acts to relax the urinary system by interrupting the parasympathetic nervous input to the bladder, ureter, and urinary sphincters. Because it is given orally, it frequently has systemic side effects, such as dry eyes, intestinal effects, and arrhythmias. In addition, long-term oral use may impair memory and cognitive development. Our objective was to create stable nanoparticles that can contain and predictably release the water-soluble compound oxybutynin directly to the bladder muscle without causing systemic distribution.
Methods: Liposomes were formed around oxybutynin from phosphatidylcholine and cholesterol (PC-CHOL). Alternative formulations were created, including a polymeric form of sodium alginate and Eudragit RLPO polymer. Each was tested for maximum capture of oxybutynin. All oxybutynin levels were determined using HPLC (free, loaded on nanoparticles, and in tissue). Drug movement through tissue was determined using a Franz diffusion cell, containing a donor and receiver compartment separated by pig bladder tissue. The cell was tested for leaks using methylene blue in the donor compartment. Free oxybutynin was first tested in the donor compartment to determine pharmacodynamics of its movement through the bladder tissue. Following this, various nanoparticles were tested in the donor compartment, and their pharmacodynamics determined. Fluorescent microscopy was used to visualize tagged nanoparticle penetration into the bladder tissue.
Results: PC-CHOL was found to have an oxybutynin capture efficiency of 5-7%. Sodium alginate, after optimization, was found to have a capture efficiency of 87-95%. Eudragit RPLO polymer particles had a capture efficiency of 97%. When comparing free oxybutynin to the liposomal formulation, the liposomal oxybutynin stayed in the tissue for a longer period of time (figure 1) and at higher concentrations than the free oxybutynin. Liposomal particles were seen within the tissue layers of the pig bladder segment (figure 2).
Oxybutynin can be loaded into liposomes with therapeutic doses. Alternative formulations of nanoparticles are extremely efficient at loading oxybutynin. Nanoparticles can penetrate bladder mucosa, remain in the muscle and deliver oxybutynin to its target avoiding system exposure. This novel method of intravesical drug delivery provides high drug dose to the target tissue without systemic exposure, avoiding significant toxicity and side effects.