Intravesical drug delivery

Delivering drugs directly to the target bladder site allows for maximizing drug delivery while minimizing systemic effects. Delivering the treatment directly to the site allows for more effective dosages to be given since high concentrations of drug in the bladder can be reached. This becomes especially important when patients have a urinary bladder disease that is drug resistant. The delivery of drugs directly to the bladder is a large improvement over systemic delivery which only allows a small fraction of the drug to reach the bladder, causing lower concentrations of drug leading to systemic treatments being ineffective. There is currently a lack of interest in treating urinary tract infections using intravesical delivery. ==Disadvantages of Intravesical Drug Delivery==

While intravesical delivery shows distinct advantages over systemic drug delivery it has several problems to overcome. When giving a drug intravesically it is diluted by urine and washed out when urine is voided. Additionally, the low permeability of the urothelium which lines the bladder creates a hurdle that must be overcome if the bladder wall needs to be treated. These issues create the need for more frequent dosing, which causes urinary catheter site irritation and compliance issues with treatments. Intravesical drug dilution occurs as urine accumulates in the bladder, lowering the concentration of drug in the bladder as overall volume increases. The voiding of drug with urine when using traditional drug formulations in the bladder has become a hurdle to overcome as well, since residence time of the drug inside the bladder is directly tied to the treatment's efficacy. Creating formulations which adhere to the bladder wall has been targeted as one way to improve intravesical dug efficacy,. The low adherence of drugs to the bladder wall and low permeability into the bladder wall contributes to low drug retention in the bladder. When modifying drug formulations for intravesical delivery gels or viscosity increasing formulations are sometimes used to increase retention, though this can cause issues with urethra obstruction, an additional hurdle in intravesical drug delivery. Permeability issues with the bladder wall can be attributed to the urothelium, the lining of the bladder wall made up of umbrella cells, intermediate cells, and basal cells.,. The impermeability can be attributed to the umbrella cells which form tight junctions with each other to make up the innermost layer of the urothelium and have the ability to change shape to adapt to the bladder's varying size. The umbrella cells are covered in a dense layer of plaques which further prevents the absorption of particles through the urothelium and a layer of mucin composed of glycosaminoglycans (GAGs) which prevents both hydrophobic and negatively charged molecules from adhering to the bladder wall. Overcoming the impermeability of the mucin layer and the urothelium is a large focus of many intravesical drug formulations, and is key to an efficacious intravesical treatment == Improvements ==

The main ways researchers are currently overcoming the problems in intravesical drug delivery are through developing formulations using mucoadhesives, nanoparticles, liposomes, polymeric hydrogel, expandable delivery devices, and electromotive drug administration. By forming these bonds, the mucoadhesive, and the drug it carries, can maintain sustained contact with the bladder wall, enhancing retention of the drug in the bladder. Among mucoadhesive materials Chitosan often stands out due to its biocompatibility, biodegradability, and permeability enhancing factors. Studies have also found that the modification of chitosan formulations with thiomers, which can form covalent bonds with mucus, can significantly improve the mucoadhesion of the chitosan formulations In situ gelling polymeric hydrogels Polymeric hydrogels for intravesical drug delivery take advantage of characteristics of the bladder or urine to gel, or may use external manipulation to cause the hydrogel to form. These gels can take advantage of pH or temperature differences, or external input like UV lasers, to form gels inside the bladder after instillation of the formulation in liquid form. Drawbacks of using polymeric hydrogel formulations include the concern of urethral obstruction, the varying conditions of the urine which make pH or ionic controlled gelling formulations less controlled, and the bladder wall inflammation which can occur with mucoadhesive polymeric hydrogels. Chemical methods revolve around adding a chemical agent to enhance drug uptake and increase permeability. To enhance drug permeability through physical or chemical methods both the mucin layer and the umbrella cells of the urothelium must undergo a structural or chemical change. Protamine sulphate causes disruption to the mucus layer of the urothelium and can cause large disruption of bladder permeability which can be modified by adding defibrotide. Chemically enhancing bladder permeability can lead to negative side effects such as incontinence, pain, and uncontrolled leakage of molecules other than intended drug from the urine into the bladder wall. Nanoparticle and liposome drug carriers Nanoparticle and liposome drug carrier formulations allow for increased drug uptake, especially in the case of liposomes which allow for greater uptake via endocytosis. Liposomes generally must be shielded via modification with a Polyethylene glycol molecule to overcome issues with instability and aggregation in urine. Nanoparticle and Liposome drug carriers can be loaded into a in situ forming hydrogel to gain the advantages of mucoadhesive properties Empty liposomes by themselves have been noted to improve interstitial cystitis, most likely due to formation of a lipid film on damaged urothelium. The variety of types of nanoparticles which can be made to carry drugs in intravesical formulations, combined with the tunability of many of these particles in regards to drug loading and release rates makes nanoparticles and liposomes a highly versatile and useful tool in intravesical drug delivery. == References ==