Device for introducing liquids into the urinary tract

Abstract

A catheter assembly for introducing a viscous fluid into the urinary tract of a patient is provided. The disclosed catheter assembly includes a commercially available urinary catheter equipped with a catheter funnel, and a Luer adapter (e.g., a female Luer lock connector) with an end adapted for insertion into the catheter funnel to provide a point of attachment for a syringe. The Luer adapter and catheter funnel are secured with a funnel connector clamp which provides circumferential inwards clamping pressure to the junction of the catheter funnel and the conical end of the Luer adapter inserted into the catheter funnel. The circumferential clamping force of the funnel clamp provides a leak-proof seal when flowing / injecting viscous fluids through the catheter assembly, at pressures of up to 2,000 kPa. The catheter assembly of the present disclosure is suited for rapid and leak-free introduction of thermally reversible hydrogels into the urinary tract of a patient, and for repeated interchange of syringes for multiple injections into, or irrigation, flushing and drainage of, the intravesical anatomies.

Description

[0001] 3048-21-2

[0002] DEVICE FOR INTRODUCING LIQUIDS INTO THE URINARY TRACT

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] Benefit is claimed to US Provisional Patent Application No. 63 / 679,216, filed August 5, 2024, the contents of which are incorporated by reference herein in their entirety.

[0005] BACKGROUND OF THE INVENTION

[0006] Urinary catheters are long, flexible tubes made of medical grade materials such as polyvinyl chloride (PVC), polyurethane, latex rubber, or silicone rubbers, designed to be inserted into the bladder through the urethra. Urinary catheters can be used to drain urine from the bladder, or for the injection of liquid compositions into the bladder in order to treat or diagnose bladder conditions. There are several common designs of urinary catheters, including indwelling (e.g., Foley) catheters which have an inflatable balloon at the tip inserted into the bladder. When inflated, the balloon helps retain the catheter within the bladder (Fig. 1). Intermittent (e.g., Robinson) catheters are similar in design, but do not include a balloon and are intended for short term use. Urinary catheters can also be coated with a hydrophilic coating to lubricate the exterior of the catheter and facilitate insertion. The end of the catheter intended for insertion has lateral openings through which urine can drain through the lumen of the catheter to an external collector, or through which a diagnostic or therapeutic composition can be injected, e.g., via a syringe affixed to the external opening of the catheter, into the bladder. The external opening of a urinary catheter, whether indwelling or intermittent, typically terminates in a catheter funnel, a flexible, typically conical member which can be used as a connector to affix the external opening of the catheter lumen to a receptacle such as a urine collection bag.

[0007] Because urinary catheters are typically used for low viscosity liquids (e.g., draining urine or introducing aqueous medicinal formulations), the appropriate size of the catheter selected for a patient or for a particular use is based on the size of the patient's urinary tract; i.e., children generally use smaller diameter catheters, while male adults use larger catheters. Similarly, patients requiring catheterization to drain clear urine require smaller diameter catheters than patients whose urine includes debris or particles, and patients passing blood clots in their urine require still larger diameter catheters. Catheter length also can vary, with catheters for females and children being shorter than those for adult males.

[0008] If it is desirable to attach a syringe to a catheter equipped with a catheter funnel, an adapter ("Luer adapter") can be provided which has a Luer lock fitting compatible for connection with a Luer lock syringe. Various types of Luer adapters are commercially available, 3048-21-2 including Luer adapters available from Vygon, Baxter Healthcare, Medline, and others (Fig. 2). Luer adapters are tubular in shape, with a conical, often ridged end on one end which inserts into the catheter funnel, and on the opposing end, a female Luer lock fitting. The lumen of the Luer adapter connects the end inserted into the catheter funnel with the female Luer end to provide a continuous flow path from the Luer end of the Luer adapter, through to the end of the catheter tip inserted into the patient's urinary tract. A syringe with a male Luer lock end can thus be affixed to the Luer end of the Luer adapter to permit intravesical administration of liquid therapeutics through the catheter, into the urinary tract of a patient.

[0009] Standard urinary catheters equipped with a Luer adapter affixed to the catheter funnel are suitable for intravesical administration of low viscosity solutions into the urinary tract because the low viscosity of such solutions allows relatively rapid administration at low injection pressures even through small diameter catheters, without significant risk of leakage at the catheter funnel. However, highly viscous medicinal solutions, particularly those comprising thermally reversible hydrogels, and more particularly those containing cytotoxic drugs such as mitomycin C, cannot be administered safely with conventional urinary catheter assemblies. Also, repeated interchange of syringes for multiple injections into, or irrigation, flushing and drainage of, the intravesical anatomies (i.e., urethra, urinary bladder) are also prone to risk of leakage due to potential wetting of the connection between the Luer adapter and the catheter funnel during the removal and insertion of syringes.

[0010] The present disclosure provides improved urinary catheter assemblies, and methods of use thereof, specially adapted for the unique requirements of intravesical administration of thermally reversible hydrogels, particularly those containing cytotoxic drugs such as mitomycin C, or for treatments requiring repeated intravesical injection, irrigation, flushing and drainage.

[0011] BRIEF DESCRIPTION OF THE FIGURES

[0012] Fig. 1 : A typical Foley catheter design, including a balloon port, urinary drainage port (catheter funnel), openings for introducing or draining liquids through the catheter lumen, and balloon (en.wikipedia.org / wiki / Foley_catheter).

[0013] Fig. 2: Examples of commercially available Luer adapters.

[0014] Fig. 3: Exploded diagram of an embodiment of a two-piece clamping device, a Luer adapter and a urinary catheter.

[0015] Fig. 4: Diagram of an embodiment of a two-piece clamping device with the clamp component in the open position, and the Luer adapter inside the catheter funnel. 3048-21-2

[0016] Fig. 5: Diagram of an embodiment of a two-piece clamping device with the clamp component in the closed position, and the Luer adapter inside the catheter funnel.

[0017] Fig. 6: Diagram and section view of an embodiment of a fully assembled two-piece clamping device with the cover closed over the clamp component, and the Luer adapter inside the catheter funnel.

[0018] Fig. 7: Diagram an embodiment of a fully assembled two-piece clamping device with the cover closed over the clamp component, and the Luer adapter inside the catheter funnel, and a syringe attached to the Luer end of the Luer adapter.

[0019] Fig. 8: Diagram of an embodiment of a fully assembled two-piece clamping device with the cover closed over the clamp component, and the Luer adapter inside the catheter funnel of a two-way Foley catheter.

[0020] Fig. 9: Diagram of an additional embodiment of a one-piece clamping device.

[0021] Fig. 10: Diagram of an additional embodiment of a one-piece clamping device in the open position, with the Luer adapter inside the catheter funnel.

[0022] Fig. 11: Diagram of an additional embodiment of a one-piece clamping device in the closed and locked position, with the Luer adapter inside the catheter funnel.

[0023] DETAILED DESCRIPTION

[0024] The present invention provides, inter alia, improved urinary catheter assemblies, components of such assemblies, and methods of use of such assemblies, designed for the unique requirements of intravesical administration of thermally reversible hydrogels, and in some embodiments, thermally reversible hydrogels containing therapeutic agents for example cytotoxic drugs such as but not limited to mitomycin C, and for intravesical procedures requiring multiple interchange of syringes connected to the urinary catheter.

[0025] Urinary catheters are designed to balance competing design objectives - the outside diameter of the catheter should be as small as possible to minimize any discomfort associated with inserting or withdrawing the catheter from the patient's urinary tract, while the inside diameter should be as large as possible to allow the flow of fluids drained from or injected into the intravesical anatomy. Because urine and most therapeutic compositions are low viscosity aqueous solutions, small bore urinary catheters are more than adequate to provide sufficient fluid flow in and out of the catheter. The size of urinary catheters is conventionally described using the "French units" (Fr) scale. Each French unit is equivalent to 0.33 mm of catheter 3048-21-2 diameter, and typical urinary catheter sizes range from 6 Fr to 26 Fr. Typical catheter sizes for adult men range from 14-16 Fr, and for adult women, 10-12 Fr.

[0026] Because conventional aqueous therapeutic formulations (solutions) for intravesical administration into the bladder have low viscosities, the pressure required to inject such formulations through a urinary catheter into the bladder is low. Accordingly, the Luer adapter connecting the syringe used to inject the therapeutic formulation can be simply press-fitted into the catheter funnel to provide an adequate seal. However, it has been discovered that the intravesical administration of thermally reversible (also referred to herein as thermoreversible) hydrogel formulations, including but not limited to those described by its reference but not limited to in US Patent Nos. 9,040,074 and 9,950,069 (both of which are incorporated by reference herein in their entirety) requires modifications to conventional urinary catheter assemblies in order to administer such formulations safely and reliably to the urinary tract of a patient.

[0027] Described herein are catheter assemblies that allow for intravesical administration of a viscous solution to a subject. Such viscous solutions include thermoreversible hydrogel compositions that are used to deliver an active pharmaceutical ingredient to a subject, including chemotherapeutic s, small molecule pharmaceuticals, and biological agents such as antibodies, nucleic acids, peptides and viral agents, such as oncolytic viruses.

[0028] In particular embodiments, the thermoreversible hydrogel composition includes one or more components including poloxamer, methylcellulose, hydroxypropylmethylcellulose, alginates, cellulose acetophathalate, carbopol, gellan gum, xyloglucan, pectin, chitosan, and any combination thereof.

[0029] In particular embodiments, the gel component of the thermoreversible hydrogel compositions comprises 5%-45% (w / w) and ranges therein of the composition, such as 10%- 35%, 20%-45%, 15%-35%, 20%-40%, 20%-30%.

[0030] In particular embodiments, the thermoreversible hydrogel comprises an A-B-A type polymer, wherein A or B is selected from PEG (polyethylene glycol), PLGA (poly(lactic-co- gly colic) acid, PLA (poly lactic acid) and PPG (polypropylene oxide). More preferably, A is PEG, and B is PPO (poloxamer) compound or A-B-A is PEG (Poly(ethylene oxide)) / PPO block copolymer.

[0031] In a particular embodiment the thermoreversible hydrogel composition comprises 5% to 45% (w / w), and any range therein, of a PEO / PPO block copolymer and comprises at least one of a mucoadhesive enhancing agent, dissolution rate controlling agent, gelation temperature controlling agent, pH controlling agent, absorption enhancer / tight junction modifier / cell 3048-21-2 membrane permeability enhancer, pharmacodynamics enhancing agent, or an agent to produce an exothermic reaction.

[0032] In particular embodiments, the mucoadhesive enhancing agent can include, but is not limited to, agarose, chitosan, gelatin, hyaluronic acid, carrageenan, pectin, sodium alginate, polyacrylic acids, polymers based on poly(meth)acrylic acid, carbopol, polycarbophil, polyacrylic acid, polyacrylates, copolymer of acrylic acid and polyethylene glycol, copolymer of methylvinyl ether and methacrylic acid, poly-2-hydroxyethylmethacrylate, copolymer of acrylic acid and ethylhexylacrylate, polymethacrylate, polyalkylcyanoacrylates: polyisobutylcyanoacrylate, polyisohexylcyanoacrylate, cellulose derivatives (for example methylcellulose (MC), hydroxy-propylcellulose (HPC), hydroxyl propylmethyl cellulose (HPMC), hydroxy ethyl cellulose, thiolated CMC other hydroxyalkylcelluloses and hydroxyalkylmethylcelluloses, carboxy-methylcelluloses (CMC) and salts thereof), polymethacrylates, starch or starch derivatives including starch phosphate esters at various degrees of substitution, as well as gums like guar gum, locust beam gum and xanthan gum and their derivatives. Polyvinylpyrrolidone (PVP) and its copolymers (N-vinyl-2-pyrrolidone), Poly- N-2-hydroxypropylmethacrylamide, polyhydroxyethylene, polyvinyl alcohol (PVA), and thiolated polymers.

[0033] In particular embodiments, dissolution rate controlling agents can include, but are not limited, to silicon dioxide or any derivatives thereof, nanoparticles or microparticles of Poly (Lactide-co-Glycolide (PLGA), polylactic acid (PLA), Polyglycolic acid (PGA), PLA-PEG or PLGA-PEG copolymers, nanoparticles or microparticles polystyrene or polymethyl methacrylate (PMMA), calcium carbonate, microcrystalline cellulose, aluminum hydroxide, Eudragit.RTM. NE, Eudragit. RTM. RS and RL, cellulose acetate and cellulose acetate butyrate, crospovidones, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethylstarch, thickening agents, soy, iodinated aromatic compounds, cyclodextrin, and cholesterol.

[0034] In particular embodiments, gelation temperature controlling agents include, but are not limited to, urea, polyethylene glycol, short chain fatty acid and their salts (sodium octanoate, sodium dodecyl sulfate), ethanol, Glyceryl monostearate, Isopropyl myristate, and Polysorbate surfactants.

[0035] In some embodiments, tight junction modifier / cell membrane permeability enhancers include, but are not limited to, anionic surfactants, non-anionic surfactants, charged polymers, dimethyl sulfoxide (DMSO), decylmethyl sulfoxide, tert-butyl cyclohexanol, fatty acids their 3048-21-2 esters and salts, ethanol, nicotinamide, urea, perfluoropoly ether, monoterpene ketones, disodium citrate, succinic acid, alkyl saccharides, hyaluronidase and tris.

[0036] In another embodiment, the thermorev ersible hydrogel comprises between 20% and 35% (w / w) EPO / PPO block copolymer and between 0.05% and 0.5% (w / w) hydroxypropylmethylcellulose (HPMC) or Polyvinylpyrrolidone (PVP).

[0037] In other embodiments the thermoreversible hydrogel comprises between 10% and 35% (w / w) EPO / PPO block copolymer and between 0.05% and 0.5% (w / w) hydroxypropylmethylcellulose (HPMC) or Polyvinylpyrrolidone (PVP) and between 0.01% and 2.5% (w / w) polyethylene glycol (PEG)-400; and the balance water.

[0038] In other particular embodiments, the thermally reversible compositions useful in the catheter assemblies and methods of the present disclosure comprise about 23% to 25% w / w of Poloxamer 407 (Polyethylene oxide / polypropylene oxide / polyethylene oxide tri-block copolymer, with approximate block lengths of 101 / 56 / 101), about 0.15%-0.18% w / w HPMC, about 1% w / w PEG-400, about 0.1% to 0.5% mitomycin C with Mannitol and water. In particular embodiments, the thermally reversible compositions useful in the catheter assemblies and methods of the present disclosure comprise about 24% w / w of Poloxamer 407, about 0.16% w / w HPMC, about 1% w / w PEG-400, about 1.33mg / ml mitomycin C composition for solution and water for injection.

[0039] Thermally reversible hydrogel formulations have several unique characteristics which differ from conventional liquid therapeutic formulations for intravesical administration into the bladder. First, thermally reversible hydrogel formulations have substantially higher viscosities compared to conventional aqueous solution-type intravesical formulations. Aqueous solutions typically have a viscosity of about 1 cP at room temperature, whereas the thermally reversable hydrogel formulations of the present disclosure have viscosities of 100 - 500 cP at temperatures below the gel transition temperature (for example about 14 °C for UGN-102), and 100,000 cP or more above the gel transition temperature. At room temperature and above (e.g., body temperature, about 37 °C), the thermally reversible hydrogel formulations of the present disclosure are essentially gel-like or solid. Accordingly, not only does the higher viscosity of thermally reversible hydrogel formulations require much higher injection pressure (e.g., up to about 2,000 kPa), but because these thermally reversible hydrogels are administered at temperatures below the gel transition temperature, the injection must be completed relatively quickly. If the thermally reversible hydrogel warms to a temperature near or above the gel transition temperature, the viscosity will become too high to allow intravesical administration. The amount of time available to inject the thermally reversible hydrogel formulations of the 3048-21-2 present disclosure will vary depending on the initial temperature of the formulation (typically about 1 °C -6 °C for formulations of the present disclosure). Usually, injection using a syringe (depending on the syringe volume / diameter) are difficult to impossible after about 2-5 minutes. Accordingly, the methods for intravesical administration of the thermally reversible hydrogels using the catheter assemblies of the present disclosure require that administration be completed prior to the thermally reversible hydrogel reaching its gel transition temperature, about 2, about 3, about 4, or about 5 minutes from initiating the injection. Incomplete administration due to gelling of the thermally reversible hydrogel formulation is problematic in that an insufficient dose of the therapeutic agent will be administered, and it may be difficult to determine how much of the therapeutic agent was successfully delivered to the patient.

[0040] The catheter assemblies described herein can be used to safely administer a viscous solution, such as, but not limited to a thermally reversible hydrogel to a subject. In particular embodiments, the viscous solution includes a pharmaceutically active agent. For example, particular thermally reversible hydrogel formulations that can be delivered through use of the described catheter assemblies comprise an active pharmaceutical ingredient for example a cytotoxic agent such as but not limited to mitomycin C (e.g., active ingredient in ZUSDURI™ or JELMYTO®). When such viscous pharmaceutical solutions are administered to a subject by way of a catheter, leakage of, for example, mitomycin C-containing formulations from a catheter assembly, such as at the junction between the catheter funnel and Luer adapter, can be hazardous to the patient and the medical staff. Moreover, leakage of the formulation could also likely result in the delivery of an insufficient dose of the therapeutic agent to the patient and would make it difficult to determine the actual dose given to the patient. Accordingly, it has been determined that urinary catheter assemblies useful in safely and accurately administering thermally reversible hydrogel formulations, particularly those containing cytotoxic therapeutic agents such as mitomycin C, require a securing element that requires clamping the junction of the catheter funnel with the Luer adapter with a specially designed funnel adapter clamp. The funnel adapter clamp provides circumferential (360°) clamping force to the junction of the Luer adapter and the catheter funnel. Applicant has found that unless the clamping force is evenly applied around this junction, leakage or even disconnection will occur at the injection pressures required for highly viscous liquid formulations such as but not limited to the thermally reversible hydrogel formulations for use with the catheter assemblies of the present disclosure. As noted above, injection of the thermally reversible hydrogel formulations may exceed an injection pressure of 700 kPa (e.g., using a 20 mL Beckton and Dickinson syringe). 3048-21-2

[0041] For intravesical procedures involving multiple exchanges of syringes and other devices connected to the urinary catheter (e.g. urinary drainage bag), the repeated interchange of devices reduces the tight seal between the catheter funnel and the Luer adapter. The reduced seal can lead to leakage of the fluids passing through the Luer adapter (e.g. injected drug or drained urine which could be chemically or biologically hazardous) or altogether disconnection of the Luer adapter from the catheter funnel. Accordingly, Applicant has determined that urinary catheter assemblies are useful in safely and accurately performing intravesical treatments requiring multiple exchanges of syringes, require the same securing device that requires clamping the junction of the catheter funnel with the Luer adapter with a specially designed funnel adapter clamp.

[0042] In one embodiment, the funnel adapter clamp that provides a circumferential force according to the present disclosure is shown in Figures 3-6, and includes a clamping case 100 and clamping cover 200. An exploded view is shown in Figure 3 with the clamping case 100 in its open configuration showing the two halves (sides) of the circumferential internal cavity 101 on both sides of the hinge 104, as well as the two halves (sides) of the clamp case thread 102 and the two closure tabs 103. The clamping cover 200 is shown comprising of a Luer connector opening 201 and gripping surface 203. A Luer adapter 300 is also shown, consisting of a ridged conical end 301 and a female Luer lock end 302. A urinary catheter 400 (e.g. an intermittent catheter) is also shown consisting of a catheter funnel 401 and catheter shaft 402. Figure 4 shows the conical end 301 of the Luer adapter 300 inserted into the catheter funnel 401 which is placed in one half of the internal cavity 101 of the clamping case 100, with the catheter shaft 402 coming out of the clamping case at the end with the hinge 104. The arrow shows the direction of closing the two halves of the clamping case 100 about the hinge 104. Figure 5 shows the two halves of the clamping case 100 closed over the catheter funnel 401 by pinching the two closure tabs 103 to bring them together, as the two halves rotate about the hinge 104. The clamping cover 200 is advanced towards the closed clamping case 100, over the Luer adapter 300, so that the thread inside the clamping cover (not shown) engages the unified clamping case thread 102 and two parts are screwed together. Figure 6 shows the final urinary catheter assembly with the clamping cover 200 screwed on tight onto the clamping case 100 and the Luer end 302 of the Luer adapter 300 comes out of the Luer opening 201. The section view also shown in Figure 6 shows the clamping cover thread 202 fully engaged with the clamping case thread 102, the Luer end 302 passed through the Luer opening 201 and the conical end 301 secured inside the catheter funnel 401, as circumferential clamping force is applied by the closed internal cavity 101. The urinary catheter shaft 402 (as shown in Figure 3) can now be (or 3048-21-2 has previously been) inserted into the patient’s urinary tract and a syringe 500 can be attached to the Luer adapter 300 as required per the intravesical procedure, as shown in Figure 7. The volume capacity of the syringe for use in the described catheter assemblies will vary depending on the use. In particular embodiments, the syringe is a standard 20 mL syringe. In other embodiments, the syringe can be any syringe from a volume of 1-60 mL and all incremental volumes in between, such as but not limited to 1 mL, 5 mL, 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, or 60 mL. It will be appreciated that smaller and larger volume syringes and those of nonstandard volumes can also be employed with the described catheter assemblies.

[0043] In another embodiment shown in Figure 8, the clamping case 100 has a slot 105 between the closure tabs 103 to accommodate the balloon port 403 protruding from the side of the catheter funnel connector 401 (as shown in Figure 3), when the catheter 400 is an indwelling (e.g. Foley, two-way) catheter. In yet another embodiment (not shown), the clamping case has two slots for a catheter that has two protruding side ports (e.g. for inflating a balloon and for irrigation and instillation of fluids, three-way catheter).

[0044] In yet another embodiment shown in Figure 9, the clamping cover 200 is integrated with the Luer adapter 300 to form one whole part. Figure 9 shows the conical end 301 of the integrated Luer adapter surrounded by the clamping cover thread 202. In this embodiment, the conical end of the integrated Luer adapter 301 may be smooth or have one or multiple ridges or ribs to enhance the connection with the catheter funnel. In yet another embodiment (not shown) the clamping cover 200 is provided to the end user with the Luer adapter 300 pre-assembled (i.e. a separate part that was glued or otherwise irreversibly connected during manufacturing) and ready to be inserted into the catheter funnel.

[0045] In another embodiment, the funnel adapter clamp that provides circumferential force of the present disclosure comprises two clamping sections 600 as shown in Figures 10-11, connected via a hinge 602 or other means for orienting and rotationally connecting the two clamping sections of the funnel adapter clamp at one end of each, so that when opened, the catheter funnel 401 with the Luer adapter 300 inserted in the funnel can be located within an internal cavity 601 formed when the two halves of the funnel adapter clamp are closed. One half of the funnel adapter clamp includes one or more snaps 604 that, when the two halves of the clamps are closed by pressing the closure tabs 603, engage and lock into mating surfaces 605, maintaining the two halves of the funnel adapter clamp in a closed position around the junction of the catheter funnel and the Luer adapter.

[0046] In all the embodiments of the present disclosure, the profile of the internal cavity (101 and 601) is shaped to provide a circumferential, uniform, inwards force on the junction between 3048-21-2 the catheter funnel and the Luer adapter, sufficient to prevent leakage at pressures of at least 700 kPa , or a range of pressures of about 500 - 2,000 kPa, including any values between such as but not limited to 500 kPa, 750 kPa, 1,000 kPa, 1,250 kPa, 1,500 kPa, 1,500 kPa, 2,000 kPa including all ranges between any of these values. These internal cavities may have zero, one or multiple ribs 606 (e.g., Figure 10) to increase the pressure on the catheter funnel.

[0047] In various other embodiments, the locking mechanism can include one or more screws, a circular belt lock, or adhesive agents to securely affix the two halves of the clamp together (in place of the snaps 604 shown in Figures 10-11).

[0048] The funnel adapter clamp(s) of the present disclosure can be fabricated from any standard engineering plastic used in medical devices, which can be sterilized by conventional methods such as ethylene oxide gas or gamma radiation. A non-limiting list of suitable medical grade polymers includes polypropylenes (PP), polycarbonates (PC), polysulfones (PSU), polyamides (PA), polyesters (PE), polystyrenes (ABS), etc.

[0049] Due to the high viscosities of the thermally reversible hydrogel formulations of the present disclosure, in most embodiments, suitable urinary catheter diameters range from about 10 Fr to about 18 Fr, including 10 Fr, 12 Fr, 14 Fr, 16 Fr, 18 Fr, and any range between any of these values. A non-limiting list of suitable urinary catheters for use in the catheter assemblies (including a funnel adapter clamp) and methods of the present disclosure include SIMPEASTIC catheters 14 Fr, 16 Fr, and 18 Fr; available from Medline), Tiemann-type catheters (12 Fr, 14 Fr; available from various manufacturers such as Teleflex), COEOPEAST catheters (12 Fr), TELEFLEX catheters (12 Fr) and CURE catheters (12 Fr). One of skill in the art will appreciate that other similar commercially available brands of urinary catheter can also be employed in the catheter assemblies and methods of the present invention provided they have a size in the range of about 10 Fr to about 18 Fr. In particular embodiments, the urinary catheter used in the methods and catheter assemblies of the present disclosure range in size from about 12 Fr to about 16 Fr. In very particular embodiments, the catheter size is 16 Fr.

[0050] A non-limiting list of suitable Luer adapters include VYCONNECTOR (Ref # 801.00; available from Vygon) and Large Catheter Adapter (Ref. # 8039; available from Procedure Products). Those of skill in the art will understand that other Luer adapters can be employed for the catheter assemblies and methods of the present invention, provided the funnel adapter clamp of the present disclosure is modified to accommodate the external shape of other similar Luer adapters.

[0051] Suitable catheter assemblies of the present disclosure include, in various embodiments, a urinary catheter ranging in size from 10 Fr to 18 Fr, a Luer adapter, and a funnel adapter clamp 3048-21-2 as described herein. In some embodiments, the catheter assembly is provided as a kit together with the thermally reversible hydrogel as described herein. In other embodiments, the catheter assembly is connected together, such that the Luer adapter is inserted into the catheter funnel, and the funnel adapter clamp is locked in place over the junction of the catheter funnel and the inserted Luer adapter. In still other embodiments, the catheter assembly is attached to a syringe via the Luer adapter. In yet other embodiments, the syringe is filled with any of the thermally reversible hydrogel formulations as disclosed herein. In still other embodiments, a closed system transfer device (CSTD, e.g. OnGuard available from B. Braun, PhaSeal available from Becton Dickinson, etc.) is employed between the syringe and the Luer adapter.

[0052] In particular embodiments, the syringe is filled with a thermally reversible hydrogel formulation comprising mitomycin C, for example UGN-102.

[0053] Methods suitable for intravesical administration of thermally reversible hydrogels disclosed herein include assembling a catheter assembly comprising a urinary catheter (10 Fr to 18 Fr, optionally 16 Fr) equipped with a catheter funnel, a Luer adapter inserted into the catheter funnel, closing over the junction of the catheter funnel and inserted Luer adapter in a funnel adapter clamp with an internal cavity fitted to the external shape of the junction of the catheter funnel and inserted Luer adapter, whereby when the funnel adapter clamp is locked into place, the funnel adapter clamp provides a circumferential inwards force which prevents leakage of fluids from the junction of the catheter funnel and inserted Luer adapter at pressures of up to 2,000 kPa. The catheter is inserted into a patient suffering from a bladder cancer or other bladder condition. One or more syringes (typically 20 mL or smaller) are filled with hydrogel formulations, as described herein, chilled to a temperature of between about 1 °C - 6 °C. The filled syringe is attached by its Luer fitting, to the catheter assembly (and possibly via CSTD adapters), then the thermally reversible hydrogel formulation is injected through the catheter into the bladder of the patient within about 5 minutes or less, such that the thermally reversible hydrogel formulation does not warm to its gel temperature during the injection.

[0054] Methods suitable for intravesical procedures involving multiple exchanges of syringes and other devices connected to the urinary catheter disclosed herein include assembling a catheter assembly comprising a urinary catheter (10 Fr to 18 Fr, optionally 16 Fr) equipped with a catheter funnel, a Luer adapter inserted into the catheter funnel, closing over the junction of the catheter funnel and inserted Luer adapter in a funnel adapter clamp with an internal cavity fitted to the external shape of the junction of the catheter funnel and inserted Luer adapter, whereby when the funnel adapter clamp is locked into place, the funnel adapter clamp provides a circumferential inwards force which prevents leakage of fluids from the junction of the 3048-21-2 catheter funnel and inserted Luer adapter or disconnection of the Luer adapter from the catheter funnel. The catheter is inserted into a patient suffering from a bladder cancer or other bladder condition. A drainage bag can be connected to the Luer adapter to drain the bladder. Then, one or more syringes (typically between 5 mL to 60 mL) are filled with formulations, as described herein. The filled syringe is attached by its Luer fitting, to the catheter assembly (and possibly via CSTD adapters), then the formulation is injected through the catheter into the bladder of the patient. The syringes and drainage bag can be repeatedly interchanged as needed for said intravesical procedure, whilst the catheter assembly with the funnel adapter clamp described herein secures the connection between the Luer adapter and the catheter funnel.

[0055] The methods of the present invention are suitable for treating a variety of conditions, such as conditions that involve a need to administer a drug to any cavity such as but not limited to bladder, kidneys, ureters, colon, stomach, intestines, anus, and the like.

[0056] All documents cited herein, including patents and patent applications are herein incorporated by reference for all purposes.

[0057] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The term “comprises” means “includes.” The term “consists essentially of’ or “consisting essentially of’ indicates that the active ingredient, element, or step of the described device or method includes only the expressly recited ingredient, element, or step, but that non-active ingredients, non-essential elements, or non-critical steps are included even if not expressly recited. This is in contrast to “consists” or “consisting” of which indicates that only the recited ingredients or steps are included in the claim. It is to be understood, for example, that compositions that “comprise” a given ingredient can also in other embodiments “consist essentially of’ or “consist of’ that ingredient. Similarly, methods that “comprise” a given set of steps can also in other embodiments “consist essentially of’ or “consist of’ the expressly indicated set of steps. The abbreviation, “e.g.,” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.,” is synonymous with the term “for example.” Terms such as “suitable for” are used in certain contexts, synonymously with “adapted for,” “adapted to,” “configured for,” and “configured to.” 3048-21-2

[0058] In case of conflict, the present specification, including explanations of terms, will control. All materials, methods, and examples are illustrative and not intended to be limiting. References cited herein are incorporated by reference herein with respect to the technical aspects described (chemical structure, sequence modifications, etc.).

[0059] List of Reference Numbers

Claims

3048-21-2CLAIMS1. A catheter assembly for introducing a viscous fluid into the body cavity of a patient comprising:(a) a urinary catheter comprising an end suitable for insertion into the urinary tract of a patient, and an opposing end having a catheter funnel for introducing or draining fluids from the catheter;(b) a Luer adapter comprising on one end a female Luer lock connector, and on the opposing end of the Luer adapter, a tubular conical member capable of insertion into the opening of catheter funnel, whereby after insertion of the tubular member of the Luer adapter into the catheter funnel, the Luer adapter provides means for connection to a syringe equipped with a male Luer lock connector, and a path for fluids to flow through the catheter assembly into and out of the urinary tract of the patient; and(c) a funnel adapter clamp providing circumferential inwards equally distributed force when the tubular member of the Luer adapter is inserted into the catheter funnel of the catheter, whereby a leak-proof seal is formed between the Luer adapter and the catheter funnel when subjected to fluid pressures of up to 2,000 kPa.

2. The catheter assembly of claim 1, wherein the catheter is a urinary catheter having a size of 12-18 Fr.

3. The catheter assembly of claim 2, wherein the urinary catheter size is 14-16 Fr.

4. The catheter assembly of claim 2, wherein the urinary catheter size is 16Fr.

5. The catheter assembly of any one of claims 1-4, further comprising a syringe equipped with a male Luer lock connector, affixed to the female Luer connector of the Luer adapter.

6. The catheter assembly of claim 5, wherein the syringe volume ranges in volume from about 1 mL to about 60 mL, and all incremental volumes in between.

7. The catheter assembly of any one of claims 1-6, filled with a viscous material comprising active pharmaceutical ingredient.3048-21-28. The catheter assembly of claim 7, wherein the viscous material is a thermally reversible hydrogel comprising Poloxamer 407 and an active ingredient.

9. The catheter assembly of claim 8, wherein the thermally reversible hydrogel volume is about 20-60 mL.

10. The catheter assembly of any one of claim 8 or claim 9, wherein the thermally reversible hydrogel has a viscosity of less than about 500 cP at temperatures below about 12 °C, and a viscosity above 1,000,000 cP at above about 19 °C.

11. The catheter assembly of any one of claims 8-10, wherein the thermally reversible hydrogel has a gel transition temperature of about 14 °C.

12. The catheter assembly of any one of claims 7-11, wherein active pharmaceutical ingredient is mitomycin C.

13. A method of treating a cancer or any disease of a body organ or a body cavity comprising:(a) filling a syringe having a male Luer lock connector with a thermally reversible hydrogel comprising mitomycin C, cooled to a temperature of about 1-6 °C;(b) inserting the end of a catheter of a catheter assembly of any one of claims 1-5 into the bladder of a patient suffering from a bladder cancer;(c) connecting the male Luer lock connector of the syringe to the Luer adapter of the catheter assembly, wherein the Luer adapter is a female Luer lock connector; and(d) injecting the thermally reversible hydrogel through the catheter assembly: from the syringe, through the Luer adapter, through the catheter, and into the bladder of the patient; wherein the duration of said injecting of step (d) is less than about 5 minutes.

14. The method of claim 13, wherein the thermally reversible hydrogel comprises about 23- 27% w / w of Poloxamer 407, about 0.18% w / w HPMC, and about 1% w / w PEG-400, and water.3048-21-215. The method of claim 13 or claim 14, wherein the thermally reversible hydrogel volume is about 20-60 mL.

16. The method of any one of claims 13-15, wherein the thermally reversible hydrogel has a viscosity of less than about 500 cP at temperatures below about 12 °C, and a viscosity above 1,000 cP at about 37 °C.

17. The method of any one of claims 13-16, wherein the thermally reversible hydrogel comprises about 0.1 % w / w to about 1 % w / w mitomycin C.

18. The method of any one of claims 13-17, wherein the bladder cancer is a low-grade upper tract urothelial cancer or low-grade, intermediate-risk, non-muscle-invasive bladder cancer.

19. A catheter assembly for administration of a therapeutic composition into the bladder of a patient, comprising: a) a urinary catheter comprising an end suitable for insertion into the urinary tract of a patient, and an opposing end having a catheter funnel for introducing or draining fluids from the catheter;(b) a Luer adapter comprising on one end a female Luer lock connector, and on the opposing end of the Luer adapter, a tubular conical member capable of insertion into the opening of the catheter funnel, whereby after insertion of the tubular member of the Luer adapter into the catheter funnel, the Luer adapter provides means for connection to a syringe equipped with a male Luer lock connector, and a path for fluids to flow through the catheter assembly into and out of the urinary tract of the patient; and(c) a funnel adapter clamp configured to apply inward circumferential force around the catheter funnel, wherein the clamp maintains a fluid-tight seal between the Luer adapter and the catheter funnel during repeated interchanges of syringes, thereby preventing leakage that would otherwise result from mechanical stress, deformation, or misalignment at the adapterfunnel interface.3048-21-220. The catheter assembly of claim 19, wherein the therapeutic composition comprises an active pharmaceutical ingredient that is suspended in a pharmaceutically acceptable carrier for intravesical administration.

Images