Methods of treatment and maintenance therapy for bladder cancer using gemcitabine

Abstract

To provide methods of treating urothelial carcinomas of the lower urinary tract.SOLUTION: A method comprises administering gemcitabine continuously and / or locally to the bladder of an individual in an induction therapy and / or maintenance therapy.SELECTED DRAWING: None

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is a sequel to U.S. Provisional Patent Application No. 62 / 583,394, filed November 8, 2017. This application claims the benefit of all claims filed under 18 U.S.C. 61 / 133,511, filed on Oct. 23, 2007, which is incorporated by reference in its entirety for all purposes. . [Background technology]

[0002] Bladder cancer is a significant medical problem and currently available treatment options are inadequate for a number of reasons. Generally, bladder cancer is classified as muscle invasive bladder cancer (MIBC) or non-muscle invasive bladder cancer (NMBC). The pathological classification and staging of bladder cancer are as follows: pTa (urothelial invasion), pTis (high-risk urothelial invasion), and pT1 (lamina propria) pT2 (muscle layer invasion), pT3 (perivesical fat invasion), and pT4 (pelvic organ involvement) Bladder cancer is also classified as grade 1 / 3 (well differentiated), grade 2 / 3 (moderately differentiated), grade Bladder cancer can also be classified by grade, from grade 3 / 3 (poorly differentiated) to grade 4 / 5 (mature). Cancer can be classified according to stage as stage 0 to IV (these stages are Stage 0 is limited to the urothelium, and stage IV is , which refers to cancer that has penetrated the full thickness of the bladder wall, invading adjacent organs or tissues. Bladder cancer is a transitional cell carcinoma of epithelial origin and is confined to the inner lining of the bladder. At initial presentation, most bladder cancers are classified as superficial NMIBC. These include stages pTa, pTis, and pT1 disease. These include T2, pT3, and pT4.

[0003] Radical cystectomy for patients with locally advanced muscle-invasive bladder cancer (MIBC) is the standard treatment, and chemotherapy is administered either before or after surgery (American Cancer Society, 2016b). National comprehen National Cancer Network (NCCN) and European Association The Emergency Urology (EAU) also recommends that patients with MIBC Radiation therapy and chemotherapy (when available) are used as initial potentially curative treatment. C is recommended (NCCN, 2017; Gakis, 2013). For patients who are not candidates for treatment, palliative radiation therapy alone or transurethral resection of the bladder tumor ( Only TURBT is recommended.

[0004] Patients who are not suitable for definitive treatment with curative intent may undergo palliative TURBT with repeated or debulking procedures. These non-cure, undertreated disease pathways attempt to limit the local progression of the disease. Healing strategies also often involve bleeding, blockage, and pain, often requiring repeated first aid. It is used to attempt to alleviate the worsening pathological symptoms caused by invasive tumors.

[0005] U.S. Patent Application Publication Nos. 2012 / 0203203 and 2013 / 0158675; Same No. 2015 / 0360012, Same No. 2015 / 0165177, Same No. 2015 / 0 165178, 2016 / 0199544, WO 2014 / 145638 No. 2015 / 200752 and No. 2011 / 031855 are hereby incorporated by reference. All other references disclosed herein are incorporated by reference in their entirety. The entirety is incorporated by reference. Summary of the Invention [Means for solving the problem]

[0006] In some embodiments, provided herein are methods of providing maintenance therapy to an individual. Maintenance therapy is given after at least one prior therapy and includes gemcitabine is delivered locally to the bladder of the individual, and during one or more delivery periods, the individual is administered The method comprises administering tabine once or twice or more consecutively, each delivery period lasting at least one week. with at least one week (e.g., at least one month) of rest between each delivery period. and the individual has urothelial carcinoma of the lower urinary tract.

[0007] Provided herein is a method for treating urothelial carcinoma of the lower urinary tract in an individual, comprising: The method comprises: a) continuously administering to the individual an effective amount of gemcitabine during an induction period; and b) and continuously administering to the individual an effective amount of gemcitabine during the maintenance phase. is delivered locally to the bladder of the individual, with induction and maintenance phases separated by rest periods, The period is approximately 12 weeks.

[0008] Also provided herein is a method of bladder preservation in an individual, the method comprising: a) an induction phase; b) administering to the individual an effective amount of gemcitabine during a maintenance phase; and and continuously administering gemcitabine to the individual, wherein the gemcitabine is administered locally to the individual's bladder. The induction and maintenance phases are separated by rest periods, and the induction phase lasts approximately 12 weeks. , the individual has urothelial carcinoma of the lower urinary tract.

[0009] In some embodiments, gemcitabine is delivered into the bladder by an intravesical device. In some embodiments, the intravesical device contains about 225 mg of gemcitabine. nothing.

[0010] In some embodiments, each delivery period is 3 weeks. The rest period is about 0 to 3 months (e.g., 3 months).

[0011] In some embodiments, gemcitabine is administered at a dose of about 1 mg / day to about 300 mg / day during the delivery period. In some embodiments, the concentration of gemcitabine in urine is In some embodiments, the urinary The average concentration of mucitabine is approximately 5-20 µg / mL during the delivery period.

[0012] In some embodiments, the individual is ineligible for cisplatin-based chemotherapy or Or rejected it.

[0013] In some embodiments, the individual is unsuitable, ineligible for radical cystectomy, Or rejected it.

[0014] In some embodiments, the individual has muscle-invasive bladder cancer.

[0015] In some embodiments, the individual has non-muscle invasive bladder cancer.

[0016] In some embodiments, the rest period between the induction phase and the maintenance phase is about 1 to 3 months.

[0017] In some embodiments, the maintenance phase comprises two or more gemcitabine delivery periods. In some embodiments, the duration of gemcitabine delivery during the maintenance phase (the "maintenance phase gemcitabine delivery period") (also called 'intervention periods') are separated by a rest period of about one to three months.

[0018] In some embodiments, the maintenance gemcitabine delivery periods are each 1-3 weeks. . [Brief description of the drawings]

[0019] [Figure 1] 1 shows the study protocol described in Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] As used herein, a method for treating urinary tract disease comprising administering gemcitabine locally to the bladder is provided. A method for treating urothelial carcinoma is provided as a maintenance therapy. As used herein, an effective amount of gemcitabine is administered during the induction phase and / or an effective amount of gemcitabine is administered during the maintenance phase. US20100232633A1 - Method for treating urothelial carcinoma of the lower urinary tract comprising locally administering to the bladder a dose of gemcitabine of -1,0 ... In some embodiments, the induction phase is about 2, 3, 4, or 5 or more times. In some embodiments, the delivery period includes two or more delivery periods, such as a delivery period of The periods are consecutive. In some embodiments, between consecutive delivery periods during the induction phase: There is no break or minimum break (e.g., a break of less than one week). In one embodiment, the induction phase includes about four delivery periods (e.g., four consecutive delivery periods), each The delivery period is about 3 weeks (e.g., 18-24 days). In some embodiments, the maintenance phase is: In some embodiments, each delivery period during the maintenance phase lasts for about 3 weeks. In some embodiments, the delivery period during the maintenance phase is between about 18-24 days. The rest period is about 2 months (e.g., about 65 to 75 days). In some embodiments, the urothelial cancer is bladder cancer. In some embodiments, the bladder cancer is muscle invasive bladder cancer. In some embodiments, the bladder cancer is organ-confined, muscle-invasive bladder cancer (non-metastatic MIB C (i.e., M0 MIBC), for example, M0 N0 MIBC). In some embodiments, the bladder cancer is T2 or T3 bladder cancer. The cancer is mostly T2 or T3 M0 bladder cancer (such as T2 or T3M0 N0 MIBC). .

[0021] Radical cystectomy (RC) continues to be used for MIBC (e.g., organ-confined (OC) MIBC) This is the standard treatment for patients who cannot receive curative intent therapy (CIT). The natural history is not well understood. Reasons for inability to undergo CIT are typically , the patient's underlying comorbidities, frailty, and / or age. In these cases, patients are diagnosed with clinical stage T2-T3 M0 (OC) disease, but these patients are treated with CIT. In Sweden, 1997–20 In 2014, he was diagnosed with T2-T4 MIBC and underwent curative intent therapy (e.g., radical cystectomy). Analysis of patients who did not receive chemotherapy or other chemotherapy-induced vasoconstriction revealed that this patient population experienced substantial disease-specific mortality. They were found to have frequent hospitalizations during the final year of their life and to have died primarily from progression of bladder cancer. The present application is directed to patients, particularly those not suitable for undergoing curative intent therapy such as radical cystectomy. A patient population that is unable to tolerate, is unfit for, or unwilling to undergo a voiding urine test, Treating urothelial carcinoma of the urinary tract (e.g., bladder cancer, MIBC (organ-confined MIBC)) For example, the present application provides a method for treating a patient who is not suitable for undergoing radical cystectomy. Frail patients, including elderly patients, who are ineligible or unwilling to receive gemcitabine The study included four consecutive delivery periods, each of which lasted approximately three weeks (e.g., 18 to 24 days). This application demonstrates that these patients are able to tolerate pulmonary therapy well. The study showed that a 50% complete response and 80% response rate were achieved on a protocol-based basis. The method may be used to treat bladder cancer, such as reducing the frequency of hematuria, relieving pain, and / or reducing the severity of previous treatments or symptoms of bladder cancer. It also demonstrates that the drug can effectively improve symptoms associated with current treatments. Preferably, the methods provided provide for sustained efficacy for at least about 100 days following induction therapy. These results demonstrate efficacy and therefore provide the basis for an effective maintenance therapy as described herein. It is being done.

[0022] I. Methods of the Invention As used herein, gemcitabine is administered locally to the bladder multiple times over a period of several months. The present invention provides a method for treating urothelial carcinoma of the lower urinary tract by administering For example, it may be useful as maintenance therapy to prevent recurrence and in bladder-preserving protocols. be.

[0023] As used herein, the terms "continuous" or "continuously" refer to a period of time. Refers to continuous administration of gemcitabine.

[0024] As used herein, the term "individual" refers to a mammal, such as a human. Examples of such animals include, but are not limited to, rats, bovine, equine, feline, canine, rodent, or primate. In some embodiments, the individual is a human.

[0025] Reference herein to "about" a value or parameter relates to the value or parameter itself. For example, "about 21 days" includes 21 days.

[0026] As used herein, the term "about X to Y" has the same meaning as "about X to about Y". .

[0027] As used herein, the term "effective amount" refers to an amount of a compound that is effective to treat a particular disorder, condition, or disease. , e.g., ameliorating, alleviating, reducing, and / or delaying one or more of the symptoms thereof. refers to an amount of a compound or composition sufficient to inhibit or reduce cancer or other unwanted cell proliferation. Thus, an effective amount will shrink the tumor and / or reduce the rate of growth of the tumor (e.g., to inhibit tumor growth) or to prevent or slow other undesirable cell proliferation In some embodiments, an effective amount includes an amount sufficient to slow progression. In some embodiments, an effective amount is an amount sufficient to prevent or delay the onset and / or recurrence of An effective amount is an amount sufficient to cause a cancer to progress. In the case of cancer, an effective amount may be administered in one or more doses. or the composition may (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) To some extent, the infiltration of cancer cells into peripheral organs can be inhibited, delayed, or slowed down. (iv) can inhibit tumor metastasis (i.e., to some extent (v) may inhibit tumor growth; (vi) may slow down or preferably stop tumor growth; may prevent or delay the appearance and / or recurrence of tumors; and / or ii) may alleviate to some extent one or more of the symptoms associated with the cancer.

[0028] In some embodiments, the methods provided herein are intended to improve the quality of life of a patient. For example, the methods provided herein are useful in treating patients who are unable to undergo cystectomy. In some embodiments, the methods described herein may be used to provide chronic treatment to patients with chronic conditions. The methods provided herein can be used as palliative care. Methods of reducing pain in an individual with cancer are provided.

[0029] Medication Regimen The following sections describe various aspects (embodiments) of administration and therapeutic areas, all of which are all apply to the methods described herein.

[0030] In some embodiments, the method described herein includes administering the method after at least one prior therapy. A method of maintenance therapy for an individual is provided, the method comprising administering to the individual a bladder containing a urinary tract infection during a delivery period. In some embodiments, the present invention includes administering gemcitabine continuously and locally. In accordance with the disclosure, a method of providing maintenance therapy to an individual is provided, the maintenance therapy comprising administering to the individual at least one dose of and maintenance therapy is administered to an individual for two or more delivery periods following a prior therapy of gemcitabine. The method includes administering two or more consecutive doses of In some embodiments, the resting periods are separated by about or at least about 1 to 12 months, e.g., at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months , about 6 months, or about 1 year. In some embodiments, the dwell time is about 3 months. In some embodiments, the resting period is about 65-75 days, for example, 68-72 days. In some embodiments, the method described herein includes administering the method after at least one prior therapy. A method of maintenance therapy for an individual is provided, the method comprising administering to the individual two or more consecutive delivery periods The method includes administering gemcitabine sequentially and locally to the bladder of an individual two or more times during the treatment. In some embodiments, two or more consecutive delivery periods are followed by a rest period of about 0 to 12 months. In some embodiments, two or more consecutive delivery periods are followed by a rest period of about 0 to 12 months. In some embodiments, the individual has cT2 or cT3 bladder cancer (cT2 In some embodiments, the individual has organ-confined T3 MIBC. Muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N In some embodiments, the individual has cT2 or cT3 M0 Some patients have MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In embodiments, the individual has responded (complete response, partial response, and / or have stable disease), at least one prior therapy included gemcitabine This includes administering the compound continuously and / or locally to an individual (e.g., to the bladder of an individual). In some embodiments, there is a rest period between the previous therapy and the maintenance therapy. In some embodiments, the rest period between the previous therapy and the maintenance therapy is about or at least about 1 to 12 months. , for example, at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, or about 1 year. In some embodiments, the rest period between the previous therapy and the maintenance therapy is In some embodiments, the individual is Respond (e.g., have a complete response, partial response, and / or stable disease) to prior therapy In some embodiments, the individual is provided with at least one prior therapy. If the patient has a complete response, they are selected for maintenance therapy. , gemcitabine is continuously administered into the individual's bladder for at least one week (e.g., 12 weeks) and locally administering at least one induction phase therapy.

[0031] In some embodiments, provided herein are methods of providing maintenance therapy to an individual. Maintenance therapy is given after at least one prior therapy, and maintenance therapy is given after two or more prior therapy sessions. and administering gemcitabine to the individual two or more consecutive times during the delivery period, each delivery period being , separated by rest periods of at least one month, with each delivery period being at least about one week. In some embodiments, each delivery period is about 1 week, 2 weeks, or 3 weeks. In some embodiments, each delivery period is about 3 weeks (e.g., 18-24 days). In an embodiment, the individual has cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, the individual has organ-confined, muscle-invasive bladder cancer (non-metastatic M IBC (i.e., M0 MIBC), for example, M0 N0 MIBC. In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or In some embodiments, the individual has at least All patients had responded to one prior therapy (complete response, partial response, and / or stable disease) At least one prior therapy consisted of continuous and / or localized gemcitabine In some embodiments, the individual is administered Respond (e.g., complete response, partial response, and / or In some embodiments, the individual has stable disease. In some embodiments, if the patient has a complete response to the therapy, the patient is selected for maintenance therapy. Prior response was determined by administering gemcitabine to the individual for at least 1 week (e.g., 12 weeks). The method includes at least one induction phase therapy comprising administering continuously and locally to the bladder of

[0032] In some embodiments, provided herein are methods of providing maintenance therapy to an individual. Maintenance therapy is given after at least one prior therapy, and maintenance therapy is given after two or more prior therapy sessions. and administering gemcitabine to the individual two or more consecutive times during the delivery period, each delivery period being , separated by rest periods of at least one month, with each delivery period being at least about one week. Gemcitabine is delivered locally to the bladder by an intravesical device. In some embodiments, the device contains about 225 mg of gemcitabine. The delivery period is approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, or approximately 6 months of suspension. In some embodiments, the downtime is about 3 months. In embodiments, the individual has cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, the individual has organ-confined, muscle-invasive bladder cancer (non-metastatic MIB C (i.e., M0 MIBC), for example, M0 N0 MIBC). In some embodiments, the individual is diagnosed with cT2 or cT3 M0 MIBC (e.g., In some embodiments, the individual has at least Responded to one prior therapy (complete response, partial response, and / or stable disease) At least one prior therapy consisted of administering gemcitabine continuously and / or locally to the individual. In some embodiments, the individual is administered at least Respond (e.g., complete response, partial response, and / or stable disease) to at least one prior therapy In some embodiments, the individual has at least one prior treatment. In some embodiments, if the patient has a complete response to the therapy, they are selected for maintenance therapy. Prior response may be determined by administering gemcitabine to the bladder of an individual for at least one week (e.g., 12 weeks). At least one induction phase therapy including continuous and local administration to the bladder.

[0033] In some embodiments, maintenance therapy comprises about 225 mg of gemcitabine about every 3 months. In some embodiments, the method comprises administering about 225 mg of gemcitabi The drug is administered about every 3 months for 3, 4, 5, 6, 7 times, or for the life of the individual. In some embodiments, the individual has cT2 or cT3 bladder cancer (cT2 or In some embodiments, the individual has organ-confined, muscle-layer invasive disease. Invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 M In some embodiments, the individual has cT2 or cT3 M0 MIB C (e.g., cT2 or cT3 N0 M0 MIBC). In this study, an individual is considered to have responded (having achieved a complete response, partial response, and / or stable disease) to a previous therapy. The previous therapy may have been continuous and / or local administration of gemcitabine to the individual (e.g. , into the bladder of the individual.

[0034] In some embodiments, maintenance therapy is about 225 mg / kg every two months for about one year. g of gemcitabine to the individual, wherein the gemcitabine is delivered locally to the bladder. In some embodiments, about 225 mg of gemcitabine is administered for about one year. The individual is administered about 225 mg of gemcitabine every three months. In some embodiments, the individual is administered about every 22 months for about one year. 5 mg of gemcitabine is administered to an individual approximately every 5 months for approximately one year. In one embodiment, about 225 mg of gemcitabine is administered to an individual every six months. In some embodiments, the individual has muscle invasive bladder cancer. In some embodiments, the individual has non-muscle invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused chemotherapy. Unfit, ineligible, or refused radical cystectomy. In some embodiments, the individual has cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In some embodiments, the individual is diagnosed with organ-confined muscle-invasive bladder cancer (non-metastatic MIBC ( That is, M0 MIBC), for example M0 N0 MIBC). In embodiments, the individual is diagnosed with cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 In some embodiments, the individual has a history of refractory disease to prior therapy. and the patient responded (e.g., had a complete response, partial response, and / or stable disease) to the previous therapy. Administering gemcitabine continuously and / or locally to the individual (e.g., to the individual's bladder). Includes.

[0035] In some embodiments, the gemcitabine-releasing device comprises about 225 mg of gemcitabine. The device is placed into the individual's bladder for at least one week about every three months for about one year. In some embodiments, the gemcitabine releasing device comprises about 225 mg of gemcitabine. The drug is placed into the individual's bladder for two weeks approximately every three months for approximately one year. In an embodiment, a gemcitabine releasing device containing about 225 mg of gemcitabine is administered for about one year. In some embodiments, the bladder is placed in the individual for three weeks approximately every three months. The gemcitabine-releasing device contains approximately 225 mg of gemcitabine for the lifetime of the individual. The individual is placed in the bladder for three weeks approximately every three months. Having T2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In this condition, an individual is diagnosed with organ-confined, muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0-MIBC)). In some embodiments, an individual has a pulmonary edema, such as M0, N0, IBC, or M1, N2, MIBC. cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MI In some embodiments, the individual has responded (complete response) to a previous therapy. Prior therapy consisted of continuous gemcitabine and / or locally to the individual (e.g., to the bladder of the individual).

[0036] In some embodiments, the method comprises: (i) administering a first gemcitabine-releasing bladder injection into the bladder of the individual; 2. Placing an intravesical (intravesical) device, comprising: The first gemcitabine-releasing intravesical (intravesical) device remains in the bladder. (ii) for about 3 weeks (e.g., 18 to 24 days) ) followed by removing the first gemcitabine-releasing intravesical (intravesical) device; and (ii) i) Approximately 3 months after placement of the first gemcitabine-releasing intravesical (intravesical) device in the bladder placing a second gemcitabine-releasing intravesical (intravesical) device in the individual's bladder. wherein the second gemcitabine-releasing intravesical (intravesical) device remains in the bladder for 3 weeks. and a second gemcitabine-releasing intravesical (intravesical) device delivers approximately 225 mg of gemcitabine. and (iv) removing the second gemcitabine releasing device. In some embodiments, steps i-iv are performed for about 1 year, 2 years, 3 years, or the lifetime of the individual. In some embodiments, the individual is treated with a muscle-invasive bladder transplant, and the treatment is repeated about every three months. In some embodiments, the individual has non-muscle invasive bladder cancer. In an embodiment, the individual is ineligible for or refuses cisplatin-based chemotherapy. In some embodiments, the individual is unfit or ineligible for radical cystectomy. In some embodiments, the individual has or has rejected cT2 or cT3 bladder cancer. (e.g., cT2 or cT3 MIBC). Localized muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g. In some embodiments, the individual has cT2 or cT3 Some people have M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the individual has responded (complete response, partial response, and / or other) to a previous therapy. or have stable disease), prior therapy consisted of gemcitabine administered sequentially and / or locally. This includes administering to the individual (eg, into the bladder of the individual).

[0037] In some embodiments, provided herein are methods of providing maintenance therapy to an individual. Maintenance therapy is given after at least one prior therapy, and maintenance therapy is given after two or more prior therapy sessions. administering gemcitabine to the individual two or more consecutive doses during the period of time required for the administration of gemcitabine is delivered locally to the bladder of the individual, each delivery period being at least about one week, The drug is delivered at a dose of about 15 mg / day to 100 mg / day during the delivery period. In an embodiment, gemcitabine is administered at a dose of about 5 mg / day to about 250 mg / day, about 10 mg / day to about 200 mg / day, about 15 mg / day to about 100 mg / day, or about 15 mg / day to about 50 mg In some embodiments, gemcitabine is delivered at a dose of about 1 mg / day, about 5mg / day, about 10mg / day, about 15mg / day, about 20mg / day, about 23mg / day, about 2 5mg / day, about 30mg / day, about 35mg / day, about 40mg / day, about 45mg / day, about 5 0mg / day, approx. 55mg / day, approx. 60mg / day, approx. 75mg / day, approx. 100mg / day, approx. 125 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, or about 30 0 mg / day. In some embodiments, the rest period is about 3 months. In some embodiments, the individual has responded (has a complete response) to at least one prior therapy. At least one prior therapy was administering mucitabine continuously and / or locally to an individual (e.g., to the bladder of an individual); In some embodiments, the individual is responsive to at least one prior therapy. (e.g., having a complete response, a partial response, and / or stable disease). An individual may be treated with maintenance therapy if the individual has had a complete response to at least one prior therapy. In some embodiments, the prior response is selected from the group consisting of at least one week (e.g., The study involves the continuous and local administration of gemcitabine to the individual's bladder for a period of 12 weeks. This includes at least one induction therapy.

[0038] In some embodiments, provided herein are methods of providing maintenance therapy to an individual. Maintenance therapy is given after at least one prior therapy and includes gemcitabine gemcitabine is administered twice to the individual during two or more delivery periods in which the or more consecutive administrations, each delivery period being at least about one week, and The concentration of gemcitabine in the medicament is about 1 μg / mL to about 10 μg / mL during the delivery period. In some embodiments, the concentration of gemcitabine in the urine during the delivery period is about 1.0 μg / mL to Approximately 100μg / mL, approximately 5.0μg / mL to approximately 90μg / mL, approximately 10μg / mL to approximately 8 0 μg / mL, about 20 μg / mL to about 70 μg / mL, or about 30 μg / mL to about 50 μg / mL In some embodiments, the concentration of gemcitabine in the urine is about 1.0 μg / mL. / mL, approx. 5μg / mL, approx. 10μg / mL, approx. 15μg / mL, approx. 20μg / mL, approx. 25μg / mL, approximately 30μg / mL, approximately 40μg / mL, approximately 50μg / mL, approximately 60μg / mL, about 70 μg / mL, about 80 μg / mL, about 90 μg / mL, or about 100 μg / mL In some embodiments, the rest period is about 3 months. In the example, the individual has cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, the individual has organ-confined, muscle-invasive bladder cancer (non-metastatic MIBC ( i.e., M0 MIBC), for example, M0 N0 MIBC. In embodiments, the individual is diagnosed with cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 In some embodiments, the rest period is about 3 months. In some embodiments, the individual has responded (completely) to at least one prior therapy. At least one prior therapy (e.g., with response, partial response, and / or stable disease) Administering gemcitabine continuously and / or locally to the individual (e.g., to the individual's bladder). In some embodiments, the individual is responsive to at least one prior therapy. (e.g., have a complete response, a partial response, and / or stable disease). In the present study, an individual is considered to have had a complete response to at least one prior therapy. In some embodiments, the prior response is selected for therapy after at least one week (e.g., The study involves the continuous and local administration of gemcitabine to the bladder of an individual for a period of 12 weeks. Includes at least one induction phase therapy.

[0039] In some embodiments, the prior therapy, as described herein, lasts for about 12 weeks. and administering an induction phase therapy comprising continuous and localized delivery of gemcitabine to the individual's bladder. In some embodiments, the delivery comprises four delivery periods (e.g., four consecutive deliveries). In some embodiments, each delivery period is about 3 weeks (e.g., 18-24 days). During the delivery period, the individual's urine The concentration of mucitabine is at least about 0.1 μg / mL (e.g., from about 0.1 μg / mL to about 90 μg / mL). In some embodiments, at least about 1 to 2 out of 3 weeks. Over the course of a week, the average concentration of gemcitabine in urine is approximately 5-20 μg / mL. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the prior therapy includes two or more induction phase therapies. The two or more induction phases are consecutive (i.e., there is no rest period between the two or more induction phases). In some embodiments, there is a rest period between two or more induction phase therapies. In some embodiments, the rest period is about one month to one year. In some embodiments, the resting period is about or at least about 1 month, about 2 months, or about 3 months.

[0040] In some embodiments, the present invention relates to individual administration of gemcitabine for about 12 weeks. Cystectomy (e.g., radical cystectomy), including continuous and localized delivery of Methods for treating muscle invasive bladder cancer in individuals who are unsuitable or ineligible for uterine cancer therapy are provided. In some embodiments, the individual is at least about 70 years old (at least about 70 years old, about In some embodiments, the individual is about 75 years old, about 80 years old, about 85 years old, or about 90 years old. In some embodiments, the individual has a cT2 or cT3 immune system. In some embodiments, the patient has organ-confined MIBC (e.g., N0 M0 MIBC). , the delivery includes four delivery periods (e.g., four consecutive delivery periods), each delivery period lasting approximately In some embodiments, the delivery period is 3 weeks (e.g., 18 to 24 days). Over a period of at least about 1-2 weeks, the individual's urine concentration of gemcitabine is at least The concentration is usually about 0.1 μg / mL (for example, about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the urinary gemcitabine concentration is 0.01 to 0.01% for at least about 1 to 2 weeks out of 3 weeks. The average concentration of tabine is about 5-20 μg / mL. In some embodiments, each delivery period In some embodiments, the method comprises administering about 225 mg of gemcitabine during the In some embodiments, the method further comprises 12 weeks of maintenance therapy following gemcitabine delivery. Generally, there is a rest period of approximately 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the resting period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, the maintenance therapy comprises administering gefitinib or gefitinib for one, two, or more delivery periods. mucitabine is administered continuously and locally to the bladder of an individual about or at least about once, about twice or more. In some embodiments, each delivery period of the maintenance phase comprises about or at least about In some embodiments, the maintenance phase delivery period is about 1 week, about 2 weeks, or about 3 weeks. Approximately 3 weeks, and during the delivery period, the individual The concentration of gemcitabine in urine is at least about 0.1 μg / mL (e.g., about 0.1 μg In some embodiments, during each delivery period of the maintenance phase, , approximately 225 mg of gemcitabine is administered.

[0041] In some embodiments, the method described herein includes at least two induction phase therapies. , in individuals who are not suitable or eligible for cystectomy (such as radical cystectomy) A method of treating intracellular invasive bladder cancer is provided, wherein each induction phase therapy comprises administering gemcitabine for approximately 12 weeks. In some embodiments, the method comprises continuously and locally delivering tabine to the bladder of the individual. The individual has a complete response, a partial response, and / or stable disease after a first induction therapy. In some embodiments, the individual responds to a first or prior induction phase therapy. In some embodiments, the individual has a partial response or stable disease at or after the first When an individual has a partial response or stable disease to one or the previous induction phase therapy, the individual may be administered a second In some embodiments, the individual is at least about 70 years of age (or at least At least about 70 years old, about 75 years old, about 80 years old, about 85 years old, or about 90 years old, etc. In embodiments, the individual has a compromised immune system. In some embodiments, the individual has: Patients with cT2 or cT3 organ-confined MIBC (e.g., N0 M0 MIBC) In some embodiments, the delivery includes four delivery periods (e.g., four consecutive delivery periods). In some embodiments, the delivery period is about 3 weeks (e.g., 18-24 days). During the period, for at least about 1 to 2 weeks out of the 3 weeks, gemcitabine in the individual's urine The concentration of is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). mL) for at least about 1-2 weeks out of the 3 weeks. Therefore, the average concentration of gemcitabine in urine is about 5-20 μg / mL. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In yet another embodiment, the method further includes a maintenance therapy following gemcitabine delivery for about 12 weeks. In some embodiments, there is a rest period of about 12 weeks between the delivery of gemcitabine and the maintenance therapy. In some embodiments, the resting period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, the maintenance therapy is one, two, or more gemcitabine is continuously and locally administered to the bladder of the individual for about or at least about 1 In some embodiments, each delivery period of the maintenance phase comprises administering the For about or at least about 1 week, about 2 weeks, or about 3 weeks. The delivery period of the maintenance phase is about 3 weeks, and during the delivery period, at least about 1 to 2 weeks Over a period of time, the individual's urine will have a concentration of gemcitabine of at least about 0.1 μg / mL (e.g. For example, about 0.1 μg / mL to about 90 μg / mL. During each delivery period, approximately 225 mg of gemcitabine is administered.

[0042] In some embodiments, the present invention relates to at least two induction phase therapies and at least one and at least one maintenance therapy, The present invention provides a method for treating muscle-invasive bladder cancer in individuals who are not eligible or who are unable to receive treatment with the bladder cancer treatment. Each induction regimen involves the continuous and local administration of gemcitabine into the individual's bladder for approximately 12 weeks. In some embodiments, the two or more induction phase therapies are delivered to a maintenance therapy. In some embodiments, the method described herein is for about 12 weeks. Continuous and localized delivery of gemcitabine to the bladder of the individual (e.g., delivery four consecutive delivery periods, each delivery period being approximately three weeks), an individual (e.g., a bladder resection Muscle invasion in individuals who are not suitable or eligible for surgical removal (such as radical cystectomy) Methods for treating bladder cancer are provided, in which an individual is administered induction and maintenance therapy (as described herein). In some embodiments, the induction phase therapy is , including four delivery periods (e.g., four consecutive delivery periods), each delivery period lasting approximately three weeks ( In some embodiments, the delivery period is at least 3 weeks. For at least about 1-2 weeks, the concentration of gemcitabine in the individual's urine is at least about 0. 1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In an embodiment, the concentration of gemcitabine in urine is reduced for at least about 1 to 2 weeks out of 3 weeks. The average concentration is about 5-20 μg / mL. In some embodiments, the average concentration is about 2 25 mg of gemcitabine is administered. In some embodiments, at least one maintenance The therapy comprises continuously administering gemcitabine to the individual's bladder for one, two or more delivery periods. and topically administering about or at least about once, about twice or more. In some embodiments, each delivery period of the maintenance phase lasts for about or at least about 1 week, about 2 weeks, or about 3 weeks. In some embodiments, a rest period (at least about 1 months, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 12 months). In some embodiments, the delivery period of at least one maintenance phase is about 3 weeks, and the delivery period During the study, the individual's urine had a low level of gemcitabine for at least about 1-2 weeks out of the 3-week period. The concentration is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, about 225 mg of gemcitabine is administered during each delivery period of the maintenance phase. Tabine is administered.

[0043] In some embodiments, the present invention relates to individual administration of gemcitabine for about 12 weeks. A method of bladder conservation in an individual is provided, comprising continuously and locally delivering a urinary bladder to the body of the individual. In some embodiments, the individual is at least about 70 years old (at least about 70 years old, In some embodiments, the individual is about 75 years old, about 80 years old, about 85 years old, or about 90 years old. The body has a compromised immune system. In some embodiments, the individual has cT2 or cT3 In some embodiments, the patient has organ-confined MIBC (e.g., N0 M0 MIBC). The delivery includes four delivery periods (e.g., four consecutive delivery periods), each of which is In some embodiments, the delivery period is about 3 weeks (e.g., 18 to 24 days). Over the course of at least about 1-2 weeks, the concentration of gemcitabine in the individual's urine was low. Both are about 0.1 μg / mL (for example, about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the urinary gemcitabine concentration is low for at least about 1-2 weeks out of 3 weeks. The average concentration of cytabine is about 5-20 μg / mL. In some embodiments, each delivery phase About 225 mg of gemcitabine is administered during the treatment. Further comprising about 12 weeks of maintenance therapy following gemcitabine delivery. In this setting, there is a rest period of approximately 12 weeks between gemcitabine delivery and maintenance therapy. In some embodiments, the resting period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, the maintenance therapy comprises administering, during one, two or more delivery periods: Gemcitabine is administered continuously and locally to the bladder of an individual about once or at least about twice or more. In some embodiments, each delivery period of the maintenance phase comprises administering about or at least In some embodiments, the maintenance phase delivery period is about 1 week, about 2 weeks, or about 3 weeks. The delivery period is about 3 weeks, and during the delivery period, for at least about 1 to 2 weeks out of the 3 weeks, The concentration of gemcitabine in the urine of the body is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL). In some embodiments, during each delivery period of the maintenance phase, Approximately 225 mg of gemcitabine is administered.

[0044] In some embodiments, the present invention relates to individual administration of gemcitabine for about 12 weeks. and administering the compound to a subject in need of treatment with bladder cancer. In some embodiments, alleviating the symptoms includes reducing the occurrence of obstruction. In some embodiments, alleviating the symptoms includes reducing hematuria, urinary incontinence, In some embodiments, the administration of Alleviating the pain includes reducing the frequency or severity of the pain. The condition may be about or at least about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 100 days, about 120 days, about 150 days, about 180 days, or about 200 days In some embodiments, the individual is at least about 70 years of age (or at least At least about 70 years old, about 75 years old, about 80 years old, about 85 years old, or about 90 years old, etc. In embodiments, the individual has a compromised immune system. In some embodiments, the individual has: Patients with cT2 or cT3 organ-confined MIBC (e.g., N0 M0 MIBC) In some embodiments, the delivery includes four delivery periods (e.g., four consecutive delivery periods). In some embodiments, the delivery period is about 3 weeks (e.g., 18-24 days). During the period, for at least about 1 to 2 weeks out of the 3 weeks, gemcitabine in the individual's urine The concentration of is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). mL) for at least about 1-2 weeks out of the 3 weeks. Therefore, the average concentration of gemcitabine in urine is about 5-20 μg / mL. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In yet another embodiment, the method further includes a maintenance therapy following gemcitabine delivery for about 12 weeks. In some embodiments, there is a rest period of about 12 weeks between the delivery of gemcitabine and the maintenance therapy. In some embodiments, the resting period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, the maintenance therapy is one, two, or more gemcitabine is continuously and locally administered to the bladder of the individual for about or at least about 1 In some embodiments, each delivery period of the maintenance phase comprises administering the For about or at least about 1 week, about 2 weeks, or about 3 weeks. The delivery period of the maintenance phase is about 3 weeks, and during the delivery period, at least about 1 to 2 weeks Over a period of time, the individual's urine will have a concentration of gemcitabine of at least about 0.1 μg / mL (e.g. For example, about 0.1 μg / mL to about 90 μg / mL. During each delivery period, approximately 225 mg of gemcitabine is administered.

[0045] In some embodiments, the present invention relates to individual administration of gemcitabine for about 12 weeks. The present invention relates to a method for improving the quality of life of individuals with bladder cancer, including the continuous and localized delivery of In some embodiments, improving quality of life is a method for treating bladder cancer. Relieving symptoms associated with hematuria, such as reducing the incidence of obstruction and reducing the frequency and severity of hematuria. reducing the frequency or severity of pain, reducing the frequency or severity of pain, and / or reducing emergency In some embodiments, the symptoms include reducing gemcitabine delivery, etc. About or at least about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 100 days after the start of the treatment Relief is provided for about 120 days, about 150 days, about 180 days, or about 200 days. In some embodiments, the individual is at least about 70 years old (at least about 70 years old, about 75 years old, In some embodiments, the individual is about 80 years old, about 85 years old, or about 90 years old. In some embodiments, the individual has a cT2 or cT3 organ-confined immune system. In some embodiments, the patient has non-stagenic MIBC (e.g., N0 M0 MIBC). The method includes four delivery periods (e.g., four consecutive delivery periods), each delivery period lasting approximately three weeks. In some embodiments, the delivery period is at least 3 weeks (e.g., 18-24 days). For at least about 1-2 weeks, the individual's urine has a concentration of gemcitabine of at least about 0.01 mg / kg. 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In an embodiment, the amount of gemcitabine in urine is about 1 to 2 weeks out of 3 weeks. In some embodiments, the average concentration of is about 5-20 μg / mL during each delivery period. 225 mg of gemcitabine is administered. In some embodiments, the method comprises administering In some embodiments, the method further includes a maintenance therapy following gemcitabine delivery for a period of time. There is a rest period of approximately 12 weeks between the delivery of mucitabine and maintenance therapy. In embodiments, the resting period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, the maintenance therapy comprises administering gemcitate for one, two, or more delivery periods. The bottle is continuously and locally administered to the bladder of the individual about once or at least about twice or more. In some embodiments, each delivery period of the maintenance phase comprises about or at least about 1 week. In some embodiments, the maintenance phase delivery period is about 3 weeks. and for at least about 1-2 weeks out of the 3-week delivery period, The concentration of gemcitabine in In some embodiments, during each delivery period of the maintenance phase, the 25 mg of gemcitabine is administered.

[0046] In some embodiments, the present invention relates to individual administration of gemcitabine for about 12 weeks. In individuals with a history of hematuria, including continuous and localized delivery to the urinary bladder, Methods for treating urothelial carcinoma of the distal ureter are provided. In some embodiments, the hematuria is chronic Some implementations include chronic hematuria, gross hematuria, episodic hematuria, and / or recurrent gross hematuria. In one embodiment, the individual experiences reduced hematuria symptoms (reduced frequency of hematuria and In some embodiments, the individual has at least one inflammatory response after gemcitabine delivery. At least about 3 weeks, about 6 weeks, about 9 weeks, about 12 weeks, about 120 days, about 150 days, about 18 Reduced hematuria symptoms (reduced frequency and / or severity of hematuria) for 0 days or for approximately 200 days In some embodiments, the individual is at least about 70 years old (at least In some embodiments, the patient may be about 70 years old, about 75 years old, about 80 years old, about 85 years old, or about 90 years old. In some embodiments, the individual has a compromised immune system. or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). In an embodiment, the delivery includes four delivery periods (e.g., four consecutive delivery periods), each The delivery period is about 3 weeks (e.g., 18-24 days). In some embodiments, the delivery period is , the concentration of gemcitabine in the individual's urine for at least about 1-2 weeks out of the 3-week period. is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL) In some embodiments, for at least about 1 to 2 weeks out of the 3 weeks, The average concentration of gemcitabine in urine is about 5-20 μg / mL. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. The method further includes a maintenance therapy following gemcitabine delivery for about 12 weeks. In this embodiment, there is a rest period of about 12 weeks between the delivery of gemcitabine and the maintenance therapy. In some embodiments, the resting period is at least about 1 month, about 2 months, or about In some embodiments, the maintenance therapy is one, two, or more deliveries. During the period, gemcitabine is continuously and locally administered to the individual's bladder about or at least about once, about In some embodiments, each delivery period of the maintenance phase is about or In some embodiments, the maintenance phase is at least about 1 week, about 2 weeks, or about 3 weeks. The delivery period is about three weeks, and during the delivery period, the Therefore, the concentration of gemcitabine in the urine of the individual is at least about 0.1 μg / mL (e.g., In some embodiments, each of the maintenance phase During the delivery period, approximately 225 mg of gemcitabine is administered.

[0047] In some embodiments, the present invention relates to individual administration of gemcitabine for about 12 weeks. and administering the compound to the bladder in a continuous and localized manner. In some embodiments, the prevention of progression is from about or at least about 1 The program will last for about a month, about two months, about three months, about four months, about five months, or about six months. In one embodiment, the individual is at least about 70 years old (at least about 70 years old, about 75 years old, about 80 years old, about In some embodiments, the individual is 85 years old, or 90 years old. In some embodiments, the individual has cT2 or cT3 organ-confined MIBC (e.g., In some embodiments, the delivery comprises four deliveries. A period of time (e.g., four consecutive delivery periods), each of which lasts approximately 3 weeks (18-24 days) In some embodiments, the delivery period is at least about 1 to 3 weeks. Over a two-week period, the individual's urine has a concentration of gemcitabine of at least about 0.1 μg / mL. (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, Over at least 1-2 weeks of the 3-week period, the mean urinary concentration of gemcitabine was approximately In some embodiments, about 225 mg of gel is administered during each delivery period. In some embodiments, the method comprises administering about 12 weeks of gemcitabine. In some embodiments, the delivery of gemcitabine further comprises a maintenance therapy administered after the delivery of gemcitabine. There is a rest period of about 12 weeks between the administration and the maintenance therapy. The resting period is at least about 1 month, about 2 months, or about 3 months. In the present study, maintenance therapy involves the administration of gemcitabine to an individual's bladder for one, two, or more delivery periods. This includes administering the composition continuously and locally to the bladder about or at least about once, about twice or more. In some embodiments, each delivery period of the maintenance phase lasts for about or at least about 1 week, about 2 weeks, or In some embodiments, the delivery period of the maintenance phase is about 3 weeks. During the period, for at least about 1 to 2 weeks out of the 3 weeks, gemcitabine in the individual's urine The concentration of is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In some embodiments, during each delivery period of the maintenance phase, about 225 mg of gemcitabine is administered. Cytabine is administered.

[0048] In some embodiments, the method of treating urothelial carcinoma of the lower urinary tract in an individual comprises administering to the individual at least about 1 It involves continuous and localized delivery of gemcitabine to an individual's bladder for a period of two weeks. In some embodiments, the prevention of progression is for about or at least about 1 month, about 2 months, about 3 months, In some embodiments, the individual is administered a 2-month, 3-month, 4-month, 5-month, or 6-month treatment. At least about 70 years old (at least about 70 years old, about 75 years old, about 80 years old, about 85 years old, or about 90 years old, etc. In some embodiments, the individual has a compromised immune system. In embodiments, the individual has cT2 or cT3 organ-confined MIBC (e.g., N0 M0 M In some embodiments, the delivery comprises four delivery periods (e.g., four IBCs). Each delivery period is about 3 weeks (e.g., 18 to 24 days). In some embodiments, the individual is administered for at least about 1-2 weeks out of the 3 week delivery period. The concentration of gemcitabine in the urine of the body is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL). In some embodiments, the concentration is about 100 μg / mL to about 90 μg / mL for at least 3 weeks. In both cases, the average concentration of gemcitabine in urine was approximately 5-20 μg / mL over a period of approximately 1-2 weeks. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In some embodiments, the method is performed after about 12 weeks of gemcitabine delivery. In some embodiments, between the delivery of gemcitabine and the maintenance therapy, In some embodiments, the resting period is at least about 12 weeks. In some embodiments, the maintenance therapy is for about 1 month, about 2 months, or about 3 months. Gemcitabine is continuously and locally administered to the individual's bladder during one, two or more delivery periods. In some embodiments, administering the compound to a patient at least about once, about twice or more. Each delivery period during the maintenance phase is about or at least about 1 week, about 2 weeks, or about 3 weeks. In some embodiments, the delivery period of the maintenance phase is about 3 weeks, and during the delivery period, For at least about 1-2 weeks, the individual's urine concentration of gemcitabine is at least About 0.1 μg / mL (for example, about 0.1 μg / mL to about 90 μg / mL). In some embodiments, about 225 mg of gemcitabine is administered during each delivery period of the maintenance phase. .

[0049] In some embodiments, the present invention relates to at least one A method of maintenance therapy following a previous therapy is provided, the method comprising administering one or two Gemcitabine is continuously and locally administered to the individual's bladder for one or more (e.g., two or more) delivery periods. The present invention includes administering the drug once, twice, or more times (e.g., two or more times) at regular intervals, each delivery period being At least one week, with a rest period of at least one month between each delivery period In some embodiments, the individual is at least about 70 years old (at least about 70 years old, about 75 years old, aged, about 80 years old, about 85 years old, or about 90 years old. In some embodiments, the individual is In some embodiments, the individual has a cT2 or cT3 organ-limited immune system. In some embodiments, the patient has localized MIBC (e.g., N0 M0 MIBC). At least one prior therapy involved continuous and local administration of gemcitabine to the individual's bladder. the regimen comprising four delivery periods (e.g., four consecutive delivery periods); Each delivery period is about 3 weeks (e.g., 18-24 days). During the delivery of the method, the individual's urine The concentration of cytabine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 9 In some embodiments, the concentration is at least about 1-2 weeks out of 3 weeks. Over the course of the treatment, the average concentration of gemcitabine in urine is approximately 5-20 μg / mL. In some embodiments, about 225 mg of gemcitabine is administered during each delivery period. In an embodiment, there is a rest period of about 12 weeks between the previous therapy and the maintenance therapy. In some embodiments, the resting period is at least about 1 month, about 2 months, or about 3 months. In some embodiments, each delivery period of the maintenance phase lasts for about or at least about 1 week, about 2 In some embodiments, the maintenance phase delivery period is about 3 weeks. During the delivery period, the individual's urine will contain the gemcitabine for at least about 1-2 weeks out of the 3-week period. The concentration of cytabine is at least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 9 In some embodiments, during each delivery period of the maintenance phase, the g of gemcitabine is administered.

[0050] In some embodiments, a method of treating urothelial carcinoma of the lower urinary tract in an individual is provided. The method comprises: a) administering an effective amount of gemcitabine continuously into the bladder of an individual during a lead-in period of approximately 12 weeks; and b) administering an effective amount of gemcitabine to the bladder of the individual during a maintenance phase. and administering to the individual a continuous and localized dose to the bladder, the induction and maintenance phases being separated by rest periods. In some embodiments, the resting period is at least about 1 month, about 2 months, , about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, or about 12 months. In some embodiments, the individual is at least about 70 years old (at least about 70 years old, about 75 years old, about 8 years old, In some embodiments, the individual is at or near the age of about 0, about 85, or about 90 years old. In some embodiments, the individual has a cT2 or cT3 organ-confined MI. In some embodiments, the induction phase comprises: The induction phase involves the continuous and local administration of gemcitabine to the individual's bladder, with the administration of four doses of gemcitabine. Includes delivery periods (e.g., four consecutive delivery periods), each lasting approximately 3 weeks (18–2 In some embodiments, the induction phase is delivered for at least 3 weeks. For at least about 1-2 weeks, the concentration of gemcitabine in the individual's urine is at least about 0. 1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL). In an embodiment, the concentration of gemcitabine in urine is reduced for at least about 1 to 2 weeks out of 3 weeks. The average concentration is about 5-20 μg / mL. In some embodiments, the average concentration is about 2 25 mg of gemcitabine is administered. In some embodiments, the rest period is at least In some embodiments, the maintenance therapy is for about 1 month, about 2 months, or about 3 months. Gemcitabine is continuously and locally administered to the individual's bladder during one, two or more delivery periods. In some embodiments, administering the compound to a patient at least about once, about twice or more. Each delivery period during the maintenance phase is about or at least about 1 week, about 2 weeks, or about 3 weeks. In some embodiments, the delivery period of the maintenance phase is about 3 weeks, and during the delivery period, For at least about 1-2 weeks, the individual's urine concentration of gemcitabine is at least About 0.1 μg / mL (for example, about 0.1 μg / mL to about 90 μg / mL). In some embodiments, about 225 mg of gemcitabine is administered during each delivery period of the maintenance phase. .

[0051] In some embodiments, the method of bladder preservation in an individual with urothelial carcinoma of the lower urinary tract is The method includes: a) administering an effective amount of gemcitabine to the bladder of an individual during a lead-in period of about 12 weeks; b) administering to the individual an effective amount of gemcitabine during a maintenance phase. and administering to the individual continuously and locally to the individual's bladder, wherein the induction and maintenance phases are resting. In some embodiments, the resting period is at least about one month, Approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, approximately 9 months, or approximately 12 months In some embodiments, the individual is at least about 70 years old (at least about 70 years old, about 75 years old, aged, about 80 years old, about 85 years old, or about 90 years old. In some embodiments, the individual is In some embodiments, the individual has a cT2 or cT3 organ-limited immune system. In some embodiments, the patient has localized MIBC (e.g., N0 M0 MIBC). The induction phase involves continuous and local administration of gemcitabine to the individual's bladder, and the induction phase involves , including four delivery periods (e.g., four consecutive delivery periods), each delivery period lasting approximately three weeks ( In some embodiments, the induction phase delivery period is 3 weeks. Over a period of at least about 1-2 weeks, the individual's urine concentration of gemcitabine is at least The concentration is usually about 0.1 μg / mL (for example, about 0.1 μg / mL to about 90 μg / mL). In some embodiments, the urinary gemcitabine concentration is 0.01 to 0.01% for at least about 1 to 2 weeks out of 3 weeks. The average concentration of tabine is about 5-20 μg / mL. In some embodiments, each delivery period In some embodiments, the rest period is: In some embodiments, the maintenance treatment is at least about 1 month, about 2 months, or about 3 months. The method comprises administering gemcitabine continuously into the bladder of an individual for one, two or more delivery periods. In some embodiments, the method includes administering the composition of the present invention locally about or at least about once, about twice or more. In this embodiment, each delivery period of the maintenance phase is about or at least about 1 week, about 2 weeks, or about 3 weeks. In some embodiments, the delivery period of the maintenance phase is about 3 weeks, and during the delivery period, Over a period of at least about 1-2 weeks, the concentration of gemcitabine in the individual's urine is low. At least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL) In some embodiments, about 225 mg of gemcitabine is administered during each delivery period of the maintenance phase. It is given.

[0052] In some embodiments, the individual is diagnosed with urothelial cancer of the lower urinary tract (such as bladder cancer, e.g., A method of treating MIBC is provided, the method comprising: a) four successive delivery periods. administering to the individual an effective amount of gemcitabine continuously and locally to the individual's bladder during the induction phase. each delivery period is about three weeks; and b) includes at least two delivery periods. and administering to the individual an effective amount of gemcitabine continuously and locally to the individual's bladder during a maintenance phase including Each delivery period is about 3 weeks, and there is at least one delivery period between two or more delivery periods of the maintenance phase. The induction and maintenance phases each include a rest period of about 2 months. In some embodiments, the individual is separated by a rest period of one month. A method of treating urothelial cancer (such as bladder cancer, e.g., MIBC) is provided, the method comprising: a) administering an effective amount of gemcitabine continuously into the individual's bladder during a loading phase that includes four consecutive delivery periods; and locally administering to an individual, each delivery period being about 3 weeks; and b) A maintenance phase including two or more delivery periods during which an effective amount of gemcitabine is administered continuously and locally to the individual's bladder. each delivery period being about 3 weeks, and two or more maintenance phases being administered topically to the individual; The induction and maintenance phases are approximately 2 months in length, with a rest period of approximately 2 months between each delivery period. In some embodiments, the individual is separated by a 3 month rest period. 70 years old (e.g., at least about 70 years old, about 75 years old, about 80 years old, about 85 years old, or about 90 years old) In some embodiments, the individual has a compromised immune system. The individual has cT2 or cT3 organ-confined MIBC (e.g., N0 M0 MIBC). In some embodiments, during the induction and / or maintenance delivery periods, a 3 week delivery period is provided. Over a period of at least about 1-2 weeks, the concentration of gemcitabine in the individual's urine is At least about 0.1 μg / mL (e.g., about 0.1 μg / mL to about 90 μg / mL) In some embodiments, at least one of the three week delivery periods for the induction and / or maintenance phases is administered. Over at least 1-2 weeks, the average concentration of gemcitabine in urine was approximately 5-20 μg / mL. In some embodiments, the delivery time is about 225 minutes during each induction and / or maintenance phase. g of gemcitabine is administered.

[0053] In some embodiments, the method of bladder preservation in an individual comprises administering an effective amount of gemcitabine to the individual. The method includes administering gemcitabine locally to the individual's bladder for approximately 12 weeks. In some embodiments, the individual has bladder cancer. The method includes administering to the individual an effective amount of gemcitabine, the gemcitabine being administered four times. delivery periods (e.g., four consecutive delivery periods), each of which Approximately 3 weeks (e.g., 18-24 days) and the individual has cT2 bladder cancer. In one embodiment, a method of bladder preservation in an individual comprises administering to the individual an effective amount of gemcitabine. gemcitabine is administered locally to the bladder during four delivery periods (e.g., four consecutive delivery periods). Each delivery period lasts for approximately 3 weeks (e.g., 18 to 24 days), and each delivery period lasts for approximately 2 25 mg of gemcitabine is administered and the individual has cT2 bladder cancer. In this study, an individual was randomized to receive 100 mg / kg / day of bladder cancer treatment, and 100 mg / kg / day of bladder cancer treatment was randomized to receive 100 mg / kg / day of bladder cancer treatment. In some embodiments, the individual has M0, N0, MIBC, etc. , cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIB In some embodiments, two adjacent delivery periods are separated by a rest period. In some embodiments, the resting period is about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or less than 1 day or less.

[0054] In some embodiments, the method of treating urothelial carcinoma of the lower urinary tract in an individual comprises: The method includes administering to the individual a therapeutically effective amount of gemcitabine, the gemcitabine being administered for about 12 weeks. In some embodiments, the method is further comprising the steps of: locally delivering the therapeutic agent to the bladder of an individual, the individual having cT2 bladder cancer. A method of treating urothelial carcinoma of the lower urinary tract in an individual includes administering to the individual an effective amount of gemcitabine. Gemcitabine may be administered for four delivery periods (e.g., four consecutive delivery periods). The drug is delivered locally to the bladder during each delivery period, with each delivery period lasting approximately 3 weeks (e.g., 18 to 24 days) In some embodiments, the individual has cT2 bladder cancer. The method of treating comprises administering to an individual an effective amount of gemcitabine, , delivered locally to the bladder during four delivery periods (e.g., four consecutive delivery periods), The duration is approximately 3 weeks (e.g., 18 to 24 days), and approximately 225 mg of gemcitabi is administered during each delivery period. In some embodiments, the individual is administered a medicament for treatment of bladder cancer. Localized muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g., M In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, two adjacent delivery periods are separated by a rest period. In embodiments, the resting period is about 7 days, about 6 days, about 5 days, about 4 days, about 3 days, about 2 days, or about 1 day. days or less.

[0055] In some embodiments, the methods provided herein include methods of bladder conservation in an individual. In some embodiments, the method described herein can be used as a bladder retention test in an individual. The existing method involves administering to an individual an effective amount of gemcitabine during an induction phase and administering to an individual an effective amount of gemcitabine during a maintenance phase. and administering to the individual an amount of gemcitabine, wherein the gemcitabine is delivered locally to the bladder. The induction and maintenance phases are separated by a rest period, and the induction phase lasts approximately 12 weeks. In some embodiments, the individual does not undergo a radical cystectomy. The resting period is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. In some embodiments, the induction phase comprises administering about 900 mg of gemcitabine to the individual. In some embodiments, the individual has non-muscle invasive bladder cancer. In this condition, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual has cT2 or cT3 bladder cancer (cT2 or cT3 MI). In some embodiments, the individual has organ-confined, muscle-invasive bladder cancer (e.g., BC). Non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 MIBC In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., In some embodiments, the patient has cT1, cT2, or cT3 N0 M0 MIBC. The phase included placement of a gemcitabine-releasing device every 3 weeks for a total of 12 weeks. Each device releases 225 mg of gemcitabine. The suspension period is about 2 to 3 months, for example, about 65 to 75 days, for example, 68 to 27 days. Phase 1: Gemcitabine-releasing drug containing 225 mg of gemcitabine every 3 months for 1 year In some embodiments, the dwell time includes placing the device in the individual's bladder. In some embodiments, the individual responds (has a complete response) to the induction phase therapy. , partial response, and / or stable disease).

[0056] As used herein, a method of bladder conservation in an individual includes administering an effective amount of gemcitabine during an induction phase. and administering to the individual an effective amount of gemcitabine during a maintenance phase. Gemcitabine is delivered locally to the bladder, and the induction and maintenance phases are separated by a rest period. The induction phase is about 12 weeks, and the individual has cT2 bladder cancer. The method of bladder preservation in the body comprises administering to an individual an effective amount of gemcitabine during an induction phase. and administering to the individual during the maintenance phase an effective amount of gemcitabine, wherein the gemcitabine is administered to the bladder. and the induction phase includes four delivery periods (e.g., four consecutive delivery periods). Each delivery period is about 3 weeks (e.g., 18 to 24 days), and the maintenance period is about every 3 months. The induction and maintenance phases are separated by a rest period, and the individual The individual has cT2 bladder cancer. As used herein, the method of bladder preservation in an individual includes administering administering to the individual an effective amount of gemcitabine during the maintenance phase; and administering to the individual an effective amount of gemcitabine during the maintenance phase. and administering gemcitabine locally to the bladder, the induction phase comprising four doses of Includes delivery periods (e.g., four consecutive delivery periods), each lasting approximately three weeks (18-24 days) Approximately 225 mg of gemcitabine is administered during each delivery period, and the maintenance period is 3 to 5 weeks. There are three-week delivery periods each month (i.e., maintenance delivery periods), and during each maintenance delivery period, 225 mg of gemcitabine was administered, with the induction and maintenance phases separated by rest periods. The individual has cT2 bladder cancer. In some embodiments, the maintenance phase is for about 1 year, 2 years, 3 years, 5 years, 10 years, for the life of the individual, or until disease progression or toxicity. In some embodiments, the resting period is about 2 to 3 months, e.g., about 65 to 75 days, e.g., For example, 68 to 72 days. In some embodiments, the rest period is about 3 months. In some embodiments, the individual responds to the induction therapy (complete response, partial response, and In some embodiments, the individual has organ-confined muscle-layer involvement. Invasive bladder cancer (e.g., non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N0 M In some embodiments, the individual has cT2 or cT3 M0 MIB C (e.g., cT2 or cT3 N0 M0 MIBC).

[0057] Also provided herein is a method of treating urothelial carcinoma of the lower urinary tract in an individual, comprising administering to said individual a therapeutically effective amount of The method comprises administering to an individual an effective amount of gemcitabine during an induction phase and administering to an individual an effective amount of gemcitabine during a maintenance phase. and administering to the individual a dose of gemcitabine, wherein the gemcitabine is delivered locally to the bladder. The induction and maintenance phases are separated by a rest period, with the induction phase lasting approximately 12 weeks. In an embodiment, the method of treating urothelial carcinoma of the lower urinary tract in an individual comprises administering to the individual an effective amount of the compound during the induction phase. administering to the individual an effective amount of gemcitabine during the maintenance phase; and administering to the individual an effective amount of gemcitabine during the maintenance phase. and administering gemcitabine to the bladder, wherein the induction and maintenance phases are paused. The induction period is separated by periods of about 84 days. In some embodiments, the rest period is , 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. In some embodiments, the individual has muscle invasive bladder cancer. In some embodiments, the individual has non-muscle invasive bladder cancer. In some embodiments, the individual has bladder cancer. In some embodiments, the individual has undergone or has rejected radical cystectomy. In some embodiments, the individual is unsuitable for, ineligible for, or has refused , cT2 or cT3 bladder cancer (e.g., cT2 or cT3 MIBC). In embodiments, the individual is diagnosed with organ-confined, muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 In some embodiments, the IL-16 receptor agonist (IL-16) is selected from the group consisting of M0, N0, and MIBC. The individual may have cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 In some embodiments, the pause is about 3 months. In embodiments, the individual responds to the induction phase therapy (by achieving a complete response, a partial response, and / or have stable disease, etc.

[0058] Also provided herein is a method of treating urothelial carcinoma of the lower urinary tract in an individual, comprising administering to said individual a therapeutically effective amount of The method comprises administering to an individual an effective amount of gemcitabine during an induction phase and administering to an individual an effective amount of gemcitabine during a maintenance phase. and administering to the individual a dose of gemcitabine, wherein the gemcitabine is delivered locally to the bladder. The induction and maintenance phases were separated by rest periods, the induction phase lasting approximately 12 weeks, and individuals were T2 bladder cancer. As used herein, treating urothelial carcinoma of the lower urinary tract in an individual Also provided is a method, comprising administering to an individual an effective amount of gemcitabine during an induction phase. and administering to the individual during the maintenance phase an effective amount of gemcitabine, wherein the gemcitabine is administered to the bladder. and the induction phase includes four delivery periods (e.g., four consecutive delivery periods). Each delivery period is about 3 weeks (e.g., 18 to 24 days), and the maintenance period is about every 3 months. The induction and maintenance phases include administering a bottle to an individual, the induction and maintenance phases being separated by rest periods, The stage is about 12 weeks and the individual has cT2 bladder cancer. Also provided is a method of treating urothelial carcinoma of the lower urinary tract, the method comprising administering an effective amount of a gemcitabine during an induction phase. administering to the individual an effective amount of gemcitabine during the maintenance phase. and gemcitabine is delivered locally to the bladder, and the induction phase includes four delivery periods (four (e.g., consecutive delivery periods of 18-24 days each), The maintenance phase involves administering gemcitabine to the individual about every three months, and the induction and maintenance phases are The induction phase is approximately 12 weeks, separated by rest periods, and the individuals have cT2 bladder cancer. Also provided herein is a method of treating urothelial carcinoma of the lower urinary tract in an individual, the method comprising administering to said individual a therapeutically effective amount of The method comprises administering to the individual an effective amount of gemcitabine during an induction phase and administering to the individual an effective amount of gemcitabine during a maintenance phase. administering gemcitabine to the individual, wherein the gemcitabine is delivered locally to the bladder; The induction phase includes four delivery periods (e.g., four consecutive delivery periods), each lasting approximately three weeks. The maintenance phase involves administering gemcitabine to the individual approximately every 3 months. the induction phase includes four delivery periods (e.g., four consecutive delivery periods), each delivery period including The duration is approximately 3 weeks (e.g., 18 to 24 days), and approximately 225 mg of gemcitabi is administered during each delivery period. The maintenance phase consists of a 3-week delivery period every 3 months (i.e., the maintenance delivery period). Approximately 225 mg of gemcitabine is administered during each maintenance delivery period, and the induction and maintenance are separated by quiescent periods and the individual has cT2 bladder cancer. The maintenance phase may last for approximately 1 year, 2 years, 3 years, 5 years, 10 years, the life of the individual, or Until disease progression or toxicity. In some embodiments, the resting period is about 2-3 months. In some embodiments, the rest period is about 65 to 75 days, for example, about 68 to 72 days. The cessation time is about 3 months. In some embodiments, the individual is responsive to induction therapy. In some embodiments, the patient has a complete response, a partial response, and / or stable disease. , an individual is classified as having organ-confined, muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC) In some embodiments, the individual has c T2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC) has.

[0059] In some embodiments, the method of treating urothelial carcinoma of the lower urinary tract in an individual comprises introducing administering to the individual an effective amount of gemcitabine during the maintenance phase; and administering to the individual an effective amount of gemcitabine during the maintenance phase. and administering to the individual a therapeutically effective amount of gemcitabine, wherein gemcitabine is delivered locally to the bladder and during the induction and maintenance phases. The induction phase is separated by a rest period, with the induction phase lasting 12 weeks and the rest period lasting approximately 3 months. In some embodiments, the induction phase comprises about 900 mg of gemcitabine for 12 weeks. In some embodiments, the individual has muscle invasive bladder cancer. In some embodiments, the individual has non-muscle invasive bladder cancer. In this case, the individual is ineligible for or has refused cisplatin-based chemotherapy. In some embodiments, the individual is unfit, ineligible, or unable to undergo radical cystectomy. rejected this. In some embodiments, the individual is diagnosed with cT2 or cT3 bladder cancer (cT2 In some embodiments, the individual has organ-confined T3 MIBC. Muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N In some embodiments, the individual has cT2 or cT3 M0 Some patients have MIBC (e.g., cT2 or cT3 N0 M0 MIBC). In some embodiments, the rest period is about 3 months. Response to (e.g., having a complete response, partial response, and / or stable disease).

[0060] In some embodiments, the method comprises administering gemcitabine to an individual for 12 weeks. This is followed by a rest period of about 2 to 3 months and a maintenance period, which includes at least The method also includes administering gemcitabine to an individual every three months for one year, In some embodiments, the method comprises administering to the bladder a 12 week period. This involves administering gemcitabine to an individual at a dose of 100 mg / kg / day, followed by a rest period of about 2-3 months, a maintenance The maintenance phase lasts for approximately one year, during which gemcitabine is delivered locally to the bladder. The method includes administering about 225 mg of gemcitabine to the individual every three months. In some embodiments, the maintenance phase is about 1 year, about 2 years, about 3 years, about 5 years, about 10 years, or In some embodiments, the maintenance phase is administered twice, three times, four times, or every three months for the life of the individual. The method includes delivering gemcitabine once, five times, six times, or for the life of the individual. In some embodiments, the maintenance delivery period is about 3 weeks (eg, 18-24 days) each. In some embodiments, the maintenance phase delivery period is about 1 week, about 2 weeks, or about 3 weeks. In some embodiments, the individual has muscle-invasive bladder cancer. In some embodiments, the individual has non-muscle invasive bladder cancer. In some embodiments, the individual is ineligible for or has refused chemotherapy. The body is not suitable, ineligible, or has refused radical cystectomy. In an embodiment, the individual has cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In some embodiments, the individual has organ-confined, muscle-invasive bladder cancer (non-metastatic M IBC (i.e., M0 MIBC), for example, M0 N0 MIBC. In some embodiments, the individual has cT2 or cT3 M0 MIBC (e.g., cT2 or In some embodiments, the pause time is about 3 In some embodiments, the individual responds to 12 weeks of gemcitabine. (e.g., have a complete response, partial response, and / or stable disease).

[0061] In some embodiments, a method for administering a therapeutic agent to an individual comprising an induction phase and a maintenance phase is provided herein. The present invention provides a method for treating urothelial carcinoma of the lower urinary tract using a steroid agonist, the induction phase lasting approximately 12 weeks. The maintenance phase includes administering to the individual 900 mg of gemcitabine for at least one year. administering about 225 mg of gemcitabine to the individual about every three months for Cytabine is delivered locally to the bladder, with induction and maintenance phases separated by a rest period of approximately 2-3 months. In some embodiments, the individual is diagnosed with cT2 or cT3 bladder cancer (cT2 In some embodiments, the individual has organ-confined T3 MIBC. Muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g., M0 N In some embodiments, the individual has cT2 M0 MIB In some embodiments, the rest period is about 3 months. In the present study, individuals respond to induction therapy (complete response, partial response, and / or stable disease). (e.g. having).

[0062] In some embodiments, a method for administering a therapeutic agent to an individual comprising an induction phase and a maintenance phase is provided herein. The present invention provides a method for treating urothelial carcinoma of the lower urinary tract using a steroid agonist, the induction phase lasting approximately 12 weeks. The maintenance phase includes administering to the individual 900 mg of gemcitabine for at least one year. administering about 225 mg of gemcitabine to the individual about every three months for Cytabine is delivered locally to the bladder, with induction and maintenance phases separated by a rest period of approximately 2-3 months. Thus, the individual has cT2 bladder cancer. Localized muscle-invasive bladder cancer (such as non-metastatic MIBC (i.e., M0 MIBC), e.g. In some embodiments, the individual has cT2 M0 In some embodiments, the induction and maintenance phases are described herein. A method of treating urothelial carcinoma of the lower urinary tract in an individual is provided, the method comprising the steps of: The maintenance phase comprises administering to the individual about 900 mg of gemcitabine for two weeks. The individual is administered about 225 mg of gemcitabine about every three months for at least one year. wherein gemcitabine is delivered locally to the bladder, and the induction and maintenance phases last for about 2 to 4 hours. Separated by a 3 month rest period, the individual has cT3 bladder cancer. In some embodiments, the downtime is about 3 months. The patient responds (e.g., has a complete response, partial response, and / or stable disease) to the treatment.

[0063] In some embodiments, the induction phase comprises four delivery periods (e.g., four consecutive delivery periods). In some embodiments, each delivery period is about 3 weeks (e.g., 18-24 days). The induction phase includes four delivery periods (e.g., four consecutive delivery periods), and each delivery period Approximately 3 weeks (e.g., 18 to 24 days) with approximately 225 mg of gemcitabine delivered during each delivery period. In some embodiments, an intravesical debuccant containing about 225 mg of gemcitabine is administered. The chair is inserted into the bladder every 3 weeks for 12 weeks during the induction phase. In some embodiments, the individual has muscle invasive bladder cancer. In some embodiments, the individual has bladder cancer. In some embodiments, the individual is ineligible for or has refused radical cystectomy. In some embodiments, the individual is not suitable, ineligible, or has refused surgical removal. The body has cT2 or cT3 bladder cancer (such as cT2 or cT3 MIBC). In one embodiment, the individual has organ-confined, muscle-invasive bladder cancer (non-metastatic MIBC (i.e., In some embodiments, the β-amino acid ... The individual may have cT2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M In some embodiments, the rest period is about 3 months. In some embodiments, the individual responds (complete response, partial response, and / or or have stable disease).

[0064] In some embodiments, as used herein, four delivery periods (four consecutive delivery periods) Each delivery period is about 3 weeks (e.g., 18 to 24 days), followed by a break period. and a maintenance period comprising two or more gemcitabine delivery periods separated by about three months. A method of treating urothelial carcinoma of the lower urinary tract in an individual is provided, comprising administering to said individual, during each delivery period, About 225 mg of gemcitabine is administered. In some embodiments, the individual is In some embodiments, the patient has cT3 bladder cancer (such as cT2 or cT3 MIBC). , an individual is classified as having organ-confined, muscle-invasive bladder cancer (non-metastatic MIBC (i.e., M0 MIBC) In some embodiments, the individual has c T2 or cT3 M0 MIBC (e.g., cT2 or cT3 N0 M0 MIBC) In some embodiments, the downtime is about 3 months. In some cases, individuals respond (have a complete response, partial response, and / or stable disease) to induction therapy. have, etc.).

[0065] In some embodiments, the maintenance phase is a treatment phase following at least one primary therapy. In some embodiments, the first-line therapy is an induction therapy comprising administering gemcitabine. In some embodiments, the maintenance therapy is separated by periods of at least one month. The method includes administering two or more gemcitabine delivery periods, each delivery period comprising administering about 225 mg of gemcitabine. In some cases, gemcitabine is delivered locally to the bladder. In embodiments, the maintenance phase delivery period is about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. In some embodiments, the maintenance phases are separated by a period of about three months. The method includes administering about 225 mg of gemcitabine to an individual in two or more delivery periods. In some embodiments, gemcitabine is delivered locally to the bladder of the individual. The maintenance phase consists of approximately 225 mg of gemcitabine administered approximately every 3 months for approximately 1 year. In some embodiments, the method further comprises placing a gemcitabine releasing device comprising: In the case of the 1st generation, the maintenance phase delivery period is about 1 week, about 2 weeks, or about 3 weeks, respectively. In this embodiment, the maintenance delivery period is about 3 weeks (e.g., 18-24 days) each. In some embodiments, the individual has muscle invasive bladder cancer. The body has non-muscle invasive bladder cancer. In some embodiments, the individual is treated with cisplatin-based chemotherapy. In some embodiments, the individual is ineligible for or has refused chemotherapy. were unsuitable, ineligible, or refused radical cystectomy. In embodiments, the rest period is about 3 months. Respond to one first-line therapy (complete response, partial response, and / or stable disease) degree).

[0066] Patient population The methods provided herein are useful for treating a range of individuals with urothelial carcinoma. For example, in some embodiments, the urothelial cancer is bladder cancer. In some embodiments, the bladder cancer is locally advanced bladder cancer. In some embodiments, the cancer is metastatic In some embodiments, the bladder cancer is muscle invasive bladder cancer. In embodiments, the bladder cancer is non-muscle invasive bladder cancer. In some embodiments, the bladder cancer is BCG (bacille Calmette-Guerin) refractory. In some embodiments, the bladder cancer is papillary bladder cancer. In some embodiments, the bladder cancer is grade 1 / 3, 2 / 3, or 3 / 3. Bladder cancer can be stage I, stage II, stage III, or stage IV bladder cancer. In some embodiments, the bladder cancer is a high-grade invasive papillary urothelial carcinoma. In some embodiments, the bladder cancer is a high-grade non-invasive urothelial carcinoma. In one embodiment, the bladder cancer is a high-grade multifocal invasive urothelial carcinoma. In some embodiments, the bladder cancer is cT2 or cT3. The patient had cT2 with intradermal carcinoma.

[0067] In some embodiments, the cisplatin-based neoadjuvant Methods for treating bladder cancer (e.g., MIBC) in individuals who are ineligible for therapy are provided. The method includes administering gemcitabine locally to the bladder. Herein, we provide a method for treating individuals who reject cisplatin-based neoadjuvant therapy. The present invention provides a method of treating bladder cancer (e.g., MIBC) in a subject comprising administering gemcitabitobacter (Gemcitabine) to a subject in need thereof. In some embodiments, the method includes administering a medicament to the bladder. The patient has cT2 disease and is highly susceptible to lymphovascular invasion (LVI), hydronephrosis, and concomitant neoplasia in situ (CIS). Methods for treating bladder cancer (e.g., MIBC) in individuals without risk characteristics are provided. The method includes administering gemcitabine locally to the bladder. In this case, patients who are scheduled to undergo radical cystectomy but are receiving cisplatin-based chemotherapy are Treating bladder cancer (e.g., MIBC) in individuals who are ineligible for neoadjuvant therapy A method is provided which comprises locally administering gemcitabine to the bladder. In some of these embodiments, the individual has cT2 cancer. In this study, an individual was randomized to receive 100 mg / kg / day of bladder cancer treatment, and 100 mg / kg / day of bladder cancer treatment was randomized to receive 100 mg / kg / day of bladder cancer treatment. In some embodiments, the individual The body has cT2 M0 N0 MIBC.

[0068] In some embodiments, the individual is diagnosed with a condition that is associated with poor performance status, poor renal function, hearing loss, peripheral neuropathy, Patients who are ineligible for cisplatin-based therapy based on risk of recurrence, toxicity, and comorbidities such as cardiac disease. In some embodiments, the individual is diagnosed with lymphovascular invasion (LVI), hydronephrosis, and associated intraepithelial neoplasia. The patient does not have one or more high-risk features, such as chronic sarcoma (CIS), and therefore is not a candidate for cisplatin-based therapy. Be eligible.

[0069] Thus, in some embodiments, cisplatin-based therapy is described herein. The present invention provides a method of treating an individual who is ineligible for gemcitabine therapy, the method comprising administering gemcitabine every three months. to the individual, wherein the gemcitabine is administered to the individual's bladder for at least one week. In some embodiments, about 225 mg of gemcitabine is delivered locally to about It is administered about every three months for about a year, about two years, about four years, or for the life of the patient. In some embodiments, gemcitabine is administered at about 1 week, about 2 weeks, or about 3 weeks during the delivery period. The drug is delivered continuously over a period of time.

[0070] In some of these embodiments, the method comprises administering the drug about every three months for about two years. These embodiments include administering about 225 mg of gemcitabine to the individual for three weeks. In some of these, the method involves administering about 225 mg of gemcitabine every three months for about three years. In some of these embodiments, the individual is administered cytabine for three weeks. The method comprises administering about 225 mg of gemcitabine to an individual for about three months over the individual's lifetime. In some embodiments, the method includes a 12 week lead-in period. , followed by a maintenance phase.

[0071] Until now, neoadjuvant therapy followed by radical cystectomy, or removal of the bladder, has been the primary treatment for myocardial infarction. The current standard of care for the treatment of endothelial invasive bladder cancer is palliative care. Patients undergoing standard transurethral resection of the bladder (TURBT) for untreated and undertreated disease Such treatment attempts to limit the local progression of the disease. It can provide a temporary relief, but is not intended to be a cure. The present invention provides a method for treating cystectomy by administering gemcitabine locally to the bladder. The present invention provides a method for treating bladder cancer (e.g., MIBC) in individuals who are unable or unfit to receive the treatment. Provide.

[0072] In some embodiments, the method described herein provides for the delivery of gemcitabine locally to the bladder. Treating bladder cancer (e.g., MIBC) in individuals who are ineligible for cystectomy, including In some embodiments, methods are provided herein for administering gemcitabine locally. bladder cancer (e.g., bladder cancer) in individuals who are ineligible for cystectomy, including topically delivering In some embodiments, methods of treating MIBC are provided herein. and locally delivering gemcitabine to the bladder to treat bladder cancer in frail individuals. (e.g., MIBC). In patients with bladder cancer, gemcitabine was administered locally to the bladder. Methods for treating bladder cancer (e.g., MIBC) in individuals unable to receive In some embodiments, the method described herein delivers gemcitabine locally to the bladder. detecting bladder cancer (e.g., MIBC) in an individual without removing the individual's bladder. In some embodiments, methods are provided herein for treating cystectomy. Treating bladder cancer (e.g., MIBC) in individuals who are unsuitable or ineligible for Methods are provided that include locally delivering gemcitabine to the bladder. In some embodiments, the methods described herein treat bladder cancer (e.g., MIBC) in an individual. In some embodiments, methods of treating bladder cancer are provided, wherein the bladder cancer is metastatic bladder cancer. In the literature, in individuals with cT2-cT3 disease (e.g., cT2-cT3 M0 disease), A method of treating bladder cancer (e.g., MIBC) using gemcitabine is provided, the method comprising administering gemcitabine to a subject in need thereof. This includes delivering it locally to the bladder.

[0073] In some embodiments, as used herein, a subject who is not suitable or ineligible for cystectomy is A method of treating muscle invasive bladder cancer in an individual is provided, the method comprising administering at least one dose every three months. The present invention provides a method for continuously and locally delivering gemcitabine to the bladder of an individual for at least about one week. In some of these embodiments, gemcitabine is administered chronically or It may be delivered to the bladder continuously throughout the life of the individual, improving the quality of life of the individual. In some embodiments, about 225 mg of gemcitabine is administered for about 1 year, about 2 years, about 4 years, or is administered about every three months for the life of the patient. The drug is delivered continuously for about 1 week, about 2 weeks, or about 3 weeks during the delivery period.

[0074] In some embodiments, the individual is ineligible for cisplatin-based chemotherapy or In some embodiments, the individual is not suitable for radical cystectomy. was not able to, was ineligible for, or refused to

[0075] In some embodiments, the individual is Under the National Cancer Network (NCCN) guidelines, For example, an individual may be unsuitable for definitive therapy due to frailty. Prior to this procedure, such individuals typically received palliative radiation therapy (3.5%) without chemotherapy. Gy / fraction - 10 treatments; or 7Gy / fraction - 7 treatments; TURBT; or no treatment In some embodiments, the individual is not suitable for platinum-based chemotherapy. In some embodiments, chemotherapy prior to radiation therapy is not recommended for the individual. In embodiments, the individual does not receive curative or systemic chemotherapy. , the individual has cT2 to cT3 disease (such as cT2 to cT3 M0 disease).

[0076] In some embodiments, the individual is a member of the American Society of Anesthesia. Tolerate radical cystectomy according to American College of Anesthesiology (ASA) guidelines For example, individuals who cannot tolerate a radical cystectomy may be unable to tolerate general anesthesia or may be deemed medically unfit for surgery requiring epidural anesthesia.

[0077] In another embodiment, the individual is an American Society of Anesthesia Comprehensive Geriatrics provided by esiologists Postoperative care infrastructure or Under these guidelines, Cumulative illness RA with severe nutritional disorders, cognitive impairment, or comorbidities ting scale for geriatrics (CISR-G) grade 3 to 4 An individual is considered frail if they exhibit

[0078] The methods of the present invention also provide significant and predictive improvement in bladder function compared to standard treatment regimens that call for removal of the bladder. The present invention also provides a therapeutic effect for patients who are eligible for cystectomy but have not undergone cystectomy. It has the advantage of being useful as a bladder-preserving protocol for those who choose not to undergo bladder surgery. The method may allow patients to retain their bladder after having bladder cancer compared to currently available treatments. Thus, in some embodiments, the present invention provides a method for the treatment of a pulmonary artery disease, which can result in a significant improvement in the quality of life of individuals receiving the treatment. The disclosure relates to a method for treating bladder cancer in an individual, the method comprising locally delivering gemcitabine to the bladder. In some embodiments, the present invention provides a bladder-preserving method for treating bladder cancer (e.g., MIBC). The present disclosure relates to a method for administering gemcitabine to an individual's bladder, comprising administering gemcitabine locally to the bladder. Also provided herein are methods of treating bladder cancer (e.g., MIBC) without the need for removal of the tumor. In the literature, bladder cancer (e.g., A method for treating MIBC is provided that delivers gemcitabine locally to the bladder. In some embodiments, the term "cystectomy eligible" is used herein to refer to a patient who is eligible for cystectomy. However, it is known that the present invention provides a method for treating bladder cancer (e.g., MIBC) in individuals who choose not to receive it. Methods are provided that include locally delivering gemcitabine to the bladder. In some embodiments, bladder retention is referred to herein as an alternative to radical cystectomy. The current invention provides a method for treating bladder cancer, the method comprising locally delivering gemcitabine to the bladder. In some embodiments, as used herein, an individual who chooses not to undergo a cystectomy A method of treating bladder cancer (e.g., MIBC) in a subject comprising administering In some embodiments, the method described herein includes locally delivering a vial to the bladder. The present invention provides a method for preserving the bladder of an individual, comprising locally delivering gemcitabine to the bladder. In some embodiments, methods are provided herein, without removing the individual's bladder, A method of treating bladder cancer (e.g., MIBC) in an individual is provided, the method comprising administering In some embodiments, the method includes delivering cytabine locally to the bladder. to treat CT2 urothelial carcinoma in individuals who would otherwise undergo cystectomy A method is provided which comprises locally delivering gemcitabine to the bladder.

[0079] In some embodiments, the method includes administering to a patient, typically a patient who has undergone a radical cystectomy, followed by a nephrectomy. It is particularly suitable for the treatment of individuals who are CT2 patients who will be undergoing adjuvant therapy. The method provides local / regional (loco-regional) control of disease, such as nodules, and thus This method can be used for long-term treatment in the bladder-preserving population. These results resulted in freedom from bladder pain, good long-term bladder function, and low rates of salvage cystectomy. This is important in an older, relatively frail population of individuals with bladder cancer, with a mean age of 70 years. do.

[0080] In some embodiments, the method provides for the treatment of hematuria (chronic hematuria, gross hematuria, recurrent gross hematuria). The method is applicable to subjects with a history of chronic hematuria (such as chronic hematuria, chronic urinary incontinence, or recurrent hematuria). The present invention provides a method for reducing and / or controlling the symptoms of hematuria over a period of time.

[0081] In some embodiments, the individual has muscle invasive bladder cancer (MIBC). In an embodiment, the individual has non-muscle invasive bladder cancer (NMIBC).

[0082] In some embodiments, the individual has non-metastatic (M0) bladder cancer (e.g., MIBC). In some embodiments, the individual has N0 bladder cancer (e.g., MIBC). In some embodiments, the individual has N1, N2, or N3 bladder cancer (e.g., MIBC). In some embodiments, the individual has a cT2 bladder tumor or a cT3 bladder tumor (e.g., In some embodiments, the individual has Ta, Tis, T1, T2 (e.g., MIBC). T2a and / or T2b), T3 (e.g., T3a and / or T3b), T4 (e.g., For example, patients with T4a and / or T4b) bladder cancer (e.g., MIBC). In some embodiments, the individual has N0 and M0 bladder cancer (e.g., MIBC). In some embodiments, the individual has cT2, N0, M0 MIBC. The individual has cT3, N0, M0 MIBC.

[0083] In some embodiments, the individual is at least about 60, about 65, about 70, about 75 years of age. In some embodiments, the individual is about 80 years old, about 85 years old, or about 90 years old. have an immune system that

[0084] In some embodiments, the individual is a human.

[0085] II. Intravesical (intravesical) devices Device shape In some embodiments, the methods provided herein include intravesical (intravesical) decontamination. In some embodiments, the method further comprises administering gemcitabine to the bladder using a vesical device. An intravesical (intravesical) device includes a deployment configuration and a retention configuration. For example, the device may be configured to For example, a relatively straight or non-coiled shape suitable for insertion through the urethra into an individual's bladder. The device is elastically movable between a deployed shape and a retention shape suitable for retaining the device within the bladder. For the purposes of this disclosure, a "relatively expanded shape" or a "relatively large Terms such as "retaining shape" or "retention shape" generally refer to the shape of the device that is intended for implantation. means any shape suitable for holding a device in the bladder; Prezel shapes or other coil shapes (e.g., bi-elliptical or overlapping coils), The retention shape is such that when an individual urinates, the device is taken up in the urine and excreted. Similarly, terms such as "relatively small outline shape" or "configuration shape" , generally means any shape suitable for placing a drug delivery device in the body, e.g. , through the working channel of a catheter, cystoscope, or other placement instrument positioned within the urethra. Examples of shapes include, but are not limited to, straight or elongated shapes suitable for placing devices on the In some embodiments, the drug delivery device does not naturally assume a relatively expanded shape. It may be envisioned that a relatively small device may be inserted into the body, either manually or with the aid of an external device. For example, the external device may be an inserter configured for transurethral insertion. Once deployed, the intravesical (intravesical) device may be in an initial, relatively expanded shape. In some embodiments, the deoxyribonucleic acid (DRI) can spontaneously or naturally revert to a normal, cellular state and be retained in the body. The vice behaves like a spring and deforms in response to a compressive load (e.g., when placing a device). shape) but spontaneously return to the retained shape when the load is removed.

[0086] In some embodiments, the deformation function of the intravesical (intravesical) device described in the previous paragraph. such as those disclosed in the above-referenced published patent applications, which are incorporated herein by reference. By including a shape-retaining frame (i.e., a "retaining frame") in the device In some embodiments, the device may include a retaining frame lumen, A retaining frame is fixed within the wire, which may be a superelastic alloy such as Nitinol. The holding frame may be, for example, a "Pro" type, such as those disclosed in the previously incorporated patent applications. It may be configured to spontaneously return to a retained shape, such as a "Rotzel" shape or another coiled shape. In particular, the retention frame may retain the device within the body, for example, within the bladder. The retaining shape prevents the device from being taken up and excreted in the urine when the individual urinates. For example, the retention frame may allow the device to be introduced into the body with a relatively small profile. and allowing the device to return to a relatively expanded shape once inside the body, The device responds to anticipated forces, such as contractions of the blood vessels and fluid forces associated with urination, to compare pressures within the body. The elastic limit and modulus of elasticity may be such that the material is prevented from assuming an extremely small external shape. The device, when deployed, may be retained within the individual's bladder, limiting accidental discharge, i.e., preventing Stop.

[0087] In some other embodiments, the deformation function of the intravesical (intravesical) device is at least By forming the device housing partially from a thermally shaped elastic polymer, This can be brought about by:

[0088] The material used to form the device body (i.e., housing) determines the placement and retention shape. The device may be at least partially elastic or flexible to allow the device to be moved between the When the device is in the retained configuration, the retaining frame portion is positioned over the drug reservoir portion as shown. In other cases, the retaining frame portion may tend to be located inside the drug reservoir. The portion may be located inside, outside, above, or below the device body. The material may be water permeable, so that when the device is placed in the bladder, the solubilization fluid ( For example, urine) enters the drug reservoir and is contained within the drug reservoir. The present invention relates to a method for treating a soluble form of gemcitabine, an immunomodulatory agent, an additional therapeutic agent, a functional agent, or a combination thereof. For example, silicone or another biocompatible elastomeric material may be used. In other embodiments, the device body may be formed, at least in part, from a water-impermeable material. It may be done.

[0089] In some embodiments, the device body is made of an elastic, biocompatible polymeric material. The material may be non-absorbable or absorbable. Examples of non-absorbable materials include poly( ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone) ), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxane) Poly(oxane), poly(ethylene), poly(tetrafluoroethylene), and other fluorinated poly Exemplary absorbents include synthetic polymers selected from the group consisting of poly(siloxanes), poly(ethylene glycol) copolymers, and poly(ethylene glycol) copolymers. Absorbent materials, specifically biodegradable or biodegradable polymers, include poly(amides), ... Poly(esters), poly(ester amides), poly(anhydrides), poly(ortho esters), Polyphosphazenes, pseudopoly(amino acids), poly(glycerol-sebacate), poly( lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(caprolactone) Poly(caprolactone) (PC)-introduced bodies, amino alcohol-based poly(ester acetate) Poly(ethylene glycol) (PEA) and poly(octanediol citrate) (POC), as well as other curing agents. The synthetic polymers selected from the group consisting of PC-based polymers and PC-based polymers are bioabsorbable elastomers. In order to obtain rubber-like elasticity, lysine diisocyanate or 2,2-bis(e-caprolactone) Copolymers, mixtures, and Combinations of the above materials may also be used.

[0090] In some embodiments, the device body is made of a material selected from the group consisting of silicone, thermoplastic polyurethane, ethylene, and the like. In some embodiments, the polymer may comprise ethylenediaminetetraacetate (EDTA), ethylenediaminetetraacetate (EVA), or a combination thereof. The device body comprises two different thermoplastic materials, one of which is a hydrophilic thermoplastic polymer. The urethane is drug-permeable, and the other is drug-impermeable. , hydrophilic polyurethane, hydrophilic polyester, and hydrophilic polyamide The device body may be configured as described in U.S. Patent Publication No. 2016 / 0310715. As described above, one or more of these materials may be used in an extrusion or co-extrusion process. The device may include an annular tube formed by a gas.

[0091] Drug Core In embodiments in which the antimetabolite is delivered from an intravesical (intravesical) drug delivery device, The agent may be administered via a specific mechanism by which the device controllably releases the agent into the fluid (e.g., urine) within the bladder. The agent may be contained within the device in a variety of forms depending on the needs of the individual. In some embodiments, the agent is It may be provided in a solid, semi-solid, or other non-liquid form and thus may be advantageously dissolved prior to use of the device. This can facilitate stable storage of the drug, advantageously when the drug is contained in the form of a liquid solution. This may allow for a smaller drug loading volume of the device to be stored than would otherwise be possible. In embodiments, the non-liquid form is a tablet, granule, powder, semi-solid (e.g., ointment, cream, paste, etc. In one embodiment, the composition is selected from the group consisting of a capsule, a toast, or a gel, a capsule, and combinations thereof. The drug may be packaged in multiple tablets, such as mini-tablets as described in U.S. Pat. No. 8,343,516. It is in the form of:

[0092] For example, the antimetabolite may be formulated as a suspension, solution, or emulsion in an oily or aqueous medium. and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The active ingredient can be constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use. In order to obtain the desired properties, the powder form may be obtained by aseptic isolation of a sterile solid or by lyophilization from a solution. It may be.

[0093] In one embodiment, gemcitabine is released from a release opening in the device housing as a solubilized gemcitabine. Formulated with one or more excipients, including a viscosity enhancing agent to control the release of cytabine. In another embodiment, the device reservoir contains both gemcitabine and a viscosity enhancing agent. However, these are not co-formulated, but instead are administered in separate regions within a reservoir, e.g., as separate tablets. Examples of suitable polymers include, but are not limited to, polyethylene oxide (PEO). Suitable viscosity enhancing agents are known in the pharmaceutical art. The viscosity enhancer may be provided, for example, formulated with urea or another penetrating agent. good.

[0094] In one embodiment, gemcitabine is administered to the individual with a solubility enhancer. In one embodiment, the solubility enhancer is urea. In one embodiment, the urea is provided in a tablet or other solid form. and loading the drug reservoir of an intravesical (intravesical) drug delivery device with gemcitabine. Urea also acts as an osmotic agent to facilitate the generation of osmotic pressure within the drug reservoir, depending on the device. In certain embodiments, gemcitabine and a penetrating agent may be used as the As described in International Publication WO 2015 / 026813 (Lee et al.), which is incorporated herein by reference. as separate tablets (or other solid forms) located within different regions of the drug reservoir. It is composed of:

[0095] In some embodiments, the device may include a drug reservoir lumen. In some of the configurations, each drug reservoir lumen contains one or more drug tablets or other solid objects. In one embodiment, the device may hold multiple separate drug reservoirs. The lumen holds about 10 to 100 cylindrical pharmaceutical tablets (such as mini tablets). In an embodiment, the mini-tablets are each, for example, about 1.0 to about 3 mm, such as about 1.5 to about 3.1 mm. 0.3 mm in diameter and a length of about 1.5 to about 4.7 mm, e.g., about 2.0 to about 4.5 mm may have

[0096] Drug Housing The release of gemcitabine from the intravesical (intravesical) devices described herein operates in different ways. In various embodiments, the drug may be delivered to the drug housing. through one or more defined openings in the wall of the drug housing by diffusion through the wall of the drug housing. By diffusion through the drug housing, by osmotic pressure through openings in the drug housing, one or more temporary The osmotic pressure through the microchannels formed in the bladder causes the formulation to permeate the urine. from an intravesical (intravesical) drug delivery device, by food, or a combination of both In some embodiments, the drug release occurs through a portion of the device housing. Controlled by drug diffusion through a defining drug-permeable polymer or matrix component In one embodiment, the device comprises a drug-permeable polymer component.

[0097] The size of the housing, including wall thickness, is determined in particular by the drug (and function, if any) contained therein. The volume of the formulation, the desired rate of delivery of the drug from the device body / housing, The intended implantation site of the device, the desired mechanical integrity for the device, resistance to water and urine The desired release rate or permeability to the body, the desired introduction time before the onset of the initial release, and the desired time for insertion into the body are considered. In embodiments where the housing is a tube, the desired method or route of entry may be selected. The pipe wall thickness may be determined based on the mechanical properties and water permeability of the pipe material. A tube wall that is too thick may not have sufficient mechanical integrity, while a tube wall that is too thick may cause the device to break down. The initial drug release from the chair may have an undesirably long induction time and / or may be or other narrow body lumens. This is because.

[0098] In some embodiments, the housing comprises an elongated ring having an inner diameter of about 2 mm to about 5 mm. The drug and functional agent, if present, may be substantially equal to the inner diameter of the elongated annular tube. In some embodiments, the housing may be a solid tablet having the same diameter. One or more first drug units containing a drug and one or more second drug units facilitating the release of the drug. One or more of the tablets of the first unit are positioned within about 1 of the lumen of the tube. The length of the tablet may be filled from about 3 cm to about 1 cm, and one or more of the tablets of the second unit may be filled in the tube. The lumen may be filled to a length of about 10 cm to about 15 cm. In one embodiment, the first unit The ratio of the volume of the first unit to the volume of the second unit is about 0.05 to about 0.5. Lengths and proportions are envisaged.

[0099] In some embodiments, the housing has a wall thickness of about 0.1 mm to about 0.2 mm. The housing material may be one or more biocompatible materials. The housing material may include a synthetic elastomer. For example, the wire may be selected to have a durometer of 25A, 50A, 65A, 70A, or 80A. It is okay to do so.

[0100] In various embodiments, the intravesical (intravesical) device releases drug continuously or intermittently. and continuous treatment of the drug in urine in the bladder as described in the methods provided herein. A concentration of drug in the bladder that produces an effective concentration may be achieved, for example, over a period of 1 hour to 1 month. For example, over a period of 2 hours to 2 weeks, 6 hours to 1 week, 24 hours to 72 hours, etc. In certain embodiments, the intravesical (intravesical) device may release 1 mg / day to 10 00mg / day, for example, 20mg / day to 300mg / day, or 25mg / day to 300mg / day In certain embodiments, these release rates are in accordance with the present invention. In certain embodiments, these release rates are provided over a treatment period as described herein. Degrees are provided over a treatment period of 14 to 21 days.

[0101] Osmosis and diffusion systems Following in vivo placement, the device releases the drug. As noted above, release occurs via An osmotic pressure gradient between the inside and outside of the device, and one or more orifices or Release can occur due to drug passing through the passage pores. Release can also occur by diffusion, which Thus, the drug is distributed to one of the cells in the device due to a drug concentration gradient between the inside and outside of the device. orifices or passage holes, and / or drug-permeable walls of the device. Combinations of these emission modes within a device are possible, and in some embodiments: Overall drug release profile that cannot be easily achieved by any of the individual modes This is preferable for achieving

[0102] In some embodiments where the device contains a drug in solid form, elution of the drug from the device This occurs after dissolution of the drug within the device. Body fluids enter the device, come into contact with the drug, and dissolve it. The drug is then solubilized and the dissolved drug diffuses out of the device or is absorbed under osmotic or diffusive pressure. For example, if the device is placed in the bladder, the drug will flow through the urinary In certain embodiments, the water permeable wall portion of the housing may be solubilized upon contact with an aqueous solution. The drug is permeable to the drug in the drug carrier, and the solubilized drug is released through the wall portion. After the device is implanted, water or urine can penetrate through the wall. The functional agent and / or drug enter the reservoir and solubilize the functional agent and / or drug. The drug is then released into the device. Due to the drug concentration gradient between the inside and outside, the drug diffuses directly through the wall at a controlled rate. For example, The housing and / or any water or drug permeable wall portions may be made of silicone, thermoplastic polymer, polyurethane, ethylene-co-vinyl acetate (EVA), or a combination of these That's fine.

[0103] In some embodiments, the intravesical (intravesical) device contains about 225 mg of gemcitabi. In some of these embodiments, the device may include a unit concentration of About 100 to about 225 mg of gemcitabine (e.g., about 140 mg, about 1 60 mg, about 180 mg, about 200 mg, or about 220 mg of gemcitabine The device may be configured to deliver the

[0104] In certain embodiments, the drug delivery device is a Incorporated International Publication No. WO 2014 / 145638 and U.S. Patent Application Publication No. 2016 / 0 The optical fiber may include a transmission system such as that described in US Pat. No. 3,107,155. In the present invention, a drug delivery device is bounded by a first wall structure and a hydrophilic second wall structure. and a formulation containing gemcitabine contained within the drug reservoir lumen. and a housing having a first wall structure that is permeable or impermeable to water. and impermeable to the drug, and the second wall structure is permeable to gemcitabine. do.

[0105] In some embodiments, the device housing comprises a first wall structure. a drug reservoir of the device made of a material and a second material that functions as a second wall structure. The barrier has a wall that bounds and defines the barrier, and therefore drug release is essentially solely via the second material. In one embodiment, the device does not include an opening and drug release occurs through a second wall structure. As used herein, the term "impermeable to a drug" refers to a substance that is impermeable to a drug. "Permeable" and "water-impermeable" refer to a wall structure that is substantially impermeable to the drug or water. Thus, the drug or water essentially remains in the wall structure over the therapeutic release period. For use in the bladder, the device is flexible ( It is desirable for the device to be easy to bend and soft to the touch. To avoid or reduce discomfort and irritation. Therefore, the first and second materials of the structure The durometer of the material is a design consideration, and the proportion of high durometer material is important to ensure that it is well suited for use in the bladder. In constructing a device housing of a given size while still being able to fit For example, Tecophilic™ thermoplastic polyurethanes (Lubr izol Corp.) can have a Shore hardness of over 70A, such as 80A to 65D. The silicone tube may have a Shore hardness of 50A to 70A. Therefore, the silicone tube is water-swelling and hydrophilic. Rather than fabricating the entire device from a second drug-permeable material, these two different It may be advantageous to utilize a combination of polymeric materials.

[0106] The arrangement of the first and second wall structures can take a variety of forms. The first wall structure is a cylindrical tube, and the second wall structure is disposed at at least one end of the cylindrical tube. or the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube. That is, drug release occurs through a drug permeable structure that defines a portion of the occlusive device housing. The drug permeable wall structure allows the desired drug release from the device to be controlled by drug diffusion through the drug composition. The catheter may be positioned, sized, and have material properties to provide a controlled rate of drug diffusion. In one embodiment, the drug permeable wall is disposed within the lumen of the tube at or near the end of the tube. Optionally, the disk may be sandwiched and stabilized between an inner washer and an outer washer. In another embodiment, the drug permeable wall is a portion of the side wall of the tubular housing or The end plug is part of the end of the housing.

[0107] The length and width, e.g., the wall portion formed of a water-permeable material, are determined by the device housing. In one embodiment, the flow rate is selected to provide a desired rate of water flow into the defined reservoir. The width of the water-permeable wall portion is determined by the arc angle that defines the wall when viewed in cross section perpendicular to the luminal axis. The water permeable area of ​​the device housing may be quantified by the osmotic water absorption of a selected area. Therefore, the device is preferably made of a suitable biocompatible elastomer to provide the desired speed. Advantageously, the force applied to the vise may be controlled to maintain a suitable overall size and elasticity. The structure of the water permeable region is achieved by forming the device housing through a co-extrusion process. The material variations can be produced in conventional coextrusion devices by selecting the processing parameters. thereby advantageously providing the ability to cost-effectively manufacture multiple structural device configurations. In some embodiments, the length of the water permeable region extends along only a portion of the length of the device. Thus, in such an embodiment, a larger arc angle of the permeable region may be used. while maintaining the drug release rate at a desirable level for an extended period of time. can be done.

[0108] In some embodiments, the wall may have a varying thickness around the circumference of the wall, e.g. The drug-permeable portion may have a thickness less than the thickness of the drug-impermeable portion. The thin drug-permeable wall structures are positioned at various positions relative to the adjacent thicker drug-impermeable wall structures. In some embodiments, the drug release may be located within a portion of the occlusive device housing. The drug diffusion is controlled by drug diffusion through a drug-permeable component that defines a drug-permeable wall structure. are positioned and dimensioned to provide a desired rate of controlled drug diffusion from the device. and may have material properties.

[0109] In some embodiments, the drug delivery devices are adjacent to each other and define a drug reservoir lumen. a first wall structure and a second wall structure that together form a tube that defines a drug reservoir lumen; and a housing comprising: (i) a second wall structure, or a first wall structure and (ii) the first wall structure is permeable to water, and (iii) the second wall structure is impermeable to a drug. and the second wall structure is permeable to the drug, such that the drug penetrates the second wall structure. (iii) a second The wall structure, in a cross section perpendicular to the longitudinal axis of the tube, does not include less than 90 percent of the cross-sectional area of ​​the tube. and (iv) the first wall structure comprises a first polyurethane composition.

[0110] In some embodiments, the device extends between a first closed end and a second closed end. An elongated elastic housing having a drug reservoir lumen and a drug contained within the drug reservoir lumen. (i) the housing is formed entirely of a first material that is impermeable to the drug; and a first annular segment formed of at least a portion of a second material that is permeable to the drug. The second annular segment is formed by diffusion through the second material in the second annular segment. a second annular segment configured to release the agent in vivo by (ii) the first annular segment is integral with a first end of the second annular segment; The first end is formed and connected.

[0111] In some embodiments, the walls defining the drug reservoir lumen may have varying thicknesses. A housing having walls of different thicknesses can vary the flexibility, compressibility, or both of the housing. The different wall thicknesses can also aid in anchoring the solid drug unit within the drug reservoir lumen. This is possible.

[0112] In some embodiments, the intravesical (intravesical) device body or housing is assembled. The openings (e.g., , at opposite ends of the annular tube. Any of these defined openings or ends of a housing, such as a housing unit, may be If blocking of the mouth is desired, it may be sealed. This sealing may be achieved by a sealing material or structure. The sealing structure may be made of a material selected from the group consisting of metals such as stainless steel, polymers such as silicone, ceramics, and the like. Biocompatible, such as acrylic, sapphire, adhesive, or a combination of these The sealing substance or structure may be biodegradable or biodegradable. In one embodiment, a medical grade silicone adhesive or other adhesive is provided in a fluid or effective form. The resin fills the opening at a constant temperature and then hardens within the housing opening, sealing the opening. In some embodiments, the housing includes one or more predetermined apertures for releasing the agent from the device. These drug release openings are sealed and are not defined openings. In an embodiment, the housing does not include a predetermined drug release opening.

[0113] In some embodiments, the device has a predetermined drug release opening (i.e., an orifice Drug release from a device without a designated drug release opening. Release can be driven by diffusion or osmotic pressure. Examples of ejection systems are described in WO 2014 / 14406, which is incorporated herein by reference. No. 6 (TB130) and U.S. Patent Application Publication No. 2014 / 0276636 (TB134). It is described in.

[0114] In certain embodiments, the drug delivery device is a Patent Application Publication No. 2016 / 0199544, U.S. Patent No. 8,679,094, and U.S. The present invention may include an infiltration system such as that described in Patent Publication No. 2016 / 0008271. stomach.

[0115] In some embodiments, the device includes a housing defining a reservoir and a a first unit contained in the first unit, the first unit including a drug; a second unit housed in the reservoir at a different location, the second unit being adapted to extract the drug from the housing; and a second unit comprising a functional agent that facilitates in vivo release of the In some embodiments, the first unit comprises at least one drug, such as gemcitabine. the second unit comprises one or more solid tablets (e.g., urea In some embodiments, the housing comprises a first and a second The tablet has a lumen (i.e., a reservoir) in which all of the solid tablets of the unit are aligned and housed. The solid tablet is in the form of an elongated elastomeric tube that is inserted into the cavity of the tablet. The diameter of the solid tablet is substantially the same as the diameter of the lumen. It may be the same.

[0116] If osmotic release is the desired drug release mode, the functional agent in the second unit acts to mediate the osmotic release of the drug. For example, the osmotic agent may be a stimulant that solubilizes and / or enhances the release of the stimulant. The solubility of the drug may be greater than that of the drug, so as to facilitate subsequent drug release. low dissolution from osmotic delivery-based devices, which are typically delivered solely by diffusion The device allows for the delivery of sufficient amounts of functional agents and / or other drugs. An induction period may be performed during which the solution is solubilized to establish an osmotic gradient.

[0117] The device then exhibits a zero order release rate for an extended period of time, followed by a decay period. The desired delivery rate can be determined by adjusting various parameters of the device. These parameters can be achieved by controlling / selecting the meter, such as water permeability, The surface area and thickness of the wall, the water permeability of the material used to form the wall, the shape of the openings, These include the size, number, and arrangement of the drug and functional agent, as well as the dissolution profile of the drug and functional agent. Not limited to.

[0118] The devices described herein also provide for delivery of vasopressin by diffusion alone or in combination with osmotic release. The device may also be configured to release the drug in a housing. The device may be configured to allow passage through one or more openings in or on a portion of the housing.

[0119] Alternatively, or in combination with the water-permeable wall portion, the housing may be adapted to prevent fluid from entering the in vivo The reservoir may include at least one opening configured to allow entry into the reservoir. The housing may also include one or more tubings configured to allow passage of the solubilized drug. The opening or passage hole may include

[0120] In some embodiments of the osmotic system, the device housing comprises a first The present invention relates to a method for manufacturing a hose comprising the steps of: forming a hose comprising: a housing; and a second elastomeric material that is water impermeable, the second elastomeric material being formed by a housing having a housing and a housing that is water impermeable. The encapsulation layer is selected to be impermeable to the agent contained within the encapsulation layer.

[0121] Erosion-Based System In some embodiments that may be used with tablets containing low solubility drugs, the drug is The present invention provides a method for the preparation of a tablet-shaped composition comprising the steps of: exposing the composition to the outside of the tablet; and fixing the composition to the device. As described in ,816, the release of drug from the device is controlled by erosion / dissolution. In some embodiments, the device includes a modular housing. A modular housing typically comprises at least two separate housings. Each unit is formed of at least one solid drug unit. The material from which the housing unit is formed is at least one material capable of housing the solid drug unit. Each of the drug reservoir lumens defines a drug reservoir lumen. The drug reservoir lumen includes one or more defined openings. For example, the drug reservoir lumen may have at least one drug reservoir lumen contained therein. and two opposing openings exposing corresponding, opposing end faces of the solid pharmaceutical unit. In certain embodiments, at least two separate houses within the modular housing may be used. The housing units are connected, directly or indirectly, by a holding frame. In an embodiment, the modular housing unit is placed on a holding frame to form a "breaker." The device may form a "threat" design. The number of housing units may depend on the holding frame to which they are connected. can be limited only by the size of

[0122] In some embodiments, one or more of the separate housing units includes a shared holding frame. In certain embodiments, each housing unit includes a retaining frame lumen through which the frame extends. The retention frame lumen and the drug reservoir lumen of the knit are arranged parallel to each other. In an embodiment, the retaining frame lumen and the drug reservoir lumen of each housing unit are mutually In a further embodiment, the retaining frame lumen and the The drug reservoir lumen may be angled at angles other than 0° (parallel) and 90° (perpendicular), e.g., 5°, 10° , 30°, 45°, 60°, or 85°. The described device has the following components: (1) a retaining frame lumen and a drug reservoir lumen; (2) the retaining frame lumen and the drug reservoir lumen are disposed substantially parallel to each other; (3) the retaining frame lumen and the drug reservoir lumen are disposed substantially perpendicular to each other; At least two of the following are arranged at angles other than 0° (parallel) and 90° (perpendicular) It includes two or more housing units.

[0123] One-piece silicone drug delivery system In some embodiments, the device is a Elastic polymer drug matrices as described in WO 2015 / 200752 may include:

[0124] Devices with multiple emitting portions In certain embodiments, the device comprises at least two drug releasing portions, at least One release portion is disclosed in WO 2011 / 023362, which is incorporated herein by reference in its entirety. As described in US Pat. No. 5,993,555, the release of the drug is at a different rate than the release of the other portions. The outlet portions can be, in particular, differently configured and can accommodate different formulations. or by using a different release mechanism, or by having a different configuration, or a combination thereof to achieve different release rates. The devices may be combined to achieve a release profile. have different onset times or lag times before the release begins, and release at different rates after the release begins or releases the drug according to a different release curve, or when the drug load is substantially depleted. release portions that release the drug for different periods of time before being inserted into the cavity, or a combination thereof; The heterogeneous release portion may exhibit a relatively short initial lag time followed by a long period of Overall, the drug delivery device exhibited sustained release at a relatively constant rate over a period of time. These may be combined to achieve a desired release profile.

[0125] In some embodiments, the device may be smaller in size than a conventional pharmaceutical tablet. The device is filled with a drug in the form of a number of solid drug tablets. To control the release of the drug, the drug itself may contain few or no excipients that control the drug release. Instead, the excipients present in pharmaceutical tablets are primarily or entirely absorbed during the tableting process. or may be present to facilitate solubilization in vivo. While providing high drug loading on a volumetric or weight basis, the device is minimally invasive. The nanoparticles may be small enough for in vivo placement in a convenient manner.

[0126] The drug housing may also be in a liquid or semi-solid form upon implantation or after in vivo solubilization. The wall allows the drug to be released either through the drug housing or along its entire length. The wall may be formed of a drug-permeable material that allows for drug flow through at least a portion of the wall. The wall may be made of a material that is partially semi-permeable to the drug depending on the drug form. may be permeable to the drug in some forms, such as a charged form, but not in uncharged forms (e.g. In other forms (e.g., base form vs. salt form), this may not be the case. The walls may also be used to prevent the drug from entering the drug housing. It contains one or more openings or passages formed completely through it that allow air to exit the housing. That's fine.

[0127] The drug housings are aligned within the drug housing in a series arrangement, with the drug housings at either end A multi-component drug housing is enclosed with a sealing structure, such as a plug, that closes the inlet opening. The space between adjacent tablets may be spaced apart from each other. The clefts allow the drug tablets to move relative to each other so that the device is stationary. It is flexible even though it is filled with a solid form of drug.

[0128] The drug moiety can have any combination of the features or configurations described herein. That is, the opening may be provided, omitted, or replaced by a through hole, or an additional opening may be provided. The housing may be reinforced with an aperture or through hole, and may have an open or closed cell structure. and the one or more degradable timing structures or release regulating structures may have a porous wall having The connector may be associated with a housing, a housing, or any combination thereof.

[0129] The drug tablets may be arranged in any configuration other than a straight line arrangement depending on the configuration of the drug housing. The drug tablet may be inserted into any part of the drug housing other than the entire drug housing as described. Any portion of the drug housing that is not filled with a drug tablet may be filled with To achieve this, a filler material such as silicone adhesive may be used, or air may be used to fill the device. The composition of the drug tablet may be the same or may be different from that of the device. The drug may also be administered in other liquid, semi-solid, or solid forms (e.g., granules), etc. It may be in a form other than a tablet.

[0130] In certain embodiments, the drug delivery device comprises at least two carriers associated with a single carrier portion. The drug moieties each comprise a separate drug moiety associated with a carrier moiety. Alternatively, the drug portion may be a single drug housing associated with the retention portion. It may be a separate area within the ring.

[0131] Each drug portion comprises a portion of a wall of the drug housing and a wall separating the drug portion from a second drug portion. The partition structure may be defined by at least one partition structure having a shape in particular of a cylinder, a sphere or a It may be a plug that is inserted into a housing such as a disk, and may be determined by its size or by its connection. The partition structure is also part of the housing and is fixed in place using a cast adhesive. or the like, directly therein.

[0132] A device having at least two separate portions can dispense at least one drug from a corresponding number of drug reservoirs. The two separate portions may be suitable for controlled release of at least two drug loadings. The two drug fills may have the same or different configurations as described herein. Content of active ingredient or excipient, form such as salt form or base form, liquid The same as each other based on the state, such as solid, semi-solid, or solid state, or a combination of these. The two separate moieties may be the same or different from each other. The two drugs can be delivered at the same or different rates via a single release mechanism or different release mechanisms. The loads may be released at the same time or at different times, or a combination thereof.

[0133] For example, some drug moieties are configured to release their drug load relatively quickly after implantation. and another drug portion may be configured to experience a loading period before the start of release; or a combination thereof. An example of a rapid release drug portion is a silicone having a relatively thin wall. The drug portion acts as a relatively fast-acting osmotic pump, such as a tube, A drug portion that is loaded with a drug in a rapid release form, such as a specially formulated solid form, and is relatively fast acting The drug moiety may be associated with a degradable timing structure, or a combination thereof. Thus, the device may release drug during an initial acute phase and during a maintenance phase.

[0134] As another example, certain drug portions may be filled at a relatively faster rate than other drug portions. For example, some drug moieties may be configured to release a drug relatively quickly after implantation. The drug may contain a drug fill having low water solubility for a rapidly initiated diffusional release, and may be combined with another drug The portion may contain a drug load that is highly water soluble for osmotic release after a loading period. For example, a drug moiety may be administered for rapid release via an aperture having a rapidly degrading timing membrane. The drug portion may contain a drug fill in a liquid state for in vivo solubility. The solid tablet may contain an additional pharmaceutical fill for delayed release after formulation. One drug portion may have a relatively solid wall, while another drug portion may increase the release rate by diffusion. a number of openings or holes formed through its walls, or a wall through which water or The may have closed cell porous walls which may increase the release rate due to increased permeation of the drug.

[0135] The release portions may be combined to achieve a desired release profile. For example: The devices may be, in particular, configured to exhibit different onset or lag times before the onset of the initial release. Releasing drugs at different rates or according to different release curves after initiation or drug loading The amount of the drug released may vary over different time periods before being substantially depleted, or a combination thereof. The heterogeneous release portions may exhibit a relatively short initial lag time. After that, the drug was released at a relatively constant rate over a long period of time. may be combined to achieve a desired release profile from the drug delivery device. .

[0136] By combining multiple separate drug moieties within a single device, the device The desired release profile of the antagonist may be exhibited. The release profile from the device may be As a whole, the release profile may be the sum of the separate portions. For example, the first portion may have the release profile: The first exhibits a minimal lag time before release begins, and the second part has a short introduction time due to the development of an osmotic gradient. The third portion exhibits a longer delay before onset as the degradable structure dissolves or degrades. Once release begins from any one site, the release rate continues for an extended period of time. The three separate parts are examples and may be relatively zero order, followed by a decay period. Any number or combination of distinct portions may be used to achieve the desired output profile. Please note that.

[0137] The different drug portions are simply separate regions within a single tubular housing, so that the device The system can advantageously be relatively simple to construct and deploy, and different drug moieties can be attached to different Different release profiles due to different drug loadings, aperture placements, and degradable timing structures The drug portion may exhibit different properties, for example, by using walls of different materials, thicknesses, or porous cell structures. In other embodiments, the housing may vary along its length or may include separate drug housings. Thus, controlled release can be achieved in a variety of ways.

[0138] gel In another embodiment, the coating material is applied to the bladder wall within the bladder cavity (e.g., to the urinary tract within the bladder). The coating material may be applied to the area of ​​the coating, and the coating material may be combined with gemcitabine or other drugs. This promotes adhesion of the drug-binding substance to the bladder wall, resulting in sustained and controlled release of the drug over the course of treatment. and one or more excipient materials that provide for the release of the coating material. The composition may be a gel, a paste, a film, an emulsion, a gel, a tablet, a polymer, or a combination thereof. The mucoadhesive formulation may be a polymer such as a hydrogel or are hydrophilic polymers, polycarbophil (i.e. Carbopol), chitosan, polyvinyl chloride, PVP, lectin, polyethylene glycol polymer, cellulose , or combinations thereof. Suitable celluloses include methyl cellulose, cellulose (MC), carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), or a combination thereof. The coating material may include a permeation enhancer. Non-limiting examples of penetration enhancers include dimethyl sulfoxide (DMSO), Sodium carboxymethylcellulose (NaCMC), lipids, surfactants, or any of these The coating material may be a combination of The catheter may be placed in the bladder such that

[0139] The coating material may be placed in the bladder using a placement device. Any device designed to navigate the natural lumen of a blood vessel to reach an intended implantation site. For placement within the bladder, the placement device may be passed through the patient's urethra to the bladder. The delivery device may be a catheter or cystoscope, or a specially designed The deployment tool may be a known device such as a device that is adapted to deliver the coating material into the body. and then removed from the body, so that the entire coating material is Once so embedded, the coating material remains embedded in the The drug may be released into the body over a period of time. Either the device or the drug can be placed in other parts of the body through other natural lumens. For example, a delivery device can be used to deliver a liquid medication by passing the delivery device through the urethra. Alternatively, the formulation may be placed in the bladder.

[0140] III. Representative Embodiments Embodiment 1. A method of providing maintenance therapy to an individual, the maintenance therapy comprising at least one Following prior therapy, maintenance therapy involves administering gemcitabine to an individual for two or more delivery periods. two or more consecutive doses, wherein gemcitabine is delivered locally to the individual's bladder; Each delivery period will be at least one week, with at least one month of rest between each delivery period. and the individual has urothelial carcinoma of the lower urinary tract.

[0141] Embodiment 2. At least one prior therapy for an individual with urothelial carcinoma of the lower urinary tract A method of maintenance therapy following administration of gemcitabine to an individual during two or more delivery periods. The method includes administering the drug to the bladder consecutively and locally two or more times, each delivery period being at least one week. and wherein there is a rest period of at least one month between each delivery period.

[0142] Embodiment 3. Gemcitabine is delivered into the bladder by an intravesical device. 3. The embodiment described in embodiment 1 or 2.

[0143] Embodiment 4. The intravesical device contains 225 mg of gemcitabine, as described in embodiment 3. How to.

[0144] Embodiment 5. A method according to any one of embodiments 1 to 4, wherein the delivery period is 3 weeks. Law.

[0145] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the rest period is about 3 months.

[0146] Embodiment 7. Gemcitabine is administered at a dose of about 1 mg / day to about 300 mg / day during the delivery period. 7. The method of any one of embodiments 1 to 6, wherein the

[0147] Embodiment 8. The concentration of gemcitabine in the urine is about 1 μg / m during the first and second delivery periods. The method according to any one of claims 1 to 7, wherein the concentration is from about 1 to about 10 µg / mL.

[0148] Embodiment 9. A method for administering gemcitabine to a subject in which the concentration of gemcitabine in the urine is about 10 μg / mL during the delivery period. 9. The method according to embodiment 8.

[0149] Embodiment 10. The individual is ineligible for or is receiving cisplatin-based chemotherapy. The method according to any one of embodiments 1 to 9, wherein the patient is rejected.

[0150] Embodiment 11. The individual is unsuitable, ineligible, or unable to undergo radical cystectomy. The method according to any one of embodiments 1 to 10, wherein the patient is rejected.

[0151] Embodiment 12. The method of any one of embodiments 1 to 11, wherein the individual has muscle-invasive bladder cancer. Method of posting.

[0152] Embodiment 13. Any one of embodiments 1 to 11, wherein the individual has non-muscle invasive bladder cancer. The method described.

[0153] Embodiment 14. Any of embodiments 1 to 13, wherein the rest period between delivery periods is about 3 months. or one of the methods described above.

[0154] Embodiment 15. A method comprising administering a therapeutic agent to a patient comprising administering to said patient four delivery periods, the rest period between each delivery period being about three months. The method according to any one of embodiments 1 to 14.

[0155] Embodiment 16. The rest period between each delivery period is about 3 months, and gemcitabine is administered to the individual The method of any one of embodiments 1-14, wherein the method is delivered every three months for the duration of the patient's life.

[0156] Embodiment 17. A method of treating urothelial carcinoma of the lower urinary tract in an individual, comprising: a) introducing b) administering to the individual an effective amount of gemcitabine during the maintenance phase; and and continuously administering gemcitabine to the individual, wherein the gemcitabine is administered locally to the individual's bladder. The induction and maintenance phases are separated by rest periods, and the induction phase lasts approximately 12 weeks. How to do it.

[0157] Embodiment 18. A method of treating urothelial carcinoma of the lower urinary tract in an individual, comprising: a) administering to an individual at least about 1 administering to the individual an effective amount of gemcitabine continuously and locally to the individual's bladder during a two week lead-in period and b) administering an effective amount of gemcitabine continuously and locally to the individual's bladder during the maintenance phase. and administering to the body, wherein the induction phase and the maintenance phase are separated by a rest period.

[0158] Embodiment 19. A method of bladder preservation in an individual, comprising: a) administering an effective amount of gemcitabine during an induction phase. b) administering to the individual an effective amount of gemcitabine during a maintenance phase. and administering gemcitabine continuously to the individual's bladder, wherein the gemcitabine is delivered locally to the individual's bladder, The induction and maintenance phases were separated by rest periods, the induction phase lasted approximately 12 weeks, and the animals were administered the lower ureteral having urothelial carcinoma.

[0159] Embodiment 20. A method of bladder preservation in an individual with urothelial carcinoma of the lower urinary tract, comprising: a) administering an effective amount of gemcitabine continuously and locally to the individual's bladder during a lead-in period of approximately 12 weeks; b) administering an effective amount of gemcitabine continuously and locally to the individual's bladder during a maintenance phase. and administering to the individual a therapeutically effective amount of the compound, the induction phase and the maintenance phase being separated by a rest period. method.

[0160] Embodiment 21. Gemcitabine is delivered by an intravesical device. The method according to any one of claims 1 to 20.

[0161] Embodiment 22. The intravesical device contains 225 mg of gemcitabine. The method described.

[0162] Embodiment 23. The rest period between the induction phase and the maintenance phase is about 3 months. 2. A method according to any one of claims 1 to 11.

[0163] Embodiment 24. The maintenance phase includes two or more gemcitabine delivery periods. 3. A method according to any one of claims 1 to 3.

[0164] Embodiment 25. The maintenance gemcitabine delivery periods are separated by rest periods of about 3 months. 25. The method of embodiment 24, wherein

[0165] Embodiment 26. The maintenance gemcitabine delivery periods are each 3 weeks. A method according to any one of claims 1 to 25.

[0166] Embodiment 27. Gemcitabine is administered in doses of about 1 mg / day to about 30 mg / day during induction or maintenance delivery. 27. The method of any of embodiments 24-26, wherein the dose is delivered at 0 mg / day.

[0167] Embodiment 28. The concentration of gemcitabine in urine is about 1 μg during induction or maintenance delivery. 28. The method of any one of embodiments 24 to 27, wherein the concentration is from about 10 μg / mL to about 10 μg / mL.

[0168] Embodiment 29. The individual is ineligible for or is receiving cisplatin-based chemotherapy. The method according to any one of embodiments 17 to 28, wherein the patient has rejected the treatment.

[0169] Embodiment 30. The individual is unsuitable, ineligible, or unable to undergo radical cystectomy. The method according to any one of embodiments 17 to 29, wherein the patient has rejected the procedure.

[0170] Embodiment 31. Any one of embodiments 17 to 30, wherein the individual has muscle invasive bladder cancer. The method described.

[0171] Embodiment 32. Any one of embodiments 17 to 30, wherein the individual has non-muscle invasive bladder cancer. The method described above.

[0172] Embodiment 33. The method of any one of claims 1 to 32, wherein the individual is a human. EXAMPLES

[0173] Example 1 Subjects received their first TAR via the TARIS Inserter transurethrally on study day 0. On study day 21 (± 3 days), this first TAR-200 was administered in a flexible or via rigid cystoscopy, followed by placement of a second TAR-200. -200 is an intravesical device containing 225 mg of gemcitabine. The procedure was performed on study days 42 (± 3 days) and 63 (± 3 days) at the third and fourth sites during the induction phase. Repeat for each administration cycle. The fourth TAR-200 is removed on day 84 (±3 days) of the study, and a 3-month response assessment is performed. See Figure 1.

[0174] During the maintenance period, 21-day administration cycles occur every quarter (3 months) (starting at approximately the 6th cycle). Subjects may continue to receive quarterly administration cycles over 3 administration cycles. Subjects may continue to receive quarterly administration cycles over 3 administration cycles.

[0175] All subjects are evaluated for clinical response every 3 months by cystoscopy, pelvic computed tomography (CT) / magnetic resonance imaging (MRI ) / positron emission tomography (PET), and biopsy (only at week 12 unless clinically indicated). In addition, subjects are evaluated for symptom control at weeks 3, 6, 9, and 12, and approximately monthly during the maintenance period. Subjects are evaluated for symptom control at weeks 3, 6, 9, and 12, and approximately monthly during the maintenance period.

[0176] The primary endpoint is the assessment of the safety and tolerability of 4 consecutive 21-day TAR-200 administration cycles.

[0177] The secondary endpoints are the proportion of subjects with a complete clinical response (cCR), a partial clinical response (cPR), stable disease (SD), and progression based on visual lesions on cystoscopy, pelvic CT / MRI / PET, and biopsy. For the purposes of this study, cCR means that no signs of disease are observed in the bladder or notes. cPR means that for previously N0 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of nodular disease are observed, and for N1-N3 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of an increase in the size of the nodular disease burden are observed, or no signs of bladder tumor progression are observed. Based on visual lesions on cystoscopy, pelvic CT / MRI / PET, and biopsy. For the purposes of this study, cCR means that no signs of disease are observed in the bladder or notes. cPR means that for previously N0 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of nodular disease are observed, and for N1-N3 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of an increase in the size of the nodular disease burden are observed, or no signs of bladder tumor progression are observed. For previously N0 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of nodular disease are observed, and for N1-N3 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of an increase in the size of the nodular disease burden are observed, or no signs of bladder tumor progression are observed. For N1-N3 subjects, downstaging of the bladder tumor burden to <pT2 disease and no signs of an increase in the size of the nodular disease burden are observed, or no signs of bladder tumor ​​​There was no evidence of downstaging of the tumor burden or a decrease in the size of the nodal disease burden. Stable disease means persistent MIBC with no evidence of metastasis. M1 disease, or disease in the bladder based on cystoscopy and CT / MRI / PET Symptom control means a significant increase in the burden of bladder pain. Other secondary endpoints were the change in bladder-related symptoms from the first Symptoms, defined as the time from the date of insertion of the TAR-200 to the date of intervention for symptom relief Time to intervention for control, from date of first TAR-200 insertion to occurrence of first progression Time to progression, defined as time to date, 3 months, 6 months, 9 months, and 12 months Percentage of subjects receiving post-treatment intervention for local symptom control at 12 months and at 12 months The proportion of subjects surviving at 1 year of age is

[0178] To be eligible to participate in this study, subjects must meet the following inclusion criteria at the time of enrollment: All of them need to be fulfilled. 1. Histological evidence of muscle-invasive urothelial carcinoma (T2-T4a) of the bladder. Subjects must have a predominant transitional cell pattern. Subjects with evidence of nodal disease may also be included (cN0-cN3, M0). 2. Subjects must have had as complete a tumor resection as possible according to physician judgment. 3. Subjects use the physician procedure code 51595 or 51596 for cystectomy. The American College of Surgeons risk calculator (http: / / www. p: / / riskcalculator.facs.org / RiskCalculat or / PatientInfo.jsp) estimates that the RC is ≥ 5%, so the risk of death is The patient must be considered ineligible for RC due to a concurrent condition with a risk of relapse. 4. Subject refuses cisplatin-based chemotherapy (and by so doing is (also understand the risks and benefits) or meet the following criteria: ≥ 2 World Health Organization (WHO) or Eastern Coo Perioperative Oncology Group (ECOG) performance status or 60– 70% Karnofsky performance status, creatinine clearance of ≤60 mL / min (total Calculated or measured value), Common Terminology Criteria of ≥ 2 for Adverse Events(CTCAE)v4 Grade, hearing loss, C Peripheral neuropathy of TCAE v4 Grade ≥ 2, New York Heart Association Society ≥ Class III heart failure. Patients must be considered ineligible for cisplatin-based chemotherapy by 5. At least 4 months lifespan. 6. Meet the following requirements within 21 days prior to administration: hemoglobin ≥ 7.0 g / d L, absolute neutrophil count (ANC) ≥ 1,500 / mm3, platelet count ≥ 75,000 / mm3; Total bilirubin ≤ 2x upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3xULN, glomerular filtration rate ≥ Adequate bone marrow, liver, and Kidney function. 7. Subject is willing to undergo cystoscopy for placement and removal of investigational product.

[0179] Example 2 Twenty-three patients were enrolled in the study described in Example 1. The age range of the enrolled patients was 50-90 years. The mean age is 82.6 and the median age is 84. Patients were treated and evaluated according to the following criteria: Complete response, partial response, and stable disease were achieved after the induction phase. The patient received maintenance treatment.

[0180] result Seven patients discontinued the study at some point during the run-in period for various reasons. Ten of 16 patients completed all four cycles of treatment during the induction period. Patients completed the 180-day evaluation. Age range of 16 patients was 50-98. The mean age was 81.75 and the median age was 84.

[0181] At the end of the run-in period (study day 84), a 50% per-protocol outcome was assessed. A complete response rate of 100% and an overall response rate (ORR) of 80% were achieved. See Table 1. On an intention-to-treat (ITT) basis (including all 23 patients enrolled), the complete response rate was 30% and A response rate of 7% was achieved. Four consecutive doses were well tolerated in all 10 patients. The evidence suggests symptom control and sustained efficacy at 180 days. The patient progressed to maintenance administration.

[0182] [Table 1] NED: No signs of disease.

[0183] Thirteen patients were evaluated for symptoms of hematuria during treatment. Four patients had hematuria (chronic hematuria). had no history of hematuria (e.g., urinary, gross, incidental, or recurrent gross hematuria), or Patients 1 (who had chronic hematuria before), 5 ( 9 (previously had incident hematuria) and 9 (previously had recurrent gross hematuria) from day 0 In particular, patient number 1 had no hematuria for 200 days. .

[0184] [Table 2] * TBD: TBD; DC: Cancelled; ND * :Not measured.

Claims

1. A pharmaceutical composition comprising gemcitabine for use in treating bladder cancer in an individual, wherein the treatment is a) In the introductory phase, i) Placing a first intravesical device containing approximately 225 mg of gemcitabine into the bladder of the individual, and removing the first intravesical device after approximately 18 to 24 days, wherein the first intravesical device continuously releases gemcitabine into the urine in the individual's bladder during a first induction delivery period of at least approximately one week. ii) Placing a second intravesical device containing approximately 225 mg of gemcitabine into the bladder of the individual, and removing the second intravesical device after approximately 18 to 24 days, wherein the second intravesical device continuously releases gemcitabine into the urine in the individual's bladder during a second induction period of at least approximately one week, and the first intravesical device is removed before the second intravesical device is placed into the individual's bladder. iii) Placing a third intravesical device containing approximately 225 mg of gemcitabine into the bladder of the individual, and removing the third intravesical device after approximately 18 to 24 days, wherein the third intravesical device continuously releases gemcitabine into the urine in the individual's bladder during a third induction phase delivery period of at least approximately one week, and the second intravesical device is removed before the third intravesical device is placed into the individual's bladder, and iv) Placing a fourth intravesical device containing approximately 225 mg of gemcitabine into the bladder of the individual, and removing the fourth intravesical device about 18 to 24 days later, wherein the fourth intravesical device continuously releases gemcitabine into the urine in the individual's bladder during a fourth induction phase delivery period of at least about one week, and the third intravesical device is removed before the fourth intravesical device is placed into the individual's bladder. The introductory period, b) During the maintenance phase, approximately every three months, an intravesical device containing approximately 225 mg of gemcitabine is placed in the bladder of the individual, wherein the intravesical device continuously releases gemcitabine into the urine in the individual's bladder during a maintenance delivery period of at least approximately one week, and the intravesical device is removed approximately 18 to 24 days later. Maintenance phase, The pharmaceutical composition comprising the above.

2. The pharmaceutical composition according to claim 1, wherein the introduction period does not include a rest period.

3. The pharmaceutical composition according to claim 1 or 2, wherein each induction period and each maintenance period is approximately three weeks.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein gemcitabine is released in a dose of approximately 5 mg / day to approximately 50 mg / day during each induction period and each maintenance period.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of gemcitabine in the urine is about 1 μg / mL to about 10 μg / mL during each induction period and each maintenance period.

6. The pharmaceutical composition according to claim 5, wherein the concentration of gemcitabine in the urine is approximately 10 μg / mL during each induction period and each maintenance period.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the individual is unsuitable for or has rejected cisplatin-based chemotherapy.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the individual is unsuitable for, unqualified for, or has refused radical cystectomy.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the individual has muscle-invasive urothelial carcinoma of the bladder.

10. The pharmaceutical composition according to any one of claims 1 to 8, wherein the individual has nonmuscle-invasive bladder cancer.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the individual has bladder cancer of type T2, T3, or T4.

12. The pharmaceutical composition according to any one of claims 1 to 9 or 11, wherein the individual has muscle-invasive bladder cancer of type cT2, cT3, T3, or T4a.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the individual has M0 or N0 bladder cancer.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the intravesical device releases about 100 mg to about 225 mg of gemcitabine over a period of about three weeks.

15. The pharmaceutical composition according to claim 14, wherein the intravesical device releases about 200 mg of gemcitabine over a period of about three weeks.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the maintenance period continues for at least about one year.

17. The pharmaceutical composition according to claim 16, wherein the maintenance period is continued for the lifespan of the individual.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the average concentration of gemcitabine in the urine is about 5 μg / mL to about 20 μg / mL for at least one week during each induction period and each maintenance period.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein a resting period exists between the introduction period and the maintenance period.

20. The pharmaceutical composition according to claim 19, wherein the pause period following the introduction period is at least about one month.

21. The pharmaceutical composition according to claim 20, wherein the pause period following the introduction period is approximately one month to approximately three months.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the average concentration of gemcitabine in the urine is about 5 μg / mL to about 20 μg / mL over a period of 1 to 2 weeks during each induction period and each maintenance period.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein the introduction period includes five or more introduction period delivery periods.

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the intravesical device comprises a housing configured for intravesical insertion and a dosage form comprising gemcitabine, the housing configured to hold the dosage form and release gemcitabine.

25. The pharmaceutical composition according to claim 24, wherein the housing defines a reservoir, and the dosage form comprises a first unit housed in the reservoir and a second unit housed in the reservoir at a different position from the first unit, the first unit comprising gemcitabine, and the second unit comprising a functional agent for facilitating the in vivo release of the gemcitabine from the housing.

26. The pharmaceutical composition according to any one of claims 1 to 25, wherein the gemcitabine is released from the intravesical device by osmosis.

27. ​​The pharmaceutical composition according to any one of claims 1 to 26, wherein the gemcitabine is in a non-liquid form.

28. The pharmaceutical composition according to claim 27, wherein the non-liquid form is selected from the group consisting of tablets, granules, powders, semi-solids, capsules, and combinations thereof.

29. The pharmaceutical composition according to claim 25, wherein the first unit comprises one or more gemcitabine minitablets, and the second unit comprises one or more urea minitablets.

30. The pharmaceutical composition according to claim 24, wherein the housing is elastically deformable between a retaining shape configured to hold the device in the bladder of the individual and a positioning shape for the passage of the device through the urethra of the individual.

31. The pharmaceutical composition according to claim 24, wherein the housing comprises at least one orifice from which the gemcitabine is released.

32. The pharmaceutical composition according to any one of claims 1 to 31, wherein the intravesical device releases gemcitabine at a zero-order release rate over a long period of time during each induction phase delivery period and each maintenance phase delivery period, and subsequently releases gemcitabine at a reduced non-zero-order release rate over a decay period.

33. The intravesical device is A housing configured for insertion into the bladder cavity, wherein the housing defines a drug reservoir lumen and a retaining frame lumen, and the drug reservoir lumen has a discharge opening, A retaining frame including a nitinol wire located within the lumen of the retaining frame, A first unit housed within the lumen of the drug reservoir, the first unit containing gemcitabine tablets, and A second unit, housed in the lumen of the drug reservoir at a different location from the first unit, the second unit contains a urea tablet, and comprises: The housing is configured to release gemcitabine from the drug reservoir lumen through the release opening via the osmotic pressure generated by the urea tablet, The pharmaceutical composition according to any one of claims 1 to 32, wherein the housing is elastically deformable between a retaining shape configured to hold the device in the bladder of the individual and a placement shape configured to allow the device to pass through the urethra of the individual.