Materials and methods for treating cancer

Abstract

The present invention relates generally to pharmaceutical compositions, means and methods for the sustained release of therapeutic agents for localized treatment, and in particular to means and methods for the localized treatment of cancer diseases by embedding lyophilized mitomycin C in a sustained-release biocompatible hydrogel that is applied to the affected tissue.

Description

Technical Field

[0001] The present invention generally relates to pharmaceutical compositions, means and methods for the sustained release of therapeutic agents for local treatment. In particular, the present invention relates to means and methods for the local treatment of cancer diseases by embedding lyophilized mitomycin C in a sustained-release biocompatible hydrogel applied to affected tissues.

Background Art

[0002] i. Topical / Local Treatment of Diseases The way in which a drug is delivered can have a major impact on its effectiveness. In many cases, the drug is introduced systemically into the bloodstream, which then delivers the drug via the bloodstream throughout the body. This form of access is widely referred to as systemic treatment. In other cases, more targeted delivery can concentrate the therapeutic effect on the target organ, provide a therapeutic benefit, and avoid side effects. Some drugs have an optimal concentration range in which the maximum benefit is obtained, and concentrations above or below this range can be toxic or may not provide any therapeutic benefit at all. In the context of the present invention, treatment that affects specific tissues or organs by directly accessing them is referred to as topical or local treatment, in contrast to the systemic treatment described above. Sustained release of a drug can typically involve a polymer that releases the drug at a controlled rate, either by diffusion out of the polymer or by dilution of the polymer over time. Topical administration of a drug can change the rate or concentration at which the drug enters the tissue and the pharmacokinetics of the drug, and thus, properly designed materials can optimize the therapeutic effect by increasing the drug level or controlling the drug release rate.

[0003] ii. Drugs Administered Topically Among the drugs that can be administered topically are drugs belonging to the following families: 1. Antineoplastic drugs 2. Chemotherapeutic agents 3. Anti-infective agents (e.g., antibacterial drugs, anti-parasitic drugs, anti-viral drugs) ( 4. Genitourinary drugs 5. Anti-inflammatory products 6. Pain relievers 7. Musculoskeletal agents 8. Drugs that act on the blood and hematopoietic organs (antihemorrhagic agents, antithrombotic agents, anti-anemia drugs) 9. Dermatological medications (antifungal agents, preservatives) 10. Gastrointestinal system (anti-obesity, acid-related disorders)

[0004] The specific characteristics of these cavities require careful consideration in the development of topical drugs suitable for treating diseases within these cavities.

[0005] iii. Chemotherapy - Anticancer drug - Mitomycin C Many chemotherapy (anti-neoplasm) drugs used in cancer treatment bind to DNA, causing synthesis inhibition and strand breaks. In some intravesical infusions, chemotherapy drugs are known to be administered at a dose concentration of approximately 1 mg / ml in 1-2 hour sessions.

[0006] In specific cases of bladder cancer treatment, bladder tissue uptake by chemotherapeutic drugs, a key parameter in treatment efficacy, shows a linear relationship with the concentration of the chemotherapeutic drug (see Gao X, Au JL, Badalament RA, Wientjes MG. Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine. Clin Cancer Res. 1998 Jan;4(1):139-43). Furthermore, chemotherapeutic drug uptake is higher in tumor tissue than in adjacent normal urothelium. Gao et al. demonstrated twice the tissue concentration of mitomycin C (MMC) when injecting 40 mg / 20 ml compared to 20 mg / 20 ml: human bladder tumors had significantly higher MMC tissue uptake than normal bladder tissue.

[0007] The antitumor effect of chemotherapy drugs depends on concentration and exposure time. Schmittgen et al. (see Schmittgen TD, Wientjes MG, Badalament RA, Au JL. Pharmacodynamics of mitomycin C in cultured human bladder tumors. Cancer Res. 1991 Aug 1;51(15):3849-56) demonstrated that in both TCC cell cultures and human bladder tumor tissue cultures, when the exposure time to MMC was shortened, higher concentrations were required to obtain a similar cytotoxic effect.

[0008] The proven conclusion is that maintaining the optimal drug concentration (therapeutic effect) over a longer treatment period will improve treatment efficacy.

[0009] iv. Characteristics necessary for local treatment of the bladder and other lumens One approach to treating diseases of internal body cavities such as the bladder is the topical application of therapeutic agents incorporated into appropriate compositions. Such compositions require one or more of the following properties: • Appropriate rheological properties (viscosity, thixotropy, G', G") - necessary for introducing material into the lumen. • Adhesion - To improve drug delivery • Mechanical properties to provide sufficient flexibility - to accommodate the natural changes in the volume and shape of the lumen during treatment. • Biocompatibility • The duration for which the composition remains in the lumen or solid tumor before it completely dissolves / decomposes. • Increased bioavailability of drugs that do not increase toxicity • Appropriate active pharmaceutical ingredient (API) - A medical drug or drug derivative selected from drugs known for use as a topical / local active ingredient. • Good loading of the drug or API in the hydrogel. For specific clinical protocols, the amount and concentration of the drug or API mixed in the hydrogel must be set to a predetermined level. The hydrogel's ability to release drugs in a controlled manner such that the actual drug concentration in the organ tissue or lining is optimized for each treatment. It is precisely the specific composition of the mixture that determines the drug release profile and its adsorption to the target tissue. For example, adding a particular drug at a given concentration provides an increased loading capacity of the composition or improved absorption by the visceral lining. • Drug viability. Hydrogels are designed and tested to ensure that the viability period of the drug or API mixed within the hydrogel is not reduced, so that the amount released throughout the treatment has the optimal therapeutic effect.

[0010] v. Limitations of treatment for superficial bladder cancer (SBC) known in this field SBC is a highly recurrent type of cancer. To reduce recurrence, it is considered necessary to treat patients with a single intravesical chemotherapy infusion immediately after transurethral resection of bladder tumor (TUR-BT).

[0011] A meta-analysis of seven randomized trials (1,476 patients with a median follow-up of 3.4 years) demonstrated that a single intravenous chemotherapy infusion immediately after transcatheter resection (TUR) reduced the relative risk of recurrence by 40% (see Sylvester RJ, Oosterlinck W, van der Meijden AP. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J Urol. 2004 Jun;171(6 Pt 1):2186-90). Timing of infusion is important: in all studies, infusions were administered within 24 hours. The study reported that the risk of recurrence doubled if the initial intravenous infusion was not administered within 24 hours (see Kaasinen E, Rintala E, Hellstrom P, Viitanen J, Juusela H, Rajala P, Korhonen H, Liukkonen T; FinnBladder Group. Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma. Eur Urol. 2002 Aug;42(2):167-74).

[0012] After resection and initial immediate treatment, patients need to be stratified according to their risk of tumor progression and recurrence: • Patients with a low risk of disease progression / recurrence (30%) - no further intravenous infusion is necessary. • Intermediate-risk patients (40-50%) typically receive an additional 6 sessions of mitomycin C (MMC) chemotherapy via intravenous infusion. • High-risk patients (20%) are treated with six intravesical infusions of Bacillus Calmette-Guerin (BCG).

[0013] The effectiveness of current standard local chemotherapy (intravesical infusion) for superficial bladder cancer is limited due to the lack of control over chemotherapy concentration and the time it takes for it to be eliminated. In attempts to extend standard treatment to two hours, some physicians instruct behavioral conditions to reduce bladder acidity, decrease urine output before infusion, and infuse the maximum concentration of chemotherapy dissolved in the minimum volume of saline.

[0014] One object of the present invention is to provide a stable composition comprising a lyophilized pharmaceutical composition containing mitomycin C and an extender, and a hydrogel, more specifically a thermoreversible hydrogel having the following properties: hydrophilic; delivers the drug well to organ tissues in a homogeneous form at sufficiently high drug concentrations (above the therapeutic threshold); is liquid at low temperatures such as about 5°C and semi-solid (non-flowing) at body temperature, and is easily applied; biocompatible; provides continuous release of the therapeutic agent; the rate of release of the therapeutic agent is determined by the concentration of the drug and the degradation / dissolution rate of the hydrogel; and after the hydrogel has degraded / dissolved, it is eliminated from the body by the body's own natural processes.

[0015] A further object of the present invention is to provide a method for treating cancer, such as urinary tract cancer, using the compositions and kits of the present invention, but not limited to these. The reconfigured components of the compositions or kits of the present invention can be applied topically or locally. Topical administration may include administration into body space or body cavity. Topical administration may include administration to or within a tumor.

[0016] A further object of the present invention is to provide rapid reconstitution of mitomycin C in the thermoreversible hydrogel of the present invention, and thus facilitate the preparation of a reconstituted mixture of the components of a composition or kit.

[0017] A further object of the present invention is to provide a composition having increased storage stability, which comprises a thermoreversible hydrogel and a lyophilized pharmaceutical composition containing mitomycin C and a bulking agent.

[0018] A further object of the present invention is to provide a composition having increased solubility, a decreased number of insoluble visible and microscopic particles, and an increased loading capacity, which comprises a thermoreversible hydrogel and a lyophilized pharmaceutical composition containing mitomycin C and a bulking agent.

[0019] A further object of the present invention is to provide a composition in which the amount of main impurities in the composition is reduced, which comprises a thermoreversible hydrogel and a lyophilized pharmaceutical composition containing mitomycin C and a bulking agent. The reduction of impurities brings, among other things, an improvement in the storage stability of the composition containing the thermoreversible hydrogel and the lyophilized mitomycin. This improved stability of the composition of the present invention provides an extension of the period during which the composition can be used, for example, administered or applied to a subject in need thereof.

[0020] When intended for infusion, it is further desirable for the composition to exhibit a specific viscosity profile over different temperatures, enabling infusion at low viscosity, avoiding outflow of the composition from the cavity after infusion and at higher temperatures, and enabling a sufficiently high viscosity to allow for a sufficient residence time within the cavity.

Prior Art Documents

Non-Patent Documents

[0021]

Non-Patent Document 1

Outdoor Tool2

Outdoor Tools3

Outdoor Tools 4

[0022] The present invention, as defined in the claims, is designed to satisfy the above-mentioned objectives. The present invention comprises a series of systems particularly suitable for the local treatment of diseases concentrated in the lumen, combining a biocompatible mucosal adhesive thermoreversible hydrogel with a lyophilized pharmaceutical composition.

[0023] In one embodiment, the present invention relates to a composition comprising a biocompatible mucosal-adhering, thermoreversible hydrogel containing about 15% to about 35% (w / w) of at least one reverse-thermal gelling agent, about 0.01% to about 5% (w / w) of a mucosal-adhering polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the remainder being water, and a therapeutically effective amount of lyophilized pharmaceutical composition containing mitomycin C and a urea-containing bulking agent.

[0024] In another embodiment, the present invention relates to a kit comprising components (a) and (b), wherein component (a) comprises a biocompatible mucosal-adhering, thermoreversible hydrogel comprising about 15% to about 35% (w / w) of at least one inverse heat gelling agent, about 0.01% to about 5% (w / w) of a mucosal-adhering polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the remainder being water, and component (b) comprises a therapeutically effective amount of lyophilized pharmaceutical composition comprising mitomycin C and a urea-containing extender.

[0025] In another aspect, the present invention relates to a lyophilized pharmaceutical composition for use in the treatment of cancers such as urinary tract cancer, comprising mitomycin C and a urea-containing extender in combination with a biocompatible mucosal-adhering, thermoreversible hydrogel containing about 15% to about 35% (w / w) of at least one reverse-thermal gelling agent, about 0.01% to about 5% (w / w) of a mucosal-adhering polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the remainder being water.

[0026] In another embodiment, the present invention relates to a composition for use in the treatment of cancers such as urinary tract cancer.

[0027] In another aspect, the present invention relates to a method for treating cancer such as urinary tract cancer, comprising the step of locally administering a composition according to the present invention into a body cavity such as the urinary tract, or to a subject in need thereof.

[0028] In another embodiment, the present invention relates to a kit for use in the treatment of cancers such as urinary tract cancer.

[0029] In another aspect, the present invention relates to a method for treating cancer such as urinary tract cancer, comprising the steps of: providing components (a) and (b) of a kit according to the present invention; reconstituting component (b) in component (a); and locally administering a reconstituted mixture of component (a) and component (b) into a body cavity such as the urinary tract, or to a subject in need thereof.

[0030] In some aspects, cancer may be located within internal body cavities, such as the urinary tract, GI duct, or intestines, but not limited to these.

[0031] In other embodiments, the present invention relates to a method for treating solid cancer by local administration of a composition according to the present invention to a subject requiring such treatment, for example, by injection into a solid tumor, without limiting the scope of the method.

[0032] In other embodiments, the present invention relates to a method for treating a solid tumor by local administration, for example, by injection into a solid tumor, the method comprising the steps of: providing components (a) and (b) of a kit according to the present invention; reconstituting component (b) in component (a); and locally administering a reconstituted mixture of component (a) and component (b) to a solid tumor of interest requiring the treatment. [Brief explanation of the drawing]

[0033] [Figure 1] Figure 1 shows the mechanical resistance of compositions G and E to a constant shear stress. [Modes for carrying out the invention]

[0034] The following description outlines various aspects of the present invention. Specific details are provided to provide a complete understanding of the invention for illustrative purposes. It will be apparent to those skilled in the art that other embodiments of the invention exist, differing in detail but not affecting the essential nature of the invention. Therefore, the invention is not limited by what is described herein, but only by what is set forth in the appended claims, and the appropriate scope is determined solely by the broadest interpretation of those claims.

[0035] The following definitions are provided in the context of the present invention.

[0036] As used herein, the singular forms "a," "an," and "the" refer to both singular and plural nouns unless explicitly stated otherwise. As used herein, the term “comprising” should be interpreted as encompassing both “including” and “consisting of,” the meanings of which are specifically intended and therefore disclosed separately for the embodiments of the present invention.

[0037] The use of the term "about" and, in general, "range," whether modified by the term "about," means that the number understood is not limited to the exact number described herein, but is intended to refer to the range encompassed by the cited range, as long as it does not deviate from the scope of the invention. Where used herein, "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. Where there is a use of a term that is not clear to those skilled in the art in the context in which it is used, "about" means up to ±10%, e.g., up to ±5%, of a particular term or value.

[0038] As used herein, the term “lumen” is used to describe a part of the body that is accessible through openings such as the mouth, brain, lymph nodes, bladder, intestines, esophagus, rectum, lungs, vagina, stomach, and renal pelvis, or accessible by minimally invasive surgery, such as the pleura, abdomen, peritoneum, and pelvis. The definition includes artificially created or enlarged cavities within adipose tissue accessible by image-guided laparoscopy techniques, and fibrous capsules within viscera, such as the kidneys, heart, and intestines.

[0039] As used herein, the term “therapeutic dose” means the dose, tissue concentration, or plasma concentration of the drug in a subject that provides a specific pharmacological effect when the drug is administered to a subject requiring such treatment. For convenience, exemplary doses, drug delivery amounts, therapeutic doses, and therapeutic levels are provided below for adult subjects. Those skilled in the art can adjust such doses as necessary in accordance with standard practice to treat specific subjects and / or conditions / diseases.

[0040] As used herein, the terms “gel” or “hydrogel” refer to a biocompatible, mucosal-adherent, thermoreversible hydrogel as defined in the present invention, which is liquid at low temperatures (e.g., about 5°C) and solidifies at higher temperatures (above 14°C). Such gels are solid in vivo. The terms “solid” and “semi-solid” are used interchangeably herein. This means that a solid or semi-solid material is a material that is not liquid and therefore cannot flow.

[0041] The terms “drug,” “active ingredient,” “pharmaceutical active ingredient,” “API,” and “therapeutic agent” are used interchangeably herein. Mitomycin C and MMC are used interchangeably in this specification.

[0042] The present invention relates to compositions and kits comprising a biocompatible mucosal-adhering, thermoreversible hydrogel and a lyophilized pharmaceutical composition of mitomycin C. All embodiments listed herein, unless otherwise specified, will be understood to refer to both the compositions and kits according to the present invention, including methods and therapeutic use.

[0043] As described above, one aspect of the present invention is a biocompatible mucosal-adhering, thermoreversible hydrogel comprising about 15% to about 35% (w / w) of at least one reverse-thermal gelling agent, about 0.01% to about 5% (w / w) of a mucosal-adhering polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the remainder being water, and a therapeutically effective amount of lyophilized pharmaceutical composition comprising mitomycin C and a urea-containing bulking agent.

[0044] A further aspect of the present invention is a kit comprising components (a) and (b), wherein component (a) comprises a biocompatible mucosal-adhering, thermoreversible hydrogel comprising about 15% to about 35% (w / w) of at least one inverse heat gelling agent, about 0.01% to about 5% (w / w) of a mucosal-adhering polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the remainder being water, and component (b) comprises a therapeutically effective amount of a lyophilized pharmaceutical composition comprising mitomycin C and a urea-containing extender.

[0045] A further aspect of the present invention is a lyophilized pharmaceutical composition for use in the treatment of internal coelom cancers, such as urinary tract cancer, or for injection into solid tumors, comprising mitomycin C and a urea-containing extender in combination with a biocompatible mucosal-adhering, thermoreversible hydrogel containing about 15% to about 35% (w / w) of at least one reverse-thermal gelling agent, about 0.01% to about 5% (w / w) of a mucosal-adhering polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the remainder being water.

[0046] Accordingly, the present invention provides a biocompatible, mucosal-adherent, thermoreversible hydrogel with sustained-release properties, mixed with lyophilized mitomycin C (MMC). This hydrogel can be inserted into a body cavity, such as the urinary tract, via a catheter or any other means, but is not limited to this. The hydrogel solidifies within the body cavity, forming a drug reservoir in the intended treatment area, e.g., the bladder or renal pelvis. Diffusion of MMC from the gel and erosion of the gel by urine deliver the drug to the tissue, resulting in high local drug concentrations over a long period, while systemic exposure is low. Thus, this system enhances bioavailability, reduces toxicity, and improves therapeutic efficacy. Furthermore, by loading the hydrogel with a significant concentration of MMC and applying the hydrogel substantially directly over the tumor for an extended period, unresectable tumors in close contact with the hydrogel can be removed.

[0047] The present invention provides the design of such gel compositions based on the characteristics of the lumen to be treated and the specific requirements of the treatment, in order to determine the necessary properties of a hydrogel system that can satisfy all of these requirements.

[0048] The present invention also includes the use of novel compositions and kits for manufacturing pharmaceuticals intended for the treatment and / or prevention of disorders in humans. These pharmaceuticals can be combined with means of administration, thereby enabling the introduction of compositions into body cavities in a minimally invasive manner, providing prolonged and enhanced exposure of cavity tissue to the drug, and thus improving therapeutic efficacy with respect to improved therapeutic effects of the drug and reduced tissue damage. The hydrogels of the present invention are biocompatible and dissolve in body fluids, such as urine, serous fluid, and lymph, and are subsequently excreted from the body. The hydrogels do not occlude cavities, and the body fluids flow within the cavities, adapting to natural changes in volume and shape.

[0049] Mitomycin C (MMC) The purpose of long-term exposure of target tissue to MMCs released from hydrogels is to enhance the efficacy of the drug in local treatment of that target tissue while reducing potential systemic adverse effects on other organs. Specifically, the purpose of long-term exposure of cancer cells to anticancer drug MMCs released from hydrogels is to enhance the efficacy of drugs that kill cancer cells, and therefore potentially reduce the recurrence rate of cancer tumors while reducing the systemic effects of chemotherapy on other parts of the patient's body.

[0050] Depending on the type and location of the cancer, there may be limitations on the amount of biocompatible mucosal-adherent, thermoreversible hydrogel containing MMC that can be applied, for example, due to limited spatial conditions. Furthermore, there may be cancer types that require higher doses of MMC applied via biocompatible mucosal-adherent, thermoreversible hydrogel.

[0051] MMC can be present in the compositions and kits of the present invention in a wide range based on the total weight of the composition. In one embodiment, MMC is present in the composition of the present invention at a concentration of about 0.05 w / v.% to about 1 w / v.% based on the total weight of the composition. In another embodiment, MMC is present in the kit of the present invention at a concentration of about 0.05 w / v.% to about 1 w / v.% based on the total weight of components (a) and (b) of the kit.

[0052] When high doses of MMC are required, it is substantially necessary to provide high concentrations of MMC in a biocompatible, mucosal-adherent, thermoreversible hydrogel. Therefore, there is a need to develop pharmaceutical compositions that exhibit improved solubility within the hydrogel, i.e., compositions that have the potential to effectively increase both the saturation concentration and the MMC concentration in the gel.

[0053] In one embodiment, the saturation concentration of mitomycin C in the biocompatible mucosal-adhering thermoreversible hydrogel is about 4 mg / mL to about 7 mg / mL based on the total weight of the composition. Preferably, the saturation concentration of mitomycin C in the biocompatible mucosal-adhering thermoreversible hydrogel is about 5.2 mg / mL to about 7 mg / mL based on the total weight of the composition. In another embodiment, the saturation concentration of mitomycin C in the biocompatible mucosal-adhering thermoreversible hydrogel is about 4 mg / mL to about 7 mg / mL, preferably about 5.2 mg / mL to about 7 mg / mL, based on the total weight of component (a) and component (b) after reconstitution of the kit according to the present invention.

[0054] MMC: Ratio of bulking agent Preferably, the active ingredient (MMC) is in a freeze-dried form. The active ingredient may be in crystalline and / or amorphous form, or any mixture thereof.

[0055] In one embodiment, mitomycin C and the bulking agent are present in the lyophilized pharmaceutical composition in a ratio of about 1:3 to about 1:20, for example, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:11, about 1:12, about 1:13, about 1:14, about 1:15, about 1:16, about 1:17, about 1:18, about 1:19, or about 1:20. Preferably, mitomycin C and the bulking agent are present in the lyophilized pharmaceutical composition in a ratio of about 1:4 to about 1:15. More preferably, mitomycin C and the bulking agent are present in the lyophilized pharmaceutical composition in a ratio of about 1:6 to about 1:10, for example, about 1:7 to about 1:9. Even more preferably, mitomycin C and the bulking agent are present in the lyophilized pharmaceutical composition in a ratio of about 1:8. It should be understood that any mention of the ratio of MMC to bulking agent refers to the weight ratio.

[0056] The compositions and kits of the present invention include a lyophilized pharmaceutical composition comprising mitomycin C and a urea-containing bulking agent. Preferably, the bulking agent is urea.

[0057] In one embodiment, in addition to MMC, further APIs may be present in the composition or kit of the present invention.

[0058] Drugs that can be administered topically and may be further included in the composition or kit of the present invention include drugs belonging to the following families: 1. Antineoplastic drugs 2. Chemotherapy agents 3. Anti-infective agents (e.g., antibacterial agents, antiparasitic agents, antiviral agents) 4. Anti-inflammatory products 5. Drugs that act on the blood and hematopoietic organs (antihemorrhagic agents, antithrombotic agents, anti-anemia drugs) 6. Anticancer drugs 7. Anesthetics 8. Immunotherapy drugs 9. Vaccine 10. Living cells 11. Survival organisms 12. Growth factors and substances that promote wound healing 13. Immunomodulators

[0059] The present invention provides a biocompatible, mucosal-adherent, thermoreversible hydrogel that releases MMC alone or in combination with other active ingredients (APIs) in a controlled manner over a long period of time. Such a period can last up to 30 hours.

[0060] Furthermore, the compositions of the present invention may provide a specific release profile for MMC. As a non-restrictive example, the average release rate of the active ingredient may vary between 80% in 3 hours and 80% in 24 hours. Preferably, 80% of the MMC is released in about 3 to 12 hours. More preferably, 80% of the MMC is released in about 4 to 8 hours.

[0061] As a guideline, chemotherapy drugs are administered at the highest concentration level tolerable by the patient. Further improvements in efficacy can be achieved by increasing the exposure time to chemotherapy drugs. This invention is designed to achieve this by increasing the residence time of the active drug throughout organs and tissue exposure.

[0062] Longer exposure times for APIs offer clear advantages, and prolonged exposure to APIs in the use of pharmaceuticals with controlled release of (one or more) active ingredients is expected to substantially extend the time frame in which improved treatment can be achieved. The use of the pharmaceutical form of the present invention with controlled release of MMCs is expected to achieve substantially more consistent drug levels, avoid the occurrence of level peaks, and thus improve therapeutic efficacy, for example, and reduce the frequency and intensity of undesirable side effects.

[0063] Furthermore, the use of the compositions and kits of the present invention enables a reduction in the frequency of administration, and therefore results in improved acceptance and compliance by patients.

[0064] Similarly, controlled release of MMCs is expected to extend exposure without increasing side effects or negatively impacting the reliability and safety of the treatment.

[0065] Hydrogel: The hydrogels contained in the compositions and kits of the present invention include at least one inverse heat gelling agent. Preferably, the inverse heat gelling agent is poloxamer. Poloxamers represent a group of tri-block copolymers called PEG-PPG-PEG (PEG = polyethylene glycol and PPG = polypropylene glycol) that produce inverse heat gelling compositions, namely, having the characteristic that viscosity increases with increasing temperature until viscosity decreases again. In particular, poloxamer 407 has a gelling temperature above 10°C but below human body temperature, i.e., 37°C. This property can impart to a composition containing a compound the ability to be injected or infused into a body cavity in a liquid state at low temperatures, and then, when the composition is warmed, solidify into a semi-solid gel that functions as a drug reservoir for optimal delivery to the inner wall of the body cavity.

[0066] The hydrogel of the present invention provides uniform delivery and continuous release of a therapeutic agent onto the inner surface of an internal body cavity.

[0067] In general, the hydrogel of the present invention can be applied directly to various internal body cavities, including the bladder, mouth, nose and sinuses, gallbladder, esophagus, rectum, lungs, vagina, uterus, stomach, renal pelvis, pleura, abdomen, peritoneum, pelvis, liver, kidneys, heart, intestines, brain, lymph nodes and spine, for topical treatment, or to solid tumors by injection or any similar means.

[0068] Poloxamer 407 (PF-127) is a nonionic surfactant composed of polyoxyethylene-polyoxypropylene triblock copolymer. Low concentration (10 -4 ~10 -5 At %), they form monomolecular micelles, but at higher concentrations, they produce multimolecular aggregates consisting of a hydrophobic central core and hydrophilic polyoxyethylene chains facing the external medium. While we do not wish to be bound by any theory, micelle formation occurs in dilute solutions of block copolymers in a selected solvent at a given temperature, above the critical micelle concentration. At concentrations higher than the critical gel concentration, micelles can be ordered into a lattice.

[0069] Commonly used poloxamers include poloxamer 188 (F-68 grade), poloxamer 237 (F-87 grade), poloxamer 338 (F-108 grade), and poloxamer 407 (F-127 grade), all of which are freely soluble in water. F-127 has good solubilizing ability and low toxicity, and is therefore considered a good medium for drug delivery systems.

[0070] In one embodiment, at least one poloxamer is selected from poloxamer 188, poloxamer 338, and poloxamer 407. Preferably, at least one poloxamer is poloxamer 407.

[0071] At least one reverse thermal gelling agent is included in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of about 15% to about 35% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel. In a preferred embodiment, the reverse thermal gelling agent is polyxamer 407, and is included in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of about 15% to about 35% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel.

[0072] The compositions and kits of the present invention further comprise polyethylene glycol having an average molecular weight of approximately 300 g / mol to approximately 1000 g / mol. In one embodiment, the polyethylene glycol is PEG-400 or PEG-800. Preferably, the polyethylene glycol is PEG-400.

[0073] Polyethylene glycol having an average molecular weight of approximately 300 g / mol to approximately 1000 g / mol is included in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of approximately 0% to approximately 2.5% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel. Preferably, polyethylene glycol having an average molecular weight of approximately 300 g / mol to approximately 1000 g / mol is included in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of approximately 0.1% to approximately 1.8% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel. In preferred embodiments, the biocompatible mucosal-adhering thermoreversible hydrogel contains approximately 0.1% to approximately 1.8% (w / w) of PEG-400.

[0074] The compositions and kits of the present invention further comprise a mucosal adhesive polymer.

[0075] In one embodiment, the mucosal adhesive polymer is selected from the group consisting of cellulose, microcrystalline cellulose, cellulose derivatives, PVP, vinylpyrrolidone / vinyl acetate copolymer, polyethylene glycol, polyethylene oxide, polymethacrylate, polyvinyl alcohol (PVA), fats and fatty acid derivatives, or any combination thereof. Preferably, the mucosal adhesive polymer is a cellulose derivative. In one embodiment, the cellulose derivative is selected from the group consisting of alkylcellulose, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, carboxymethylcellulose, carbomer, alginate, and combinations thereof.

[0076] Preferably, the cellulose derivative is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), low-substituted hydroxypropyl cellulose (L-HPC), ethylcellulose, and hydroxypropyl methylcellulose acetate succinate (HPMCAS). More preferably, the cellulose derivative is hydroxypropyl methylcellulose (HPMC).

[0077] In one embodiment, the mucosal adhesive polymer includes hydroxypropyl methylcellulose (HPMC). Preferably, the mucosal adhesive polymer is hydroxypropyl methylcellulose (HPMC).

[0078] The mucosal-adhering polymer is contained in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of approximately 0.01% to approximately 5% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel.

[0079] In one embodiment, the mucosal-adhering polymer is contained in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of about 0.01% to about 4.5% (w / w), for example, about 0.01% to about 4% (w / w), about 0.01% to about 3.5% (w / w), about 0.01% to about 3% (w / w), about 0.01% to about 2.5% (w / w), about 0.01% to about 2% (w / w), or about 0.01% to about 1.5% (w / w), based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel. Preferably, the mucosal-adhering polymer is contained in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of about 0.01% to about 1% (w / w), based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel. More preferably, the mucosal-adhering polymer is contained in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of about 0.01% to about 0.5% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel. Even more preferably, the mucosal-adhering polymer is contained in the biocompatible mucosal-adhering thermoreversible hydrogel in an amount of about 0.01% to about 0.3% (w / w) based on the total weight of the biocompatible mucosal-adhering thermoreversible hydrogel.

[0080] In preferred embodiments, the biocompatible, mucosal-adhering, thermoreversible hydrogel contains about 0.01% to about 0.5% (w / w), preferably about 0.01% to about 0.3% (w / w) of hydroxypropyl methylcellulose (HPMC).

[0081] In a preferred embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel comprises about 15% to about 35% (w / w) poloxamer 407, about 0.01% to about 5% hydroxypropyl methylcellulose (HPMC), about 0% to about 2.5% PEG-400, and the remainder being water.

[0082] In another preferred embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel comprises about 15% to about 35% (w / w) poloxamer 407, about 0.01% to about 0.5% hydroxypropyl methylcellulose (HPMC), about 0% to about 2.5% PEG-400, and the remainder being water.

[0083] In another preferred embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel comprises about 20% to about 30% (w / w) poloxamer 407, about 0.1% to about 0.3% hydroxypropyl methylcellulose (HPMC), about 0.1% to about 1.8% PEG-400, and the remainder being water.

[0084] The compositions and kits of the present invention can be adapted for local administration, such as direct injection or intravenous infusion. The compositions and kits of the present invention are preferably adapted for intravesical infusion.

[0085] According to one embodiment of the present invention, the hydrogel described herein is (a) Thickening compounds; (b) pH adjusting substances; (c) Solubilizers; and (d) Tight junction modifiers and permeability enhancers It may include at least one additional component selected from the following.

[0086] Thickening compounds include polycarbophil (a polymer of acrylic acid crosslinked with divinyl glycol), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP). Similarly, other natural, synthetic, or partially synthetic polymers, such as methylcellulose (MC), hydroxypropylcellulose (HPC), other hydroxyalkylcelluloses and hydroxyalkylmethylcelluloses, carboxymethylcellulose and its salts, polyacrylic acid, polymethacrylate, gelatin, carbopol, starch or starch derivatives, and gums such as guar gum and xanthan gum may also be used.

[0087] pH adjusting agents include acids, bases, and buffers. The addition of these substances allows for the stabilization of the API.

[0088] Preferred solubilizing compounds include PEG, DMSO, diethylene glycol monoethyl ether, and cyclodextrin.

[0089] Examples of tight junction modifiers and permeability enhancers include DMSO, hydrogen peroxide, propylene glycol, oleic acid, cetyl alcohol, benzalkonium chloride, sodium lauryl sulfate, isopropyl myristate, Tween 80, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, sodium lauroyl sarcosinate, sorbitan monolaurate, and methylsulfonylmethane.

[0090] Release rate of MMCs within body cavities The biocompatible, mucosal-adhering, thermoreversible hydrogel according to the present invention, which features controlled release of the active ingredient, preferably has an average release rate of 80% over time intervals of 3 to 24 hours (80% at 3 hours and 80% at 24 hours).

[0091] In a particularly preferred embodiment, mitomycin C is released into internal body cavities such as the urinary tract at a rate of approximately 80% under the following conditions: at body temperature; in a pH range of approximately 4.5 to approximately 8.0; and over a time range of approximately 3 to approximately 24 hours.

[0092] It should be emphasized that the compositions of the present invention having controlled release of the active ingredient refer to all compositions in which the release of the active ingredient is modified, in particular, significantly slower, compared to rapidly-released intravesical fluid solutions containing MMC.

[0093] Preferably, mitomycin C is in a lyophilized form. The lyophilized MMC can be presented in crystalline form, amorphous form, or any mixture thereof.

[0094] According to one embodiment of the present invention, compositions and kits intended for topical use are provided. It is therefore useful to have a device that allows the pharmaceutical composition to be applied to an organ of the body through an opening (either natural or artificial) so that a drug reservoir can be formed in a body cavity using the hydrogel. Such a composition (i) allows for the controlled release of one or more drugs in a body cavity; (b) allows for the stepwise dilution of the hydrogel; and (c) is eliminated from the body within a reasonable period of time.

[0095] The composition of the present invention may further contain, in addition to mitomycin C (MMC), various drugs for more efficient treatment of cancer.

[0096] Viscosity of the composition In one embodiment, the composition of the present invention has a viscosity of less than about 500 mPa·s at a temperature of about 4°C to about 12°C. Preferably, the composition of the present invention has a viscosity of less than about 200 mPa·s at a temperature of about 4°C to about 12°C.

[0097] In one embodiment, the composition of the present invention has a viscosity of about 50 mPa·s to about 1500 mPa·s at a temperature of about 4°C to about 6°C. In one embodiment, the composition of the present invention has a viscosity of less than about 300 mPa·s at a temperature of about 4°C to about 6°C. Preferably, the composition of the present invention has a viscosity of less than about 200 mPa·s at a temperature of about 4°C to about 6°C. In one embodiment, the composition of the present invention has a viscosity of less than about 300 mPa·s at a temperature of about 5°C. Preferably, the composition of the present invention has a viscosity of less than about 200 mPa·s at a temperature of about 5°C.

[0098] In one embodiment, the composition of the present invention has a viscosity of less than 1000 mPa·s at a temperature of about 13°C to about 15°C. In one embodiment, the composition of the present invention has a viscosity of less than 300 mPa·s at a temperature of about 13°C to about 15°C. In one embodiment, the composition of the present invention has a viscosity of less than 200 mPa·s at a temperature of about 13°C to about 15°C. In one embodiment, the composition of the present invention has a viscosity of less than 500 mPa·s, for example, less than 200 mPa·s, at a temperature of about 14°C.

[0099] In one embodiment, the composition of the present invention has a viscosity of about 3000 Pa·s to about 10000 Pa·s at a temperature of about 18°C ​​to about 20°C. In one embodiment, the composition of the present invention has a viscosity of about 3500 Pa·s to about 7000 Pa·s at a temperature of about 18°C ​​to about 20°C. In one embodiment, the composition of the present invention has a viscosity of about 3800 Pa·s to about 6500 Pa·s at a temperature of about 18°C ​​to about 20°C. In one embodiment, the composition of the present invention has a viscosity of about 4000 Pa·s to about 6000 Pa·s at a temperature of about 19°C.

[0100] In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the kit of the present invention has a viscosity of less than 500 mPa·s at a temperature of about 4°C to about 12°C when component (b) is reconstituted in the hydrogel. Preferably, the biocompatible mucosal-adhering thermoreversible hydrogel included in the kit of the present invention has a viscosity of less than 200 mPa·s at a temperature of about 4°C to about 12°C when component (b) is reconstituted in the hydrogel.

[0101] In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of approximately 50 mPa·s to approximately 1500 mPa·s at a temperature of approximately 4°C to approximately 6°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than approximately 300 mPa·s at a temperature of approximately 4°C to approximately 6°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than approximately 200 mPa·s at a temperature of approximately 4°C to approximately 6°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than approximately 300 mPa·s at a temperature of approximately 5°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the kit of the present invention has a viscosity of less than 200 mPa·s at a temperature of about 5°C when component (b) is reconstituted in the hydrogel.

[0102] In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than 1000 mPa·s at a temperature of about 13°C to about 15°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than 300 mPa·s at a temperature of about 13°C to about 15°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than 200 mPa·s at a temperature of about 13°C to about 15°C when component (b) is reconstituted in the hydrogel. In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the present invention kit has a viscosity of less than 500 mPa·s, for example less than 200 mPa·s, at a temperature of about 14°C when component (b) is reconstituted in the hydrogel.

[0103] In one embodiment, the biocompatible, mucosal-adhering, thermoreversible hydrogel included in the kit of the present invention has a viscosity of approximately 3,000 Pa·s to approximately 10,000 Pa·s at a temperature of approximately 18°C ​​to approximately 20°C when component (b) is reconstituted in the hydrogel.

[0104] In one embodiment, the biocompatible, mucosal-adhering, thermoreversible hydrogel included in the kit of the present invention has a viscosity of approximately 3500 Pa·s to approximately 7000 Pa·s at a temperature of approximately 18°C ​​to approximately 20°C when component (b) is reconstituted in the hydrogel.

[0105] In one embodiment, the biocompatible, mucosal-adhering, thermoreversible hydrogel included in the kit of the present invention has a viscosity of approximately 3800 Pa·s to approximately 6500 Pa·s at a temperature of approximately 18°C ​​to approximately 20°C when component (b) is reconstituted in the hydrogel.

[0106] In one embodiment, the biocompatible mucosal-adhering thermoreversible hydrogel included in the kit of the present invention has a viscosity of about 4000 Pa·s to about 6000 Pa·s at a temperature of about 19°C when component (b) is reconstituted in the hydrogel.

[0107] The viscosity of the biocompatible, mucosal-adherent, thermoreversible hydrogel according to the present invention can be determined by conventional methods known in the art, such as using a Brookfield viscometer. For example, viscosity can be tested as a function of temperature using "low viscosity" (LV) and "normal viscosity" (RV) Brookfield viscometers, which include a spindle SC4-14, a thermocouple, and a small sample adapter chamber SC4-6R(P). The viscosity of the LV Brookfield viscometer can be measured using a spindle speed of 100 rpm or 200 rpm at temperatures below the gelation point. The viscosity of the RV Brookfield viscometer can be measured using a spindle speed of 0.1 rpm at temperatures above the gelation point.

[0108] The gelation point can be determined as the temperature at which a rapid increase in viscosity is observed.

[0109] While we do not wish to be bound by any theory, the release of drugs from biocompatible, mucosal, thermoreversible hydrogels is thought to be due to two phenomena that occur simultaneously after the gel is applied to the body: (1) drug diffusion from the gel into an aqueous medium (e.g., urine); and (2) dissolution of the gel itself into an aqueous medium.

[0110] Furthermore, while we do not wish to be bound by any theory, in non-limiting examples of biocompatible mucosal-adhering thermoreversible hydrogels in the context of the present invention, the hydrophilicity of the composition is considered an advantageous feature: it allows the drug to be released essentially, and the polymer composition to gradually dissolve in the urine after the treatment session is completed without leaving any foreign polymer composition residue in a lumen such as the bladder.

[0111] The biocompatible, mucosal-adherent, thermoreversible hydrogel contained in the composition and kit of the present invention has reverse thermal gelling (RTG) properties, allowing it to be injected as a free-flowing, low-viscosity liquid at low temperatures, and forming a gel upon exposure to body temperature. The composition and kit containing the biocompatible, mucosal-adherent, thermoreversible hydrogel and MMC present excellent rheological properties, high bioadhesion ability, and high therapeutic efficacy.

[0112] Gelation point The gelation temperature (gelling point) is one parameter in the design of a composition. It should be such that it allows for delivery of the composition to the target tissue and allows for mixing of components (a) and (b) before infusion and solidification after administration. The gelation temperature is also thought to be related to the strength and dissolution rate of the hydrogel and therefore should be the temperature required for long-term exposure.

[0113] The flexibility of the hydrogel is necessary to allow it to adapt to the volume and shape, as well as natural changes, through the cycles of muscle expansion / contraction or flexion. For example, if the bladder volume is 100 ml when the composition of the present invention is administered intravenously, the bladder volume may increase to 300 ml, or even more, when naturally filled with urine. The composition of the present invention is designed to withstand such expansion and contraction cycles due to its physical strength, which derives from its high viscosity at body temperature (i.e., 4000 Pa·s to about 6000 Pa·s).

[0114] solubility The inventors have surprisingly found that when the bulking agent of a lyophilized pharmaceutical composition containing MMC contains urea, a higher saturation concentration of MMC can be obtained in a biocompatible, mucosal-adhering, thermoreversible hydrogel.

[0115] The composition and reconstituted mixture of components (a) and (b) of the kit according to the present invention is desirable to have better solubility without containing undissolved visible particles and small amounts of microparticles. While we do not wish to be bound by any theory, the inventors believe that the composition and reconstituted mixture according to the present invention, with a reduced number of visible and microparticles, will result in a hydrogel with greater uniformity and higher efficacy.

[0116] The inventors have surprisingly found that a biocompatible, mucosal-adhering, thermoreversible hydrogel, when combined with the lyophilized pharmaceutical composition according to the present invention containing urea as a bulking agent, results in a hydrogel with a significantly reduced number of undissolved visible and microparticles. Visible particles according to the present invention are particles larger than 100 μm. Microparticles according to the present invention should be understood as particles having a size in the range of 1 μm to 100 μm. The number of microparticles can be determined by any conventional means applicable in the art, such as flow imaging microscopy. It is believed that using urea as a bulking agent can significantly reduce the number of visible and microparticles compared to other bulking agents such as mannitol.

[0117] Preferably, the composition according to the present invention, as determined by flow imaging microscopy, has 10,000 or fewer microparticles larger than 10 μm per ml, preferably 9,000 or fewer microparticles larger than 10 μm per ml, and more preferably 8,000 or fewer microparticles larger than 10 μm per ml.

[0118] Preferably, the composition according to the present invention, as determined by flow imaging microscopy, has 5,000 or fewer microparticles larger than 20 μm per ml, preferably 3,000 or fewer microparticles larger than 20 μm per ml, and more preferably 2,000 or fewer microparticles larger than 20 μm per ml.

[0119] Preferably, the composition according to the present invention, as determined by flow imaging microscopy, has 100 or fewer microparticles larger than 50 μm per ml, preferably 80 or fewer microparticles larger than 50 μm per ml, and more preferably 60 or fewer microparticles larger than 50 μm per ml.

[0120] More preferably, the composition according to the present invention, as determined by flow imaging microscopy, has 50 or fewer particles larger than 100 μm per ml, preferably 30 or fewer particles larger than 100 μm per ml, and more preferably 20 or fewer particles larger than 100 μm per ml.

[0121] Preferably, when component (b) of the kit according to the present invention is reconstituted in component (a), the reconstituted mixture, as determined by flow imaging microscopy, has no more than 10,000 microparticles larger than 10 μm per ml, preferably no more than 9,000 microparticles larger than 10 μm per ml, and more preferably no more than 8,000 microparticles larger than 10 μm per ml.

[0122] Preferably, when component (b) of the kit according to the present invention is reconstituted in component (a), the reconstituted mixture, as determined by flow imaging microscopy, has 5,000 or fewer microparticles larger than 20 μm per ml, preferably 3,000 or fewer microparticles larger than 20 μm per ml, and more preferably 2,000 or fewer microparticles larger than 20 μm per ml.

[0123] Preferably, when component (b) of the kit according to the present invention is reconstituted in component (a), the reconstituted mixture, as determined by flow imaging microscopy, has no more than 100 microparticles larger than 50 μm per ml, preferably no more than 80 microparticles larger than 50 μm per ml, and more preferably no more than 60 microparticles larger than 50 μm per ml.

[0124] More preferably, when component (b) of the kit according to the present invention is reconstituted in component (a), the reconstituted mixture, as determined by flow imaging microscopy, has 50 or fewer particles larger than 100 μm per ml, preferably 30 or fewer particles larger than 100 μm per ml, and more preferably 20 or fewer particles larger than 100 μm per ml.

[0125] The present invention also includes the use of novel compositions and kits for manufacturing pharmaceuticals intended for the treatment and / or prevention of disorders in humans.

[0126] In one embodiment, the composition and kit according to the present invention are for use in the treatment of urinary tract cancer.

[0127] In one embodiment, the present invention provides a method for treating urinary tract cancer, comprising the step of administering a composition of the present invention into the urinary tract of a person requiring it.

[0128] In one embodiment, the administration step includes introducing the composition of the present invention into the internal body cavity of the urinary tract, applying the composition to at least a portion of the inner surface of the internal body cavity of the urinary tract, and adhering the composition to the inner surface of the internal body cavity of the urinary tract.

[0129] In one embodiment, the present invention provides a method for treating urinary tract cancer, comprising the steps of: providing components (a) and (b) of the present invention's kit; reconstituting component (b) in component (a); and administering the reconstituted mixture of component (a) and component (b) into the urinary tract of a person requiring it.

[0130] The inventors have surprisingly found that when the extender of the lyophilized pharmaceutical composition of component (b) of the kit of the present invention contains urea, rapid reconstitution of components (a) and (b) can be provided. That is, the reconstitution of component (b) in component (a) takes only 15 minutes or less, for example 10 minutes or less, preferably 7 minutes or less, and more preferably 5 minutes or less. Preferably, component (b) dissolves completely in component (a) in 10 minutes or less, more preferably 7 minutes or less, and even more preferably 5 minutes or less.

[0131] Furthermore, the compositions of the present invention are thought to have excellent stability and produce fewer degradation products. The same applies to the kit according to the present invention after reconstitution of components (a) and (b).

[0132] The reconstituted mixture of components (a) and (b) is stable and, more preferably, can be stored for a certain period before administration to a patient. Surprisingly, the inventors have found that when the bulking agent of the lyophilized pharmaceutical composition containing MMC contains urea, the storage stability increases after the reconstitution of components (a) and (b), and the reconstituted mixture can be stored and used for a longer period. Therefore, the composition according to the present invention also exhibits increased storage stability. In this regard, the inventors have surprisingly found that when the bulking agent of the lyophilized pharmaceutical composition contains urea, the amount of impurities can be reduced compared to other bulking agents such as mannitol. In one embodiment, the composition of the kit according to the present invention and the reconstituted mixture of components (a) and (b) can be stored for up to 48 hours, up to 36 hours, or up to 24 hours.

[0133] In one embodiment, the impurity is selected from 1,2-trans-1-hydroxy-2,7-diaminomitosene, 1,2-cis-1-hydroxy-2,7-diaminomitosene, or a combination thereof. In one embodiment, if these compounds are present, they are present in the composition in an amount of less than 0.5% w / w, preferably less than 0.1% w / w. In one embodiment, if 1,2-trans-1-hydroxy-2,7-diaminomitosene and / or 1,2-cis-1-hydroxy-2,7-diaminomitosene are present in the reconstituted mixture of component (a) and component (b) in an amount of less than 0.5% w / w, preferably less than 0.1% w / w immediately after reconstitution (T=0 hours). In one embodiment, if 1,2-trans-1-hydroxy-2,7-diaminomitocene and / or 1,2-cis-1-hydroxy-2,7-diaminomitocene are present, they are present in the reconstituted mixture of component (a) and component (b) in an amount of less than 0.5% w / w after 8 hours of reconstitution, and preferably 1.0% after 24 hours of reconstitution. Impurities can be determined by any suitable method known in the art, such as high-performance liquid chromatography (HPLC).

[0134] In one embodiment, the administration step includes introducing a reconstituted mixture of component (a) and component (b) into the internal lumen of the urinary tract, applying the reconstituted mixture of component (a) and component (b) to at least a portion of the inner surface of the internal lumen of the urinary tract, and adhering the reconstituted mixture of component (a) and component (b) to the inner surface of the internal lumen of the urinary tract.

[0135] Preferably, the internal body cavity of the urinary tract is the bladder or the upper urinary tract.

[0136] Preferably, the urinary tract cancer is bladder cancer or upper urothelial carcinoma (UTUC).

[0137] The non-limiting examples presented below demonstrate the versatility provided by diverse compositions, whose engineering properties allow for different release profiles, flow characteristics, drip infusion temperatures, coating layer thicknesses, and additional features required by the specific treatment applied to the lumen.

[0138] In one embodiment, a mixture of the composition of the present invention or the reconfigured components (a) and (b) of the kit of the present invention is inserted into an essentially empty bladder using a catheter. The composition is inserted at a low temperature in the range of about 1°C to about 18°C, more preferably in the range of about 10°C to about 18°C, and the viscosity of the material is low enough to flow freely within the bladder. Once the liquid material flows into the bladder, it is naturally heated by body temperature and eventually reaches that temperature. When the temperature of the composition reaches its gelation temperature, it transitions from a liquid phase to a viscous gel phase. The method of the present invention is designed to ensure that the composition delivers an effective amount of the active substance to the tissue.

[0139] The versatility of the compositions of the present invention and the ability to control their physicochemical properties may enable the incorporation and optimization of sustained-release dosing of additional active ingredients desired in chemotherapy treatments, including pain relief and avoidance of inflammation and other undesirable effects. Therefore, in addition to the active ingredient MMC, which acts as an anticancer agent, other drugs such as anesthetics (e.g., lidocaine), coagulants (e.g., proconvertin), anticoagulants (such as heparin), and anti-inflammatory drugs (steroids and non-steroidal) can be incorporated into the gel composition, utilizing the sustained-release effect of various active ingredients for optimal treatment, according to the medical needs of patients with SBC.

[0140] The compositions and kits of the present invention contain MMC as an active ingredient. Specifically, the anticancer drug mitomycin C (MMC) has been experimentally used in an in vitro setting and applied to the bladder wall of animal specimens and in vivo studies. MMC, with or without another API, is released in a controlled manner, and the bladder residence time is up to approximately 30 hours, instead of the habitual 1-2 hours (until urination).

[0141] The present invention is designed to satisfy the requirements of desirable properties for a pharmaceutical composition for the delivery of MMC into internal body cavities, as defined above and in the claims. The properties of the composition of the present invention are as follows: (a) Overcoming / withstanding the highly liquid environment within the lumen, which greatly affects the gel's ability to sustain drug delivery for a considerable period (the gel dissolution rate should be as low as possible to increase the duration of treatment and therefore the therapeutic effect); (b) To gel at a desired temperature (e.g., body temperature) that allows for easy intravenous infusion without the risk of clogging of syringes / medical devices; (c) Having a viscosity low enough to enable catheter-delivered gel infusion and a viscosity high enough to allow for long retention in the lumen (longer residence time). (d) Having sufficient mucosal adhesion to allow for increased local drug delivery, without being too viscous to enable catheter-assisted intravenous infusion despite the highly fluid environment within the urinary tract; (e) Stable for a period of time long enough to effectively deliver the drug to the target area and for a long period of use.

[0142] It will be apparent to those skilled in the art that the embodiments disclosed herein are merely examples of a number of possibilities. Therefore, the embodiments shown herein should not be understood as forming limitations on these features and configurations. Any possible combinations and configurations of the described features can be selected in accordance with the scope of the invention. All embodiments and preferred embodiments described herein in relation to one particular aspect of the invention (e.g., a composition of the invention) are equally applicable to all other aspects of the invention, such as kits, pharmaceutical compositions, uses, and methods according to the present invention.

[0143] The present invention will be further illustrated by the following embodiments, which should not be construed as limiting. [Examples]

[0144] In the following examples, formulations comprising a thermoreversible hydrogel and either i) a lyophilized composition containing MMC and urea as an extender, or ii) a lyophilized composition containing MMC and mannitol as an extender were tested. The thermoreversible hydrogel used in this example contained poloxamer 407 (PF-127) (27.0% w / w); polyethylene glycol, average MW=400 (PEG-400) (1.0% w / w); hydroxypropyl methylcellulose (HPMC) (0.2% w / w); and the remainder (71.8%) was redistilled water.

[0145] A freeze-dried composition containing MMC and mannitol was made up of MMC:mannitol in a 1:2 w / w ratio and was commercially available, for example, from Accord Healthcare.

[0146] Lyophilized compositions containing MMC and urea were prepared according to the method described in U.S. Patent Application No. 2016 / 256391, with the following mitomycin / urea ratio: a)1:4 w / w MMC:Urea b)1:5 w / w MMC:Urea c)1:6 w / w MMC:Urea d)1:8 w / w MMC:Urea e)1:10 w / w MMC:Urea f)1:15 w / w MMC:Urea

[0147] Table 1 summarizes lyophilized compositions containing MMC reconstituted in a thermoreversible hydrogel. Table 1: Lyophilized composition [Table 1]

[0148] The MMC concentration in the hydrogel was 4 mg / mL unless otherwise specified in the following examples. In the following examples, unless otherwise specified, the lyophilized composition containing MMC was reconstituted in a thermoreversible hydrogel according to the following protocol: 2 ml of sterile water for injection was mixed with 4 ml of hydrogel as a pre-wetting solution, the lyophilized composition containing MMC was mixed with the pre-wetting solution, and then 14 mL of hydrogel was added to the mixture.

[0149] Example 1a: Reconstructed visible particles The visible particles were tested in compositions A (reference composition), E, ​​and F after mixing with the hydrogel. The number of visible particles was determined using a FlowCam® instrument (dynamic image analysis). Samples for FlowCam® instrument testing were diluted 1:1 with water before testing. The results are summarized in Table 2. Table 2: Number of visible particles in the composition [Table 2]

[0150] As shown in Table 2, compositions E and F according to the present invention, which contain urea as a bulking agent, showed no visible particles at all compared to composition A.

[0151] Example 1b: Visible particles during retention time at -20°C Compositions A and E were tested after being mixed with hydrogel and stored at -20°C for up to 9 days to obtain visible particles. The number of visible particles was determined by visual observation. The results are summarized in Table 3. Table 3: Visible particles after storage at -20°C [Table 3] NT: Untested

[0152] As shown in Table 3, composition E according to the present invention, which contains urea as a bulking agent, showed no visible particles after storage at -20°C for at least 9 days, while composition A, which contains mannitol as a bulking agent, showed many visible particles after storage for 4 days.

[0153] Regarding solubility and visible particles, composition E has been clearly observed to have a longer retention time during use compared to composition A. Therefore, the storage stability after reconstitution is significantly increased, and the composition can be stored and used for a longer period.

[0154] Example 2: Microparticles The number and distribution of microparticles were tested for composition A (reference composition) and compositions E and G according to the present invention. The number and distribution of microparticles were determined using a FlowCam® instrument (dynamic image analysis). Samples were diluted 2-fold before testing. The results are summarized in Table 4. Table 4: Number of microparticles [Table 4] *A stick is a particle having an aspect ratio (ratio of diameters) of 0.01 to 0.74 and a diameter (area-based diameter) of 7 to 500 μm.

[0155] As shown in Table 4, compositions E and G according to the present invention, which contain urea as a bulking agent, showed significantly fewer microparticles compared to composition A, which contains mannitol as a bulking agent.

[0156] Example 3: Reconstruction time Lyophilized compositions must be reconstituted into solution before patient administration, and in this respect, long reconstitution times are undesirable. Reconstitution time is a very important parameter in the development of lyophilized drugs. Lyophilized compositions containing MMC were reconstituted in a thermoreversible hydrogel according to the following protocol: 2 ml of sterile water for injection was mixed with 4 ml of hydrogel as a pre-wetting solution, the lyophilized composition containing MMC was mixed with the pre-wetting solution, and then 14 ml of hydrogel was added to the mixture. The reconstitution time for composition preparation was estimated as the time it took for substantially all of the mitomycin to dissolve in the gel. Table 5: Reconfiguration time [Table 5]

[0157] As shown in Table 5, composition E, containing urea in a 1:8 (MMC:urea) ratio, exhibits a significantly shorter reconstitution time. This significantly shorter reconstitution time is a crucial parameter for simplifying product use.

[0158] Example 4: Evaluation of impurities The impurities in composition A (reference composition) and compositions E and G according to the present invention were determined.

[0159] The impurities 1,2-trans-1-hydroxy-2,7-diaminomitocene and 1,2-cis-1-hydroxy-2,7-diaminomitocene are generally known impurities of mitomycin that occur in polar solvents.

[0160] The impurities 1,2-trans-1-hydroxy-2,7-diaminomitosene and 1,2-cis-1-hydroxy-2,7-diaminomitosene were tested at a mitomycin concentration of 4 mg / mL in composition A (reference composition) and E according to the present invention, immediately after composition reconstitution (T=0), and after storage at 30°C for 8 hours (T=8 hours) and 24 hours (T=24 hours).

[0161] Lyophilized compositions containing MMC were reconstituted in thermoreversible hydrogels according to the following protocol: 2 ml of sterile water for injection was mixed with 4 ml of hydrogel as a pre-wetting solution, the lyophilized composition containing MMC was mixed with the pre-wetting solution, and then 14 ml of hydrogel was added to the mixture. Impurities were tested using high-performance liquid chromatography (HPLC). The results are summarized in Tables 6 and 7, respectively. Table 6: Impurities in Compositions A and E at T=0, 4 mg / ml MMC [Table 6] Table 7: Impurities in 4 mg / ml MMC of compositions A and E after storage at 30°C for 8 hours and 24 hours. [Table 7]

[0162] As shown in Tables 6 and 7, Composition E of the present invention, which contains urea as a bulking agent, exhibits significantly fewer impurities at T=0, T=8, and T=24 hours after reconstitution compared with Composition A, which contains mannitol as a bulking agent. In particular, the amounts of impurities 1,2-trans-1-hydroxy-2,7-diaminomitocene and 1,2-cis-1-hydroxy-2,7-diaminomitocene are significantly lower in the composition according to the present invention. Therefore, storage stability is significantly improved after reconstitution, and the reconstituted mixture can be stored and used for a longer period. Longer stability after reconstitution is an important parameter that simplifies the use of the product.

[0163] The impurities 1,2-trans-1-hydroxy-2,7-diaminomitocene and 1,2-cis-1-hydroxy-2,7-diaminomitocene were further determined in composition A (reference composition), E and G according to the present invention, at a final MMC concentration of 1.33 mg / mL, immediately after composition reconstitution (T=0), and after storage at 30°C for 8 hours (T=8 hours), 24 hours (T=24 hours), and 48 hours (T=48 hours). The lyophilized composition containing MMC was reconstituted in a thermoreversible hydrogel according to the following protocol: 2 ml of sterile water for injection was mixed with 4 ml of hydrogel as a pre-wetting solution, the lyophilized composition containing MMC was mixed with the pre-wetting solution, and then 14 mL of hydrogel was added to the mixture. Impurities were tested using high-performance liquid chromatography (HPLC). The results are summarized in Table 8. Table 8: Impurities in Compositions A, E, and G, 1.33 mg / ml MMC, stored at T=0 and 30°C for 24 and 48 hours. [Table 8]

[0164] As shown in Table 8, compositions E and G of the present invention, when prepared with an MMC concentration of 1.33 mg / ml, showed fewer impurities compared to composition A at T=0, T=24 hours, and T=48 hours after reconstitution. In particular, the amounts of impurities 1,2-trans-1-hydroxy-2,7-diaminomitocene and 1,2-cis-1-hydroxy-2,7-diaminomitocene were significantly lower. Therefore, by replacing mannitol with urea, storage stability was significantly improved.

[0165] Example 5: Viscosity and gelation temperature The viscosity and gelation temperature of a composition containing urea as a bulking agent according to the present invention were determined and compared with composition A (reference composition) containing mannitol.

[0166] The viscosity of the test compositions was tested as a function of temperature using "low viscosity" (LV) and "normal viscosity" (RV) Brookfield viscometers, including a spindle SC4-14, thermocouple, and miniature sample adapter chamber SC4-6R(P). The viscosity of the LV Brookfield viscometer was measured using spindle speeds of 100 rpm or 200 rpm at temperatures below the gelation point. The viscosity of the RV Brookfield viscometer was measured using a spindle speed of 0.1 rpm at temperatures above the gelation point. The gelation point was determined as the temperature at which a sharp increase in viscosity was observed.

[0167] Table 9 summarizes the viscosity determined at 14°C and 19°C, as well as the gelation temperatures of composition A (reference composition) and compositions B-G. Table 9: Viscosity at 14°C, 19°C, and gelling temperature [Table 9]

[0168] As shown in Table 9, the viscosity and gelation points of compositions A and B-F are in the range of 4600 Pa·s to 5700 Pa·s. The inventors believe that a lower gelation point and higher viscosity contribute to a longer residence time and prolonged exposure to the active ingredients.

[0169] Example 6: Mechanical properties The mechanical resistance to constant shear stress in an aqueous environment was determined for compositions G and E by flow peak hold tests. This test was developed to simulate the stress state of the urinary system and predict the comparative behavior of different compositions within the urinary system. Compositions exhibiting mechanical failure at longer stress times are preferred for use in the urinary system and are expected to provide longer exposure times.

[0170] Using a DHR-1 rheometer (TA-Instruments), a flow peak hold test was applied as a function of time under a constant shear stress of 250 Pa and an axial force of 1 N.

[0171] As shown in Figure 1, the mechanical resistance of composition E to a constant shear stress in an aqueous environment is higher than that of composition G (i.e., it takes longer for mechanical failure to occur, as indicated by a rapid decrease in viscosity). Therefore, surprisingly, it was found that a 1:8 MMC:urea ratio (composition E) results in superior mechanical properties for the hydrogel.

[0172] Example 7: Solubility in Hydrogel The solubility of lyophilized MMC containing urea or mannitol in hydrogels was tested. Lipo-dried MMC was added in excess to the hydrogel (lypo-dried MMC:hydrogel in a 1:2 weight ratio) and stirred at 2-8°C for 1 hour. The particle-free portion of the sample obtained by centrifugation and subsequent filtration through a 0.45 μm filter was analyzed by HPLC.

[0173] The results are summarized in Table 10. Table 10: Solubility of MMC in hydrogel [Table 10]

[0174] As shown in Table 10, composition E of the present invention, which contains urea as a bulking agent, exhibits higher MMC solubility in a thermoreversible hydrogel compared to composition A, which has mannitol as a bulking agent.

Claims

1. a) a biocompatible thermoreversible hydrogel comprising about 15% to about 35% (w / w) of at least one inverse thermogelling agent, about 0.01% to about 5% (w / w) of a mucoadhesive polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the balance water; b) a therapeutically effective amount of a lyophilized pharmaceutical composition comprising mitomycin C and a urea-containing bulking agent; A composition comprising:

2. a) mitomycin C is present in the composition at a concentration of about 0.05% w / v to about 1% w / v, based on the total weight of the composition; and / or b) the saturation concentration of mitomycin C in the biocompatible thermoreversible hydrogel is from about 4 mg / mL to about 7 mg / mL based on the total weight of the composition; or c) the saturation concentration of mitomycin C in the biocompatible thermoreversible hydrogel is about 5.2 mg / g to about 7.0 mg / g based on the total weight of the composition; The composition of claim 1.

3. The composition of claim 1 or 2, wherein mitomycin C and the bulking agent are present in the lyophilized pharmaceutical composition in a ratio of about 1:3 to about 1:20, preferably in a ratio of about 1:4 to about 1:15, more preferably in a ratio of about 1:6 to about 1:10, and even more preferably mitomycin C and the bulking agent are present in the lyophilized pharmaceutical composition in a ratio of about 1:

8.

4. a) the bulking agent is urea; b) said at least one inverse thermal gelling agent comprises a poloxamer, preferably said poloxamer is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 338, and combinations thereof, more preferably said at least one inverse thermal gelling agent is poloxamer 407; c) the biocompatible thermoreversible hydrogel comprises about 0.1% to about 1.8% (w / w) polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol; and / or d) the polyethylene glycol is PEG-400 or PEG-800, preferably PEG-400; Preferably, the biocompatible thermoreversible hydrogel comprises about 0.1% to about 1.8% (w / w) PEG-400. A composition according to any one of claims 1 to 3.

5. a) the biocompatible thermoreversible hydrogel comprises about 0.01% to about 1% (w / w) of a mucoadhesive polymer, preferably about 0.01% to about 0.5% (w / w), more preferably about 0.01% to about 0.3% (w / w); b) the mucoadhesive polymer is selected from the group consisting of cellulose, microcrystalline cellulose, cellulose derivatives, PVP, vinylpyrrolidone / vinyl acetate copolymers, polyethylene glycol, polyethylene oxide, polymethacrylates, polyvinyl alcohol (PVA), fats and fatty acid derivatives, or any combination thereof; Preferably, said mucoadhesive polymer is a cellulose derivative; Optionally, the cellulose derivative is selected from the group consisting of alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, carboxymethyl cellulose, carbomer, alginate, and combinations thereof, or the cellulose derivative is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose (MC), low substituted hydroxypropyl cellulose (L-HPC), ethyl cellulose, and hydroxypropyl methylcellulose acetate succinate (HPMCAS); and / or c) the mucoadhesive polymer comprises hydroxypropyl methylcellulose (HPMC), preferably the mucoadhesive polymer is hydroxypropyl methylcellulose (HPMC); Preferably, the biocompatible thermoreversible hydrogel comprises about 0.01% to about 0.5% (w / w), preferably about 0.01% to about 0.3% (w / w) hydroxypropylmethylcellulose (HPMC); A composition according to any one of claims 1 to 4.

6. adapted for instillation or local administration into a body cavity; and / or In the form of a hydrogel, 6. The composition according to any one of claims 1 to 5.

7. having no more than 5000 microparticles greater than 20 μm per ml, preferably no more than 3000 microparticles greater than 20 μm per ml, more preferably no more than 2000 microparticles greater than 20 μm per ml, as determined by flow imaging microscopy; and / or further comprising 1,2-trans-1-hydroxy-2,7-diaminomitosene and / or 1,2-cis-1-hydroxy-2,7-diaminomitosene, each of which, if present, is present in the composition in an amount of less than 0.5% (w / w); A composition according to any one of claims 1 to 6.

8. 1. A composition for use in the treatment of cancer, comprising: Optionally, the cancer is a urinary tract cancer, preferably the urinary tract cancer is bladder cancer or upper tract urothelial carcinoma (UTUC); A composition according to any one of claims 1 to 7.

9. 9. A composition according to any one of claims 1 to 8 for use in the treatment of cancer, wherein the composition is administered to a subject, intracavity or topically.

10. a) the cancer is a urinary tract cancer, preferably bladder cancer or upper tract urothelial carcinoma (UTUC), and the composition is administered into the urinary tract of a subject in need thereof; and / or b) administering includes introducing the composition into an internal body cavity, such as the urinary tract, and applying the composition to at least a portion of the inner surface of the internal body cavity, such as the urinary tract; Optionally, i) the internal body cavity is the urinary tract, preferably the bladder or upper urinary tract; ii) Administration of mitomycin C is under the following conditions: at body temperature; at a pH range of about 4.5 to about 8.0, and at a rate of about 80% in a time range of about 3 to about 24 hours; and / or further comprising releasing said urinary tract into an internal body cavity; iii) the composition remains within the internal body cavity for at least 4 hours; The composition of claim 9.

11. A kit comprising components (a) and (b), component (a) comprises a biocompatible thermoreversible hydrogel comprising about 15% to about 35% (w / w) of at least one inverse thermogelling agent, about 0.01% to about 5% (w / w) of a mucoadhesive polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the balance water; component (b) comprises a therapeutically effective amount of a lyophilized pharmaceutical composition comprising mitomycin C and a urea-containing bulking agent; Optionally, component (b) is reconstituted in component (a); Further optionally, the reconstitution takes about 15 minutes or less. kit.

12. The kit described in claim 11, wherein component (a) and / or component (b) are defined in any one of claims 3 to 5.

13. and / or upon reconstitution of component (b) in component (a), said reconstituted mixture comprises 1,2-trans-1-hydroxy-2,7-diaminomitosene and / or 1,2-cis-1-hydroxy-2,7-diaminomitosene, respectively, in an amount of less than 0.5% (w / w) after 8 hours of reconstitution, preferably less than 1.0% (w / w) after 24 hours of reconstitution; and / or When component (b) is reconstituted in component (a), the reconstituted mixture has no more than 5000 microparticles greater than 20 μm per ml, preferably no more than 3000 microparticles greater than 20 μm per ml, more preferably no more than 2000 microparticles greater than 20 μm per ml, as determined by flow imaging microscopy.

13. The kit according to claim 11 or 12.

14. A kit for use in the treatment of cancer, preferably urinary tract cancer, comprising: Optionally, the urinary tract cancer is bladder cancer or upper tract urothelial carcinoma (UTUC). A kit according to any one of claims 11 to 13.

15. 15. The kit of any one of claims 11 to 14, for use in the treatment of cancer, the treatment comprising the steps of providing components (a) and (b) of the kit, reconstituting component (b) in component (a), and administering the reconstituted mixture of components (a) and (b) intracavitarily or locally to a subject in need thereof.

16. a) the cancer is a urinary tract cancer, preferably bladder cancer or upper tract urothelial carcinoma (UTUC), and the reconstituted mixture of components (a) and (b) is administered into the urinary tract of a subject in need thereof; and / or b) administering introducing the reconstituted mixture of components (a) and (b) into an internal body cavity, such as the urinary tract; and applying the reconstituted mixture of components (a) and (b) to at least a portion of the interior surface of the internal body cavity; Optionally, i) the internal body cavity is the urinary tract, preferably the upper urinary tract or the bladder; ii) Administration of mitomycin C is under the following conditions: at body temperature; at a pH range of about 4.5 to about 8.0, and at a rate of about 80% in a time range of about 3 to about 24 hours; and / or the step of releasing the composition into said internal body cavity of the urinary tract; iii) the composition remains within the internal body cavity for at least 6 hours; The kit of claim 15.

17. 1. A lyophilized pharmaceutical composition for use in the treatment of cancer comprising mitomycin C and a urea-containing bulking agent in combination with a biocompatible thermoreversible hydrogel comprising about 15% to about 35% (w / w) of at least one inverse thermogelling agent, about 0.01% to about 5% (w / w) of a mucoadhesive polymer, about 0% to about 2.5% (w / w) of polyethylene glycol having an average molecular weight of about 300 g / mol to about 1000 g / mol, and the balance water; Optionally, the cancer is a urinary tract cancer, preferably bladder cancer or upper tract urothelial carcinoma (UTUC); Lyophilized pharmaceutical composition.

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