Drug delivery systems and methods for treating bladder cancer with gemcitabine

Abstract

The invention relates to drug delivery systems and methods for treating bladder cancer with gemcitabine. Drug delivery devices and methods are provided for administering gemcitabine to a patient in need of treatment of bladder cancer by administering gemcitabine into the bladder of the patient in an intravesical manner to achieve a sustained concentration of the gemcitabine in urine in the bladder, the sustained concentration of gemcitabine is sufficient to produce a therapeutically effective concentration of gemcitabine in tissue of the bladder. In embodiments, the topical administration into the bladder of the patient is at a median average amount of the gemcitabine (FBE) of from 1 mg / day to about 300 mg / day.

Description

[0001] The application is a divisional application with the same invention name as the parent case. The Chinese application number of the parent case is 201580011259.9, the international application number is PCT / US2015 / 019262, and the application date is March 6, 2015.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 61 / 949,215, filed March 6, 2014, which is incorporated herein by reference. Field of the Invention

[0004] The present invention relates generally to the treatment of cancer and, more particularly, to compositions, devices and methods for treating urinary bladder cancer. background

[0006] Bladder cancer is a significant medical problem, and currently available treatment options are unsatisfactory for several reasons.

[0007] In general, bladder cancer is classified as muscle-invasive bladder cancer (MIBC) or non-muscle-invasive bladder cancer (NMIBC). The pathological classification and staging of bladder cancer are as follows: pTa (urothelium involvement); pTis (high-risk urothelium restriction); pT1 (lamina propria invasion); pT2 (muscle-layer invasion); pT3 (perivesical fat infiltration); and pT4 (pelvic organ spread). Bladder cancer can also be classified by grade: grade 1 / 3 (well-differentiated); grade 2 / 3 (moderately differentiated); grade 3 / 3 (poorly differentiated). In addition, bladder cancer can be classified by stage as stage 0-IV. Most bladder cancers are transitional cell carcinomas of epithelial origin and are classified as non-muscle-invasive carcinomas (NMIBC) confined to the lining of the bladder. At the time of initial appearance, most bladder cancers are superficial NMIBC and include stage pTa, pTis, and pT1 disease. MIBC includes stage pT2, pT3, and pT4.

[0008] The typical clinical scheme of early bladder cancer is cystoscopy visualization, followed by surgical resection of the tumor, which is referred to as transurethral resection (TUR). However, there is a high recurrence rate after surgery, and cancer can progress to muscle-invasive disease. Therefore, surgery is often combined with the auxiliary intracapsular device (directly applying chemotherapeutics in the bladder by catheter) of chemotherapeutics or immunotherapeutics to help prevent or delay the incidence and severity of recurrence. Bacillus Calmette-Guerin (BCG) is this immunotherapeutic agent, and is usually instilled into the bladder after surgery. However, many patients do not respond to BCG, and BCG treatment can also induce a series of adverse effects that cause treatment to be stopped. Chemotherapeutics are usually retained for patients with BCG therapy failure. Chemotherapy is usually applied in an intravesical manner so that chemotherapeutics are concentrated at the tumor position and eliminate any residual tumor after resection, while avoiding systemic exposure of medicine.

[0009] One of the chemotherapeutic agents used in clinical trials for the treatment of bladder cancer is gemcitabine. Gemcitabine (2', 2'-difluorodeoxycytidine) is a pyrimidine analog with anti-metastatic bladder cancer activity. Gemcitabine can also be used in clinical trials to treat superficial bladder cancer and NMIBC by instillation in the bladder with various weekly schedules. Gemcitabine is usually in a range of 500mg to 2000mg, usually dissolved in up to 100ml of saline, instilled once or twice a week over 1 to 2 hours for several weeks.

[0010] It is known that the preparation is discharged from the bladder before reaching full efficacy. The shorter residence time of 1 to 2 hours limits the therapeutic benefit. In addition, high concentrations (40 mg / ml) and high doses (up to 2 grams per instillation) are used in attempts to reach therapeutic tissue levels in order to strive to overcome the residence time limit. However, the use of intravesical high-dose gemcitabine can lead to significant systemic absorption and cause gastrointestinal, bladder and bone marrow toxicity, further limiting the clinical utility except for local tolerance issues.

[0011] The literature also reports that intravenous systemic administration of gemcitabine by bolus injection (e.g., over 1 to 2 minutes) is better tolerated by patients than intravenous infusion (e.g., over 90 minutes). This suggests that prolonged exposure to gemcitabine increases toxicity and should be avoided.

[0012] Therefore, there remains a need for improved drug delivery methods and systems for treating bladder cancer.For example, there remains a need to administer therapeutic levels of gemcitabine to patients over a sustained period of time while avoiding or mitigating the toxicity and tolerability issues that have been observed to limit the clinical utility of gemcitabine. Brief description

[0014] In one aspect, a medicament comprising gemcitabine is provided for treating bladder cancer by locally administering gemcitabine to a patient's bladder to achieve a sustained concentration of gemcitabine in the urine in the bladder, the sustained concentration of gemcitabine being sufficient to produce a therapeutic concentration of gemcitabine in the bladder tissue, wherein the local administration to the patient's bladder is a median average amount of gemcitabine free base equivalent (FBE) of 1 mg / day to about 300 mg / day. In embodiments, the local administration to the patient's bladder is a median average amount of gemcitabine (FBE) of 1 mg / day to 200 mg / day, 5 mg / day to 100 mg / day, 10 mg / day to 50 mg / day, or 15 mg / day to 25 mg / day. In one instance, the local administration to the patient's bladder is a median average amount of gemcitabine (FBE) of about 20 mg / day. The topical administration to the patient's bladder may be continuous or intermittent. In embodiments, the continuous or intermittent administration is over a period of 1 day to 30 days, 1 day to 14 days, or 1 day to 7 days.

[0015] In a preferred embodiment, gemcitabine is delivered to the bladder from an intravesical drug delivery device, which continuously releases gemcitabine into the urine in the bladder over a sustained period. In another embodiment, gemcitabine is delivered to the bladder from a coating material applied to the bladder, which (e.g., a mucoadhesive preparation) releases gemcitabine into the urine in the bladder over a sustained period. In yet another embodiment, gemcitabine in liquid form is pumped into the bladder over a sustained period by a urethral catheter or suprapubic catheter deployed in the bladder.

[0016] In another embodiment, there is provided a drug delivery device for applying gemcitabine to a patient who needs to treat bladder cancer, the drug delivery device is applied to the patient's bladder by intravesical mode to reach a sustained concentration of gemcitabine in the urine in the bladder, and the sustained concentration of the gemcitabine is enough to produce a therapeutically effective concentration of gemcitabine in the tissue of the bladder. In a specific embodiment, the drug delivery device includes a housing configured for intravesical insertion and a dosage form comprising gemcitabine, wherein the housing keeps the dosage form and is configured to release gemcitabine into the bladder with an amount effective in treatment of prostate, wherein the device is configured to release gemcitabine into the bladder with a median average amount of gemcitabine from 1mg / days to about 300mg / days. In a preferred embodiment, the housing releases gemcitabine without a predefined release aperture. In the specific version of this preferred embodiment, the housing releases gemcitabine by diffusion through a drug permeable polymer wall. The housing containing gemcitabine and controllably releasing gemcitabine is elastically deformable between a retention shape configured to retain the device in a patient's bladder and a deployed shape for passing the device through the patient's urethra.

[0017] In yet another embodiment, a method for treating bladder cancer is provided, the method being achieved by locally administering gemcitabine to the patient's bladder to achieve a sustained concentration of gemcitabine in the urine in the bladder, the sustained concentration of gemcitabine being sufficient to produce a therapeutic concentration of gemcitabine in the bladder tissue. In an embodiment, a median average amount of gemcitabine (FBE) of 1 mg / day to about 300 mg / day is administered locally to the patient's bladder. In one embodiment, the method further comprises administering at least a second therapeutic agent to the patient. The second therapeutic agent can be administered intravesically. In another embodiment, the method further comprises administering urea or another solubility modifier to the bladder in an amount that effectively enhances or otherwise changes the dissolution of gemcitabine. In an embodiment, the second therapeutic agent and / or the solubility modifier are released from an intravesical device that releases gemcitabine. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1A-1B One embodiment of an intravesical drug delivery device as described herein that can be used to administer gemcitabine is shown.

[0020] Figure 2A-2B Another embodiment of an intravesical drug delivery device as described herein that can be used to administer gemcitabine is shown.

[0021] Figures 3A-3C Yet another embodiment of an intravesical drug delivery device as described herein that can be used to administer gemcitabine is shown.

[0022] Figure 4A-4B A method of inserting an intravesical drug delivery device into a patient's bladder to locally administer gemcitabine as described herein is shown.

[0023] Figure 5A Shown is material applied to the inner surface of the bladder wall for local administration of gemcitabine as described herein.

[0024] Figure 5B A method of applying a coating material as described herein to the inner surface of the bladder wall for topically administering gemcitabine is shown.

[0025] Figure 6 A method of administering a liquid drug or drug formulation into the bladder is shown.

[0026] Figure 7 Shown are the concentrations of gemcitabine in the prostate following intravesical instillation and intravenous administration.

[0027] Figure 8 Plasma levels of gemcitabine following intravesical instillation and intravenous administration are shown.

[0028] Fig. 9 Shown is the bladder instillation and intravenous administration of 14 C Gemcitabine concentration.

[0029] Fig. 10A -C shows an embodiment of an intravesical drug delivery device for releasing gemcitabine via a permeation disk. Fig. 10A is a plan view of the device. Fig. 10B yes Fig. 10A A cross-sectional view of one of the four drug reservoir modules of the device shown in , showing the drug tablets and osmotic discs of each module. Fig. 10C yes Fig. 10A A perspective view of a partial housing / body portion of the device shown in FIG. 1 prior to assembly with other components of the device.

[0030] Figure 11-12 It is shown that in vitro Fig. 10A -C is a graph showing the accumulated amount of gemcitabine released from the device.

[0031] Figure 13-14 is a graph showing the urine concentrations of each of gemcitabine, dFdU, and the combination thereof from animal studies. Details

[0033] It has been found that continuous delivery of gemcitabine via intravesical administration produces unexpected drug distribution across the bladder wall and achieves drug levels at or above the expected therapeutic threshold in all bladder layers - without significant plasma / systemic exposure. Thus, the compositions, systems, and methods described herein can be used to achieve therapeutically effective amounts of gemcitabine in bladder tissue in need while also being well tolerated by normal bladder tissue and minimizing systemic exposure.

[0034] As used herein, the term "gemcitabine" includes the compound gemcitabine, and pharmaceutically acceptable salts, esters, amides, solvates and prodrugs thereof. Specifically, the hydrochloride of gemcitabine is included. Gemcitabine can be formulated with one or more suitable pharmaceutically acceptable excipients.

[0035] In certain embodiments, a controlled amount of gemcitabine can be dissolved in the urine of the patient's bladder at a concentration and time period sufficient to produce and maintain therapeutic concentrations of the drug in the bladder tissue. However, since the bladder limits the absorption of urine components into the systemic circulation, systemic exposure of the drug is advantageously minimized.

[0036] Various methods can be used to reach the desired urine concentration of gemcitabine. In one embodiment, the drug can be provided by instilling a simple solution directly into the bladder. For example, during treatment, a solution of the drug can be pumped to the bladder in a continuous or pulsatile manner by a urethral catheter or a suprapubic catheter. In another embodiment, the drug is released from a device or composition deployed in the bladder, wherein the device or composition releases the drug (continuously or intermittently) at a rate that effectively produces the desired drug concentration in urine during a specified treatment period. For example, the drug can be released into the bladder from a device inserted into the bladder, and then the drug diffuses into the bladder. At the end of the treatment period, the device can be retrieved from the bladder, or the device can be removed by reabsorption, dissolution, excretion, or a combination thereof.

[0037] In a preferred embodiment, gemcitabine is administered to the bladder from an intravesical device. Examples of intravesical drug delivery devices that can be adjusted to achieve the dosage regimens described herein, and methods of deploying those devices into the bladder, are described in the following U.S. patent applications published: US2012 / 0203203 (Lee et al.); US2012 / 0089122 (Lee et al.); US 2012 / 0089121 (Lee et al.); US2011 / 0218488 (Boyko et al.); US2011 / 0202036 (Boyko et al.); US2011 / 0152839 (Cima et al.); US2011 / 0060309 (Lee et al.); US2010 / 0331770 (Lee et al.); US2010 / 0330149 (Daniel et al.); US 2010 / 0003297 (Tobias et al.); US 2009 / 0149833 (Cima et al.); US 2007 / 0202151 (Lee et al.); WO 2014 / 144066 (Lee et al.); US 2014 / 0276636 (Lee et al.); and WO 2015 / 026813 (Lee et al.).

[0038] In the embodiment of delivering gemcitabine from an intravesical drug delivery device, the drug can be packaged in the device in different forms, which may depend on the specific mechanism used by the device to controllably release the drug into the fluid (e.g., urine) in the bladder. In some embodiments, the drug is provided in a solid, semi-solid or other non-liquid form, which can advantageously promote the stable storage of the drug before using the device, and can advantageously enable the drug payload of the device to be stored in a volume smaller than the volume possible when the drug is packaged in the form of a liquid solution. In one embodiment, the non-liquid form is selected from tablets, granules, semi-solids (e.g., ointments, creams, pastes or gels), capsules and combinations thereof. In one embodiment, the drug is in the form of a variety of tablets, such as the miniature tablets described in U.S. Patent No. 8,343,516. In other embodiments, the drug can be packaged in a liquid form (such as, a solution with one or more pharmaceutically acceptable excipients).

[0039] Figure 1A 1 shows an embodiment of a drug delivery device 100. The device 100 includes a device body having a drug reservoir portion 102 and a retainer portion 104. In FIG1 , the device 100 is shown in a relatively expanded shape suitable for being retained in the body. After being deployed in the body, the device 100 can assume a relatively expanded shape to retain the drug delivery device in a body cavity or lumen.

[0040] For the purposes of this disclosure, terms such as "relatively expanded shape", "relatively high profile shape" or "retention shape" generally refer to any shape suitable for maintaining the device in the intended implantation position, including but not limited to the double-circle biscuit shape shown in Figure 1 that is suitable for maintaining the device in the bladder. Similarly, terms such as "relatively low profile shape" or "deployment shape" generally refer to any shape suitable for deploying the drug delivery device into the body, including linear or slender shapes suitable for deploying the device through a working channel of a catheter, cystoscope or other deployment instrument positioned in the urethra. In an embodiment, the drug delivery device can naturally assume a relatively expanded shape and can be deformed into a relatively low profile shape by hand or with the aid of an external device for insertion into the body. Once deployed, the device can spontaneously or naturally return to the initial relatively expanded shape in order to be maintained in the body.

[0041] In the illustrated embodiment, the drug reservoir portion 102 and the retaining frame portion 104 of the drug delivery device 100 are longitudinally aligned and connected to each other along their length, although other configurations are also possible. The drug delivery device 100 includes an elastic or flexible device body 106 that defines a drug reservoir lumen 108 (i.e., a drug housing) and a retaining frame lumen 110. The drug reservoir lumen 108 is designed to encapsulate a drug formulation containing the drug. In the illustrated embodiment, the drug formulation containing gemcitabine is in the form of a plurality of solid drug units 112, which may be tablets. The retaining frame lumen 110 is designed to be equipped with a retaining frame 114 to form the retaining frame portion 104. The lumen 108, 110 shown are separate from each other, although other configurations are also possible.

[0042] like Figure 1B As shown in the cross-sectional view of , the device body 106 includes a tube or wall 122 defining a drug reservoir lumen 108 and a tube or wall 124 defining a retention frame lumen 110. The tubes 122, 124 and the lumens 108, 110 can be generally cylindrical, wherein the drug reservoir lumen 108 has a relatively larger diameter than the retention frame lumen 110, although other configurations can be selected based on, for example, the amount of drug to be delivered, the diameter of the retention frame, and deployment considerations, such as the inner diameter of the deployment instrument. The wall 124 defining the retention frame lumen 110 can extend along the entire length of the wall 122 defining the drug reservoir lumen 108, so that the retention frame lumen 110 has the same length as the drug reservoir lumen 108, as shown, although in other embodiments one wall can be shorter than the other. In the illustrated embodiment, the two walls 122, 124 are attached along the entire length of the device, although intermittent attachment can be used.

[0043] like Figure 1A, the drug reservoir lumen 108 is loaded with many drug units 112 (comprising gemcitabine) in a serial arrangement. In practice, any number of drug units, for example, may be used, depending on the size of the reservoir and the drug units. The drug reservoir lumen 108 includes a first end opening 130 and an opposite second end opening 132. Once the drug units 112 are loaded, the inhibition plug 120 is disposed in the openings 130 and 132. In this embodiment, the constraint plug 120 is a cylindrical plug fixed to the openings 130, 132. In other embodiments, the openings 130 and 132 are closed using other structures or materials, which may include holes or water-permeable or drug-permeable walls that facilitate the entry or exit of water or drugs during use, depending on the specific embodiment.

[0044] In other embodiments, the drug reservoir lumen can be loaded with gemcitabine forms other than as solid drug units. For example, gemcitabine can be in the form of suspensions, solutions or emulsions such as in oily or aqueous vehicles, and can contain preparatons, such as suspending agents, stabilizers and / or dispersants. Alternatively, active ingredients can be in the form of powders obtained by aseptic separation of sterilized solids or by lyophilized solutions, and are reconstituted with suitable vehicles (e.g., sterile, pyrogen-free water) before use.

[0045] In one embodiment, gemcitabine is formulated with one or more excipients including a viscosity enhancer to control the release of dissolved gemcitabine from the release aperture in the device housing. In another embodiment, the device reservoir includes gemcitabine and a viscosity enhancer, but they are not co-formulated and are instead provided in a discrete region in the reservoir (e.g., as a separate tablet). Suitable viscosity enhancers including but not limited to polyethylene oxide (PEO) are known in the pharmaceutical field. In some variations of the embodiment, the viscosity enhancer may be provided (e.g., formulated) with urea or another osmotic agent.

[0046] In one embodiment, gemcitabine is administered to the patient together with a solubility enhancer. In one embodiment, the solubility enhancer is urea. In one embodiment, urea is provided in tablets or other solid forms, and is loaded in the drug reservoir of the intravesical drug delivery device together with gemcitabine. Depending on the device, urea can also be used as an osmotic agent and play a role to promote the generation of osmotic pressure in the drug reservoir. In a specific embodiment, gemcitabine and an osmotic agent are configured to be positioned in the separate tablets (or other solid forms) in the different zones of the drug reservoir as described in PCT WO 2015 / 026813 (Lee et al.), and the application is incorporated herein by reference.

[0047] The retention frame lumen 110 is loaded with a retention frame 114, which may be an elastic wire, for example, a superelastic alloy such as nitinol. The retention frame 110 may be configured to spontaneously recover to a retention shape, such as the exemplary "burrito" shape shown or another spiral shape, such as those disclosed in the previously incorporated applications. Specifically, the retention frame 114 may retain the device 100 in the body, such as in the bladder. For example, the elastic limit and modulus of the retention frame 114 may allow the device 100 to be introduced into the body in a relatively low-profile shape, allowing the device 100 to recover to a relatively expanded shape once it enters the body, and preventing the device from assuming a relatively low-profile shape in the body in response to an expected force (such as the hydrodynamic force associated with detrusor contraction and urination). Therefore, once the device 100 is implanted, it can be retained in the body, thereby limiting or preventing accidental discharge.

[0048] The material used to form the device body 106 can be at least partially elastic or flexible to allow the device 100 to move between the deployed shape and the retention shape. When the device is in the retention shape, the retention frame portion 104 can tend to be located inside the drug reservoir portion 102, as shown, although in other cases, the retention frame portion 104 can be located inside, outside, above, or below the drug reservoir portion 102.

[0049] The material used to form the device body 106 can be water permeable so that once the device is implanted, a solubilizing fluid (e.g., urine) can enter the drug reservoir portion 102 to dissolve the drug unit 112. For example, silicone or another biocompatible elastic material can be used. In other embodiments, the device body can be at least partially formed of a water-impermeable material.

[0050] Figure 2A Another embodiment of an intravesical drug delivery device 200 is shown, which includes a drug reservoir 202 loaded with a drug 212, and a retention structure including two filaments 220, 222 associated with a fastener 230. As shown, the drug reservoir 202 is deployable in a relatively linear configuration (such as, Figure 2A shape shown) and a relatively circular retaining shape (such as, Figure 2BThe device 200 can be a thin and elongated tube that is deformed between the two shapes shown in the figure. The drug 212 can be loaded in a tube in a flexible form so that the drug reservoir 202 can move between the two shapes. For example, the drug 212 can be a number of solid drug tablets, liquids or gels. The filaments 220, 222 can be attached to the opposite ends of the drug reservoir 202 and combined by fasteners 230. The fasteners 230 can be adjusted to adjust the position of one filament 220 relative to another filament 222, thereby adjusting the position of one end of the drug reservoir 202 relative to the other end. By adjusting the filaments 220, 222 to pull the two ends of the drug reservoir 202 more closely together, the device 200 can present a holding shape, and thereafter by preventing the fasteners 230 from being used to adjust the filaments 220, 222, the device 200 can be kept in a holding shape. In such an embodiment, after the device 200 is inserted into the bladder, the device 200 is manually adjusted to a holding shape by manually adjusting the filaments 220, 222.

[0051] In the illustrated embodiment, the fastener 230 is a compression nut that allows the portions of the filaments 220, 222 between the ends of the drug reservoir and the compression nut to be shortened, but prevents these portions of the filaments 220, 222 from extending. Thus, by pulling one or both of the filaments 220, 222 with the compression nut, the ends of the drug reservoir 202 can be pulled closer together, causing the device 200 to assume a holding shape. Once the filaments 220, 222 are adjusted in this way, the compression nut prevents the filaments 220, 222 from extending, thereby maintaining the device in the holding shape. Thus, once the device 200 is implanted, manually adjusting the device 200 to the holding shape only requires pulling one or both of the filaments 220, 222, although other fasteners 230 that require separate operations may be used. Other fasteners may also be used.

[0052] Figures 3A-3C Another embodiment of an intravesical drug delivery device is shown in FIG. In this embodiment, the device includes a housing 300 having a single continuous structure having a plurality of separate drug reservoir lumens 320 and optionally at least one retainer lumen 330 in which a retainer 360 is disposed. Each drug reservoir lumen 320 has two defined openings, such as Figure 3B The housing is shaped like a cross-sectional view shown in FIG. 1 and is sized to accommodate at least one solid drug unit 340. For example, the solid drug unit 340 may be a drug tablet or capsule. In another embodiment (not shown), each drug reservoir lumen has a single defined opening. The housing may be formed of a flexible polymer such as silicone. Figure 3B Yes Figure 3A A cross-sectional view of a plane bisecting along line 3B-3B in the drug reservoir lumen 320 of the housing shown. Figure 3BAs shown, the monolithic housing 300 has two defined openings (350a, 350b) in its drug reservoir lumen 320 that contact both ends of the solid drug unit 340. In this embodiment, the cage lumen 330 is aligned parallel to the longitudinal axis of the housing and perpendicular to the drug reservoir lumen 320. Figure 3C When Figure 3A The device 300 is shown in a perspective view of a portion of an embodiment of the device when it is in its retained shape, the perspective view being obtained when the retainer 360 is disposed in the retainer lumen 330. The drug reservoir lumen 320 and the retainer lumen 360 in the housing of this embodiment are oriented so that the drug reservoir lumen 320 is outside the arc of the retainer 360. Alternatively, the Figure 3C The housing in the device is rotated 180 degrees around the holder 360 to produce a configuration in which the drug reservoir lumen 320 is arranged within the arc of the holder 360. With this embodiment, when deployed and retained in the bladder, the device provides sufficient direct contact between the solid drug unit and the urine surrounding the device. In an embodiment, the release of the drug from the device is controlled by the corrosion of the contacting portion of the surface of the solid drug unit, so that the drug release rate from the drug delivery device can be proportional to and limited by the total contact surface area of ​​the solid drug unit.

[0053] The release of gemcitabine from the intravesical device described herein can be driven and controlled by different mechanisms of action. In different embodiments, the drug can be released from the intravesical drug delivery device by diffusion through the drug housing wall, by diffusion through one or more limited holes in the drug housing wall, by osmotic pressure through the holes in the drug housing, by osmotic pressure through one or more instantaneously formed microchannels, by corrosion of the drug formulation contacted with urine in the bladder, or by a combination thereof. In a preferred embodiment, drug release is controlled by drug dissolution through a drug permeable polymer or matrix component of a limited portion device housing. In one embodiment, the device includes a drug permeable polymer component.

[0054] In a specific embodiment, the drug delivery device comprises a housing having a closed drug reservoir lumen constrained by a first wall structure and a hydrophilic second wall structure; and a drug formulation comprising gemcitabine, contained in the drug reservoir lumen, wherein the first wall structure is permeable or impermeable to water and impermeable to the drug, and the second wall structure is permeable to gemcitabine. The wall of the drug reservoir that constrains and defines the device is made of a first material as a first wall structure and a second material as a second wall structure, so that drug release occurs substantially only through the second material. In one embodiment, the device does not include a hole; drug release occurs only through the second wall structure by diffusion. As used herein, the terms "impermeable to the drug" and "impermeable to water" refer to a wall structure that is substantially impermeable to the drug or to water, so that substantially no drug or water is released through the wall structure during the therapeutic release period. For use in the bladder, it is desirable that the device be compliant (i.e., foldable, soft-feeling) during detrusor contraction in order to avoid or alleviate discomfort and irritation to the patient. Thus, the durometer of the first and second materials of construction is a design consideration, and the proportion of high durometer materials can be limited when constructing a device housing of a given size while maintaining appropriate compliance within the bladder. TM Thermoplastic polyurethane (Lubrizol Corporation) may have a Shore durometer greater than 70A, such as 80A to 65D, while the silicone tubing may have a Shore durometer of 50A to 70A. Therefore, it may be advantageous to utilize a combination of these two different polymer materials rather than making the device entirely of a water-swellable, hydrophilic, drug-permeable second material.

[0055] Continuing with this specific embodiment, the first wall structure may be formed of silicone. For example, the housing may include a silicone tube, the wall of which serves as the first wall structure. In other embodiments, the first wall structure may be formed of other water-permeable materials. The drug is preferably in solid form (e.g., a tablet or multiple tablets), and the first wall structure is water-permeable to allow the drug to dissolve in vivo when in the drug reservoir lumen. For example, the first wall structure may be formed of silicone with a Shore hardness value of about 50A to about 70A. The second wall structure may be a hydrophilic polymer that is designed to absorb water. For example, the second wall structure may be a hydrophilic elastic material that is at least partially made of a hydrophilic polyurethane, a hydrophilic polyester, or a hydrophilic polyamide. In a preferred embodiment, the second wall structure includes a thermoplastic polyurethane, such as a Tecophilic TM Thermoplastic polyurethane, HydroThane TM Thermoplastic polyurethane (AdvanSource Biomaterials Corp.), Quadraphilic TMThermoplastic polyurethanes (Biomerics, LLC) (ALC grades are aliphatic polycarbonate-based hydrophilic polyurethanes, and ALE grades are aliphatic polyether-based hydrophilic polyurethanes), HydroMed TM (AdvanSource Biomaterials Corp.) or (HEXPOL TPE). Another hydrophilic polymer is polyether block amide MV 1074 SA 01 MED (Arkema), the polymer is a thermoplastic elastomer made of a flexible and hydrophilic polyether and a rigid polyamide. For example, the hydrophilic material of the second wall structure may have a Shore hardness value of about 70A to about 65D. The specific material and its thickness and wall area may be selected to control the water and drug permeation rate and thus achieve a specific release profile of gemcitabine.

[0056] The arrangement of the first and second wall structures can adopt various forms.In certain embodiments, the first wall structure is a cylindrical tube and the second wall structure is an end wall arranged at least one end of the cylindrical tube, or the first wall structure and the second wall structure are adjacent to each other and form a cylindrical tube together.That is to say, control drug release through the permeable parts of the drug by drug diffusion, and the parts define a part for the closed device housing. The permeable wall structure of the drug can be positioned, set in size and have material properties, to provide the controlled rate of drug diffusion from the device.In one embodiment, as described in Example 4 below, the first wall structure is a cylindrical tube and the second wall structure is an end wall arranged at least one end of the cylindrical tube.

[0057] Figure 4A and 4B 1 shows one embodiment of inserting an intravesical device 400 for subsequent controlled release of the drug into the bladder. Here, the device 400 is shown as assuming a retained shape when it leaves a deployment instrument 402. The deployment instrument 402 can be any suitable device. The deployment instrument can be a luminal device such as a catheter, a urethral catheter, or a cystoscope. The deployment instrument 402 can be a commercially available device or a device that is particularly suitable for use with the drug delivery device of the present invention. Figure 4B Device 400 is shown inserted into the bladder, wherein the adult male anatomy is shown by way of example. Deployment instrument 402 is inserted through the urethra to the bladder, and device 400 may be passed / through deployment instrument 402, driven by a stylet or lubricant flow or a combination thereof until device 400 exits into the bladder and is in a retained shape as shown.

[0058] From the research described in the following examples, it has been surprisingly found that the device embodiment with extremely small release holes or orifices is preferred, and the device embodiment that releases the drug in the absence of a predefined orifice is more preferred. This is because it is observed that these embodiments can effectively eliminate or at least substantially reduce the incidence of urothelial damage compared to the device embodiment utilizing a relatively large release orifice. Without being bound by any theory, it is believed that the larger orifice can form a local high drug concentration of gemcitabine at the surface of the urothelial tissue in the area adjacent to the device release hole, and these local tissue areas can therefore be damaged. In contrast, in the case where the device system utilizes a release mechanism without a predefined orifice or with a very small release orifice, the local high drug concentration is unlikely to occur. Examples of such suitable "no orifice" release systems are described in PCT Patent Application Publication No. WO 2014 / 144066 (TB 130) and U.S. Patent Application Publication No. 2014 / 0276636 (TB 134), which are incorporated herein by reference.

[0059] In some embodiments where the device includes a drug in solid form, elution of the drug from the device occurs after the drug within the device dissolves. Bodily fluid enters the device, contacts and solubilizes the drug, and thereafter the dissolved drug diffuses out of the device under osmotic pressure or by diffusion or flows out of the device. For example, where the device is implanted in the bladder, the drug may dissolve upon contact with urine.

[0060] In various embodiments, the intravesical device can release the drug continuously or intermittently, so as to reach the drug concentration of the therapeutically effective concentration of the drug produced in the prostate in the bladder within a duration of 1 hour to 1 month (e.g., 2 hours to 2 weeks, 6 hours to 1 week, 24 hours to 72 hours, etc.). In certain embodiments, the intravesical device can release gemcitabine in an amount of 1 mg / day to 1000 mg / day (e.g., 20 mg / day to 300 mg / day or 25 mg / day to 300 mg / day). In certain embodiments, these release rates are provided within a 14-day to 21-day treatment period.

[0061] In another embodiment, the coating material can be applied to the bladder wall (e.g., to the urothelial area within the bladder) in an intravesical manner, wherein the coating material comprises gemcitabine or other drugs and one or more excipient materials that promote adhesion of the coating material to the bladder wall and provide continuous controlled release of the drug during treatment. The coating material can be a mucoadhesive preparation, such as a gel, an ointment, a cream, a paste, a film, an emulsion, a tablet, a polymer, or a combination thereof. The mucoadhesive preparation polymer may include a hydrogel or a hydrophilic polymer, polycarbophil (i.e., Carbopol, etc.), chitosan, polyvinyl pyrrolidone (PVP), a lectin, a polyethylene glycol polymer, a cellulose, or a combination thereof. Suitable celluloses include methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC), or a combination thereof. The coating material may include a penetration enhancer. Non-limiting examples of penetration enhancers include dimethyl sulfoxide (DMSO), sodium carboxymethylcellulose (NaCMC), lipids, surfactants, or a combination thereof. As Figure 5A As shown, the coating substance 500 can be deployed in the bladder 550 such that the coating substance 500 engages the bladder wall 552 .

[0062] The coating material may be deployed into the bladder using a deployment instrument. Figure 5B 5 is a sagittal view of the male urogenital system showing that the coating material 500 is being deployed into the implantation site by the deployment instrument 502. By way of example, the male anatomy is shown and the implantation site is shown as the bladder 550. The coating material 500 may be an embodiment of one of the coating materials described herein. The deployment instrument 502 may be any device designed to pass through the natural lumen of the body in order to reach the intended implantation site. In order to be deployed in the bladder 550, the deployment instrument 502 is sized and shaped so as to pass through the patient's urethra 560 to reach the bladder 550, as shown. The deployment instrument 502 may be a known device, such as a catheter or cystoscope, or a specially designed device. The deployment instrument 502 is used to deploy the coating material 500 into the body and then remove it from the body, thereby completely implanting the coating material 500 into the body. Once so implanted, the coating material 500 can release the drug into the body over an extended period of time. A similar process can be used to deploy any of the devices or drugs described herein into other parts of the body through other natural lumens. For example, as Figure 6 As shown in , a deployment instrument 602 may be used to deploy a liquid drug or drug formulation 600 into a bladder 650 by passing the deployment instrument 602 through a urethra 660 .

[0063] In one embodiment, a second therapeutic agent is administered to the patient. Relative to the administration of gemcitabine, the second agent may be administered simultaneously, sequentially or in an overlapping manner. The second therapeutic agent may be administered intravesically. The methods and systems described herein may be used to administer a second therapeutic agent intravesically. The second therapeutic agent may include a cytotoxic agent, an analgesic, an anti-inflammatory agent, or a combination thereof. The second agent may play a role through a mechanism of action different from that of gemcitabine, and / or may play a role synergistically with gemcitabine. In one embodiment, the second therapeutic agent prevents, treats or improves cystitis of the bladder. In yet another embodiment, gemcitabine is first used as a chemoimmunotherapeutic (e.g., during the first week after TURBT), wherein bacillus Calmette-Guérin (BCG) is periodically administered thereafter for a period of time that continues thereafter. See, for example, Cho et al., J. Int'l Med. Res. 37: 1823-30 (2009).

[0064] In various embodiments, gemcitabine may be administered intravesically to the patient before TURBT, after TURBT, before or after TURBT, or without TURBT.

[0065] In one embodiment, intravesical gemcitabine is used in the treatment of non-muscle invasive bladder cancer (NMIBC). In another embodiment, intravesical gemcitabine is used in BCG-refractory NMIBC. In yet another embodiment, it is used in a repeated dose manner with an induction phase, followed by a series of maintenance doses, e.g., one-week treatment once a month for three months, followed by a one-week maintenance dose once every three months, as appropriate.

[0066] As used herein, the term "patient" or "subject" refers to a human or other mammal, such as in veterinary, livestock, and clinical research applications. In specific embodiments, the patient or subject is an adult. In other embodiments, the patient or subject includes cattle, dogs, cats, goats, sheep, and pigs.

[0067] The present invention may be further understood with reference to the following non-limiting examples.

[0068] Example 1: Uptake of gemcitabine from the bladder by the prostate

[0069] Administer via intravesical catheterization as a 6-hour or 24-hour continuous instillation or by a single IV bolus 14 Gemcitabine was studied in male Sprague Dawley rats. 6.9 mg and 26.6 mg of gemcitabine were instilled into the bladder over a 6-hour or 24-hour continuous infusion, respectively. A single intravenous bolus consisted of 5.0 mg of gemcitabine.

[0070] The blood ( Figure 8 ), urine, and tissue samples (eg, bladder, prostate) ( Figure 7 and 9 ) were collected and analyzed for gemcitabine content. The results are shown in Figure 7-9 These results indicate that sustained gemcitabine urine concentrations have been found to produce significant gemcitabine levels in bladder tissue that meet or exceed therapeutic concentrations based on in vitro bladder cancer cell experiments. Fig. 9 Gemcitabine levels in the bladder are shown in , which also depicts significantly lower gemcitabine concentrations in the bladder 24 hours after clinically relevant IV dosing. Fig.14 Observed gemcitabine levels in each of the bladder epithelium, lamina propria, muscularis, and adventitia are shown in , which also shows the target effective range of gemcitabine tissue concentrations.

[0071] Example 2: Gemcitabine Study in Large Mixed Breed Hounds

[0072] Two gemcitabine delivery systems designed to release therapeutic levels (4 mg / day and 40 mg / day) into the urine were screened. Figure 1A-1B The device uses a laser drilled orifice or a perforated orifice to release gemcitabine. The tested system was compared to an intravesical instillation designed to simulate a standard intravesical dose used clinically. The test animals were large mixed breed beagle dogs with N=3 for each group.

[0073] Each system shows different gemcitabine release rates in vitro. In vivo, a system produces extremely low urine and tissue concentrations, but is well tolerated by the tested animals. Another system produces target urine concentrations, but is poorly tolerated by the tested animals. The urine curve is still variable, and the duration of drug release is unacceptably short. It is also observed that intravesical administration has produced significant urothelial damage that meets the symptoms reported in the literature.

[0074] In conclusion, this study demonstrates that device / tablet formulation design influences gemcitabine urine concentrations and bladder tolerance over time.

[0075] Example 3: Gemcitabine intravesical instillation study in minipigs

[0076] Varying concentrations of gemcitabine were infused into pigs for 7 days, N=5 (2 males and 3 females per treatment group). The animals were dosed at concentrations selected to include the target dose for bladder cancer in humans. For comparison, a gemcitabine release device (e.g., a 10-mm-long) with a large bore end cap (a restraining plug with large holes through which the drug is released) was placed in a 10-mm-long tube. Figure 1A-1BThe wide-bore end caps (shown in Figure 2) were deployed in separate animal groups with moderate in vitro release rates. All perfusion groups tolerated gemcitabine well, including the highest perfusion dose. In contrast, the gemcitabine release device produced moderate urine concentrations but was not well tolerated.

[0077] Example 4: Modular device for releasing gemcitabine via an osmotic system

[0078] Gemcitabine hydrochloride was tested in a four-module apparatus 1000, which is shown in FIG. Fig. 10A -C. Fig. 10A The device 1000 is shown to include four drug reservoir modules 1010A, 1010B, 1010C, and 1010D. For clarity, Fig. 10C Only the housing portion of the device is shown (with other components omitted), and only with respect to drug reservoir modules 1010A and 1010D. Fig. 10C 1010A and 1010D are shown as being integrally connected by the wall portion 1012 and the retainer lumen 1014. The reservoir sidewalls 1040A and 1040D, as well as the wall portion 1012 and the retainer lumen 1014, are formed by cutting away the dual lumen silicone tubing. (A four-module device is made by cutting away three spacer segments of the dual lumen silicone tubing). Each drug reservoir module includes a silicone tubing made of MED-4750 (Nusil) with a size of 2.64 mm ID and 0.20 mm wall thickness. The silicone tubing includes a retainer lumen with a 0.51 mm ID and a 0.20 mm wall thickness. A nitinol retainer is inserted into the retainer lumen 1014. Fig. 10B The structure of drug reservoir module 1010A is shown, including disc 1060, through which dissolved drug is released by diffusion. (The other three drug reservoir modules are identical in construction to module 1010A.) Disc 1060 is stabilized within the lumen of cylindrical tube sidewall 1040A by sandwiching it between outer gasket 1100 and inner gasket 1120. Each disc 1060 is made of HP-93A-100 ( The silicone tube 1040A is made of thermoplastic polyurethane (TPU), and the dimensions of each disk 1060 are approximately 0.5 mm thickness and 3.0 mm OD. The OD of the disk (3.0 mm) is larger than the silicone tube ID (2.64 mm), so the disk fits frictionally into the silicone tube. The inner and outer silicone washers 1120, 1100 are made of MED-4780 (Nusil) and are located next to the disk 1060, with silicone adhesive applied around the washers 1120, 1100 to secure them in the silicone tube 1040A. The dimensions of the ID, OD, and length of the silicone outer washer 1100 are approximately 2.5 mm, 3.2 mm, and 2 mm, respectively, and the dimensions of the ID, OD, and length of the silicone inner washer 1120 are approximately 1.58 mm, 2.77 mm, and 2 mm, respectively.

[0079] A plurality of drug tablets 1080 having an OD of 2.6 mm were loaded into the silicone tube 1040A, after which both ends of the reservoir were closed with a disk 1060 and inner and outer gaskets 1120 and 1100. The tablet formulation was 90% gemcitabine hydrochloride, 5% PVP, 2.5% magnesium aluminum silicate, and 2.5% magnesium stearate. The total mass of tablets loaded into each four-module device was approximately 800 mg.

[0080] In vitro release experiments were performed at 37°C using three units (R204-4 to 6). The release medium was deionized water and time point samples were collected. Gemcitabine release was controlled by diffusion across the Tecophilic disk. The cumulative amount and release rate (in free base equivalent (FBE)) are shown in Fig.11 and Fig.12 Each error bar is the standard deviation around the mean (n=3). Some error bars are smaller than the symbol.

[0081] Three Göttingen minipigs were used to test devices of the same design in vivo. Each device was inserted non-surgically through the urethra via a cystoscope into the bladder of each animal. Urine concentrations of gemcitabine and 2',2'-difluoro-2'-deoxyuridine (dFdU) were measured over an 8-day period. After the 8-day study, each device was removed non-surgically through the urethra via a cystoscope and forceps. Urine concentrations of combined gemcitabine and dFdU are shown in Fig.13 middle.

[0082] Example 5: Gemcitabine Delivery Device Screening Study in Minipigs

[0083] A series of prototype screening studies were conducted to improve the design of drug delivery systems based on the inherent gemcitabine tolerance found in the minipig infusion studies described above. In this study, three prototype devices were designed to release therapeutic levels of gemcitabine into the urine. Two devices had Figure 1A-1Bdesign (with wide-bore end caps or laser-drilled orifices for drug release), and one device has Figures 10A-10C Design (Drug Permeable Disc for Drug Release). Three studies were completed, each testing a single prototype design in three minipigs, in which blood and urine samples were collected centrally over a 7-day period.

[0084] Discovery of a wide-diameter end cap for drug release Figure 1A-1B The designed device produced consistent urothelial injury in animals. However, it was found that Figure 1A-1B The designed device, which contains a viscosity enhancer and gemcitabine, reduces the incidence of urothelial injury. Figures 10A-10C The designed non-orifice device completely eliminates the incidence of urothelial injury. It is believed that this device prevents transient high local gemcitabine concentrations (at the tissue surface adjacent to the drug release orifice of the device) that are believed to contribute to the incidence of urothelial injury.

[0085] Example 6: Gemcitabine Delivery Device Screening Study in Minipigs

[0086] In this study, the permeability prototype device is designed to release the gemcitabine of therapeutic level into urine. As generally described in PCTWO 2015 / 026813, the device is configured to use the gemcitabine tablet and the osmotic agent tablet positioned in the separate position in the drug reservoir, and the application is incorporated in the relevant part of this paper. The first subset of the device each includes a silicone tube, which has a 75 micron laser-drilled orifice in the center of the zone between the tube ends for drug release. The lumen of the tube is loaded with a tablet of a mixture of gemcitabine and urea in the central area near the release orifice, and is loaded with a tablet of urea / Lubritab in the terminal area of ​​the lumen. The second subset of the device each includes a silicone tube, which has a 150 micron laser-drilled orifice in the center of the zone between the tube ends for drug release. The lumen of the tube is loaded with a tablet of a mixture of gemcitabine and urea in the central area near the release orifice, and is loaded with a tablet of urea / PEO in the terminal area of ​​the lumen. The device was tested in miniature pigs and in vitro, measuring the gemcitabine accumulated and released on average in 7 days. The gemcitabine release rate from the 75 micron orifice device was approximately 120 mg in 7 days, and the gemcitabine release rate from the 150 micron orifice device was approximately 140 mg in 7 days. Using urea / PEO preparations, when compared with urea / Lubritab preparations, it was observed that the urine concentration changes over time were moderately smaller. The viscosity of the drug solution dissolved in the device lumen can therefore be a factor in controlling drug release.

[0087] Conclusions from the Examples

[0088] Literature studies that provide target concentrations - in vitro concentrations across tumor cell lines generally have IC50 values ​​ranging between 0.5 μg / g and 3.0 μg / g (micrograms / gram) for responding cell lines (see, Jeon et al., J. Urol. 186(5):2084-93 (2011)). The literature also suggests that high urine concentrations (e.g., 2000 mg in up to 50 mL) are required for efficacy, but intravesical instillation to achieve such concentrations is associated with safety and tolerability issues, systemic toxicity issues, and reduced urinary tract symptoms (LUTS) (see, Cattel et al., Annals Oncol. 17(5th Supplement):v142-47 (2006)).

[0089] However, from the studies described in the preceding examples, the concentrations of gemcitabine in urea needed to achieve these therapeutic tissue concentrations have been determined and found to be tolerated by the urothelium. In other words, high intravesical urine concentrations are not required. Specifically, it has been found that an intravesical system that delivers 1 / 100 of these levels (e.g., 20 mg in up to 50 mL) can be effective.

[0090] Furthermore, it has been found that in contrast to the literature presented regarding intravesical instillation of gemcitabine, prolonged intravesical delivery of gemcitabine can be performed without damage to the urothelium.

[0091] The publications cited herein and the materials for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be apparent to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to be within the scope of the appended claims.

Claims

1. A medicament comprising gemcitabine for treating bladder cancer by topically administering the gemcitabine to a patient's bladder to achieve a sustained concentration of the gemcitabine in the urine in the bladder, the sustained concentration of the gemcitabine being sufficient to produce a therapeutic concentration of the gemcitabine in the bladder tissue, wherein said topical administration to said patient's bladder is a median mean amount of said gemcitabine (FBE) ranging from 1 mg / day to about 300 mg / day.

2. The medicament of claim 1, wherein the local administration into the bladder of the patient is a median average amount of the gemcitabine (FBE) ranging from 1 mg / day to 200 mg / day.

3. The medicament of claim 1, wherein the local administration into the bladder of the patient is a median average amount of the gemcitabine (FBE) ranging from 5 mg / day to 100 mg / day.

4. The medicament of claim 1, wherein the local administration into the bladder of the patient is a median average amount of the gemcitabine (FBE) ranging from 10 mg / day to 50 mg / day.

5. The medicament of claim 1, wherein the local administration into the bladder of the patient is a median average amount of the gemcitabine (FBE) between 15 mg / day and 25 mg / day.

6. The medicament of claim 1, wherein the local administration to the patient's bladder is at a median average amount of the gemcitabine (FBE) of about 20 mg / day.

7. The medicament of any one of claims 1 to 6, wherein the local administration into the patient's bladder is continuous over a period of 1 to 30 days.

8. The medicament of any one of claims 1 to 6, wherein the topical administration into the patient's bladder is intermittent over a period of 1 to 30 days.

9. The medicament of any one of claims 1 to 6, wherein the local administration into the bladder of the patient is intermittent or continuous over a period of 1 to 14 days.

10. The medicament of any one of claims 1 to 6, wherein the local administration into the bladder of the patient is continuous over a period of 1 to 7 days.

11. The medicament of any one of claims 1 to 6, wherein the gemcitabine is delivered into the bladder from an intravesical drug delivery device that continuously releases the gemcitabine into the urine in the bladder over a sustained period of time.

12. The medicament of claim 11, wherein the intravesical drug delivery device releases the gemcitabine continuously into the urine in the bladder over a period of 1 to 14 days.

13. The medicament of claim 12, wherein the intravesical drug delivery device comprises a housing that contains the gemcitabine and controllably releases the gemcitabine and is elastically deformable between a retention shape configured to retain the device in a patient's bladder and a deployed shape for passing the device through the patient's urethra. The agent according to claim 13 , wherein the gemcitabine contained in the shell is in a non-liquid form.

15. The medicament of claim 14, wherein the non-liquid form is selected from the group consisting of tablets, granules, semisolids, capsules, and combinations thereof.

16. The medicament of any one of claims 1 to 6, wherein the gemcitabine is delivered into the bladder from a coating material applied to the bladder, the coating material releasing the gemcitabine into the urine in the bladder over a sustained period of time.

17. The medicament of claim 16, wherein the coating material comprises a mucoadhesive preparation.

18. The medicament of claim 17, wherein the topical administration into the patient's bladder is continuous over a period of 1 to 14 days.

19. The medicament of claim 17, wherein the topical administration into the patient's bladder is continuous over a period of 1 to 7 days.

20. The medicament of any one of claims 1 to 6, wherein the local administration comprises pumping the gemcitabine in liquid form into the bladder via a urethral catheter or a suprapubic catheter deployed into the bladder.

21. The medicament of claim 20, wherein the local administration into the patient's bladder is continuous or intermittent over a period of 1 to 7 days.

22. A drug delivery device comprising a medicament according to any one of the preceding claims, the drug delivery device being configured to release the gemcitabine when the drug delivery device is inserted into the bladder.

23. A method of administering a drug to a patient in need of treatment for bladder cancer, the method comprising: Gemcitabine is administered intravesically into the bladder of the patient to achieve a sustained concentration of the gemcitabine in the urine in the bladder, the sustained concentration of the gemcitabine being sufficient to produce a therapeutically effective concentration of the gemcitabine in the tissue of the bladder.

24. The method of claim 23, further comprising administering to the patient at least a second therapeutic agent.

25. The method of claim 24, wherein the second therapeutic agent is administered intravesically.

26. The method of claim 23, further comprising administering urea or another solubility altering agent to the bladder in an amount effective to enhance or otherwise alter the dissolution of the gemcitabine.

27. The method of claim 26, wherein urea or other solubility altering agent is released from an intravesical device that releases the gemcitabine.

28. A drug delivery device comprising: a housing configured for intravesical insertion; as well as A dosage form comprising gemcitabine, wherein the housing holds the dosage form and is configured to release the gemcitabine into the bladder in an amount therapeutically effective for treating the bladder, wherein said device is configured to release gemcitabine into said bladder in a median mean amount of 1 mg / day to about 300 mg / day of said gemcitabine.

29. The device of claim 28, wherein the housing releases the gemcitabine by diffusion through the drug permeable polymer wall.

30. The device of claim 28, wherein the housing releases the gemcitabine without a predefined release orifice.

31. The device of claim 28, wherein the housing comprises a release orifice in communication with a drug reservoir, the gemcitabine contained in the drug reservoir along with: (i) a viscosity enhancer, (ii) an osmotic agent, or (iii) a combination of a viscosity enhancer and an osmotic agent.

32. The device of claim 31, wherein the gemcitabine is provided in a first zone comprising one or more tablets and the osmotic agent and / or viscosity enhancing agent is provided in a second zone comprising one or more tablets, wherein the first and second zones are discrete spaces within the drug reservoir.

Images