Compositions and methods for drug infusion into the bladder - Patents.com

Abstract

The present invention relates to a biphasic composition for injection into a body cavity, such as the bladder or kidney, for delivery of an active agent comprising an A phase, where the A phase is a hydrophilic hydrogel and the B phase is a liquid organic solution (B phase) of a hydrophobic polymer, silicone or wax, and upon injection of the B phase into the A phase, a core is formed in situ within the bladder, which core entraps the active agent and allows for extended release of the active agent. Additionally, methods and kits for delivering an active agent into a body cavity, as well as methods for treating or ameliorating a disease or condition associated with the bladder, are provided.

Description

[Technical field]

[0001] The present invention relates to compositions and methods for instilling drugs and active agents into body cavities, such as the bladder. [Background technology]

[0002] The bladder is a muscular, hollow pelvic organ whose primary functions include urine storage and discharge. The relative impermeability of the bladder epithelium minimizes systemic absorption of drugs and side effects. The bladder is easily accessible using a catheter or cystoscope through the urethra, a simple procedure that can be performed by a medical professional or even by the patient himself. However, drugs or agents instilled intravesically into the bladder have limited effectiveness due to periodic dilution and wash-out during urine formation and voiding. This reduces the time that the drug has in contact with the target tissue. This delivery method is cumbersome as it requires repeated and frequent bladder catheterization and drug infusion. Therefore, research has focused on increasing the residence time and absorption of intravesical drugs with the development of novel intravesical drug therapy systems.

[0003] Diseases of the bladder, such as bladder cancer and interstitial cystitis, cause acute damage to the bladder wall and cannot be effectively treated by systemic administration of drugs. Such conditions are advantageously treated by intravesical drug delivery (IBD), which involves instillation of drugs directly into the bladder via a catheter, achieving high local concentrations of the drug over an extended period of time and minimizing systemic effects. For example, the use of oral oxybutynin to treat overactive bladder is well documented, but despite its clinical efficacy, systemic anticholinergic side effects caused by oral administration of oxybutynin are prominent. One of the key differences that distinguishes delivery methods appears to be the ratio of the parent compound oxybutynin to the active metabolite N-desethyloxybutynin (NDO), which is responsible for many of the anticholinergic side effects associated with oxybutynin. Oxybutynin undergoes extensive upper gastrointestinal first-pass metabolism resulting in high NDO concentrations. Local instillation of oxybutynin into the bladder bypasses the first-pass effect and reduces the systemic side effects associated with NDO.

[0004] However, current IBD technology has its limitations and challenges. For the bladder, there are challenges in designing an efficient IBD due to the large amount of fluid in the bladder cavity, frequent urination, and contraction and relaxation of the detrusor muscle during filling and urination. The infused drug solution is diluted with urine and washed out of the bladder during urination, necessitating repeated infusion of the drug. Other challenges for IBD technology include the relatively short retention time of the drug in the bladder. This frequently requires reduced infusion efficacy and patient compliance, including issues with catheter or urethral obstruction during infusion, pain, and patient tolerance of off-the-shelf matrices, devices, and solids during IBD. Other remaining challenges include the large volume of infused drug formulations. Summary of the Invention [Problem to be solved by the invention]

[0005] According to some embodiments, a biphasic composition is provided that is useful for delivering an active agent to an internal cavity, such as the bladder. [Means for solving the problem]

[0006] The present invention relates to a biocompatible and biodegradable delivery system of sufficient size to act as a reservoir for one or more active agents to be released at a sustained rate within a body cavity, and more specifically, within the bladder.

[0007] According to some embodiments, a biphasic composition for forming an in-situ drug delivery system in the bladder is provided, comprising a hydrophilic hydrogel phase A, a liquid phase B including an organic solvent, a hydrophobic polymer, wax, silicone or lipid, and an active agent, where phase A is injected into the bladder and then phase B is injected into phase A to form a solid entrapping in situ, allowing for extended release of one or more active agents. The delivery system releases the active agent over an extended period of time. Phase A promotes the bulk structure formation of an amorphous spheric mass formed upon injection of phase B.

[0008] According to some embodiments, the novel compositions disclosed herein are advantageous because they are stable, easy to manufacture, and exhibit desired biological activity over time, as further detailed herein.

[0009] In some embodiments, compositions are provided that allow for a controlled release system that can be injected into a body cavity. In some embodiments, the compositions can deliver at least one active ingredient. In some embodiments, the compositions can deliver two or more active ingredients. In some embodiments, the injected compositions form a bulky solid scaffold in situ with a three-dimensional (3-D) structure.

[0010] In some embodiments, a biphasic composition for injection into the urinary system, bladder, or kidney to deliver an active agent is provided, the composition comprising: Phase A, which is a hydrophilic hydrogel; and a phase B comprising an organic solvent and one or more of a hydrophobic polymer, a lipid, or a silicone; Here, a core is formed in situ within the internal cavity upon injection of phase B into phase A, said formed core entraps one or more active agents and allows for their extended release.

[0011] In some embodiments, phase A comprises one or more hydrophilic gelling agents selected from the group consisting of carbomer, polyacrylic acid, acrylate polymers, carrageenan, polyvinyl alcohol, polyethylene glycol, sodium methylcellulose polyacylate, hydroxypropyl methylcellulose (HMPC), chitosan, guar gum, xanthan gum, gelatin, water, and optionally an alkali neutralizing agent.

[0012] In some embodiments, the hydrophobic polymer in phase B is polyglycolic acid, polylactic acid, copolymers of polylactic acid (PLA) and polyglycolic acid (PGA), poly(DL-lactide), poly(lactide-co-glycolide), poly(L-lactide), poly(ε-caprolactone), poly(DL-lactide-ε-caprolactone), methacrylic acid-methyl methacrylate copolymer, and any combination thereof.

[0013] In some embodiments, the organic solvent is DMSO (dimethyl sulfoxide), N-methyl-2-pyrrolidone, ethyl acetate, polyethylene glycol, alcohol, propylene glycol, ethyl oleate, oleic acid, liquid hydrocarbons, and any combination thereof.

[0014] In some embodiments, the lipid is one or more of a fatty acid, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, or a wax.

[0015] In some embodiments, the lipid is a wax, beeswax, Witepsol™, lauric acid, cetyl palmitate, and any combination.

[0016] In some embodiments, Witepsol™ refers to a compound consisting of glycerol esters of saturated vegetable fatty acids, primarily lauric acid. In some embodiments, Witepsol™ is H, W, S, and E.

[0017] In some embodiments, the liquid organic solvent of phase B is DMSO. In some embodiments, phase B comprises at least one PLGA copolymer. In some embodiments, phase B comprises at least two PLGA copolymers. In some embodiments, the PLGA copolymer(s) have a monomer ratio composition of poly(lactide-co-glycolide) ranging from 50:50 to 85:15. In some embodiments, the PLGA copolymer(s) have an intrinsic viscosity range of 0.15-1.7 dL / g. In some embodiments, the PLGA copolymer(s) have acid or hydroxy or ester end groups. In some embodiments, the biphasic composition comprises 0.1-45% w / w PLGA with an intrinsic viscosity range of 0.15-0.25 dL / g; and 0.1-35% w / w PLGA with an intrinsic viscosity range of 0.26-0.54 dL / g. In some embodiments, the biphasic composition comprises 0.1-45% w / w PLGA with an intrinsic viscosity in the range of 0.15-0.25 dL / g; and 0.1-35% w / w PLGA with an intrinsic viscosity in the range of 0.55-0.75 dL / g.

[0018] In some embodiments, the biphasic composition comprises an active ingredient that is a pain relieving agent, such as lidocaine and / or oxybutynin, or an anti-cancer agent, or any combination thereof.

[0019] In some embodiments, the active agent is selected from the group consisting of mitomycin C, deoxyrubicin, valrubicin, cisplatin, gemcitabine, thiotepa, etoglucide (eposil), epirubicin, pirarubicin, apaziquone, docetaxel, and vicinium, and any combination thereof.

[0020] In some embodiments, the oxybutynin or any other active ingredient is present in either phase A or phase B at a concentration of 0.02-20% w / w of phase A or phase B. In some embodiments, the biphasic composition comprising oxybutynin or any other active ingredient is present in either phase A or phase B at a concentration of 0.1-15% w / w of phase A or phase B.

[0021] In some embodiments, oxybutynin or solifenacin is present in either phase A or B at a concentration of 0.02-5% w / w of phase A or B. In some embodiments, lidocaine or bupivacaine is present in either phase A or B at a concentration of 0.1-20% w / w of phase A or B. In some embodiments, gemcitabine, cisplatin, docetaxel, or paclitaxel is present in either phase A or B at a concentration of 0.05-25% w / w of phase A or B.

[0022] In some embodiments, the biphasic composition comprises an active agent that is released continuously over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, 30 or more days.

[0023] In some embodiments, the alkaline neutralizing agent is selected from sodium hydroxide, triethanolamine, diisopropylamine, ammonium hydroxide, 2-dimethylaminoethanol, TRIS base, monoisopropanolamine, borax, or any other suitable neutralizing agent.

[0024] In some embodiments, a method for delivering a therapeutic agent into a body cavity of a subject in need thereof is provided, comprising administering a hydrophilic hydrogel (phase A) into the body cavity of a subject in need thereof, and administering a liquid organic solution (phase B) of an active agent and a hydrophobic polymer, lipid, wax or silicone into the hydrophilic hydrogel (phase A), wherein injection of phase B into phase A results in the formation of a core in situ within the internal cavity, the formed solid entrapping the active agent and allowing for extended release of the active agent, and phase A or phase B or both containing at least one active agent, thereby delivering the at least one active ingredient into the body cavity. In some embodiments, the core is a solid or semi-solid 3D structure formed in phase A, and comprises one or more of a hydrophobic polymer, silicone, wax or lipid. In some embodiments, the active agent is added to phase B during its preparation. In some embodiments, the active agent is added prior to injection of phase B into phase A.

[0025] In some embodiments, the lipid is one or more of a fatty acid, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, or a wax.

[0026] In some embodiments, a method of forming a biphasic composition includes: The method comprises the steps of dispersing a hydrophilic gelling agent in water or any other suitable hydrophilic solvent (phase A); mixing a hydrophobic polymer, lipid, wax, or silicone, or any combination thereof, with an organic solvent until a viscous liquid mixture (phase B) is obtained; and injecting phase B into phase A. As mentioned above, active agents may be added to either or both phases A or B.

[0027] In some embodiments, a kit is provided that includes a hydrophilic hydrogel, a liquid organic solution of a hydrophobic polymer, a fatty acid, a fatty acid ester, a silicone, a triglyceride, a glyceride, a phospholipid, or a wax, and a leaflet that describes the preparation of the biphasic composition in situ.

[0028] In some embodiments, the kit further comprises an active agent.

[0029] In some embodiments, a biphasic composition for drug delivery to the bladder is provided, comprising a hydrogel (phase A), 0.1-45% w / w PLGA having an intrinsic viscosity range of 0.15-0.25 dL / g, 0.1-35% w / w PLGA having an intrinsic viscosity range of 0.26-0.54 dL / g or 0.55-0.75 dL / g, 0.1-50% DMSO, and an active agent. In some embodiments, the composition further comprises 0.01-20% povidone; 0.01%-0.5% HPMC;

[0030] In some embodiments, the active agent is lidocaine, oxybutynin, an anti-cancer drug, or any combination thereof. In some embodiments, the active agent is selected from the group consisting of mitomycin C, deoxyrubicin, valrubicin, cisplatin, gemcitabine, thiotepa, etoglucide (epozil), epirubicin, pirarubicin, apaziquone, docetaxel, and vicinium. In some embodiments, the oxybutynin is present at a concentration of 0.02-5% w / w. In some embodiments, the oxybutynin is present at a concentration of 0.01-2% w / w.

[0031] In some embodiments, there is provided a method for preventing / treating / ameliorating a disease or syndrome of the bladder, urinary tract or kidney, comprising administering a hydrophilic hydrogel (phase A) to the bladder, urinary tract or kidney of a subject in need thereof; administering to the hydrophilic hydrogel (phase A) an organic solution (phase B) comprising an active agent and one or more of a hydrophobic polymer, a fatty acid, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, a silicone or a wax, wherein upon injection of phase B into phase A a core is formed in situ, the formed amorphous spheric mass trapping the active agent and allowing for sustained release of the active agent, wherein phase A, phase B or both comprise at least one active agent, whereby the at least one active agent is delivered to the bladder, urinary tract or kidney to treat a disease or syndrome of the bladder, urinary tract or kidney. In some embodiments, the bladder, urinary tract or kidney disease or syndrome includes one or more of urinary tract infection, chronic cystitis, overactive bladder, partial bladder obstruction, interstitial cystitis, urethritis, pain and bladder cancer, or any other syndrome or disease described herein. The active agent is any of the active agents suggested herein, and a physician can select the appropriate active agent depending on the disease or syndrome. [Brief description of the drawings]

[0032] The present invention is described herein, by way of example only, with reference to the accompanying drawings. With specific reference to the drawings in detail, it is emphasized that the details shown are exemplary and are for the purpose of illustrative discussion of preferred embodiments of the present invention only, and that this illustration provides what is believed to be the most useful and easily understood explanation of the principles and conceptual aspects of the present invention. In this regard, no attempt is made to show the structural details of the present invention in more detail than is necessary for a fundamental understanding of the present invention, and the description with the drawings will make clear to those skilled in the art how some forms of the present invention can be embodied in practice. [Figure 1]FIG. 1 shows the in vitro continuous release of oxybutynin from in situ masses generated from the biphasic composition of Example 2 into artificial urinary fluid (AUF) over an 8 day period (mean + / SD, n=6). [Diagram 2] FIG. 2 shows the in vitro continuous release of lidocaine into artificial urinary fluid (AUF) over an 8 day period from in situ masses generated from the biphasic composition of Example 2 (mean + / SD, n=6). [Diagram 3] Figure 3 shows an amorphous spheric mass remaining in a pig's bladder 7 days after instillation of the composition of Example 2 into the bladder, as visualized using a cystoscope. [Figure 4] FIG. 4 shows the mean lidocaine concentrations in the plasma of pigs 8 days after bladder instillation of the composition from Example 2 (mean + / -SD, n=4). [Diagram 5] FIG. 5 shows the mean oxybutynin and its metabolite N-desethyloxybutynin concentrations in the plasma of pigs 8 days after bladder instillation of the composition of Example 2 (mean + / SD, N=4). [Figure 6] FIG. 6 shows the mean oxybutynin concentrations in pig plasma 10 days after bladder instillation of the composition of Example 13 (mean + / -SD, n=2). [Figure 7] FIG. 7 demonstrates the cytotoxic effect of drug released from in situ masses generated from the composition of Example 16 containing 0.5% docetaxel and 0.5% gemcitabine on human bladder cancer T24 cell line in an MTT assay. [Figure 8] FIG. 8 demonstrates the cytotoxic effect of drug released from in situ masses generated from the composition of Example 17 containing 0.1% docetaxel and 0.1% gemcitabine on human bladder cancer T24 cell line in an MTT assay. [Figure 9] FIG. 9 demonstrates the cytotoxic effect of drug released from in situ masses generated from the composition of Example 18 containing 0.5% docetaxel, 0.5% gemcitabine and 0.5% cisplatin on human bladder cancer T24 cell line in an MTT assay. [Figure 10] FIG. 10 shows the in vitro continuous release of bupivacaine from in situ masses generated from the biphasic composition of Example 24 into artificial urinary fluid (AUF) over a 14 day period (mean + / SD, n=2). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The principles, uses, and implementations of the teachings herein may be better understood with reference to the accompanying description and drawings. Upon review of the description and drawings herein, one skilled in the art will be able to practice the teachings herein without undue effort or experimentation. In the drawings, like reference numbers refer to like parts throughout.

[0034] (definition) To facilitate the understanding of the present invention, certain terms and phrases are defined below. It is to be understood that these terms and phrases are for purposes of description and not limitation, and that a term or phrase herein should be interpreted by one of ordinary skill in the art in light of the teaching and guidance presented herein, in combination with the knowledge of such persons.

[0035] In the description and claims of this application, the words "include" and "have" and forms thereof are not limited to the members in a list with which the words may be associated.

[0036] As used herein, the term "comprising" includes the term "consisting of."

[0037] As used herein, the term "about" may be used to designate an amount or parameter value (e.g., the length of an element) within a continuous range of values ​​in the vicinity of (and including) a given (stated) value. According to some embodiments, "about" may designate a parameter value to be 80%-120% of the given value. According to some embodiments, "about" may designate a parameter value to be 90%-110% of the given value. According to some embodiments, "about" may designate a parameter value to be 95%-105% of the given value.

[0038] According to some embodiments, a biphasic composition for injection into the urinary system, bladder, urinary tract or kidney is provided, comprising a hydrogel and a solution of one or more of a polymer, silicone, wax or lipid in an organic solvent and at least one active agent, which composition forms an "in situ" core form that entraps the active agent, releasing the active agent over an extended period of time.

[0039] In some embodiments, a biphasic composition for injection into the urinary system, bladder, or kidney to deliver an active agent is provided, the composition comprising: Phase A comprising a hydrophilic hydrogel; and a phase B comprising an organic solvent and one or more of a hydrophobic polymer, a lipid, a wax, or a silicone; The hydrophobic polymer, lipid, wax, or silicone is dissolved in an organic solvent and a core is formed in situ in the internal cavity upon injection of phase B into phase A, and the formed core entraps one or more active agents and allows for extended release of the active agents.

[0040] In some embodiments, the active agent is added to either phase A or phase B, or both, prior to injection.

[0041] According to some embodiments, the organic solvent is DMSO, N-methyl-2-pyrrolidone, ethyl acetate, triacetin, polyethylene glycol, alcohol, propylene glycol, ethyl oleate, oleic acid, liquid hydrocarbons, and any combination thereof.

[0042] According to some embodiments, the composition further comprises hydroxypropyl methylcellulose and / or polyvinylpyrrolidone.

[0043] According to some embodiments, a biphasic composition for delivering an active agent to an internal cavity, such as the bladder, is provided.

[0044] According to some embodiments, a biphasic composition for forming an in situ drug delivery system in the bladder is formed, the composition comprising an A phase comprising a hydrophilic hydrogel and a B phase comprising an organic solvent, a hydrophobic polymer and an active agent, the A phase is injected into the bladder, urinary tract or kidney, and then the B phase is injected into the A phase, resulting in the formation of a biphasic composition that forms an in situ core, traps the active agent and allows for extended release of the active agent. In some embodiments, the A phase promotes the 3D structure formation of an amorphous spheroid core that is formed upon injection of the B phase into the A phase.

[0045] According to some embodiments, the compositions disclosed herein are advantageous because they are stable, easy to manufacture, and exhibit the desired biological activity over time, as further detailed herein. In some embodiments, the mass formed does not obstruct the urethra, i.e., does not prevent the excretion and removal of urine.

[0046] The dosage of the active agent can be adjusted by adjusting the dosage volume of the composition.The method described herein also allows for the administration of different active agents by continuous infusion of compositions containing different active agents through a catheter, cystoscope, or ureteroscope.The method allows for the continuous or simultaneous release of different drugs into the urinary tract, bladder, and / or kidney(s).

[0047] According to some embodiments, a biphasic composition for delivering an active agent to an internal cavity, such as the bladder, urinary tract, or kidney, is provided, wherein the biphasic composition comprises a hydrophilic colloid gel that promotes in situ 3-D amorphous spheroidal structure formation upon injection of phase B into phase A.

[0048] According to some embodiments, the B phase comprises an organic solvent such as DMSO or polyethylene glycol, one or more polymers, and one or more active agents. Optionally, the composition also contains one or more additives. The formed core releases the active agent and provides a prolonged release of the active agent to the urinary tract, bladder, and / or kidney. The release of one or more active agents from the formed core into the urine of the urinary tract, bladder, or kidney, or any other body cavity, can begin immediately after injection and can continue for several hours to several weeks. The delivery period in the urinary tract, bladder, or kidney can be adjusted by the formulation composition (i.e., polymer, solvent, active agent, additive, etc.), injection volume, and frequency of repeated injections.

[0049] The composition may further comprise at least one pharma- ceutically acceptable excipient.

[0050] In some embodiments, phase A is a hydrogel comprising one or more hydrophilic gelling agents selected from carbomer, polyacrylic acid, acrylate polymers, carrageenan, polyvinyl alcohol, polyethylene glycol, sodium methylcellulose polyacylate, hydroxypropyl methylcellulose, chitosan, guar gum, xanthan gum, gelatin, alginic acid, hyaluronic acid, and any combination thereof, water, and optionally an alkali neutralizing agent.

[0051] According to some embodiments, the alkaline neutralizing agent is selected from sodium hydroxide, triethanolamine, diisopropylamine, ammonium hydroxide, 2-dimethylaminoethanol, TRIS base, monoisopropanolamine, borax, or any other suitable neutralizing agent. According to some embodiments, the alkaline neutralizing agent is an active agent.

[0052] According to some embodiments, phase A comprises a colloidal hydrogel. In some embodiments, phase A may comprise one or more pharmaceutical additives. In some embodiments, phase A may contain one or more active agents.

[0053] According to some embodiments, phase B is a liquid comprising a hydrophobic polymer that can be dissolved in an organic solvent. In some embodiments, the polymer is polyglycolic acid, polylactic acid, copolymers of polylactic acid (PLA) and polyglycolic acid (PGA), poly(DL-lactide), poly(lactide-co-glycolide), poly(L-lactide), poly(ε-caprolactone), poly(DL-lactide-ε-caprolactone), methacrylic acid-methyl methacrylate copolymer, and any combination thereof.

[0054] According to some embodiments, phase B is a liquid comprising a lipid, fatty acid, silicone, fatty acid ester or wax that can be dissolved in an organic solvent. In some embodiments, the lipid, fatty acid, fatty acid ester or wax is beeswax, solid fat, saturated fatty acid triglyceride, Witepsol™, lauric acid, cetyl palmitate, and any combination thereof.

[0055] In some embodiments, the organic solvent in phase B is DMSO, N-methyl-2-pyrrolidone (NMP), ethyl acetate, polyethylene glycol, alcohol, propylene glycol, triacetin, ethyl benzoate, triethyl citrate, and any combination thereof.

[0056] In some embodiments, the organic solvent in phase B is ethyl oleate, oleic acid, short and medium chain liquid hydrocarbons, triglyceride oils, olive oil, sesame oil, medium chain triglycerides, triacetin, and any combination thereof.

[0057] Optionally, the composition contains one or more additives.

[0058] Optionally, the composition contains one or more drugs or active substances. Optionally, the composition contains an antibody as an active agent. Optionally, the composition contains a biological molecule. In some embodiments, the active agent is added before injection.

[0059] In some embodiments, a biphasic composition for injection into the urinary system, bladder, or kidney to deliver one or more active agents is provided, said composition comprising a hydrophilic hydrogel (phase A) and a liquid (phase B) comprising an organic solution of one or more of a hydrophobic polymer, lipid, wax, or silicone and an active agent, wherein upon injection of phase B into phase A, a core is formed in situ within the internal cavity, said formed core entraps the active agent and allows for its extended release.

[0060] In some embodiments, the lipid is one or more of a fatty acid, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, or a wax.

[0061] In some embodiments, phase A comprises one or more hydrophilic gelling agents selected from the group consisting of carbomer, polyacrylic acid, acrylate polymers, carrageenan, polyvinyl alcohol, polyethylene glycol, sodium methylcellulose polyacylate, hydroxypropyl methylcellulose, chitosan, guar gum, xanthan gum, gelatin, alginic acid, hyaluronic acid, water, and optionally an alkali neutralizing agent.

[0062] In some embodiments, phase B comprises a hydrophobic polymer, for example, but not limited to, polyglycolic acid, polylactic acid, copolymers of polylactic acid (PLA) and polyglycolic acid (PGA), poly(DL-lactide), poly(lactide-co-glycolide), poly(L-lactide), poly(ε-caprolactone), poly(DL-lactide-ε-caprolactone), methacrylic acid-methyl methacrylate copolymer, and any combination thereof.

[0063] In some embodiments, the organic solvent of phase B is DMSO, and phase B further comprises at least two PLGA copolymers.

[0064] In some embodiments, the PLGA copolymer has an intrinsic viscosity range of 0.15-0.95 dL / g. In some embodiments, phase B comprises 0.1-45% w / w PLGA with an intrinsic viscosity range of 0.15-0.25 dL / g; and 0.1-35% w / w PLGA with an intrinsic viscosity range of 0.26-0.54 dL / g, 0.55-0.75 dL / g, or 0.76-1.3 dL / g. In some embodiments, the PLGA copolymer has acid or hydroxy or ester end groups. In some embodiments, the PLGA copolymer may have a monomer molar ratio of lactic acid to glycolic acid ranging from 50:50 to 85:15.

[0065] In some embodiments, phase B can contain polylactic acid polymer (PLA), polylactic acid-polyglycolic acid copolymer (PLGA copolymer) with molar ratios of monomers of, for example, 50:50%, 75:25%, 60:40%, 65:35%, 85:15% (lactic acid to glycolic acid).

[0066] In some embodiments of the present invention, the composition may contain any pharmaceutical excipient.Illustrative examples include plasticizers, viscosity modifiers, surface active agents, permeation enhancers, diluents, preservatives, antioxidants; components that facilitate handling, stability, wettability, release kinetics; components that are required during manufacturing process or administration.In some embodiments, the active agent in either phase A or B may be lipophilic.

[0067] In some embodiments, the composition may include any pharmaceutical excipient such as Tween 20, Tween 60, Span 20, Span 80, Cremophor EL, Cremophor RH40, or Pluronic® P85.

[0068] In some embodiments, the active agent in either one of phases A or B may be hydrophilic or amphiphilic.

[0069] In some embodiments, the active agent is dissolved or suspended in either one of phase A or phase B.

[0070] In some embodiments, the active agent may be in the form of a liquid, powder, crystal, nanoparticle, microsphere, or granule.

[0071] In some embodiments, phase A and / or phase B may contain an active agent in a concentration of 0.005-30% w / w, 0.01-20% w / w, 0.01-10% w / w, 0.01-5% w / w, 5-10% w / w, 5-15% w / w, 5-20% w / w, or 0.1-10% w / w, based on the weight of either phase A or phase B.

[0072] In some embodiments, the viscosity of the hydrophilic hydrogel in phase A at 25° C. is 200-30,000 cP. In some embodiments, the viscosity of the hydrophilic hydrogel in phase A at 25° C. is 500-20,000 cP. In some embodiments, the viscosity of the hydrophilic hydrogel in phase A at 25° C. is 800-15,000 cP. In some embodiments, the viscosity of the hydrophilic hydrogel in phase A at 25° C. is between 800-10,000 cP.

[0073] In some embodiments, the size of the amorphous spherical 3-D agglomerates can be adjusted by the injection volume of phase B, by the polymer and additive concentrations used.

[0074] In some embodiments, phase B of the composition may contain polylactic acid-polyglycolic acid copolymer in a concentration of 0.5-60% w / w, 2-45% w / w, or 5-35% w / w.

[0075] In some embodiments, the Phase B composition may contain polylactic-co-glycolic acid polymers having different molecular weight ranges.

[0076] In some embodiments, the composition of Phase B may contain a polylactic-polyglycolic acid copolymer having acid, hydroxy, or ester end groups.

[0077] In some embodiments, the Phase B composition may contain a mixture of polylactic-polyglycolic acid copolymers having different intrinsic viscosities.

[0078] In some embodiments, the composition of phase B may contain a 50:50% mixture of polylactic acid and polyglycolic acid copolymers having an intrinsic viscosity of 0.15-0.25 dL / g and an intrinsic viscosity of 0.26-0.54 dL / g. In some embodiments, the composition of phase B may contain a 50:50% mixture of polylactic acid and polyglycolic acid copolymers having an intrinsic viscosity of 0.15-0.25 dL / g and an intrinsic viscosity of 0.55-0.65 dL / g.

[0079] In some embodiments, the composition may contain methylcellulose at a concentration of 0.01-10% w / w, 0.05-8% w / w, or 0.2-7% w / w.

[0080] In some embodiments, Phase B of the composition may contain glycol at a concentration of 0-90% w / w, 0-70% w / w, or 0.1-60% w / w.

[0081] In some embodiments, the composition may contain the amphiphilic polymer at a concentration of 0.1-7% w / w, 0.2-5% w / w or 0.1-4% w / w.

[0082] In some embodiments, the formed in situ 3D amorphous spherical cores have diameters ranging from 2 mm to 15 cm, 8 mm to 8 cm, or 1 to 5 cm.

[0083] In some embodiments, a biphasic composition for drug delivery to the bladder is provided, comprising a hydrogel, 0.1-45% w / w PLGA having an intrinsic viscosity of 0.15-0.25 dL / g, 0.1-35% w / w PLGA having an intrinsic viscosity of 0.26-0.54 dL / g, or 0.55-0.75 dL / g, or 0.76-0.94 dL / g, or 0.94-0.1.2 dL / g, and an active agent.

[0084] The composition may further comprise one or more of 0.01-20% povidone, 0.01%-5.0% HPMC, and 0.1-50% DMSO, in some embodiments, and any combination thereof.

[0085] In some embodiments, the composition can be infused multiple times in succession to generate multiple bodies of different sizes in the bladder, urinary tract, or kidney.

[0086] In some embodiments, the active agent may be released over a period of at least 1 hour, at least 2 hours, at least 5 hours, at least 8 hours, at least 24 hours, at least 48 hours, at least 7 days, at least 14 days, at least 21 days, at least 30 days or more.

[0087] In some embodiments, the active agent is released continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 21, 30 or more days.

[0088] In some embodiments, the active agent is released continuously for 1 week, 2 weeks, 3 weeks, 4 weeks or more.

[0089] Injection may be performed using a catheter, an endoscope, or any other suitable means or device.

[0090] In one embodiment, the invention relates to a method of administering the composition locally to the urethra, bladder or kidney by injection using a catheter, endoscope, or other suitable means or device.

[0091] In one embodiment, phase A and / or phase B of the composition may incorporate active agents selected from various therapeutic classes: antinociceptive agents, antiarrhythmic agents, anticoagulants, anesthetic agents, anti-inflammatory agents, antibiotics, muscarinic agents, mitotic agents, chemotherapeutic agents; diagnostic probes, pH buffers, radioisotopes. Non-limiting examples of active substances include antibiotics, antibodies, cannabinoids, antispasmodic agents, analgesics, antibacterial agents, antimicrobial agents, antifungal agents, antihistamines, anti-inflammatory agents, antineoplastic agents, antiviral agents, corticosteroids, cytotoxic agents, decongestants, diuretics, hormones, immunosuppressants, muscle relaxants, sex hormones, tranquilizers.

[0092] In some embodiments, the composition may include a combination of drugs. Some non-limiting illustrative examples include combinations of cytotoxic drugs, such as mitomycin and cisplatin, gemcitabine and cisplatin, local anesthetic and antimuscarinic (e.g., lidocaine and oxybutynin, bupivacaine and solifenacin), antinociceptive and anti-inflammatory drugs (e.g., lidocaine and cannabidiol, fentanyl and cannabidiol, ibuprofen and cannabidiol, THC and cannabidiol), antimitotic and anesthetic drugs, prilocaine and mitomycin, lidocaine and adriamycin.

[0093] In some embodiments, the active ingredient is lidocaine, oxybutynin, an anti-cancer drug, or any combination thereof.

[0094] In some embodiments, the active agent is selected from the group consisting of mitomycin C, deoxyrubicin, valrubicin, cisplatin, gemcitabine, thiotepa, etoglucide (epodil), epirubicin, pirarubicin, apaziquone, docetaxel, and vicinium, and any combination thereof.

[0095] In some embodiments, oxybutynin is present in either phase A or phase B at a concentration of 0.02 to 2% w / w of phase A or phase B, respectively.

[0096] In some embodiments, oxybutynin is present in either phase A or phase B at a concentration of 0.1-0.8% w / w, respectively.

[0097] In some embodiments, oxybutynin or solifenacin is present in either phase A or B at a concentration of 0.02-5% w / w of phase A or B. In some embodiments, lidocaine or bupivacaine is present in either phase A or B at a concentration of 0.1-20% w / w of phase A or B. In some embodiments, gemcitabine, cisplatin, docetaxel, or paclitaxel is present in either phase A or B at a concentration of 0.05-25% w / w of phase A or B.

[0098] In some embodiments, a method is provided for delivering a therapeutic agent into a body cavity of a subject in need thereof, the method comprising administering into the body cavity of a subject in need thereof a biphasic composition comprised of a hydrophilic hydrogel (phase A) and a liquid organic solution of a hydrophobic polymer, silicone or wax (phase B) (phase B) into said hydrophilic hydrogel (phase A), wherein upon injection of phase B into phase A a core is formed in situ within the body cavity, the formed solid entrapping an active agent and allowing for its extended release, wherein phase A or phase B or both contain at least one active agent, delivering said one active ingredient into the body cavity.

[0099] In some embodiments, the compositions and methods described herein are used to treat diseases and / or conditions in the bladder, urinary tract and / or kidney, e.g., low grade bladder cancer, high grade bladder cancer, non muscle invasive bladder cancer, muscle invasive bladder cancer, upper tract urothelial carcinoma, superficial mural carcinoma; overactive bladder, renal colic, bladder interstitial pain, interstitial cystitis, carcinoma, sphincter function, infection, incontinence, trigonitis, inflammation, chronic pain, neurogenic bladder, urinary infection, erectile dysfunction. In some embodiments, the active agent may be used for local anesthesia or may be combined with a radioactive agent and used for diagnostic purposes.

[0100] The active agent may be a therapeutic, prophylactic, or diagnostic agent for the treatment of bladder or urinary disorders. In some embodiments, the active ingredient is a small molecule. In some embodiments, the active agent is a peptide or protein or antibody or nucleic acid, a virus or a bacterium. The active agent may be a small molecule drug or biological agent, a metabolite, or a radioactive molecule. The active agent may be in its salt form, hydrate, free acid form, and free base form. The active agent may be solubilized or suspended.

[0101] In a preferred embodiment, the active agent is suitable for administration for the treatment of urogenital, bladder, kidney and prostate conditions.

[0102] In yet another embodiment, the compositions and methods described herein are for treating inflammatory conditions such as interstitial cystitis, radiation cystitis, painful bladder syndrome, prostatitis, urethritis, postoperative pain, and kidney stones.Non-limiting examples of specific drugs for these conditions include lidocaine, bupivacaine, ropivacaine, mepivacaine, levobupivacaine, nonsteroidal anti-inflammatory drugs (NSAIDs), glycosaminoglycans (e.g., chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, or combinations thereof.In the case of kidney stones, drugs can be selected to treat pain and / or promote the dissolution of kidney stones.

[0103] In yet another embodiment, the compositions and methods described herein can treat overactive bladder, bladder incontinence and motility.The examples of active substances for relieving the symptoms of overactive bladder and reducing episodes of urge incontinence include antimuscarinic compounds, antispasmodic anticholinergics, beta-2 agonists, alpha adrenergic drugs, anticonvulsants, norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers, potassium channel openers, and muscle relaxants, apomorphine, darifenacin, tolterodine, oxybutynin, propiverine, trospium, solifenacin, mirabegron, fesoterodine, and their combinations alone or with anesthetics.

[0104] In yet another embodiment, the compositions and methods described herein can treat bladder or kidney cancer, urothelial carcinoma, squamous cell carcinoma, papillary carcinoma in situ, adenocarcinoma, squamous cell carcinoma. Non-limiting examples of active agents or combinations thereof for treating bladder or kidney cancer include: anti-proliferative agents, cytotoxic agents, chemotherapeutic agents, immunomodulatory agents, biologics, monoclonal antibodies, anti-PD1 antibodies, anti-PD-L1 antibodies, anti-4CB-1 antibodies, anti-4CB-2 antibodies, antibody toxin conjugates, viruses, bacteria, TNF inhibitors, anti-leukins, kinase inhibitors or combinations thereof, apaziquone, atezolizumab, avelumab, bavencio, cetrelimab, cisplatin, doxorubicin, durvalumab, enfortumab vedotin, epirubicin, erdafitinib, 5-FU (5-fluorouracil), gemcitabine, human alpha-lactalbumin producing lethal tumor cells (HAMLET), Imfinzi, Keytruda, methotrexate, mitomycin C, nivolumab, oportuzumab These include monatox-qqrs, opdivo, pembrolizumab, pirarubicin, paclitaxel, inactivated Streptococcus pyogenes, tecentriq, thiotepa, tremelimumab, valrubicin, valbicin, barstar, IL-15 superagonists, IL-15 mutant (IL-15N72D) coupled with IL-15 receptor α / immunoglobulin G1 (IgG1) fragment crystallizable (Fc) fusion protein, and its analogs.

[0105] In yet another embodiment, the compositions and methods described herein treat bladder or kidney pain, neurogenic bladder or interstitial cystitis. Non-limiting examples of active substances or combinations thereof for treating pain, bladder pain syndrome or interstitial cystitis include anesthetics, analgesics and combinations thereof, aminoamides, lidocaine base or salts, procaine, articaine, benzocaine, bupivacaine, tramadol or tramadol salts, dibucaine, lontocaine, mepivacaine, prilocaine, ropivacaine, tanezumab, gabapentin, chloroprocaine, cocaine, cocaine analogs, proparacaine, tetracaine, cannabinoids, CBD, THC and combinations thereof, NSAIDs, diclofenac, ibuprofen, naproxen, piroxicam, acetaminophen, flufenisal, indoprofen, indomethacin and analogs thereof. Non-limiting examples of opioid agonists include benzylmorphine, buprenorphine, butorphanol, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, methadone, morphine, mylophine, opium, oxycodone, oxymorphone, papaveretam, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptadine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.

[0106] In yet another embodiment, the compositions and methods described herein may treat inflammation of the bladder or kidney. Non-limiting examples of anti-inflammatory actives or combinations thereof for treating bladder urothelial inflammation and pain include cannabinoids, NSAIDs, diclofenac, ibuprofen, corticosteroids and their analogs.

[0107] In yet another embodiment, the compositions and methods described herein may treat bladder or kidney infections. Non-limiting examples of antibiotic actives or combinations thereof for treating bladder or urinary tract infections include antibiotics, amoxicillin, ceftriaxone, cephalexin, ciprofloxacin, fosfomycin, levofloxacin, minocycline, nitrofurantoin, trimethoprim / sulfamethoxazole and analogs thereof.

[0108] In yet another embodiment, the compositions and methods described herein can be used to treat bladder fibrosis.The representative examples of drugs for treating bladder fibrosis include pentoxifylline, anti-TNF, anti-TGF, GnRH analogs, exogenous progestins, anti-progestins, selective estrogen receptor modulators, danazol and NSAIDs.

[0109] In some embodiments of the invention, there is provided a method of forming a biphasic composition according to embodiments of the invention, comprising dispersing a hydrophilic gelling agent in water or any other suitable hydrophilic solvent, mixing a liquid organic solution of a hydrophobic polymer or wax until a viscous liquid mixture (phase B) is obtained, and injecting phase B into phase A.

[0110] In some embodiments, a kit is provided that includes a hydrophilic hydrogel, a liquid organic solution of a hydrophobic polymer or wax, and a leaflet that describes the handling instructions for preparing and injecting the biphasic composition. In some embodiments, a kit is provided that includes a hydrophilic hydrogel, an organic solution, a hydrophobic polymer, silicone or wax, and a leaflet that describes the handling instructions for preparing and injecting the biphasic composition. In some embodiments, a kit is provided that includes the components for phase A, an organic solution and a hydrophobic polymer, silicone or wax, or any other components for preparing phase B, and a leaflet that describes the handling instructions for preparing and injecting the biphasic composition.

[0111] In some embodiments, the kit further comprises an active agent, In some embodiments, the kit further comprises an active agent, which is admixed with phase A, B, or both.

[0112] In some embodiments, the present invention relates to methods for preventing / treating / ameliorating urinary tract infections, chronic cystitis, overactive bladder, partial bladder obstruction, interstitial cystitis, urethritis, pain and bladder cancer. The present invention further relates to reducing pain and improving symptoms in patients suffering from pain associated with urologic procedures (EUP) or any other procedures.

[0113] Interstitial cystitis is a disease associated with non-specific chronic inflammation of the bladder, which presents symptoms such as urination frequency, increased urinary desire, urgency, and / or bladder pain, and leads to a significant deterioration in quality of life. Interstitial cystitis with pain or conditions suspected to be interstitial cystitis are sometimes included in painful bladder syndrome, bladder pain syndrome, or chronic pelvic pain syndrome. Three conditions are an example of diagnostic criteria for interstitial cystitis: (1) the presence of lower urinary tract symptoms such as urination frequency, irritable bladder, and / or bladder pain, (2) the ability to confirm endoscopic lesions of the bladder due to Hunner's ulcer and / or bleeding after bladder distention, and (3) the fact that other disorders such as infection, malignancy, or urinary stones can be excluded.

[0114] Overactive bladder (OAB) is a syndrome characterized by urge incontinence, usually symptoms of urgency with or without urgency and nocturia. OAB is one of several bladder disorders and can be characterized by urge incontinence, detrusor instability, detrusor hyperreflexia, oversensitive bladder, spastic bladder, unstable bladder, urgency, or bladder spasms. OAB often manifests as a strong and sudden urge to urinate due to bladder spasms or contractions that can lead to frequent urination, loss of urine without meaning to urinate (leakage) during the day and at night, and a sudden and urgent need to urinate (urgency). Therefore, proper bladder control requires the lower urinary tract and nervous system to work together to allow sensation and ability to respond to urgency at appropriate intervals while minimizing leakage and urgency.

[0115] The present invention relates to methods of treating urinary tract infections, chronic cystitis, overactive bladder, partial bladder obstruction, urethritis and bladder cancer.

[0116] In some embodiments, the biphasic compositions and methods of delivering one or more active agents of the present invention are used to treat urinary tract infections, chronic cystitis, overactive bladder, partial bladder obstruction, urethritis and / or bladder cancer, or any of the conditions, symptoms or diseases described herein.

[0117] As seen in the examples, in patients suffering from OAB or ICS, the terms "treating", "treatment" or "theraty" as used herein refer to partially or completely alleviating, improving, enhancing, relieving, delaying the onset, inhibiting the progression, reducing the severity, reducing the incidence, attenuating one or more of bladder diseases or symptoms, such as urinary tract infection, chronic cystitis, overactive bladder, partial bladder obstruction, interstitial cystitis, urethritis, pain and bladder cancer. Treatment can also induce remission or cure of a condition, or reduce a pathological condition, such as a reduction in urination volume, a reduction in urination frequency, an increase in smooth muscle contractility, a reduction in bladder ischemia, an increase in urethral or bladder contractility, or a combination thereof. Prevention of a disease does not require a complete absence of the disease.

[0118] The term "ameliorating" with respect to a disease or pathological condition refers to any observable beneficial effect of a treatment. A beneficial effect can be evidenced, for example, by a delay in the onset of clinical symptoms of a disease in a susceptible subject, a reduction in the severity of some or all clinical symptoms of a disease, a reduction in urination frequency, an increase in urination volume, a delay in the progression of a disease, an improvement in the overall health or well-being of a subject, or other parameters known in the art that are specific to a particular disease.

[0119] The terms "treat", "treating" or any synonym thereof are meant to include treatments utilized to improve a health problem or condition in a patient or subject. In one embodiment, the health problem or condition may be eliminated, either permanently or for a short period of time. In another embodiment, the severity of the health problem or condition, or one or more symptoms characteristic of the health problem or condition, may be reduced, either permanently or for a short period of time. The effectiveness of the treatment of interstitial cystitis or overactive bladder may be determined using any standard indicator, such as those described herein, or based on the subjective assessment of the patient. A patient is considered to be "treated" if a reduction in overactive bladder activity or symptoms associated with interstitial cystitis is reported. In one embodiment, compounds of formula (I) and / or (II) are useful for treating interstitial cystitis or overactive bladder, and these compounds may selectively modulate the nervous system that affects the sensory aspects of OAB and IC without affecting or negatively affecting motor neuron function associated with bladder and sphincter control.

[0120] The term "treatment period" refers to the period during which a drug is administered to a subject. For example, the treatment period can be from about 2 weeks to about 2 years. In some embodiments, the treatment period can be about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 24 weeks, about 52 weeks, about 76 weeks, or about 104 weeks. The efficacy of a drug against OAB can be evaluated, for example, by measuring certain parameters and calculating the change from baseline over the treatment period. Efficacy parameters include, but are not limited to, urination, urge incontinence episodes, total incontinence episodes, and urge episodes.

[0121] Other diseases or conditions that may be treated with the compositions of the present invention include the following:

[0122] Inactive bladder: Also known as inactive bladder syndrome (UAB), inactive bladder includes difficulty emptying the bladder, such as hesitation to initiate a flow, insufficient or intermittent flow, or a feeling of incomplete bladder emptying. Detrusor pressurization with insufficient strength or duration for timely and efficient bladder emptying ("detrusor underactivity or "DU"), bladder outlet obstruction, and fluid overload ("OAB") are often seen concomitantly with UAB. Various measures can be used to diagnose UAB, including a subject's or patient's voiding diary (to assess voiding volume and frequency) and postvoid residual volume; low urine volume and neurological and pelvic examinations; imaging of abnormal bladder morphology or vesicoureteral reflux / hydronephrosis; or invasive urodynamics.

[0123] Urethral dysfunction: Disorders of urethral function, such as disorders of urinary excretion function or timing. Examples of urethral dysfunction in subjects include increased oxidative stress in the urethra, increased mitochondrial dysfunction in the urethra, or decreased urethral contractility. Urethral dysfunction can occur at any age, but is more common when subjects are older adults, such as adults who are at least 50 years old.

[0124] Urinary frequency: The number of times you urinate during the day or night. "Frequent urination" is 8 or more times per day or 2 or more times per night.

[0125] Urge incontinence: The involuntary loss of urine for no apparent reason, accompanied by a sense of urgent need to urinate.

[0126] Thus, in some embodiments, there is provided a method of preventing / treating / ameliorating a disease or syndrome of the bladder, urinary tract or kidney, comprising administering a hydrophilic hydrogel (phase A) to the bladder, urinary tract or kidney of a subject in need thereof; and administering an active agent and one or more organic solutions of hydrophobic polymers, fatty acids, fatty acid esters, triglycerides, phospholipids, silicones or waxes (phase B) into the hydrophilic hydrogel (phase A), wherein a core is formed in situ upon injection of phase B into phase A, said formed solid allowing for extended release of the active agent, and phase A, phase B, or both, comprising at least one active agent, thereby delivering at least one active ingredient into the bladder, urinary tract or kidney and treating said disease or syndrome of the bladder, urinary tract or kidney. In some embodiments, the bladder, urinary tract or kidney disease or syndrome includes one or more of urinary tract infection, chronic cystitis, overactive bladder, partial bladder obstruction, interstitial cystitis, urethritis, pain and bladder cancer, or any other syndrome or disease described herein. The active agent is any of the active agents suggested herein, and a physician can select the appropriate active agent depending on the disease or syndrome. EXAMPLES

[0127] [Example 1] [Table 1]

[0128] Preparation of Phase A: Carbopol was dispersed in water while mixing with an overhead stirrer at 400 rpm to form a thin suspension dispersion without lumps. In a separate container, 2-dimethylaminoethanol was dissolved in a portion of the water and the solution was added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A gel was obtained.

[0129] Preparation of phase B DMSO was heated to 70-80 °C in a beaker using a water bath and hot plate. PLGA was added and stirred continuously at approximately 200 rpm using an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture was obtained. Heating was stopped and the remaining ingredients were added one at a time with stirring at approximately 200 rpm until dissolved. A viscous liquid mixture was obtained.

[0130] Formation of in situ drug delivery systems: Step 1: Using a 100 ml syringe attached to a 12 G catheter, 95 g of Phase A was injected into a 100 ml vial.

[0131] Step 2: Following step 1, 5 g of phase B was injected into phase A using a 10 ml syringe attached to a 12 G catheter; a spherical solid mass containing the drug was instantly generated in situ.

[0132] [Example 2] [Table 2]

[0133] Preparation of Phase A: Carbopol was dispersed in water with mixing at 400 rpm using an overhead stirrer to form a thin lump-free suspension dispersion. In a separate container, TRIS was dissolved in a portion of the water. The solution was added to the Carbopol dispersion with mixing at 400 rpm using an overhead stirrer. A gel with a viscosity of 2660 cPs was obtained.

[0134] Preparation of phase B: DMSO was heated to 70-80 °C in a beaker using a water bath and hot plate. PLGA was added and stirred continuously at approximately 200 rpm using an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture was obtained. Heating was turned off and the remaining ingredients were added one at a time with stirring at approximately 200 rpm until dissolved. A viscous liquid mixture was obtained.

[0135] Formation of in situ drug delivery systems: Step 1: Using a 100 ml syringe attached to a 12 G catheter, 70 g of Phase A was injected into a 100 ml vial.

[0136] Step 2: Following step 1, 5 g of phase B was injected into phase A generating a solid drug delivery system in situ using a 10 ml syringe attached to a 12 G catheter.

[0137] [Example 3] [Table 3]

[0138] Preparation of Phase A: Carbopol was dispersed in water with mixing at 400 rpm using an overhead stirrer to form a thin lump-free suspension dispersion. In a separate container, 2-dimethylaminoethanol was dissolved in a portion of the water. The solution was added to the Carbopol dispersion with mixing at 400 rpm using an overhead stirrer. A gel was obtained.

[0139] Preparation of phase B: DMSO was heated to 70-80 °C in a beaker using a water bath and hot plate. PLGA was added and stirred continuously at approximately 200 rpm using an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture was obtained. Heating was turned off and the remaining ingredients were added one at a time with stirring at approximately 200 rpm until dissolved. A viscous liquid mixture was obtained.

[0140] Formation of in situ drug delivery systems: Step 1: Using a 100 ml syringe attached to a 12 G catheter, 70 g of Phase A was injected into a 100 ml vial.

[0141] Step 2: Following step 1, 5 g of phase B was injected into phase A using a 10 ml syringe attached to a 12 G catheter to generate a spherical solid drug delivery system in situ.

[0142] [Example 4] [Table 4]

[0143] Preparation of Phase A: Carbopol was dispersed in water with mixing at 400 rpm using an overhead stirrer to form a thin lump-free suspension dispersion. In a separate container, 2-dimethylaminoethanol was dissolved in a portion of the water. The solution was added to the Carbopol dispersion with mixing at 400 rpm using an overhead stirrer. A gel was obtained.

[0144] Preparation of phase B Phase B was heated to 65-75°C throughout the procedure using a water bath and hot plate. 0 Prepared at C.

[0145] DMSO was added to the beaker and mixed for 10 minutes using an overhead stirring 3-blade impeller. Each component was added with mixing at approximately 200 rpm until completely dissolved. Heat was removed and allowed to cool to room temperature with mixing. A viscous liquid mixture was obtained.

[0146] Formation of in situ drug delivery systems: Step 1: Using a 100 ml syringe attached to a 12 G catheter, 50 g of Phase A was injected into a 100 ml vial.

[0147] Step 2: Following step 1, 5 g of phase B was injected into phase A using a 10 ml syringe attached to a 12 G catheter to generate a spherical solid drug delivery system in situ.

[0148] [Example 5] [Table 5]

[0149] Preparation of Phase A: Carbopol was dispersed in water with mixing at 400 rpm using an overhead stirrer to form a thin lump-free suspension dispersion. In a separate container, NaOH was mixed in water. The solution was added to the Carbopol dispersion and mixed at 400 rpm using an overhead stirrer. A hydrogel was obtained.

[0150] Preparation of phase B: DMSO was heated in a beaker to 65-75 °C using a water bath and hot plate. Each component was added with mixing at approximately 200 rpm until completely dissolved. Heating was stopped and allowed to cool to room temperature with mixing. A viscous liquid mixture was obtained.

[0151] Formation of in situ drug delivery systems: Step 1: Using a 50 ml syringe attached to a 12 G catheter, 50 g of Phase A was injected into a 100 ml vial.

[0152] Step 2: Following step 1, 1 g of phase B was injected into phase A using a 2 ml syringe attached to a 12 G catheter to generate a solid drug delivery system in situ.

[0153] [Example 6] [Table 6]

[0154] Preparation of Phase A: Carbopol is dispersed in water while mixing with an overhead stirrer at 400 rpm to form a thin lump-free suspension dispersion. In a separate container, 2-dimethylaminoethanol is mixed with a portion of the water. The solution is added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A hydrogel is obtained.

[0155] Preparation of phase B: Heat the DMSO in a beaker to 70-80 °C using a water bath and hot plate. Add the PLGA and stir continuously at approximately 200 rpm with an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture is obtained. Turn off the heat and add the remaining ingredients, one at a time, while stirring at approximately 200 rpm until dissolved. A viscous liquid mixture is obtained.

[0156] Formation of in situ drug delivery systems: Step 1: Using a 50 ml syringe attached to a 12 G catheter, inject 50 g of phase A into a 100 ml vial.

[0157] Step 2: Following step 1, 2 g of phase B is injected into phase A using a 5 ml syringe attached to a 12 G catheter to generate an in situ solid drug delivery system.

[0158] [Example 7] In Vitro Release of Active Agent The in vitro release of oxybutynin and lidocaine from the biphasic composition of Example 2 was studied. 5 g of phase B was injected into a vial containing 70 g of phase A with a 10 ml syringe attached to a 12-gauge catheter. Three-dimensional (3-D) amorphous spheroid structures containing both lidocaine and oxybutynin were formed in situ. The vial was maintained in an orbital shaker incubator at 37°C and 20 revolutions per minute. After 3 hours, 20 mL of artificial urinary fluid (AUF), representative of the components of human urine according to a published protocol (Sarigul et al., December 2019), was added to the vial. The vial was kept in an orbital shaker incubator at 37°C and 20 revolutions per minute during the study. 85 mL samples were taken every 24 hours and replaced with fresh AUF for 8 days. The oxybutynin and lidocaine concentrations in the AUF were quantitatively determined by HPLC.

[0159] result: Figures 1 and 2 show the release profile of drugs entrapped in the 3-d bulk structure of in situ generated amorphous spheroids during an 8 day experiment. As can be seen, sequential release of two drugs is achieved in vitro using the biphasic composition of the present invention.

[0160] [Example 8] In vivo testing The in vivo mean plasma concentrations of oxybutynin and lidocaine from the biphasic composition of Example 2 were studied. The plasma concentration of N-desethyloxybutynin, the active metabolite of oxybutynin, was also evaluated. 50 g of Phase A was injected into the bladder of each of four female domestic pigs, followed by injection of 5 g of Phase B into each animal. Seven days after injection, three-dimensional (3-D) amorphous spherules formed in situ were visualized using a cystoscope (Figure 3). Blood samples were taken during the 10-day experiment. Plasma concentrations of oxybutynin, N-desethyloxybutynin, and lidocaine were measured using LC-MS-MS analytical methods.

[0161] The results are shown in Figures 4 and 5, which show the release profile of the drug encapsulated in the in situ generated 3-d bulk amorphous spheroids over a 10 day experimental period. As can be seen, continuous release of the drug can be achieved in vivo for at least 7 days using the biphasic composition of the present invention. The N-desethyloxybutynin concentration in plasma was undetectable.

[0162] [Example 9] [Table 7]

[0163] Preparation of Phase A: Carbopol is dispersed in water while mixing with an overhead stirrer at 400 rpm to form a thin lump-free suspension dispersion. In a separate container, TRIS is dissolved in a portion of the water. The solution is added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A gel is obtained.

[0164] Preparation of phase B: Heat the DMSO in a beaker to 70-80 °C using a silicon oil bath and hot plate. Add the PLGA and stir continuously at approximately 200 rpm with an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture is obtained. Turn off the heat and add the remaining ingredients, one at a time, while stirring at approximately 200 rpm until dissolved. A viscous liquid mixture is obtained.

[0165] [Example 10] [Table 8]

[0166] Preparation of Phase A: Carbopol was dispersed in water while mixing with an overhead stirrer at 400 rpm to form a thin lump-free suspension dispersion. In a separate container, TRIS base was dissolved in a portion of the water. The solution was added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A gel was obtained.

[0167] Preparation of phase B Phase B was heated to 65-75°C throughout the procedure using a water bath and hot plate. 0 Prepared at C.

[0168] Each component was added with mixing at approximately 200 rpm until completely dissolved. The heat was turned off and the resulting solution was transferred to a 5 g syringe and allowed to cool to room temperature.

[0169] Formation of in situ drug delivery systems: Step 1: Using a 50 ml syringe attached to a 12 G catheter, 50 g of Phase A was injected into a 100 ml vial.

[0170] Step 2: Following step 1, 50 0 4 g of phase B, preheated to C, was injected into phase A using a 5 ml syringe attached to a 12 G catheter to generate a solid drug delivery system in situ.

[0171] [Example 11] [Table 9]

[0172] Preparation of Phase A: Carbopol was dispersed in water while mixing with an overhead stirrer at 400 rpm to form a thin lump-free suspension dispersion. In a separate container, triethanolamine was mixed in a portion of the water. The solution was added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A gel was obtained.

[0173] Preparation of phase B Phase B was prepared at room temperature throughout the procedure. DMSO was placed in a beaker. Each component was added with mixing at approximately 600 rpm using an overhead stirrer with a three-blade impeller until completely dissolved.

[0174] Formation of in situ drug delivery systems: Step 1: Using a 50 ml syringe attached to a 12 G catheter, 50 g of Phase A was injected into a 100 ml vial.

[0175] Step 2: Following step 1, 5.0 g of phase B was injected into phase A using a 10 ml syringe attached to a 12 G catheter to generate a solid drug delivery system in situ.

[0176] [Example 12] [Table 10]

[0177] Preparation of Phase A: Carbopol was dispersed in water with mixing at 400 rpm using an overhead stirrer to form a thin lump-free suspension dispersion. In a separate container, triethanolamine was added to a portion of the water. The solution was added to the Carbopol dispersion with mixing at 400 rpm using an overhead stirrer. A gel was obtained.

[0178] Preparation of phase B: Heat to 70-80 °C in a beaker using a water bath and hot plate. PLGA was added and stirred continuously at approximately 200 rpm using an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture was obtained. Heating was stopped and the remaining ingredients were added one at a time with stirring at approximately 200 rpm until dissolved. A viscous liquid mixture was obtained.

[0179] Formation of in situ drug delivery systems: Step 1: Using a 100 ml syringe attached to a 12 G catheter, 50 g of Phase A was injected into a 100 ml vial.

[0180] Step 2: Following step 1, 6 g of phase B was injected into phase A using a 10 ml syringe attached to a 12 G catheter to generate a spherical solid drug delivery system in situ.

[0181] [Example 13] [Table 11]

[0182] Preparation of Phase A: Carbopol was dispersed in water while mixing with an overhead stirrer at 400 rpm to form a thin lump-free suspension dispersion. In a separate container, TRIS base was dissolved in a portion of the water. The solution was added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A gel was obtained.

[0183] Preparation of phase B Use a water bath and hot plate to keep the temperature at 70-75°C throughout the entire process. 0 Phase B was prepared in C.

[0184] Each component was added with mixing at approximately 200 rpm until completely dissolved. The heat was turned off and the resulting solution was transferred to a 5 g syringe and allowed to cool to room temperature.

[0185] Formation of in situ drug delivery systems: Step 1: Using a 50 ml syringe attached to a 12 G catheter, 50 g of Phase A was injected into a 100 ml vial.

[0186] Step 2: Following step 1, 50 0 4 g of phase B, preheated to C, was injected into phase A using a 5 ml syringe attached to a 12 G catheter to generate a solid drug delivery system in situ.

[0187] [Example 14] In vivo testing The in vivo mean plasma concentration of oxybutynin from the biphasic composition of Example 13 was studied. 50g of Phase A was injected into each bladder of two female domestic pigs, and then 5g of Phase B was injected into each animal. Blood samples were taken during the 10-day experiment. LC-MS-MS analytical method was used to measure the plasma concentration of oxybutynin and its active metabolite N-desethyloxybutynin.

[0188] The results are shown in Figure 6, which shows the release profile of oxybutynin entrapped in the in situ generated 3-d mass structures over the course of a 10 day experiment. As can be seen, continuous release of oxybutynin was achieved in vivo for at least 10 days using the biphasic composition of the present invention, while N-desethyloxybutynin plasma concentrations were very low and undetectable after several days.

[0189] [Example 15] -Clinical Trials The clinical safety and efficacy of the following compositions were studied in patients suffering from interstitial cystitis / bladder pain syndrome (IC / BPS):

[0190] [Table 12]

[0191] Creating a Phase Carbopol was dispersed in a portion of the water while mixing with an overhead stirrer at 400 rpm to form a thin lump-free suspension dispersion. In a separate container, 2-dimethylaminoethanol was added to the remaining amount of water. The solution was added to the Carbopol dispersion while mixing with an overhead stirrer at 400 rpm. A gel with a viscosity of 2660 cPs was obtained and sterilized.

[0192] Preparation of phase B DMSO was heated to 70-80 °C in a beaker using a silicon oil bath and hot plate. PLGA was added and stirred continuously at approximately 200 rpm with an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture was obtained. Heating was turned off and the remaining ingredients were added one at a time with stirring at approximately 200 rpm until dissolved. A viscous liquid mixture was obtained and sterilized.

[0193] Clinical Trials The purpose of this study was to evaluate the safety and efficacy of the composition described in Example 15 in patients with interstitial cystitis / bladder pain syndrome (IC / BPS) in a single-center, single-arm study. The study protocol and informed consent were approved by the Institutional Review Board of the participating medical institution. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice.

[0194] The study consisted of four weekly injections (1x per week). During screening, all IC / BPS patients were diagnosed according to the American Urological Association (AUA) guidelines. All IC / BPS patients reported symptoms of at least 6 weeks duration prior to treatment. All patients had previously failed other treatments and suffered from symptoms for many years.

[0195] During the treatment period, prior to administration of the composition, residual urine in the bladder was removed using a urethral catheter. Subsequently, 50 mL of phase A was injected while holding tightly the catheter funnel connected to the syringe containing phase A, and after injection, the syringe was disconnected from the catheter funnel. Immediately, 5 mL of phase B was injected while holding tightly the catheter funnel connected to the syringe containing phase B. After injection, the syringe was disconnected from the catheter funnel and the catheter was removed.

[0196] For efficacy assessment, patients were asked to complete the Numeric Rating Scale (NRS) for bladder pain scoring and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) for quality of life assessment. Urgency was measured by voiding frequency over 24 hours recorded on a voiding log. Efficacy outcomes were reduction from baseline in pain, ICSI score, and NRS score for urgency at EOS.

[0197] patient A total of 10 patients were enrolled and administered the composition of Example 15.

[0198] result Effectiveness Patients tolerated the treatment very well and compliance was as expected. The median reduction in pain, measured by NRS score, was from 7.5 (mean 7, SD 1.63) at pretreatment to 3 (mean 3.4, SD 2.27) at EOS (p = 0.005). The change in median ICSI score was from 27.5 (mean 27.5, SD 4.48) at baseline to 22 (mean 18.9, SD 6.19) at EOS (p = 0.012). The change in median voiding frequency score was from 17.5 (mean 15.9, SD 4.36) at baseline to 10.5 (mean 10.7, SD 4.11) at EOS (p = 0.008).

[0199] [Table 13]

[0200] [Example 16] -Clinical Trials The clinical safety and efficacy of the composition of Example 15 was studied in patients suffering from pain associated with ureteral stent placement following urologic procedures (EUP).

[0201] The purpose of this study was to evaluate the safety and efficacy of the composition from Example 15 in patients suffering from pain associated with ureteral stent placement after urologic procedures (EUP) in a single-center, single-arm study. The study protocol and informed consent were approved by the Institutional Review Board of the participating medical institution. This study was conducted in accordance with the ethical principles based on the Declaration of Helsinki and Good Clinical Practice.

[0202] Patients suffering from pain associated with ureteral stent placement after EUP were treated once. The end-of-study (EOS) visit occurred on day 7 after treatment.

[0203] Patients received a single treatment. Prior to administration of the study drug, residual urine in the bladder was removed using a urethral catheter. 50 mL of phase A was then injected while firmly holding the catheter funnel connected to the syringe containing phase A, and after injection, the syringe was disconnected from the catheter funnel. Immediately, 5 mL of phase B was injected while firmly holding the catheter funnel connected to the syringe containing phase B. After injection, the syringe was disconnected from the catheter funnel and the catheter was removed.

[0204] Efficacy evaluation For efficacy evaluation, patients were asked to complete a Numeric Rating Scale (NRS) for bladder pain scoring.

[0205] Data results were evaluated for statistical significance between the baseline and ESO groups using the Wilcoxon two-sided paired nonparametric statistical test. Statistical evaluation was considered significant at P < 0.05. Statistical analysis was performed using DATAtab (DATAtab Team (2021) DATAtab eU Glaz, Austria, URL https: / / datatab.net / ).

[0206] result Patients.—A total of 16 patients aged above 18 years were enrolled to receive treatment.

[0207] Efficacy evaluation Patients tolerated the treatment very well and met compliance expectations. The median reduction in pain, as measured by NRS score, was from 9 (mean 8.56, SD 1.67) before treatment to 5 (mean 5.06, SD 2.52) at EOS. Statistical significance was p = 0.001.

[0208] [Table 14]

[0209] [Example 17] Clinical Trials The clinical safety and efficacy of the composition of Example 15 was studied in patients suffering from overactive bladder (OAB).

[0210] The purpose of this study was to evaluate the safety and efficacy of the composition from Example 15 in patients suffering from overactive bladder (OAB) in a single-center, single-arm study. The clinical trial protocol and informed consent were approved by the Institutional Review Board of the participating medical institution. The study was conducted in accordance with the ethical principles based on the Declaration of Helsinki and Good Clinical Practice.

[0211] Patients suffering from overactive bladder (OAB) received 4 weeks of infusion (once a week) treatment. Before administration of the study drug, residual urine in the bladder was removed using a urethral catheter. Subsequently, 50 mL of phase A was injected while firmly holding the catheter funnel connected to the syringe containing phase A, and after injection, the syringe was disconnected from the catheter funnel. Immediately, 5 mL of phase B was injected while firmly holding the catheter funnel connected to the syringe containing phase B. After injection, the syringe was disconnected from the catheter funnel and the catheter was removed.

[0212] Efficacy evaluation For efficacy assessment, urgency was measured by voiding frequency over a 24-hour period recorded on a voiding chart.

[0213] PATIENTS:Four patients over the age of 18 were enrolled to receive treatment.

[0214] result Efficacy evaluation The patients tolerated the treatment very well and met compliance expectations. Changes in urination frequency were significant in all four patients (Table 15). One patient reported that enuresis had ceased. Another patient reported that incontinence had ceased.

[0215] [Table 15]

[0216] [Example 18] [Table 16]

[0217] The composition was prepared in a manner similar to that described in Example 1.

[0218] Cytotoxicity (MTT assay) Media samples collected from the in vitro release study of the composition of Example 18 were used to study the cytotoxicity against T24 cell line at different release time intervals.

[0219] 1.0 g of phase B was injected into a vial containing 5.0 g of phase A with a 2 mL syringe connected to a 12 gauge catheter. A bulky solid three-dimensional structure was formed in situ. 10 min after the solid was created, 30 mL of PBS medium was added to the vial. The vial was kept in a rotary shaker at 37°C and 10 rpm. At 3, 24, 48, and 72 hours, the medium was collected and replaced with fresh PBS.

[0220] Cell culture Human bladder cancer T24 cell line 1 cells were cultured in appropriate cell culture medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 units / mL penicillin and 100 μg / mL streptomycin (SKOV-3-luc in McCoy's in MEM + 0.01 mM NEAA). Cells were kept at 37 °C with 5% CO2 and 95% humidity.

[0221] Cytotoxicity (MTT assay) Approximately 5,000 cells / well were seeded into 96-well plates. Cells were allowed to attach overnight and fresh medium containing appropriate dilutions of test compounds was added.

[0222] The cytotoxic activity of the drug released from the composition of Example 18 at time intervals of 3 hours, 24 hours, 48 ​​hours, and 72 hours was tested using MTT assay. Samples from the released medium were incubated for 24 hours. Then, the medium was discarded, and the cells were further treated with 0.5 mg / mL MTT in phosphate buffer solution (PBS) for 1 hour. Finally, the developed dye was dissolved in DMSO, and the absorbance was measured at 570 nm by a microplate reader. The results shown in Figure 7 demonstrate the cytotoxic effect of the sustained release of the drug from the composition of Example 18.

[0223] [Example 19] [Table 17]

[0224] The composition was prepared in a manner similar to that described in Example 1.

[0225] The cytotoxicity of the composition of Example 19 against T24 cell line at different release time intervals was studied using media samples taken from the in vitro release study in a similar manner as described in Example 18.

[0226] The results shown in FIG. 8 demonstrate the cytotoxic effect of sustained release of drug from the composition of Example 19.

[0227] [Example 20] [Table 18]

[0228] The composition was prepared in a manner similar to that described in Example 1.

[0229] The cytotoxicity of the composition of Example 20 against T24 cell line at different release intervals was studied using media samples taken from the in vitro release study in a similar manner as described in Example 18.

[0230] The results shown in FIG. 9 demonstrate the cytotoxic effect of sustained release of drug from the composition of Example 20.

[0231] [Example 21] [Table 19]

[0232] Preparation of Phase A Sodium alginate is dispersed in approximately half the amount of water while mixing with an overhead stirrer at 100 rpm. In a separate container, calcium carbonate is dissolved in the remaining water. This solution is added to the alginate portion while mixing with an overhead stirrer at 100 rpm. A gel is obtained.

[0233] Preparation of phase B Heat the DMSO in a beaker to 70-80 °C using a silicon oil bath and hot plate. Add the PLGA and stir continuously at approximately 200 rpm with an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture is obtained. Turn off the heat and add the remaining ingredients, one at a time, while stirring at approximately 200 rpm until dissolved. A viscous liquid mixture is obtained and sterilized.

[0234] [Example 22] [Table 20]

[0235] The preparation of phases A and B is carried out in a manner similar to that of Example 1.

[0236] [Example 23] [Table 21]

[0237] The preparation of phases A and B is carried out in a manner similar to that of Example 1.

[0238] [Example 24] In vitro release [Table 22]

[0239] The composition was prepared in a manner similar to that described in Example 1.

[0240] The in vitro release of bupivacaine from the composition of Example 24 was studied. 5 g of phase B was injected into a vial containing 70 g of phase A with a 10 ml syringe attached to a 12 gauge catheter. Three-dimensional (3D) amorphous spheroids were formed in situ. The vial was kept in an orbital shaker incubator at 37° C. and 20 revolutions per minute. After 3 hours, 20 mL of artificial urine fluid (AUF) was added to the vial. The vial was kept in an orbital shaker incubator at 37° C. and 20 revolutions per minute during the study. 85 mL samples were taken every 24 hours and replaced with fresh AUF for 14 days. The bupivacaine concentration in the AUF was quantitatively measured by HPLC.

[0241] result: Figure 10 shows the release profile of drug entrapped in 3-d amorphous spheroids generated in situ over the course of a 14 day experiment. As can be seen, continuous release of drug is achieved in vitro using the compositions described herein.

[0242] [Example 25] [Table 23]

[0243] Phases A and B were prepared in the same manner as in Example 2.

[0244] [Example 26] [Table 24]

[0245] Preparation of Phase A: Heat the aqueous phase to 80-90°C. Slowly add the HPMC into the heated water with vigorous stirring. Transfer the hot aqueous dispersion to a cold mixer and mix at 400 rpm to form a lump-free clear solution. A hydrogel is obtained.

[0246] Preparation of phase B: Using a water bath and a hot plate, heat C70-80 in a beaker. 0 Heat to 35°C. Add the PLGA and stir continuously at approximately 200 rpm with an overhead stirrer equipped with a 3-blade impeller until a viscous liquid mixture is obtained. Remove from heat and add the remaining ingredients one at a time with stirring at approximately 200 rpm until dissolved. A viscous liquid mixture is obtained.

[0247] [Example 27] [Table 25]

[0248] Preparation of Phase A: The carbopol and xanthan gum are dispersed in approximately 2 / 3 of the water while mixing with an overhead stirrer at 200 rpm to form a thin lump-free suspension dispersion. In a separate container, the lidocaine base is added to the remaining water. The lidocaine solution is added to the carbopol and xanthan gum dispersion while mixing with an overhead stirrer at 300 rpm. A gel is obtained.

[0249] Preparation of phase B: Heat the PEG 400 in a beaker to 70-80 °C using a silicon oil bath and hot plate. Add the PLGA and stir continuously at approximately 200 rpm with an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture is obtained. Turn off the heat and add the remaining ingredients, one at a time, while stirring at approximately 200 rpm, until dissolved. A viscous liquid mixture is obtained.

[0250] [Example 28] [Table 26]

[0251] Preparation of Phase A: Carbopol is dispersed in approximately 2 / 3 of the water while mixing with an overhead stirrer at 200 rpm to form a thin lump-free suspension dispersion. In a separate container, the TRIS base is added to the remaining water. The TRIS solution is added to the Carbopol dispersion while mixing with an overhead stirrer at 300 rpm. A gel is obtained.

[0252] Preparation of phase B: Heat 70% DMSO to 70-80 °C in a beaker using a silicon oil bath and hot plate. Add PLGA and stir continuously at approximately 200 rpm using an overhead stirrer equipped with a three-blade impeller until a viscous liquid mixture is obtained. Stop heating and allow the mixture to cool to room temperature.

[0253] Approximately 60 minutes prior to intended infusion, mix pembrolizumab with the remaining 30% DMSO. Mix the mixture and combine with the PLGA / DMSO solution.

[0254] During treatment, 70 g of Phase A is injected into the bladder, followed immediately by 5 g of Phase B into Phase A. An in situ amorphous spherule is formed within the bladder.

[0255] The foregoing description of specific embodiments fully reveals the general nature of the invention, which can be easily modified and / or adapted for various specific embodiments by applying current knowledge without undue experimentation and without departing from the general concept, and therefore such adaptations and modifications should be understood and should be understood within the meaning and range of equivalents of the disclosed embodiments. It should be understood that the expressions or terms used herein are for the purpose of description and not limitation. The means, materials, and steps for carrying out the various disclosed functions may take various alternative forms without departing from the invention. It should be understood that further testing is being carried out to establish clinical effectiveness.

Claims

1. 1. A biphasic composition for infusion into the bladder or kidney to deliver an active agent, comprising: a phase A comprising a hydrophilic hydrogel; and 1. A biphasic composition comprising a phase B, Phase B comprises an organic solution, an active agent, and one or more of a hydrophobic polymer, a lipid, or a silicone; A biphasic composition in which a core is formed in situ in the bladder or kidney upon injection of phase B into phase A, the formed core entrapping the active agent and allowing for extended release of the active agent.

2. 10. The biphasic composition of claim 1, wherein Phase A comprises one or more hydrophilic gelling agents selected from the group consisting of carbomer, polyacrylic acid, acrylate polymers, carrageenan, polyvinyl alcohol, polyethylene glycol, sodium polymethylcellulose acylate, hydroxypropyl methylcellulose, chitosan, guar gum, xanthan gum, gelatin, water, and optionally an alkali neutralizing agent.

3. 10. The biphasic composition of claim 1, wherein the hydrophobic polymer in Phase B is polyglycolic acid, polylactic acid, copolymers of polylactic acid (PLA) and polyglycolic acid (PGA), poly(DL-lactide), poly(lactide-co-glycolide), poly(L-lactide), poly(ε-caprolactone), poly(DL-lactide-ε-caprolactone), methacrylic acid-methyl methacrylate copolymer, and any combination thereof.

4. 10. The biphasic composition of claim 1, wherein the organic solution is dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, ethyl acetate, polyethylene glycol, alcohol, propylene glycol, ethyl oleate, oleic acid, a liquid hydrocarbon, and any combination thereof.

5. 10. The biphasic composition of claim 1, wherein the lipid is a wax, beeswax, Witepsol™, lauric acid, cetyl palmitate, a fatty acid, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, or any combination.

6. 10. The biphasic composition of claim 1, wherein the organic solution of Phase B is DMSO.

7. 10. The biphasic composition of claim 1, wherein phase B comprises at least two PLGA copolymers.

8. 8. The biphasic composition of claim 7, wherein the PLGA copolymer has a monomer ratio composition of poly(lactide-co-glycolide) ranging from 50:50 to 85:

15.

9. 9. The biphasic composition of claim 8, wherein the PLGA copolymer has an intrinsic viscosity range of 0.15 to 0.95 dL / g.

10. The biphasic composition of claim 8 , wherein the PLGA copolymer has acid or hydroxy or ester end groups.

11. 9. The biphasic composition of claim 8, comprising 0.1 to 45% w / w PLGA having an intrinsic viscosity in the range of 0.15 to 0.25 dL / g, and 0.1 to 35% w / w PLGA having an intrinsic viscosity in the range of 0.26 to 0.54 dL / g.

12. 9. The biphasic composition of claim 8, comprising 0.1 to 45% w / w PLGA having an intrinsic viscosity in the range of 0.15 to 0.25 dL / g, and 0.1 to 35% w / w PLGA having an intrinsic viscosity in the range of 0.55 to 0.75 dL / g.

13. 10. The biphasic composition of claim 1, wherein the active agent is lidocaine, oxybutynin, an anti-cancer agent, or any combination thereof.

14. 14. The biphasic composition of claim 13, wherein the active agent is selected from the group consisting of mitomycin C, deoxrubicin, valrubicin, cisplatin, gemcitabine, thiotepa, etoglucide (epozil), epirubicin, pirarubicin, apaziquone, docetaxel, and vicinium, and any combination thereof.

15. 14. The biphasic composition of claim 13, wherein the active agent is released continuously for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 30 days or more.

16. 3. The biphasic composition of claim 2, wherein the alkaline neutralizing agent is selected from sodium hydroxide, triethanolamine, diisopropylamine, ammonium hydroxide, 2-dimethylaminoethanol, TRIS base, monoisopropanolamine, or borax.

17. 1. A method for delivering a therapeutic agent into a body cavity of a subject in need thereof, comprising: administering a hydrophilic hydrogel (phase A) to a body lumen of a subject in need thereof; and administering an organic solution of a hydrophobic polymer, a fatty acid, a silicone, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, a silicone, or a wax (phase B) to a hydrophilic hydrogel (phase A), wherein injection of phase B into phase A results in the formation of a core within the internal cavity, and the formed mass entraps the active agent and allows for extended release of the active agent, wherein phase A or phase B or both contain at least one active agent, thereby delivering at least one active ingredient to a body lumen.

18. 17. A method of forming the biphasic composition of any one of claims 1 to 16, comprising: Dispersing a hydrophilic gelling agent in water or any other suitable hydrophilic solvent to obtain phase A; mixing a liquid organic solution of a hydrophobic polymer, a fatty acid, a fatty acid ester, a silicone, a triglyceride, a glyceride, a phospholipid, or a wax until a viscous liquid mixture is obtained, to obtain Phase B; injecting phase B into phase A.

19. A kit comprising a hydrophilic hydrogel, an organic solvent, one or more of a hydrophobic polymer, a fatty acid, a fatty acid ester, a silicone, a triglyceride, a glyceride, a phospholipid, or a wax, and a leaflet that describes the preparation of the biphasic composition in situ.

20. 20. The kit of claim 19, further comprising an active agent.

21. A composition for drug delivery to the bladder comprising 0.1-45% w / w PLGA having an intrinsic viscosity in the range of 0.15-0.25 dL / g, 0.1-35% w / w PLGA having an intrinsic viscosity in the range of 0.26-0.54 dL / g or 0.55-0.75 dL / g, and an active agent.

22. 22. The composition of claim 21, further comprising 0.01-20% povidone, 0.01-0.5% HPMC, 0.1-50% DMSO.

23. 22. The composition of claim 21, wherein the active agent is lidocaine, oxybutynin, an anti-cancer agent, or any combination thereof.

24. 24. The composition of claim 23, wherein the active agent is selected from the group consisting of mitomycin C, deoxrubicin, valrubicin, cisplatin, gemcitabine, thiotepa, etoglucide (epozil), epirubicin, pirarubicin, apaziquone, docetaxel, and vicinium.

25. 24. The composition of claim 23, wherein the oxybutynin is present in a concentration of 0.02 to 5% w / w.

26. 24. The composition of claim 23, wherein the oxybutynin is present in a concentration of 0.01 to 2% w / w.

27. 23. The composition of claim 22, wherein the active agent is released continuously for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 30 days or more.

28. 1. A combination of Phase A and Phase B for preventing / treating a disease or syndrome of the urinary tract, urinary tract or kidney, comprising: The A phase comprises administering a hydrophilic hydrogel (A phase) to the bladder, urinary tract, or kidney of a subject in need thereof; The B phase is administered in the hydrophilic hydrogel (A phase) as an organic solution of an active agent and one or more of a hydrophobic polymer, a fatty acid, a fatty acid ester, a fatty acid ester, a triglyceride, a glyceride, a phospholipid, a silicone, or a wax; Upon injection of phase B into phase A, a core is formed in situ in the urinary tract, urinary tract or kidney, the solid formed allowing for extended release of an active agent, wherein phase A or phase B or both contain at least one active agent, thereby delivering at least one active agent to the bladder, urinary tract or kidney and treating a disease or syndrome of the bladder, urinary tract or kidney.

29. 29. The combination of claim 28, wherein the bladder, urinary tract or kidney disease or syndrome comprises one or more of urinary tract infection, chronic cystitis, overactive bladder, partial bladder obstruction, interstitial cystitis, urethritis, pain and bladder cancer.

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