Intravesical drug delivery is the delivery of medications directly into the bladder by urinary catheter. This method of drug delivery is used to directly target diseases of the bladder such as interstitial cystitis and bladder cancer, but currently faces obstacles such as low drug retention time due to washing out with urine and issues with the low permeability of the bladder wall itself. Due to the advantages of directly targeting the bladder, as well as the effectiveness of permeability enhancers, advances in intravesical drug carriers, and mucoadhesive, intravesical drug delivery is becoming more effective and of increased interest in the medical community.
Advantages 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. The smaller fraction of drug reaching its target with systemic delivery means more drugs must be administered which can lead to problems with systemic toxicity. This is not the case when drug is administered directly to the bladder.
The layer of the bladder which comes into contact with urine, the urothelium (the transitional epithelium of the bladder, is a mostly impermeable barrier which stops molecules in the urine from being reabsorbed and prevents molecules from being secreted directly into the bladder as well. The bladder's impermeability means that any drug delivered intravesical will not absorb into the bloodstream well through the bladder wall, causing fewer systemic effects. This impermeability also causes treatment of bladder diseases to be more difficult to treat as drugs do not absorb well into the bladder wall. Intravesical drug delivery has been identified as an ideal way to treat most urinary disorders, including bladder tumors and bladder cancers, interstitial cystitis, and urinary incontinence. There is currently a lack of interest in treating urinary tract infections using intravesical delivery.
Disadvantages 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. These methods each serve to improve retention time, drug permeability through the urothelium, or some combination of the two.
Enhancing drug retention Enhancing drug retention can be achieved through changing formulation and delivery device. Often drug retention and permeability enhancement are tied, as drugs which permeate the urothelium will suffer fewer effects from urine dilution and voiding. Two of the most common methods to improve drug retention are by using a mucoadhesive formulation or using polymeric hydrogels that form in the bladder, or in situ gelling hydrogels.
Mucoadhesive formulations
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