Intravesical drug delivery

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Intravesical drug delivery through a urinary catheter Intravesical Drug Delivery.png
Intravesical drug delivery through a urinary catheter

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.

Contents

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. [1] 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. [1] 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 layers of the urothelium. Urothelium Layers.png
The layers of the urothelium.

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. [1] 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. [1] [2] [3] [4] [5] 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. [1] [2] [3] 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. [3] These issues create the need for more frequent dosing, which causes urinary catheter site irritation and compliance issues with treatments. [2] 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. [1] Creating formulations which adhere to the bladder wall has been targeted as one way to improve intravesical dug efficacy,. [1] [2] [3] [4] [5] The low adherence of drugs to the bladder wall and low permeability into the bladder wall contributes to low drug retention in the bladder. [1] 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. [2] 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.,. [1] [2] [3] [4] [5] 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. [1] [2] 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. [1] [4] 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 [1] [2] [3] [4] [5]

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. [1] [2] [3] 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. [1] [2] [3]

Mucoadhesive formulations

A mucoadhesive formulation adhered to bladder wall through interactions with urothelium's mucin layer. Mucoadhesive delivered to the bladder wall.png
A mucoadhesive formulation adhered to bladder wall through interactions with urothelium's mucin layer.

Mucoadhesive formulations can be made with both biopolymers and synthetic polymers, and usually contain polymers that are hydrophilic and can form many hydrogen bonds with the GAG-mucin. [1] Positively charged molecules typically make far better mucoadhesive as the mucin layer is negatively charged. [6] 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. [3] In experiments with chitosan, it has been shown that the mucoadhesive properties of a molecule likely increase as the molecular weight is increased. [7] 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 [8]

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. [1] [9] 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. [9] If these gels are made to be mucoadhesive they stick to the bladder wall and do not wash out or cause urethral obstruction. Polymeric hydrogels have also been formulated to float on top of the urine to avoid wash out and obstruction without having to adhere to the bladder wall. [10] 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. [2]

Enhancing drug permeability

Enhancing drug permeability can be done through physical or chemical methods, and is also achieved through nanoparticle and liposome drug carriers. [1] [2] [3] [4] [5] Physical methods include electromotive drug administration, radiofrequency-induced chemotherapeutic effect, and conductive hyperthermic chemotherapy, but electromotive drug administration seems to be the most prevalent in recent research and clinical trial focus. [1] [2] [3] [5] [11] 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. [1]

Electromotive Drug Administration (EMDA)

Placement of electrodes for EMDA on the urinary bladder. Electromotive Drug Administration.png
Placement of electrodes for EMDA on the urinary bladder.

Electromotive drug administration utilizes a small electric current flowing across the bladder wall between two electrodes, one on the skin and one placed inside the bladder via catheterization, to enhance permeability of aqueous solutions. [1] [2] [3] Electromotive drug administration best enhances ionized formulations, which diffuse poorly using standard passive diffusion. [3] This allows it to potentially assist in the delivery of many drugs that usually perform poorly in the bladder without having to change their formulations heavily. Across multiple studies and clinical trials electromotive drug administration has been shown to increase the uptake of many drugs, showing potential use in bladder cancer, urinary incontinence, urinary cystitis and pain management. [1] [2] [3] [5] Cost of local anesthesia for bladder distention using electromotive drug administration in combination with lidocaine has been shown to be cheaper and more practical than general anesthesia or spinal anesthesia. [5]

Chemically enhancing permeability

To enhance the permeability of the bladder wall, specifically the urothelium, to drugs administered locally to the bladder four chemical agents are most commonly used: DMSO, protamine sulphate, Hyaluronidase, and chitosan. DMSO is already widely used to directly treat urinary cystitis due to its anti-inflammatory and antibacterial properties. [1] [3] DMSO can penetrate tissues without causing any damage to them. [1] [3] This property of DMSO made it of particular interest as a chemical enhancer and it has been shown to increase the uptake of several chemotherapeutics used intravesically. [12] 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. [1] [3] Hyaluronidase breaks down Hyaluronic acid, a GAG molecule important to the mucin layer, causing enhanced permeability of the mucin layer to drugs administered concurrently with hyaluronidase. [1] Conversely, hyaluronic acid can be used to treat interstitial cystitis as it helps to repair damaged mucin layers. [3] Chitosan is thought to function as a permeability enhancer by binding to the mucin layer and negatively affecting tight junctions between umbrella cells in the urothelium. [1] It has been shown that chitosan increases bladder wall permeability but its effectiveness as a permeability enhancer decreases as calcium ion concentration increases. [13] 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. [1]

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. [1] [2] [3] [5] Liposomes generally must be shielded via modification with a Polyethylene glycol molecule to overcome issues with instability and aggregation in urine. [4] Nanoparticle and Liposome drug carriers can be loaded into a in situ forming hydrogel to gain the advantages of mucoadhesive properties [4] Empty liposomes by themselves have been noted to improve interstitial cystitis, most likely due to formation of a lipid film on damaged urothelium. [3] [5] 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. [1]

Related Research Articles

<span class="mw-page-title-main">Interstitial cystitis</span> Medical condition

Interstitial cystitis (IC), a type of bladder pain syndrome (BPS), is chronic pain in the bladder and pelvic floor of unknown cause. It is the urologic chronic pelvic pain syndrome of women. Symptoms include feeling the need to urinate right away, needing to urinate often, and pain with sex. IC/BPS is associated with depression and lower quality of life. Many of those affected also have irritable bowel syndrome and fibromyalgia.

<span class="mw-page-title-main">Bladder</span> Organ in humans and vertebrates that collects and stores urine from the kidneys before disposal

The bladder is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine enters the bladder via the ureters and exits via the urethra. The typical adult human bladder will hold between 300 and 500 ml before the urge to empty occurs, but can hold considerably more.

<span class="mw-page-title-main">Hydrogel</span> Soft water-rich polymer gel

A hydrogel is a biphasic material, a mixture of porous, permeable solids and at least 10% by weight or volume of interstitial fluid composed completely or mainly by water. In hydrogels the porous permeable solid is a water insoluble three dimensional network of natural or synthetic polymers and a fluid, having absorbed a large amount of water or biological fluids. These properties underpin several applications, especially in the biomedical area. Many hydrogels are synthetic, but some are derived from nature. The term 'hydrogel' was coined in 1894.

<span class="mw-page-title-main">Transitional epithelium</span> A type of tissue

Transitional epithelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching. The transitional epithelium usually appears cuboidal when relaxed and squamous when stretched. This tissue consists of multiple layers of epithelial cells which can contract and expand in order to adapt to the degree of distension needed. Transitional epithelium lines the organs of the urinary system and is known here as urothelium. The bladder, for example, has a need for great distension.

<span class="mw-page-title-main">Maleimide</span> Chemical compound

Maleimide is a chemical compound with the formula H2C2(CO)2NH (see diagram). This unsaturated imide is an important building block in organic synthesis. The name is a contraction of maleic acid and imide, the -C(O)NHC(O)- functional group. Maleimides also describes a class of derivatives of the parent maleimide where the NH group is replaced with alkyl or aryl groups such as a methyl or phenyl, respectively. The substituent can also be a small molecule (such as biotin, a fluorescent dye, an oligosaccharide, or a nucleic acid), a reactive group, or a synthetic polymer such as polyethylene glycol. Human hemoglobin chemically modified with maleimide-polyethylene glycol is a blood substitute called MP4.

<span class="mw-page-title-main">Enhanced permeability and retention effect</span>

The enhanced permeability and retention (EPR) effect is a controversial concept by which molecules of certain sizes tend to accumulate in tumor tissue much more than they do in normal tissues. The general explanation that is given for this phenomenon is that, in order for tumor cells to grow quickly, they must stimulate the production of blood vessels. VEGF and other growth factors are involved in cancer angiogenesis. Tumor cell aggregates as small as 150–200 μm, start to become dependent on blood supply carried out by neovasculature for their nutritional and oxygen supply. These newly formed tumor vessels are usually abnormal in form and architecture. They are poorly aligned defective endothelial cells with wide fenestrations, lacking a smooth muscle layer, or innervation with a wider lumen, and impaired functional receptors for angiotensin II. Furthermore, tumor tissues usually lack effective lymphatic drainage. All of these factors lead to abnormal molecular and fluid transport dynamics, especially for macromolecular drugs. This phenomenon is referred to as the "enhanced permeability and retention (EPR) effect" of macromolecules and lipids in solid tumors. The EPR effect is further enhanced by many pathophysiological factors involved in enhancement of the extravasation of macromolecules in solid tumor tissues. For instance, bradykinin, nitric oxide / peroxynitrite, prostaglandins, vascular permeability factor, tumor necrosis factor and others. One factor that leads to the increased retention is the lack of lymphatics around the tumor region which would filter out such particles under normal conditions.

<span class="mw-page-title-main">Thiomer</span>

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Bioadhesives are natural polymeric materials that act as adhesives. The term is sometimes used more loosely to describe a glue formed synthetically from biological monomers such as sugars, or to mean a synthetic material designed to adhere to biological tissue.

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Feline idiopathic cystitis (FIC) or feline interstitial cystitis or cystitis in cats, is one of the most frequently observed forms of feline lower urinary tract disease (FLUTD). Feline cystitis means "inflammation of the bladder in cats". The term idiopathic means unknown cause; however, certain behaviours have been known to aggravate the illness once it has been initiated. It can affect both males and females of any breed of cat. It is more commonly found in female cats; however, when males do exhibit cystitis, it is usually more dangerous.

A nanogel is a polymer-based, crosslinked hydrogel particle on the sub-micron scale. These complex networks of polymers present a unique opportunity in the field of drug delivery at the intersection of nanoparticles and hydrogel synthesis. Nanogels can be natural, synthetic, or a combination of the two and have a high degree of tunability in terms of their size, shape, surface functionalization, and degradation mechanisms. Given these inherent characteristics in addition to their biocompatibility and capacity to encapsulate small drugs and molecules, nanogels are a promising strategy to treat disease and dysfunction by serving as delivery vehicles capable of navigating across challenging physiological barriers within the body. 

<span class="mw-page-title-main">Bovine submaxillary mucin coatings</span> Surface treatment for biomaterials

Bovine submaxillary mucin (BSM) coatings are a surface treatment provided to biomaterials intended to reduce the growth of disadvantageous bacteria and fungi such as S. epidermidis, E. coli, and Candida albicans. BSM is a substance extracted from the fresh salivary glands of cows. It exhibits unique physical properties, such as high molecular weight and amphiphilicity, that allow it to be used for many biomedical applications.

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders. These disorders include Parkinson's disease, Alzheimer's disease, schizophrenia, depression, and brain tumors. Part of the difficulty in finding cures for these central nervous system (CNS) disorders is that there is yet no truly efficient delivery method for drugs to cross the BBB. Antibiotics, antineoplastic agents, and a variety of CNS-active drugs, especially neuropeptides, are a few examples of molecules that cannot pass the BBB alone. With the aid of nanoparticle delivery systems, however, studies have shown that some drugs can now cross the BBB, and even exhibit lower toxicity and decrease adverse effects throughout the body. Toxicity is an important concept for pharmacology because high toxicity levels in the body could be detrimental to the patient by affecting other organs and disrupting their function. Further, the BBB is not the only physiological barrier for drug delivery to the brain. Other biological factors influence how drugs are transported throughout the body and how they target specific locations for action. Some of these pathophysiological factors include blood flow alterations, edema and increased intracranial pressure, metabolic perturbations, and altered gene expression and protein synthesis. Though there exist many obstacles that make developing a robust delivery system difficult, nanoparticles provide a promising mechanism for drug transport to the CNS.

Nanocomposite hydrogels are nanomaterial-filled, hydrated, polymeric networks that exhibit higher elasticity and strength relative to traditionally made hydrogels. A range of natural and synthetic polymers are used to design nanocomposite network. By controlling the interactions between nanoparticles and polymer chains, a range of physical, chemical, and biological properties can be engineered. The combination of organic (polymer) and inorganic (clay) structure gives these hydrogels improved physical, chemical, electrical, biological, and swelling/de-swelling properties that cannot be achieved by either material alone. Inspired by flexible biological tissues, researchers incorporate carbon-based, polymeric, ceramic and/or metallic nanomaterials to give these hydrogels superior characteristics like optical properties and stimulus-sensitivity which can potentially be very helpful to medical and mechanical fields.

Nanoparticle drug delivery systems are engineered technologies that use nanoparticles for the targeted delivery and controlled release of therapeutic agents. The modern form of a drug delivery system should minimize side-effects and reduce both dosage and dosage frequency. Recently, nanoparticles have aroused attention due to their potential application for effective drug delivery.

Topical drug delivery (TDD) is a route of drug administration that allows the topical formulation to be delivered across the skin upon application, hence producing a localized effect to treat skin disorders like eczema. The formulation of topical drugs can be classified into corticosteroids, antibiotics, antiseptics, and anti-fungal. The mechanism of topical delivery includes the diffusion and metabolism of drugs in the skin. Historically, topical route was the first route of medication used to deliver drugs in humans in ancient Egyptian and Babylonian in 3000 BCE. In these ancient cities, topical medications like ointments and potions were used on the skin. The delivery of topical drugs needs to pass through multiple skin layers and undergo pharmacokinetics, hence factor like dermal diseases minimize the bioavailability of the topical drugs. The wide use of topical drugs leads to the advancement in topical drug delivery. These advancements are used to enhance the delivery of topical medications to the skin by using chemical and physical agents. For chemical agents, carriers like liposomes and nanotechnologies are used to enhance the absorption of topical drugs. On the other hand, physical agents, like micro-needles is other approach for enhancement ofabsorption. Besides using carriers, other factors such as pH, lipophilicity, and drug molecule size govern the effectiveness of topical formulation.

<span class="mw-page-title-main">Dextran drug delivery systems</span> Polymeric drug carrier

Dextran drug delivery systems involve the use of the natural glucose polymer dextran in applications as a prodrug, nanoparticle, microsphere, micelle, and hydrogel drug carrier in the field of targeted and controlled drug delivery. According to several in vitro and animal research studies, dextran carriers reduce off-site toxicity and improve local drug concentration at the target tissue site. This technology has significant implications as a potential strategy for delivering therapeutics to treat cancer, cardiovascular diseases, pulmonary diseases, bone diseases, liver diseases, colonic diseases, infections, and HIV.

Vitaliy Khutoryanskiy FRSC is a British and Kazakhstani scientist, a Professor of Formulation Science and a Royal Society Industry Fellow at the University of Reading. His research focuses on polymers, biomaterials, nanomaterials, drug delivery, and pharmaceutical sciences. Khutoryanskiy has published over 200 original research articles, book chapters, and reviews. His publications have attracted > 10000 citations and his current h-index is 48:. He received several prestigious awards in recognition for his research in polymers, colloids and drug delivery as well as for contributions to research peer-review and mentoring of early career researchers. He holds several honorary professorship titles from different universities.

Topical gels are a topical drug delivery dosage form commonly used in cosmetics and treatments for skin diseases because of their advantages over cream and ointment. They are formed from a mixture of gelator, solvent, active drug, and other excipients, and can be classified into organogels and hydrogels. Drug formulation and preparation methods depend on the properties of the gelators, solvents, drug and excipients used.

Intranasal drug delivery occurs when particles are inhaled into the nasal cavity and transported directly into the nervous system. Though pharmaceuticals can be injected into the nose, some concerns include injuries, infection, and safe disposal. Studies demonstrate improved patient compliance with inhalation. Treating brain diseases has been a challenge due to the blood brain barrier. Previous studies evaluated the efficacy of delivery therapeutics through intranasal route for brain diseases and mental health conditions. Intranasal administration is a potential route associated with high drug transfer from nose to brain and drug bioavailability.

References

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