Patent Application
20210100950
Devices that are placed within fluid filled organs, such as the bladder, which reduce the risk of bacterial infections using a combination of active agents and mechanical disruption of bacteria.
Urinary tract infections (“UTI”) are infections in any part of the urinary system, such as the kidneys, ureter, bladder, and/or urethra. The UTI typically develops in the human bladder caused by the migration of bacteria into the bladder cavity through the urethra. UTI's are one of the most common types of infections that require medical treatment. Nearly, one in five adults develops a UTI and many of these individuals are at risk for a recurring infection.
The risks associated with UTI's can be significant for persons suffering from incontinence or for older persons, as well as with traumatic changes in the central nervous system, which are accompanied by urination disorders. In many cases, chronic urinary tract infections can require continuous medication, which, leads to progressive levels of resistance to antibiotics and ultimately to kidney problems.
UTI's and complications caused by UTI's are cost-intensive due to continuous need for medication and extended hospitalization and they can be life-threatening. In many cases, UTI's significantly reduce the quality of life, in particular when kidney damage leads to kidney failure requiring dialysis or implantation of a donor kidney.
In many cases, the UTI is only treated after the infection has developed and becomes symptomatic. However, current treatment to prevent the formation of UTI's requires continuous prophylactic oral intake of medication that can potentially strain the entire body, in particular with long-term medication. However, the increase of multi-drug resistant bacteria makes it harder to treat UTI's with a standard anti-biotic regimen as the UTI can recur since all of the bacteria causing the UTI are not eliminated.
The problems arising from bladder infections is that the infection can ascend to the kidney via the ureter. In many cases women are at greater risk of developing a UTI than are men. While the infection can be limited to the bladder and produce pain, serious consequences can occur if a UTI spreads to the kidneys or other organs as sepsis (urosepsis) can occur. The problem is increased in the elderly because UTI's are especially prevalent with incomplete voiding of the bladder, weakened immune systems, dehydration, and adult diapers, where such factors increase the risk of UTI. In many cases elderly patients do not present with typical signs of infection until they become septic, at which point the patient requires hospitalization.
In Systemic delivery of drugs to treat UTIs, the volume of distribution of the therapy is equal to the total amount of urine which enters the bladder. Therefore, the therapy is voided with each emptying of the bladder and requires constant replenishment. In other cases, the drug target can be limited (i.e. the bladder wall) but cannot practically be reached without raising the concentration of the drug in the urine to the desired therapeutic concentration.
For conditions related to urinary tract infection, clearance of the bacteria is improved with complete emptying of the bladder. If the bladder does not empty efficiently, there is a retained volume of urine termed the “post void residual” which can act as a reservoir of bacteria for subsequent and ongoing infection. Detecting and minimizing this post void residual urine volume faces several challenges, namely: post void residual can be measured indirectly through ultrasound assessment, however this has limited accuracy depending on body habitus and at volumes less than 50 ml and greater than 250 ml. The post void residual can be measured and removed by draining the remaining urine through a catheter inserted retrograde through the urethra, however this is painful and can be psychologically traumatizing especially in the case of pediatric individuals.
Post void residual can also be decreased by removing the primary cause of bladder outlet obstruction, such as widening an area of urethral narrowing. However, this approach often requires a separate procedure or surgery.
Removal of the post void residual urine volume without treating the underlying cause for the retained urine is a temporary maneuver as the volume will reaccumulate by the next voiding cycle. Without a procedure or surgery, this volume will remain and can be a potential reservoir of future and ongoing infection.
Therefore, there is a need to prevent and/or reduce the survival of bacteria within the bladder, where such an approach does not cause collateral risk to the patient. Such a treatment can provide benefits for patients at risk of a UTI. Such especially benefits for incapacitated patients or the elderly, where the treatment eliminates the need for long term prophylactic administration of antibiotics and still reduces or eliminates a patient's risk of developing a UTI.
The illustrations and variations described herein are meant to provide examples of the methods and devices of the invention. It is contemplated that combinations of aspects of specific embodiments or combinations of the specific embodiments themselves are within the scope of this disclosure.
The present disclosure includes devices for reducing infections within a fluid filled organ using a combination of anti-bacterial properties and mechanical disruption of biofilms that would otherwise allow bacterial growth. The devices and methods described herein rely on particles for treating and/or preventing urinary tract infections in an individual. These particles are intended to function as implants or particle-implants that are retained by a wall of the bladder or other organ over an extended period of time and/or through multiple cycles of filling and emptying of the bladder.
The present disclosure includes device for treating and/or preventing urinary tract infections in an individual. In one example such devices include a plurality of particles where at least each particle of the plurality of particles has a buoyancy resulting in flotation of the plurality of particles in a urine contained in a bladder of the individual, where a size of each particle of the plurality of particles is within a pre-determined size range; each particle of the plurality of particles comprising an active substance having an anti-bacterial property; and wherein the plurality of particles are constrained in a delivery unit to permit passage of the plurality of particles through a urethra of the individual and into the bladder.
The particles can include one or more therapeutic substance. Such therapeutic substance can include, but are not limited to a urease inhibitor, a chelating agent, an antibacterial agent, an enzyme, and a combination thereof.
In additional variations, the particles can further include a carrier substance. Such a carrier substance can comprise a degradable material, a non-degradable material, or a combination thereof. In additional variations, the therapeutic substance is located within and/or coated on the carrier substance. Examples of carrier substances include, but are not limited to a polymer, lipid, or a glass material. Moreover, any of the particles and/or carrier substances can be porous or non-porous.
Additional variations of the devices can include a plurality of secondary particles each having therapeutic properties where at least each secondary particle of the plurality of secondary particles has a buoyancy resulting in sinking of the plurality of particles in the urine contained in the bladder of the individual.
The density of particles in the present device can be less than 1 kg/m{circumflex over ( )}3. An example of a size of the particle can include a pre-determined size range of less than 400 micrometers.
Variations of the device can include a delivery form that is a syringe or a sealed container.
The present disclosure also includes methods for treating and/or preventing urinary tract infections in an individual. For example such methods can include providing a plurality of particles each having therapeutic properties where at least each particle of the plurality of particles has a buoyancy resulting in flotation of the plurality of particles in a urine contained in a bladder of the individual, where a size of each particle of the plurality of particles falls within a pre-determined size range; and delivering the plurality of particles through a urethra of the individual into the bladder wherein the plurality of particles float to a surface of the urine, such that upon contraction of the bladder one or more rugae on a wall of the bladder contracts to form a fold in tissue, where a combination of the buoyancy and the pre-determined size range of the plurality of particles causes the one or more rugae to encase the plurality of particles in the fold of tissue such that a number of particles is retained in the bladder over a series of cycles in which the bladder refills and empties with urine.
The methods described herein can also include delivery of the plurality of particles through a urethra of the individual into the bladder to produce a mechanical disruption of a biofilm. Such mechanical disruption can occur anywhere in the fluid path of the particle such as the urethra, bladder, and/or a catheter in fluid contact with either the urethra and/or bladder.
The present disclosure can also include a method of delivering groups of differently sized particles and determining which size is best retained for treatment of an individual patient.
The present disclosure describes devices and methods for the intravesicular delivery of therapeutically active agents or materials to the bladder, urinary tract, ureters, urethera, or other privileged mammalian sites for local or systemic use. The therapy includes but is not limited to the delivery of therapeutically active substances to the human organs such as the bladder to provide local or systemic therapeutic effects. These effects may include but should not be limited to the prevention, treatment, or diagnosis of urinary tract infection, pathogen identification as to the presence of specific pathogens or colonization of the urinary tract or bladder, stimulation of the bladder to more fully expel material, reduction of inflammation, stimulation of inflammation, or other methods to otherwise modify, effect, or treat a condition of the bladder and urinary tract system.
The present methods and device can also be used to decrease the total systemic drug dose requirement for treating an infection of a contracting organ with a central lumen or cavity. In this way pathogenic cell walls and membranes could be compromised through ionic, pH, or osmotic gradient effects to weaken the pathogens or retard their growth such that other therapeutic doses of drugs or molecular active substances could be used in combination with the present invention to provide a desired therapeutic benefit for a patient.
The present disclosure also relates to devices for intravesicular drug delivery as a method for minimization or stimulation of the sensory nerves of the bladder trigone in order to provide therapeutic remedy for overactive bladder, modification of the pro-inflammatory neural cascade, or other affliction of the bladder.
The present disclosure also includes variations related to a retention of a therapy within a bladder organ such that these devices could be designed to be indwelling, at least partially, within the bladder in order to maintain a controlled release therapeutic effect over a period of time while they are indwelling in whole or in part during use. This may include devices that are retained within the bladder that degrade or adjust in configuration over time such that portions of the devices are excreted in the urine over time. Other methods of the invention may be used to extend the duration of therapy for a device within a bladder organ such as the inclusion of coatings or surface configurations which would enable the device to be retained with minimal inflammation and or complications to the bladder.
The particle-implants described herein can also improve reducing or eliminating post void residual volume from the bladder since the particles can displace urine during the voiding or contraction process.
The particle-implants described herein do not require removal using specialized tools. Moreover, the increased retention of particles solely residing in the bladder allow for increased therapeutic dosage levels that would be discouraged if administered systemically.
The present disclosure also includes particle-implants consisting of a plurality of buoyant bodies with a therapeutic agent (e.g. anti-biotic). The therapeutic agent may be present as a coating, as part or whole of the structure of the buoyant body or be contained within a cavity of the buoyant body. The coating or structure of the buoyant body may differ in thickness, composition, or structure within a single body or across the plurality of bodies so as to create a uniform or non-uniform rate of release for the therapeutic agent or a uniform or non-uniform rate of degradation of the buoyant body. The coating may degrade or not degrade as is preferred for the performance of the release profile and concentration gradient within the retained and accumulating volume of urine within the bladder. Materials that could be used to construct the buoyant bodies may include but not be limited to any of the following such as, polycaprolactone, chitosan, polyethylene glycol, poly lactic acid, poly lactic-co-glycolic acid, n′n-isopropylacrylamide, acrylamido taurate, polyethylene, polypropylene, cross linked collagen or gelatin gels, polyacrylamide gels, or glass. Therapeutic agents may comprise one or more but not be limited to, antibiotics, silver, silver ions, colloidal silver, silver nitrate, silver sulfadiazine, ascorybyl palmitate, ascorbic acid, anesthetic agents, lidocaine, bupivacaine, benzocaine, chemotherapy agents, Cisplatin, gemcitabine, methotrexate, monoclonal antibodies, cell therapeutics such as modified or unmodified CAR-T, enzymes, mRNA with or without liposomal delivery vehicles, Loop diuretics such as furosemide (Lasix), Thiazide diuretics such as hydrochlorothiazide, antifibrinolytic compounds, anticoagulant compounds, coagulant compounds, contrast agents such as gadolinium, air bubbles, iodinated contrast, barium sulfate, aluminum or aluminum oxide, iron or iron oxide, gold or gold compounds, pH or precipitate modifying compounds such as hydrochloric acid, EDTA (Ethylenediaminetetraacetic acid), sodium hydroxide, and many others, micro- or nano-encapsulated agents, and or any other combination or sole compound or structure that would enable a therapeutic effect on the desired area through application from a buoyant body delivery vehicle. It should also be noted that the therapeutic elements themselves may be the buoyant body if they are agents that would otherwise at least be partially retained due to their structure, shape, or other features such as if the ionic gradient would enable the material to want to more readily stick to the wall of the bladder or if larger beads of structures such as silver beads with air encapsulated within would result in the therapeutic agent itself in being partially or fully retained until degraded or used. Therapeutic actions may include treatment, prevention, or diagnostic of many conditions or diseases including but not limited to urinary tract infections, bladder cancer, kidney cancer, ureter cancer, urethra cancer, anti-coagulant disease, diagnostic imaging, overactive bladder, underactive bladder, retained urine, diabetes, heart failure (fluid retention and or reduction), kidney failure and or supplementary treatments with dialysis, cystitis, and many other conditions.
Wherein the buoyant bodies could comprise many different configurations with a retained free void volume. These configurations could be spheres, cubes, three-dimensional star shapes or hexagonal shapes, and or any other three-dimensional shape. These buoyant bodies could be hollow, contain a gas, contain a vacuum, contain a liquid, and or contain any other polymer or material such as PLLA, PGLA, PEG, glass, plastic, wood, ceramic, metal, foams, micelles, lipids, hydrophobic materials, hydrophilic materials, polyesters, and or other material such that the density or shape of the buoyant body would enable it to be at least partially retained for therapeutic effect over time. Properties of the materials that comprise the buoyant bodies may be but should not be limited to materials that are hydrophilic or hydrophobic, polar, non-polar, multi-polar, both hydrophobic and hydrophilic depending on pH and or temperature reactive such as with n′n-isopropyl acrylamide, and or other material properties such as electrically conductive or ionizable in solution as a salt. The material should be rapidly and effectively drained through a catheter and or introduced into the bladder through the same effective delivery vehicle or catheter as well as could be instilled with a injection through a catheter or through the tissue itself such that a plug of material, colloid, solution, or other configuration would be delivered into the desired volume in the bladder
The devices described herein are suitable for treatment of existing infections as well as for long term prophylactic administration to prevent occurrences of infection. However, unlike conventional prophylactic treatments, the current device does not present the drawbacks of current prophylactic anti-biotic treatments. Moreover, the implants disclosed herein can be intended for temporary, long term, or even permanent placement within the body.
Each of the following figures diagrammatically illustrates aspects of the invention. Variation of the invention from the aspects shown in the figures is contemplated.
It is understood that the examples below discuss uses of an implant device for either treating a bladder for an existing infection in the urinary tract or for prophylactic administration to prevent an infection from occurring. However, unless specifically noted, variations of the device and method are not limited to use only in the bladder, instead, the device can be used for general surgical procedures to prevent infections from developing in fluid filled organs. For purposes of this disclosure, the term fluid-filled organ can be substituted for bladder. Therefore, the methods and device will have applicability in various parts of the body under any minimally invasive or invasive procedure. Moreover, the invention may be used in any procedure where the benefits of the method and/or device are desired. Furthermore, because it is impractical to display each and every combination of features and aspects of various embodiments, it is understood that where possible, every aspect or feature of an embodiment of the methods and/or devices can be combined with alternate embodiments of methods and/or devices.
The inner lining of the bladder 10 is a mucous membrane of transitional epithelium that contains rugae, which are a series of ridges produced when the walls of the bladder fold during voiding or contraction of the bladder. Likewise, the rugae 17 separate when the bladder expands. When the bladder is full/expanded with urine, the muscle wall of the bladder causes contraction of the bladder causing the bladder to assume a pyramid shape. In this configuration, the rugae collapse into folds.
In both
Alternative variations of the methods described herein can include delivery of particles 110 into the bladder 10 surgically or through an endoscopic approach.
Another benefit to using a number of particles 110 is that ordinary movement of each particle 110 within the bladder 100 can cause turbulence in the urine or simple mechanical force against the bladder surface, which are additional means to prevent formation of biofilms that foster the growth of bacteria. In one variation, movement of the particles 110 during or after delivery performs a bacterial agitation within the bladder 10 or along a lining of the bladder. This bacterial agitation disrupts adherent bacteria and disrupts biofilms by mechanical action. By disrupting formation of biofilms in the bladder, the present devices 110 can reduce or eliminate bacteria growth and prevent and/or treat UTIs by preventing/maintain bacteria at levels that are unable to cause a UTI by mechanical action in addition to any therapeutic effect.
While the invention described herein can employ any range of particle size, in one example, it was found that human rugae have a cleft width of between 200-400 micrometers. Therefore, experiments have shown that sizes less than 400 micrometers show best retention. It is believed that commercially optimum retention size is around 100 micrometers However, the size of the particles will depend on the bladder size of the individual (or animal) being treated. Infants and children will likely have a different optimal particle size compared to adults.
The size and buoyancy of the particles allow benefits specific to the bladder. For example, in certain variations of the methods and devices, the size of the particles allow for passage through the urethra, when needed, to prevent blockage. The buoyancy and relatively small size of the particles aid in retention of the particles in the bladder regardless of any forces acting on the particle by the bladder walls during voiding of the bladder. Particles that are too large can be expelled by such forces during voiding. The retention of the particles also benefits patients since the particles fill any post-void residual space of the contracted bladder, which displaces any urine that would otherwise remain within the bladder and possibly cause a UTI. If the contracted bladder contains excess particles, the size of the particles allow for passing through the urethra to avoid any increase in the frequency of urination.
The variations of the implants described herein can contain any number of active agents that ultimately reduce bacterial formation or re-adherence within the organ. In one example, the particles comprise silver sulfadiazine embedded within polylactic-co-glycolic acid or silver sulfadiazine coated glass microspheres. However, any therapeutic substance can be used as an active agent.
The active agents can comprise coatings and/or can be embedded within a matrix of the carrier material that forms the particle-particle-implant whereby the matrix releases the agent (e.g. granules). Some examples of such agents includes the following (as well as combinations of various agents). In one variation, the active agent can comprise one or more substances that control pH of the urine to prevent crystallization of solute onto the device body; substances that prevent bacterial enzyme urease from activity; urease inhibitor e.g. N-(n-butyl) thiophosphoric triamide (NBPT). The agent can also decrease effective solutes for crystallization within the urine. For example, the matrix or device body can be coated with chelating agents, e.g. ethylenediaminetetraacetic acid (EDTA), dimercaptosuccinic acid, dimercaprol, penicillamine. The agent can decrease bacterial activity to prevent encrustation of the carrier material or device body. For example, the carrier material can be coated with antibacterial agents, a compound containing silver e.g. (silver nitrate, elemental silver, etc.), another substance such as an antibiotic drug, copper, zinc, gold, antibacterial nanoparticles, liposomes, aptamers, dendrimers, antimicrobial peptides, inorganic or polymeric nano-particles, smart nanoparticles. etc. The active agent can comprise a coating that prevents the formation of a biofilm. A biofilm typically comprises any syntrophic consortium of microorganisms in which cells stick to each other or to a surface. These cells become embedded within an extracellular matrix that is composed of extracellular polymeric substances. Because the matrix has a three-dimensional structure it provides a means for microbes and other bacteria to grow and multiply. By disrupting formation of biofilms in the bladder, the present devices 100 can reduce or eliminate bacteria growth within the bladder. Alternatively, the particle-implants can maintain the bacteria at levels that are unable to cause a UTI.
In those variations of particle-implants that require degradation, fracturing of the particle-implant can occur through mechanical compression (i.e. cycling of bladder emptying), fracturing of device through other mechanical action (e.g., snare, suction, scissors, etc), hydrolytic degradation in aqueous environment, introduction of enzymatic or chemical agent into bladder, environment (e.g. bladder irrigation with hydrogen peroxide or naturally over time), systemic administration of agent which changes composition of urine to trigger degradation (e.g. methenamine hippurate to acidify urine). Moreover, the carrier materials used herein can be configured such that if they become stuck in the urethra or neck of the bladder, the increased flow or turbulence of the urine attempting to flow through a restricted area will cause increased or turbulent flow. In such cases, the carrier material can be selected such that it breaks down or erodes when subject to increased flow or turbulence.
For example, such coatings include enzymes that degrade the biofilm extracellular matrix, such as dispersin B and deoxyribonuclease, nitric oxide, etc. The agent can include materials and/or coatings that decrease the affinity of crystals from attaching to the device (e.g., polyurethane, PTFE)
As for other details of the present invention, materials and manufacturing techniques may be employed as within the level of those with skill in the relevant art. The same may hold true with respect to method-based aspects of the invention in terms of additional acts that are commonly or logically employed. In addition, though the invention has been described in reference to several examples, optionally incorporating various features, the invention is not to be limited to that which is described or indicated as contemplated with respect to each variation of the invention.
Various changes may be made to the invention described. For example, the invention includes combinations of aspects of the variations of the devices described herein as well as the combination of the variations themselves. Also, any optional feature of the inventive variations may be set forth and claimed independently, or in combination with any one or more of the features described herein. Accordingly, the invention contemplates combinations of various aspects of the embodiments or combinations of the embodiments themselves, where possible. Reference to a singular item, includes the possibility that there are plural of the same items present. More specifically, as used herein and in the appended claims, the singular forms “a,” “and,” “said,” and “the” include plural references unless the context clearly dictates otherwise.
It is important to note that where possible, aspects of the various described embodiments, or the embodiments themselves can be combined. Where such combinations are intended to be within the scope of this disclosure.
This application is a non-provisional of provisional application No. 62/909,237 filed Oct. 2, 2019, this application is also a non-provisional of provisional application No. 62/910,104 filed on Oct. 3, 2019, this application is also a non-provisional of provisional application No. 63/029,296 filed May 22, 2020, the entirety of each of which is incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62909237 | Oct 2019 | US | |
| 62910104 | Oct 2019 | US | |
| 63029296 | May 2020 | US |
