Drug delivery systems and gemcitabine treatment methods for bladder cancer

Abstract

The need for improved drug delivery methods and systems for treating bladder cancer remains. It exists as such. [Solution] Gemcitabine is administered intravesically into the bladder of patients requiring treatment for bladder cancer, and then absorbed into the bladder tissue. A sustained concentration of gemcitabine sufficient to produce the above-mentioned therapeutically effective concentration By obtaining mucitabine in the urine of the bladder, the above patients can be administered gemcitabine. A drug delivery device and method are provided. In an embodiment, local delivery into the bladder of the patient. The administration is based on the average dose of gemcitabine (FBE) mentioned above, ranging from 1 mg / day to approximately 300 mg / day. That is the case.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Patent Application No. 61 / 949,215, filed on March 6, 2014 which is hereby incorporated herein by reference in its entirety.

[0002] The present invention relates to the treatment of cancer, and more particularly, to compositions, devices, and methods for the treatment of bladder cancer.

Background Art

[0003] Bladder cancer is an important medical problem, and the currently available treatment options are unsatisfactory for many reasons.

[0004] Generally speaking, 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: that is, pTa (urothelial lesion), pTis (high - risk urothelial carcinoma in situ), pT1 (lamina propria invasion), pT2 (muscle invasion), pT3 (perivesical fat invasion), and pT4 (pelvic organ extension). Bladder cancer can also be classified by grade as grade 1 / 3 (well - differentiated), grade 2 / 3 (moderately differentiated), and grade 3 / 3 (poorly differentiated). Furthermore, 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 cancers (NMIBC) that are confined to the inner wall of the bladder. In the initial stages, most bladder cancers are superficial NMIBC, including stage pTa, pTis, and pT1 diseases. MIBC includes stage pT2, pT3, and pT4. 更加に、膀胱がんは、病期0~IVとして病期によって分類することもできる。殆どの膀胱がんは上皮起源の移行上皮がんであり、膀胱の内壁に限局される筋層非浸潤性がん(NMIBC)に分類される。初期症状においては、殆どの膀胱がんは表在性NMIBCであり、病期pTa、pTis及びpT1疾患が挙げられる。MIBCとしては病期pT2、pT3及びpT4が挙げられる。

[0005] A typical clinical protocol for early-stage bladder cancer involves visualization via cystoscopy and subsequent... This is the surgical removal of a tumor (or tumor) known as urethral resection (TUR). However, Furthermore, the recurrence rate after surgery is high, and the above-mentioned cancers may progress to muscle-invasive disease. Therefore, surgery is performed in many cases to help prevent or delay the incidence and severity of recurrence. In addition, the introduction of adjunctive chemotherapy agents or immunotherapy agents into the bladder (via a catheter) This is combined with direct administration of chemotherapy agents into the bladder. (BC) G) is such an immunotherapy agent, and is generally administered intravenously into the bladder after surgery. However, B CG is ineffective for many patients, and furthermore, BCG treatment has various reasons that lead to discontinuation of treatment. It can induce side effects. Chemotherapy agents are usually used for patients who have not responded to BCG therapy. It is reserved. Chemotherapy is generally applied intrabladder, concentrating the chemotherapy agent on the tumor site. The goal is to remove any remaining tumor tissue after resection while avoiding systemic exposure to the drug.

[0006] One such chemotherapy agent used in clinical trials to treat bladder cancer is gemcitabine. Gemcitabine (2',2'-difluorodeoxycytidine) is used for metastatic bladder It is a pyrimidine analog that has activity against [unclear]. Gemcitabine is also used in superficial bladder cancer And in clinical trials to treat NMIBC, various weekly schedules are used. It has been used by intravenous infusion into the bladder. Generally, gemcitabine is generally Doses ranging from 500 to 2000 mg in a maximum of 100 ml of physiological saline, once a week. It is administered intravenously twice over several weeks, for 1-2 hours each time.

[0007] Such preparations are known to be excreted from the bladder before they can exert their full effect. The short dwell time of approximately 2 hours limits the therapeutic benefits. Furthermore, the above dwell time In an attempt to overcome the limitations, in order to obtain therapeutic tissue concentrations, high concentrations (40 mg / ml) and High doses (up to 2 grams per intravenous infusion) are used. However, gemshi High-dose intravesical administration of Tabine leads to significant systemic absorption, including in the gastrointestinal tract, bladder, and bone marrow. It can cause toxicity and, in addition to local tolerability issues, potentially limit clinical utility. There is.

[0008] The literature also states that, for example, a slow intravenous drip over 90 minutes is preferable to, for example, 1- Intravenous systemic administration of gemcitabine via a 2-minute bolus injection is more tolerable for patients. It has been reported that this is acceptable. This suggests that long-term exposure to gemcitabine increases toxicity. This suggests that this should be avoided.

[0009] Therefore, there is a need for improved drug delivery methods and systems for treating bladder cancer. They exist as such. For example, there are issues of toxicity and tolerability, and when these are recognized, gemworms To avoid or mitigate the toxicity and tolerability issues mentioned above that have limited the clinical usefulness of Tabine. While reducing the dosage, it is still necessary to administer therapeutic concentrations of gemcitabine to patients over a sustained period. It simply exists as it is. [Overview of the Initiative]

[0010] In one embodiment, gemcitabine is administered locally into the patient's bladder. And a sustained concentration sufficient to produce the above therapeutic concentration of gemcitabine in the bladder tissue. By obtaining the above gemcitabine in urine in the bladder, for use in the treatment of bladder cancer A medicament, wherein the local administration into the bladder of the patient is at an average amount of the free base equivalent (FBE) of the above gemcitabine of 1 mg / day to about 300 mg / day is provided. In an embodiment, the local administration into the bladder of the patient is at an average amount of the above gemcitabine (FBE) of 1 mg / day to 200 mg / day, of the above gemcitabine (FBE ) of 5 mg / day to 100 mg / day, of the above gemcitabine (FBE) of 10 mg / day to 50 mg / day, or of the above gemcitabine (FBE) of 15 mg / day to 25 mg / day. In one case , the local administration into the bladder of the patient is at an average amount of about 20 mg / day of the above gemcitabine (FBE ). The local administration into the bladder of the patient may be continuous or intermittent . In an embodiment, the continuous or intermittent administration is over 1 day to 30 days, 1 day to 1 4 days, or 1 day to 7 days. In a preferred embodiment, the above gemcitabine is delivered into the bladder from an intravesical drug delivery device that continuously releases the above gemcitabine into urine in the bladder over a sustained period . In another embodiment, the above gemcitabine is delivered into the bladder from a coating substance applied to the bladder, and the coating substance (e.g., a mucoadhesive formulation) releases the above gemcitabine into urine in the bladder over a sustained period

[0011] . In yet another embodiment, the above gemcitabine in liquid state is pumped into the bladder over a sustained period through a urethral catheter or a suprapubic catheter placed into the bladder .

[0012] In another aspect, to administer gemcitabine to a patient requiring treatment for bladder cancer A drug delivery device for administering gemcitabine intravesically into the bladder of the patient. A sustained concentration sufficient to produce therapeutically effective concentrations of gemcitabine in the tissue. The above administration is performed by obtaining the above amount of gemcitabine in the urine in the bladder. A chair is provided. In certain embodiments, the drug delivery device is for intravesical insertion. The device comprises a housing configured to hold the dosage form containing gemcitabine, the housing holding the dosage form. Furthermore, the above gemcitabine is configured to be released into the bladder in a therapeutically effective amount for treating bladder conditions. Therefore, the above device uses the average dose of gemcitabine, from 1 mg / day to approximately 300 mg / day. It is configured to release cytabine into the bladder. In a preferred embodiment, the housing is The gemcitabine is released without having a pre-set release opening. In a particular embodiment of the above, the housing is an expansion chamber that passes through a drug-permeable polymer wall material. The above gemcitabine is released by dispersal. The above gemcitabine is contained and released in a controllable manner. The above housing has a holding shape configured to hold the above device in the patient's bladder, The device is elastically deformable between a configuration for passing through the patient's urethra and a configuration for passing through the urethra. That's good too.

[0013] In yet another embodiment, gemcitabine is administered locally into the patient's bladder, and in the bladder tissue... To produce the above gemcitabine at a therapeutic concentration, a sustained concentration of the above gemcitabine A method for treating bladder cancer is provided by obtaining a vial in the urine of the bladder. Therefore, local administration into the bladder of the above patients is 1 mg / day to approximately 300 mg / day of the above gemcitabine. This is in the average amount of (FBE). In one embodiment, the above method is used in the above patient This further includes administering at least a second therapeutic agent. The second therapeutic agent is administered intravesically. Alternatively, in another embodiment, the above method involves adding urea or another solubility modifier to the gem. An effective amount to improve the solubilization of cytabine or to modify it into another form, in the bladder Further comprising administering the second therapeutic agent and / or the solubility described above. In embodiments, the second therapeutic agent and / or the solubility described above. The modifier is released from the intrabladder device that releases gemcitabine. [Brief explanation of the drawing]

[0014] [Figure 1A] Figures 1A and 1B illustrate one embodiment of an intravesical drug delivery device that can be used to administer gemcitabine as described herein. [Figure 1B] (As stated above.) [Figure 2A] Figures 2A-2B illustrate another embodiment of an intravesical drug delivery device that can be used to administer gemcitabine as described herein. [Figure 2B] (As stated above.) [Figure 3A] Figures 3A–3C illustrate yet another embodiment of an intravesical drug delivery device that can be used to administer gemcitabine as described herein. [Figure 3B] (As stated above.) [Figure 3C] (As stated above.) [Figure 4A] Figures 4A-4B illustrate the method of inserting an intravesical drug delivery device into a patient's bladder for topical administration of gemcitabine, as described herein. [Figure 4B] (As stated above.) [Figure 5A] This figure illustrates a substance applied to the inner surface of the bladder wall for topical administration of gemcitabine, as described herein. [Figure 5B] This figure illustrates a method for applying a coating substance to the inner surface of the bladder wall for topical administration of gemcitabine, as described herein. [Figure 6] This diagram illustrates a method for applying liquid drugs or drug formulations into the bladder. [Figure 7] This diagram illustrates the concentration of gemcitabine in the prostate after bladder irrigation and intravenous administration. [Figure 8] This diagram illustrates the plasma concentration of gemcitabine after bladder irrigation and intravenous administration. [Figure 9] This diagram illustrates the concentration of 14C gemcitabine in the bladder after bladder irrigation and intravenous administration. [Figure 10A] Figures 10A-C illustrate an embodiment of an intravesical drug delivery device for releasing gemcitabine via a permeable disk. Figure 10A is a plan view of the device. Figure 10B is a cross-sectional view of one of the four drug storage modules of the device shown in Figure 10A, showing the drug tablets and permeable disks in each module. Figure 10C is a perspective view of a portion of the housing / body of the device shown in Figure 10A, before assembly with the other components of the device. [Figure 10B] (As stated above.) [Figure 10C] (As stated above.) [Figure 11] Figures 10A-C show graphs illustrating the cumulative amount of gemcitabine released in vitro from the devices. [Figure 12] Figures 10A-C show graphs illustrating the cumulative amount of gemcitabine released in vitro from the devices. [Figure 13] This graph shows the urinary concentrations of gemcitabine, dFdU, and combinations thereof, based on animal studies. [Figure 14] This graph shows the urinary concentrations of gemcitabine, dFdU, and combinations thereof, based on animal studies. [Modes for carrying out the invention]

[0015] Continuous delivery of gemcitabine via intravesical administration results in significant plasma / systemic exposure. Without the expected result, an unexpected drug distribution in the thickness direction of the bladder wall was obtained, and in all layers of the bladder, It was found that drug concentrations at or above the measured therapeutic threshold were obtained. Therefore, The compositions, systems, and methods described herein are used in the bladder tissue where required. While it can be used to obtain a therapeutically effective amount of gemcitabine, normal bladder tissue It is well tolerable in such situations and minimizes systemic exposure.

[0016] As used herein, the term "gemcitabine" refers to the above-mentioned compound gemcitabine and its medicinal properties. This includes scientifically acceptable salts, esters, amides, solvates, and prodrugs. It contains gemcitabine hydrochloride. The gemcitabine mentioned above is one or more appropriate types. It can be formulated with pharmaceutically acceptable excipients.

[0017] In certain embodiments, therapeutic concentrations of the above drug are generated and maintained in the bladder tissue. To achieve this, a controlled amount of ge is administered into the patient's bladder urine at a sufficient concentration and for a sufficient duration. Mucitabine dissolves. However, the bladder limits the absorption of urinary components into the overall circulation, Systemic exposure to the drug is advantageously minimized.

[0018] Various methods can be used to obtain the required urinary gemcitabine concentration. In the embodiment, the drug is supplied by directly infusing a simple solution into the bladder via intravenous drip. For example, a solution of the above drug can be administered via a urethral catheter or a suprabbic catheter. It may be pumped into the bladder in a continuous or pulsed manner over the course of treatment. In another embodiment, the drug is released from a device or composition placed in the bladder. The device or composition concentrates the desired drug in the urine over a specified therapeutic period. The drug is released (continuously or intermittently) at a rate effective in producing a certain degree. For example Alternatively, the drug may be released into the bladder from the intravesical insertion device, and then the drug will be released into the bladder. It diffuses to the bladder. At the end of the treatment period, the device may be retrieved from the bladder, or The device is absorbed, dissolved, excreted, or a combination of these processes. It can be removed.

[0019] In a preferred embodiment, gemcitabine is administered into the bladder from an intravesical device. Intravesical drug delivery can be adapted to achieve the administration plan described herein. Examples of devices and methods for placing such devices in the bladder are described in the following U.S. Patent Application Publication. It is described in the publication. Specifically, US2012 / 0203203 (Lee et al.), US2012 / 0089122 (Lee et al.), US2012 / 0089121 (Lee et al.); US20 11 / 0218488 (Boyko et al.), US2011 / 0202036 (Boyko et al.) ), US2011 / 0152839 (Cima et al.), US2011 / 0060309 (L Lee et al., US2010 / 0331770 (Lee et al., US2010 / 0330149) (Daniel et al.), US2010 / 0003297 (Tobias et al.), US2009 / 0149833 (Cima et al.), US2007 / 0202151 (Lee et al.), WO2 014 / 144066 (Lee et al.), US2014 / 0276636 (Lee et al.), And WO2015 / 026813 (Lee et al.).

[0020] In an embodiment in which gemcitabine is delivered from an intravesical drug delivery device, the drug The above device can be accommodated in various forms, the form being such that the device contains the drug It may depend on specific mechanisms that control the release of fluid into the bladder (e.g., urine). In one embodiment, the agent is supplied in a solid, semi-solid, or other non-liquid state. This makes it advantageous to store the drug stably before the device is used. This makes it easier to carry the drug in the device, and also increases the drug capacity of the device when the drug is contained in the form of a liquid solution. It allows for storage in a smaller capacity than would otherwise be possible. In some cases, the non-liquid state may be a tablet, granule, or semi-solid (for example). From ointments, creams, pastes, or gels, capsules, and combinations thereof Selected. In one embodiment, the drug is described in U.S. Patent No. 8,343,516. In other embodiments, the drug is in the form of multiple tablets, such as mini-tablets. Alternatively, it may be contained in a liquid state, such as a solution containing multiple pharmaceutically acceptable excipients. .

[0021] A drug delivery device 100 according to one embodiment is shown in Figure 1A. This device 100 is The device comprises a main body having a drug storage section 102 and a holding frame section 104. (Figure 1) Therefore, device 100 is shown in a relatively wide shape suitable for retention within the body. Following placement inside, device 100 holds the drug delivery device within a body cavity or lumen. It may take a relatively expanded shape for that purpose.

[0022] For the purposes of this disclosure, "a relatively wide shape," "a relatively high cross-section shape," or Terms such as "holding shape" refer to the shape suitable for holding the device in the bladder, as shown in Figure 1. The design can be applied to the intended transplant location, including, but not limited to, a pretzel shape. This broadly represents any shape suitable for holding a vise. Similarly, "relatively low cross-section" Terms such as "shape" or "arrangement shape" refer to catheters, cystoscopes, and other devices located within the urethra. This is a straight line suitable for positioning the device through the working conduit of other placement equipment. Suitable for placing the drug delivery device in the body, including its shape or elongated form. This generally represents any shape. In the embodiment, the drug delivery device is naturally It can take on a relatively expanded shape, and can be operated either manually or with an external device. The device may be deformed into a relatively low cross-sectional shape for insertion into the body. When placed, it spontaneously, or naturally, takes on an initial, relatively expanded form for retention within the body. It can be restored to its original state.

[0023] In the illustrated embodiment, the drug storage section and holding frame section of the drug delivery device 100 102 and 104 are arranged longitudinally and joined to each other along their length. However, Other configurations are also possible. The drug delivery device 100 has a drug storage lumen 108 (i.e. A device body comprising an elastic or flexible form defining the drug housing and the retaining frame lumen 110. It comprises 106. The drug storage lumen 108 is designed to accommodate a drug preparation containing the drug. In the illustrated embodiment, the drug formulation containing gemcitabine is a large number of solid drugs. The physical unit 112 is in the form of a tablet. The retaining frame lumen 110 is Designed to accommodate the retaining frame 114, and forming the retaining frame portion 104. (Illustration) The tubular lumens 108 and 110 are separated from each other. However, other configurations are also possible.

[0024] As shown in the cross-sectional view in Figure 1B, the device body 106 defines the drug storage lumen 108. A pipe or wall material 122 and a pipe or wall material 124 that defines the retaining frame lumen 110 The pipes 122, 124 and the tubular lumens 108, 110 may be substantially cylindrical. The drug storage lumen 108 has a relatively larger diameter than the retaining frame lumen 110. For example, the arrangement of the amount of drug to be delivered, the diameter of the holding frame, and the inner diameter of the placement device. Based on these considerations, other configurations can be selected. The retaining frame defines the lumen 110. As shown in the figure, the wall material 124 has a retaining frame lumen 110 similar to the drug storage lumen 108. It extends along the entire length of the wall material 122 that defines the drug storage lumen 108, having a length of It may be so. However, in other embodiments, one wall material may be shorter than the other wall material. Good. In the illustrated embodiment, the two wall members 122 and 124 are along the entire length of the device. They are joined together in this way. However, intermittent joining can also be used.

[0025] As shown in Figure 1A, the drug reservoir lumen 108 contains numerous drug units (including gemcitabine). The 112s are filled in a series arrangement. For example, depending on the size of the storage section and the drug unit. Essentially, any number of drug units can be used. The drug storage lumen 108 is The drug unit 112 has a terminal opening 130 and a second opening 132 on the opposite side. After filling, the fixing plugs 120 are placed in the openings 130 and 132. In this case, the fixing plug 120 is a cylindrical plug and is fixed inside the openings 130 and 132. In other embodiments, the openings 130 and 132 are closed by other structures or materials. The structure or material, depending on the particular embodiment, may allow water or drugs to enter or exit during use. To facilitate this, examples include openings or wall materials that are permeable to water or drugs. ru.

[0026] In another embodiment, the drug storage lumen contains gemcitabine other than the solid drug unit. The form may be filled. Gemcitabine is, for example, in an oily or aqueous vehicle. It may be in the form of a suspension, solution, or emulsion, and may also contain a suspending agent, a stabilizer, and / or it may contain formulation agents such as dispersants. The above active ingredients should be used in a suitable vehicle before use, for example, a sterile vehicle that does not contain pyrogens. By aseptic isolation of sterile solids using water, or by freezing from solution. It may also be in the form of a powder obtained by drying.

[0027] In one embodiment, gemcitabine is released from the discharge opening of the device housing. One or more excipients containing a thickening agent to control the release of dissolved gemcitabine. It is formulated together with the agent. In another embodiment, the storage portion of the device contains gemcitabine and It contains both a gemcitabine and a thickener, but gemcitabine and the thickener are not co-formulated, for example If supplied as separate tablets, they are placed in separate areas within the storage compartment. In the pharmaceutical field, polyethylene Suitable thickeners, including but not limited to lenooxide (PEO), are known. In some variations of the above embodiments, the thickening agent is, for example, urea or another It may also be formulated and supplied together with an osmotic agent.

[0028] 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, the urea is a tablet The gemcitabine is supplied in the form of a drug or other solid, and is placed in the drug reservoir of an intrabladder drug delivery device. It is filled together with the drug. Depending on the device, the above urea also functions as an osmotic agent. Osmotic pressure can be easily generated within the storage section. In a particular embodiment, the above gem Cytabine and osmotic agents are incorporated herein by reference as PCT WO2015 / 0 As described in 26813 (Lee et al.), separate components located in different areas of the drug reservoir. It is composed of individual tablets (or other solid forms).

[0029] The retaining frame lumen 110 is filled with a retaining frame 114, and 114 is, for example, Nichino It may be an elastic wire made of a superelastic alloy such as tungsten. The retaining frame 110 is an example shown in the illustration. The "pretzel" shape or those disclosed in the application referenced above, etc. It may also be configured to naturally return to a retaining shape, such as another coiled shape. The retaining frame 114 can hold the device 100 inside the body, such as in the bladder. For example, the retaining frame 114 guides the device 100 into the body in a relatively low cross-sectional shape. It allows for insertion, and after device 100 enters the body, it returns to its relatively expanded shape. The above device enables the contraction of the detrusor muscle and the fluid dynamics associated with urination. In response to anticipated forces such as tactile forces, it prevents the body from adopting a relatively low cross-sectional shape. It may have an elastic limit and an elastic modulus. Thus, device 100 is capable of preventing accidental discharge. It can be restricted or prevented from being retained in the body after transplantation.

[0030] The material used to form the device body 106, at least partially, is the Deba To allow the chair 100 to move between the placement shape and the holding shape, elastic or flexible It may be of a certain nature. When the device is in a holding shape, the holding frame portion 104 is shown in the figure. Therefore, it may tend to be located inside the drug storage section 102. However, in other cases... In this case, the retaining frame portion 104 is located inside, outside, above, or below the drug storage portion 102. It is possible.

[0031] The material used to form the device body 106 is used after the device has been implanted. The fluid to be solubilized (for example, urine) enters the drug storage section 102 and the drug unit 112 It may be permeable to water so as to solubilize. For example, silicone or another biocompatible elastomer. Tomer material may be used. In other embodiments, the device body is at least part In part, it may be formed from an impermeable material.

[0032] Figure 2A illustrates an intravesical drug delivery device 200 of another embodiment, where 200 is a drug 21 The drug reservoir 202 filled with 2 and the 2 filaments 220 connected by a fastener 230 It includes a retaining structure including 222. As shown in the figure, the drug storage section 202 is located in Figure 2A. Relatively linear arrangements such as the shapes shown, and relatively circular arrangements such as the shape shown in Figure 2B It is an elongated tube that can be deformed between its various shapes. Drug 212 is in the drug storage section 202 It may be filled into a flexible tubular material so that it can move between the two shapes described above. For example, drug 212 may be a number of solid drug tablets, liquids, or gels. The filaments 220 and 222 are attached to both ends of the drug reservoir 202, and fasteners 23 They may be connected by 0. Adjust the fastener 230 to the position of one filament 220. The position is adjusted relative to the other 222, thereby changing the position of one end of the drug reservoir 202. The other end can be adjusted. The filaments 220 and 222 can be adjusted to deliver drugs. By bringing both ends of the storage section 202 closer together, the device 200 retains It can take on a shape, and thereafter the filaments 220, 222 are fastened by the fastener 230. By preventing adjustment, the device 200 can be held in a retained shape. In one embodiment, after the device 200 is inserted into the bladder, the filament is manually inserted. By adjusting 220 and 222, device 200 is manually adjusted to a retaining shape. ru.

[0033] In the illustrated embodiment, the fastener 230 is a cinch nut, and the cinch The nut is the filament 220 between both ends of the drug reservoir and the cinch nut. This allows for shortening the 222 portion of the filament, while also allowing for the shortening of the filament 220 and 222. This prevents the part from stretching. Thus, the film is passed through the cinch nut. By pulling either or both of the terminals 220 and 222, both ends of the drug reservoir 202 The parts can be brought closer together, allowing the device 200 to assume a holding shape. When filaments 220 and 222 are adjusted in that manner, the cinch nut is filled The components 220 and 222 are prevented from stretching, and the device is held in a retaining shape. Thus, manually adjusting the device 200 to a retaining shape after implantation is simply It is only necessary to pull either or both of the filaments 220 and 222. However, Other fasteners 230 that require separate operation can also be used. It is possible.

[0034] Another embodiment of the intravesical drug delivery device is illustrated in Figures 3A-3C. The above device has a single continuous structure with multiple separate drug storage lumens 320. Having and optionally having at least one retaining frame in which a retaining frame 360 ​​is placed The device comprises a housing 300 having a frame lumen 330. Each drug storage lumen 320 is shown in cross-section in Figure 3B. As shown in the figure, it has two defined openings and at least one solid drug unit 3 It has dimensions to hold 40. For example, the solid drug unit 340 holds a drug tablet or capsule. It may be a capsule formulation. In another embodiment not shown, each drug reservoir lumen is a single It has a defined opening. The housing is formed of a flexible polymer such as silicone. This can be done. Figure 3B shows the drug storage tube lumen 320 of the housing shown in Figure 3A along line 3B-3B. This is a cross-sectional view of a plane that divides the area into two. As shown in Figure 3B, the integrated housing 300 is the drug Two defined openings are provided in the material storage lumen 320 to expose both ends of the solid drug unit 340. It has openings (350a, 350b). In this embodiment, the retaining frame lumen 33 0 is parallel to the longitudinal axis of the housing and perpendicular to the drug storage lumen 320. They are arranged. Figure 3C is a partial perspective view of an embodiment of the device 300 shown in Figure 3A. The device is positioned such that the retaining frame 360 ​​is located within the retaining frame lumen 330. The above perspective view shows the drug storage lumen 3 in the housing of this embodiment. 20 and the retaining frame 360 ​​are such that the drug reservoir lumen 320 is outside the arc of the retaining frame 360. It is positioned as shown in Figure 3C. Alternatively, the housing in Figure 3C is positioned around the retaining frame 360. Rotated 80 degrees, the drug reservoir lumen 320 is positioned inside the arc of the retaining frame 360. It can also provide results. In this embodiment, the device is placed and held in the bladder. If this occurs, it will result in sufficient direct contact between the solid drug unit and the urine surrounding the device. In the embodiment, the release of the drug from the device is performed on the surface of the solid drug unit. The erosion of the exposed portion is controlled, and as a result, the rate of drug release from the drug delivery device The degree is proportional to and limited by the total surface area directly exposed to the solid drug unit. It is possible.

[0035] The release of gemcitabine from the intrabladder devices described herein is driven by various mechanisms of action. and can be controlled. In various embodiments, the drug is dispersed through the wall material of the drug enclosure. The drug is dispersed by diffusion through one or more defined openings in the wall material of the drug enclosure. Then, due to the osmotic pressure passing through the opening in the drug casing, one or more temporarily formed Due to osmotic pressure passing through the microchannels, the drug formulation in contact with the urine in the bladder is eroded. Alternatively, they may be released from an intravesical drug delivery device by a combination of these. In one embodiment, drug release is achieved by a drug-permeable polymer that defines a portion of the device housing. - Controlled by the diffusion of the drug through the member or drug-permeable matrix member. In one embodiment, the device comprises a drug-permeable polymer member.

[0036] In a particular embodiment, the drug delivery device comprises a first wall structure and a hydrophilic second A housing having a closed drug storage lumen enclosed by a wall structure, and the drug storage lumen The device contains a drug formulation including gemcitabine, and the first wall structure is permeable or impermeable. It is aqueous and impermeable to the above drug, and the second wall structure is gemcitabine. It is permeable to the first. The wall material that surrounds and defines the drug storage portion of the above device is the first The first material serves as a wall structure and the second material serves as a wall structure. It consists of two materials, and as a result, drug release occurs virtually solely by passing through the second material. In one embodiment, the device does not have an opening, and drug release is through the second wall structure. By diffusion only through the substrate. The term used herein means "non- "Permeability" and "impermeability" mean that the wall structure is substantially impermeable to the drug or water. It is transient, and as a result, over the therapeutic release period, the drug or water is substantially contained within the barrier. This refers to the fact that it is not released through the structure. For use in the bladder, it may cause discomfort to the patient. To avoid or reduce sensation and irritation, the above device is flexible during the contraction of the detrusor muscle. (That is, it is desirable that it bends easily and has a soft feel.) The durometer of the second material is a design consideration, and the device should be properly flexible in the bladder. In constructing a device enclosure of a predetermined size while maintaining flexibility, high durometer The proportion of materials used in the process may be limited. For example, Tecophilic® thermoplastic Plastic polyurethane (Lubrizol) is suitable for grades exceeding 70A, such as 80A to 65D. While some materials may have a hardness of 50A to 70A, silicone tubing materials may have a Shore hardness of 50A to 70A. Therefore, Rather than fabricating the entire device with a second material that is hydrophilic, swells in water, and is drug-permeable, It may be advantageous to utilize a combination of these two different polymer materials.

[0037] In this particular embodiment, the first wall structure may be formed of silicone. If the above housing is provided with a silicone pipe, the wall material of the silicone pipe is the first wall structure It may also serve the role of [another function]. In other embodiments, the first wall structure is formed with other permeable material. This can be achieved. The above drug is preferably in solid form (for example, one tablet or multiple tablets). The tablet is a first wall structure that, while the drug is in the drug reservoir lumen, controls the drug's activity. It is permeable to allow solubilization in vivo. For example, the first wall structure is approximately 50A The second wall may be formed of silicone having a Shore durometer value of approximately 70A. The structure may be a hydrophilic polymer designed to absorb water. For example, the second The wall structure is at least partially made of hydrophilic polyurethane, hydrophilic polyester, or A hydrophilic elastomer material made of a hydrophilic polyamide may be used. In a preferred embodiment, In this context, the second wall structure is Tecophilic® thermoplastic polyurethane. HydroThane (trademark) thermoplastic polyurethane (AdvanSource Bi omaterials Inc., Quadraphilic® Thermoplastic Polyurethane Biomerics, LLC) (ALC grade is aliphatic polycarbonate hydrophilic poly It is a urethane, and the ALE grade is an aliphatic polyether hydrophilic polyurethane. roMed® (trademark) (AdvanSource Biomaterials Inc.), or Thermoplastic polyurethanes such as Urflex (registered trademark) (HEXPOL TPE Corporation) Another example is the polyether block amide Pebax®. MV 1074 SA 01 MED (Arkema) is a polymer that is flexible and hydrophilic. It is a thermoplastic elastomer composed of an aqueous polyether and a rigid polyamide. For example, The hydrophilic material of the second wall structure has a Shore durometer value of approximately 70A to approximately 65D. It may be. Specific materials, their thickness, and wall surface area control the permeability of water and drugs. This allows you to select a specific release profile for gemcitabine as described above. Cut.

[0038] The arrangement of the first and second wall structures can take various forms. The first wall structure is a cylindrical pipe, and the second wall structure is a small portion of the above cylindrical pipe. It is an end wall material placed at one end, or a first wall structure and a second wall structure. The bodies are adjacent to each other and together form a cylindrical tube. That is, drug release occurs in a closed space. The diffusion of drugs is controlled by the passage of drug-permeable members that define a portion of the device's casing. The above drug-permeable wall structure controls the desired drug diffusion rate from the device. They may be arranged, have dimensions, and possess material properties to give a certain effect. One embodiment In this case, as described in Example 4 below, the first wall structure is a cylindrical pipe, and the second The wall structure is an end wall material placed at at least one end of the cylindrical pipe material described above.

[0039] An intravesical device 400 is then inserted to facilitate the controlled release of the drug into the bladder. One embodiment is shown in Figures 4A and 4B. Here, device 400 is said to be the device The above device is shown with the spline extending from the placement device 402 and taking on a holding shape. The device 402 may be any suitable device. The placement device 402 may be a catheter, urethral catheter It may be a tubular instrument such as a cystoscope or a tubular instrument. The placement instrument 402 is commercially available This may be an instrument or an instrument specially adapted to this drug delivery device. Figure 4B shows the device. The insertion of 400 into the bladder is illustrated, with an example showing the anatomical structure of an adult male. The instrument 402 is inserted into the bladder through the urethra, and the device 400 is inserted into the bladder. Until it reaches the visceral cavity, by the flow of a stylet or lubricant, or a combination thereof. It may be driven and passed from / through the placement device 402, device S400 is a retaining shape, as shown in the figure.

[0040] From the studies described in the examples below, it is surprising that an extremely small discharge opening is possible, i.e. Embodiments of devices having holes are preferred, and devices that release drugs without pre-set holes are preferred. It has been found that the chair embodiment is more preferable. This is because these embodiments are In contrast to embodiments of devices utilizing larger discharge holes, the incidence of urothelial lesions is lower. It has been observed that this may be effective in eliminating, or at least substantially reducing, it. This is due to the fact that, although not constrained by any theory, larger holes in Debye The device localizes gemcitabine to the urothelial tissue surface in the region near the discharge opening of the device. It is possible that localized high drug concentrations may form, and these localized tissue areas may result in It is possible that it may be damaged as such. In contrast, having a pre-set hole In device systems that utilize emission mechanisms with no or very small emission holes, Such localized high drug concentrations are less likely to occur. An example of such a suitable "non-porous" release system is P CT Patent Application Publication No. WO2014 / 144066 (TB 130) and U.S. Patent Application Publication These are described in Publication No. 2014 / 0276636 (TB 134), and are by reference to the present invention. It will be used as reference in the detailed document.

[0041] In some embodiments in which the above device comprises a drug in solid form, the device The elution of the drug occurs following the dissolution of the drug within the device. Body fluids within the device Entering the environment, the drug comes into contact with the substance, solubilizes the drug, and then the dissolved drug is absorbed under osmotic pressure or by diffusion. It is dispersed from the device or leaks out from the device by the above device. In cases where the drug is implanted in the bladder, the above-mentioned drug can be solubilized upon contact with urine. .

[0042] In various embodiments, the intrabladder device delivers the drug continuously or intermittently. The drug is released and sustained at a therapeutically effective concentration, for a period of 1 hour to 1 month, for example, 2 hours to It is generated in the bladder over periods such as 2 weeks, 6 hours to 1 week, 24 hours to 72 hours, etc. The drug at a certain concentration can be obtained in the bladder. In a particular embodiment, the above-mentioned bladder The device can be administered in doses of 1 mg / day to 1000 mg / day, for example, 20 mg / day to 300 mg / day. The above gemcitabine may be released in doses of 25 mg / day to 300 mg / day. Specific implementation Morphologically, these release rates are given over a treatment period of 14 to 21 days. .

[0043] In another embodiment, the coating material is the bladder wall (for example, the urothelium on the inside of the bladder) The coating material may be applied intravesically to the area, and the coating material may be gemcitabine or other Drugs and one or more additives that promote adhesion of the coating material to the bladder wall. The above coating provides continuous, controlled release of the drug over the course of treatment. The filling material includes gels, ointments, creams, pastes, films, emulsified gels, tablets, and polymers. These may be mucosal adhesive preparations, such as a combination thereof. As for the polymer, it is a hydrogel or hydrophilic polymer, polycarbophil (i.e., carbopole). (e.g., chlorine), chitosan, polyvinylpyrrolidone (PVP), lectin, polyethylene glycol Examples include cellulose polymers, cellulose, or combinations thereof. Examples of cellulose include methylcellulose (MC) and carboxymethylcellulose (CM). C) Hydroxypropyl cellulose (HPC), or combinations thereof. The above coating material may contain a permeability enhancer. Non-limiting examples of permeability enhancers Examples include dimethyl sulfoxide (DMSO) and sodium carboxymethylcellulose. Examples include (NaCMC), lipids, surfactants, or combinations thereof. See Figure 5A. As shown, the coating material 500 engages with the bladder wall 552. It may be placed within the bladder 550 in this manner.

[0044] The above coating material may be placed inside the bladder using a placement device. Figure 5B shows a male. This is a sagittal cross-sectional view of the genitourinary system of the sex, and is placed at the transplant site via the placement device 502. 500 different coating materials are illustrated. As an example, the anatomical structure of a male is shown, and The implantation site is indicated as the bladder 550. The coating material 500 is as described herein. This may be one embodiment of the coating material. The placement device 502 is within the body's natural state It may be any instrument designed to pass through a cavity and reach the intended transplant site. For placement in the bladder 550, the placement device 502 is placed in the patient's urethra as shown in the figure. The size and shape are such that 560 can pass into the bladder 550. The placement device 502 is It may be a known instrument such as a catheter or cystoscope, or a specially designed instrument. The placement device 502 is used to place the coating substance 500 into the body, Afterward, the 500 units of coating material, which have been completely implanted into the body, are removed from the body. Coating material 500, after being implanted in this manner, releases drugs into the body over a long period of time. This can be done. Using equivalent procedures, any of the devices or drugs described herein can be used with other It can be placed in other parts of the body through its natural lumen. For example, as shown in Figure 6. Then, using the placement device 602, and passing the placement device 602 through the urethra 660, A liquid drug or drug preparation 600 can be placed in the bladder 650.

[0045] In one embodiment, a second therapeutic agent is administered to the patient. This second agent is the same as the above-mentioned gem Cytabine can be administered simultaneously, sequentially, or in overlapping forms. The second therapeutic agent may be administered intravesically. Using the methods and systems described herein The second therapeutic agent may be administered intravesically. The second therapeutic agent may be a cytotoxic agent, an analgesic, Anti-inflammatory drugs, or combinations thereof, can be mentioned. The second treatment is the above gemcita It may function by a different mechanism of action than gemcitabine, and / or synergistically with gemcitabine. It may function. In one embodiment, the second therapeutic agent prevents, treats, and or improve. In yet another embodiment, initially (for example, the first week following TURBT) During the period above, gemcitabine was used as a chemoimmunotherapy agent, and in the subsequent period, carme Bacillus guarensis (BCG) is administered regularly. For example, Cho et al., J. Int' See Med. Res. 37:1823~30 (2009).

[0046] In various embodiments, intravesical administration of gemcitabine to the above patient is performed via TURBT. It can be performed before, after, both before and after, or without a turbo. It is possible.

[0047] In one embodiment, the intravesical gemcitabine is used for non-muscle-invasive bladder cancer (NMIBC). It is used in the treatment of ) In another embodiment, the intravesical gemcitabine is BC It is used in refractory NMIBC. In yet another embodiment, the above bladder worms Tabine is used in a repeated-dose regimen, with an induction period followed by a series of maintenance doses. For example, treatment might involve one week of treatment per month for three months, followed by treatment every three months as needed. A maintenance dose is administered once a week.

[0048] As used herein, the terms "patient" or "subject" refer to a human or a veterinary, animal, or other animal. and other mammals, such as those used for clinical research. In certain embodiments, the above-mentioned patients The person or subject is an adult human. In other embodiments, the above patient or subject is These include cattle, dogs, cats, goats, sheep, and pigs. [Examples]

[0049] The present invention can be further understood by referring to the following non-limiting embodiments.

[0050] Example 1: Uptake of gemcitabine from the bladder into the prostate gland In male Sprague Dolly rats, intravesical cannula, 6 hours or 24 hours By continuous perfusion, or by a single intravenous (IV) bolus, 14 C Gemushitabi The study involved administering the drug and conducting an investigation. The above 6-hour and 24-hour continuous perfusions were 6.9 m, respectively. g and 26.6 mg of gemcitabine were perfused into the bladder. The above single IV bolus was 5 It contained 0.0 mg of gemcitabine.

[0051] Blood (Figure 8), urine, and tissue samples (e.g., bladder, prostate) (Figures 7 and 9) are collected. The gemcitabine content was analyzed. The results are illustrated in Figures 7-9. These results indicate that The subsequent gemcitabine concentration in the urine leads to a significant gemcitabine concentration in the bladder tissue. It was found that the gemcitabine concentration was effective in in vitro experiments on bladder cancer cells. This indicates that the concentration is at or above the therapeutic level. The gemcitabine concentration in the bladder is shown in the figure. As shown in 9, this figure also shows gemcitabine in the bladder 24 hours after IV administration, which is clinically relevant. It shows a significantly lower concentration. Regarding the bladder epithelium, lamina propria, muscularis, and adventitia, The gemcitabine concentrations observed are shown in Figure 14, but this figure also shows gemcitabine tissue concentrations. This diagram illustrates the target effective range.

[0052] Example 2: Study of gemcitabine in large mixed-breed hunting dogs Two types of gems designed to release therapeutic concentrations (4 mg / day and 40 mg / day) into the urine. The cytabine release system (devices shown in Figures 1A-1B) was subjected to selection testing. For the release of gemcitabine as described above, either a laser-drilled hole or a punched hole. The system used was designed to mimic standard intravesical administration used clinically. This was compared to an intravesical infusion designed for this purpose. The test animals were large mixed-breed hunting dogs, and each group was... We proceeded with N=3.

[0053] Each system showed different gemcitabine release rates in vitro. One system yielded very low urinary and tissue concentrations, but showed good results in test animals. It showed good tolerability. The other system produced the target urinary concentration level, but the test movement The drug showed poor tolerability. Urine profiles also fluctuated, and drug release continued. The time was unacceptably short. Intravesical administration resulted in symptoms consistent with those reported in the literature. Significant urothelial lesions were also observed.

[0054] In summary, this study investigated how device / tablet formulation design can affect gemcitabine urinary concentration over time. It was demonstrated that it strongly affects both the tolerability in the bladder and the urinary tract.

[0055] Example 3: Investigation of gemcitabine bladder perfusion in miniature pigs Various concentrations of gemcitabine were administered to pigs for 7 days in a group of 5 (2 males and 3 females per treatment group). Perfusion was performed. The above perfused animals were selected to classify the target dose for bladder cancer in humans. The drug was administered at the selected concentration. For comparison, a large-diameter drug with a moderate in vitro release rate was used. The end cap (a stopper for securing, with a large diameter opening through which drug release is possible) A gemcitabine release device (as shown in Figures 1A-1B) having the above-mentioned stopper having a portion These were placed in separate groups of animals. All perfusion groups included the highest perfusion dose of Gemshitabi. It showed good tolerability to the drug. In contrast, the gemcitabine-releasing device showed moderate tolerability. It produced urinary concentrations, but did not exhibit good tolerability.

[0056] Example 4: Modular device that releases gemcitabine via a permeation system Gemcitabine HCl is placed in the 4-module device 1000 illustrated in Figures 10A-C. Tested. Figure 10A shows device 1000 with 4 drug storage modules 1010A and 1010 This indicates that it comprises B, 1010C, and 1010D. For clarification, see Figure 10C. This refers to the device housing portion only for drug storage modules 1010A and 1010D. (Other components are omitted). Figure 10C shows drug storage modules 1010A and 1010 Each of the storage section side wall materials 1040A and 1040D of D is a wall material segment 1012 and The diagram illustrates the configuration in which the components are integrally connected by the retaining frame lumen 1014. Storage section side wall Materials 1040A and 1040D, as well as wall material segment 1012, and retaining frame lumen 1 Object 014 was formed by cutting a fragment from a silicone tube material with a double lumen. (The devices of the four modules above are separated from a silicone tube material with a double lumen at intervals.) It was made by cutting out three fragments. Each drug storage module has an inner diameter of 2.64 m Silico manufactured by MED-4750 (Nusil) with dimensions of m and wall thickness of 0.20 mm It consisted of a silicone pipe. The above silicone pipe had an inner diameter of 0.51 mm and a wall thickness of 0.20 mm. It had a retaining frame lumen. Nitinol retaining frame retaining frame lumen 1 It was inserted into 014. Figure 10B shows that the solubilized drug is released by diffusion through it. The structure of the drug storage module 1010A, which includes the disk 1060, is illustrated. (Other 3 The drug storage module had the same structure as module 1010A. ) Disk 10 60 sandwiches the disc 1060 between the outer washer 1100 and the inner washer 1120. By doing so, the side wall material 1040A of the cylindrical tube is stabilized within the lumen. Each disc 106 0 is HP-93A-100 (Tecophilic® thermoplastic polyurethane) Each disc 1060 was made of a material with dimensions of approximately 0.5 mm in thickness and 3.0 mm in outer diameter. The outer diameter of the above disc (3.0 mm) is equal to the inner diameter of the above silicone pipe material (2.64 mm). The disc was also large, and therefore, the above disc was fitted into the above silicone tubing by friction. The inner and outer silicone washers 1120 and 1100 are MED-4780 (Nusil). They are made of ) and silicone adhesive is applied around these washers 1120 and 1100. These washers are positioned adjacent to the disc 1060 and installed inside the silicone pipe 1040A. The outer silicone washers 1100 are approximately 2.5 mm, 3.2 mm, and The inner washer 1120, made of silicone, has dimensions of 2 mm inner diameter, outer diameter, and length. The inner diameter, outer diameter, and length dimensions are approximately 1.58 mm, 2.77 mm, and 2 mm, respectively. He possessed it.

[0057] Numerous drug tablets 1080, each with an outer diameter of 2.6 mm, are placed in a silicone tube 1040A. Filled, and then by disc 1060 and inner and outer washers 1120 and 1100 The ends of the storage section were then closed. The above tablet formulation contains 90% gemcitabine HCl and 5% P The solutions were VP, 2.5% Neusillin, and 2.5% magnesium stearate. 4 of each. The total mass of the tablets filled into the module device was approximately 800 mg.

[0058] In vitro release tests were conducted at 37°C using three devices (R204-4~6). The release medium was deionized water, and samples were taken at each time point. Gemcitabine release was T Controlled by diffusion through the ecophilic disk. Free base equivalent (FBE) The cumulative amount and release rate, expressed as shown in Figures 11 and 12, respectively. Each error bar represents the average value (N This is the standard deviation centered at =3). Some error bars are smaller than the symbols representing the measurement points. stomach.

[0059] Identical devices were tested in vivo using three Göttingen miniature pigs. Each device was inserted non-surgically into the bladder of each animal through the urethra using a cystoscope. The urinary concentrations of Tabin and 2',2'-difluoro-2'-deoxyuridine (dFdU) Measurements were taken over an 8-day period. After this 8-day trial, each device was compared with a cystoscope and forceps. It was non-surgically removed through the urethra. The urine sample contained a combined amount of gemcitabine and dFdU. The medium concentration is shown in Figure 13.

[0060] Example 5: Selection of gemcitabine delivery devices in miniature pigs Based on the intrinsic tolerability of gemcitabine found in the perfusion study of miniature pigs described above. Therefore, a series of prototypes were selected and evaluated in order to improve the design of this drug delivery system. In the study, three prototype devices were designed to release therapeutic concentrations of gemcitabine into the urine. The two devices were designed as shown in Figures 1A and 1B (large diameter end cap for drug release). The device has holes drilled by a drill or laser, and one type of device is shown in Figure 10A~ The device was designed as a 10C (drug-permeable disk for drug release). Three types of studies were conducted. The process was completed, and each study involved testing one prototype design on three miniature pigs for seven days. Blood and urine samples were collected intensively over the specified period.

[0061] The device design shown in Figures 1A-1B, which has a large-diameter end cap for drug release, is consistent It was found that this caused urothelial lesions in the animals in question. However, the above gem Design of the device shown in Figures 1A-1B, which contains a thickening agent along with cytabine and has laser-drilled holes. The design was found to reduce the incidence of urothelial lesions. Figures 10A-10C show the non-porous design. The device was found to completely eliminate the development of urothelial lesions. Such a design, (Near the drug release opening of the device) is thought to contribute to the development of urothelial lesions. This is thought to prevent the temporary high local concentration of gemcitabine on the tissue surface.

[0062] Example 6: Selection of gemcitabine delivery devices in miniature pigs In this study, an osmotic prototype device was used to release a therapeutic concentration of gemcitabine into the urine. The above device is designed to be used in the PCT W, the relevant portion of which is incorporated herein. As generally described in O2015 / 026813, a separate location within the drug storage area It was configured to use gemcitabine tablets and osmotic agent tablets placed in the [location]. Each of the subset devices is a silicone tube, between both ends of the tube The central region has a 75-micron laser-drilled hole for drug release. The above silicone tubing material was provided. The lumen of the above tubing material had a central region near the discharge hole. The tube is filled with a tablet containing a mixture of gemcitabine and urea, and the urea / Lub is placed in the regions at both ends of the lumen. The ritab tablets were filled. The devices of the second subset each consisted of a silicone tube. A material having a region located in the center between both ends of the pipe, for drug release, 150 mm The silicone tubing material had holes drilled by a Chron laser. The central region near the aforementioned release hole is filled with a tablet containing a mixture of gemcitabine and urea. The tubular lumen was filled with urea / PEO tablets. The above device was subjected to in vivo testing. In miniature pigs, and in vitro, the cumulative amount released over 7 days was tested and The average gemcitabine was measured. The release rate of gemcitabine was measured using a device with a 75-micron pore. From the device, approximately 120 mg was administered over 7 days, and from the device with a 150 micron pore. The dose was approximately 140 mg over 7 days. The change in urinary concentration over time was due to urea / Lubri. Compared to tab formulations, a slightly lower level was observed when using urea / PEO formulations. Therefore, the viscosity of the solubilized drug solution in the lumen of the device controls drug release. This could be a contributing factor.

[0063] Conclusions from the Examples A literature review that provides target concentrations—in vitro concentrations across tumor cell lines—is one Generally, for effective cell lines, 0.5 μg / g and 3.0 μg / g (per gram) (Jeon et al., J. Urol. 18) has an IC50 value in the range between (Crogram) and (Jeon et al., J. Urol. 18) See 6(5):2084~93(2011). The literature also states that it is effective. This requires a high urinary concentration (for example, 2000 mg in a maximum of 50 mL), however Furthermore, intravesical infusion to obtain such concentrations is considered to be unsafe and tolerable, systemic toxic, and ill This suggests that it may be associated with problems of urinary tract symptoms (LUTS) (Cattel et al., Annal See Oncol. 17 (Appendix 5):v142~47 (2006).

[0064] However, from the studies described in the above examples, the amount of urine required to obtain these therapeutic tissue concentrations is The concentration of gemcitabine in the sample was measured, and the concentration was determined to be tolerable to the urothelium. It was found that high urinary concentrations in the bladder are not required. In particular, 1 of the above concentration An intravesical system that delivers / 100 (for example, 20 mg in a maximum of 50 mL) is effective. It was found that this is possible.

[0065] Furthermore, in contrast to what the literature teaches regarding the intravenous perfusion of gemcitabine, urothelium This allows for long-term intravesical delivery of gemcitabine without causing damage to the bladder. This was discovered.

[0066] Publications cited herein and the substances cited therein are referenced in this specification. More specifically, modifications and variations of the methods and devices described herein are referred to above. This will become clear to those skilled in the art from the detailed description. Such modifications and variations are described in the attached claims. It is intended to be included within the scope of

Claims

1. Gemcitabine is administered locally into the patient's bladder, and the gemcitabine is absorbed into the bladder tissue. A sustained concentration of gemcitabine sufficient to produce a therapeutic concentration of gemcitabine A drug used to treat bladder cancer by obtaining it in the urine in the bladder, Local administration into the bladder of the aforementioned patient is 1 mg / day to approximately 300 mg / day of the aforementioned gemworm. The drug in the average amount of Tabin (FBE).

2. Local administration into the bladder of the aforementioned patient is 1 mg / day to 200 mg / day of the aforementioned gemcitabine. The drug according to claim 1, in terms of the average amount in the bottle (FBE).

3. Local administration into the bladder of the aforementioned patient is 5 mg / day to 100 mg / day of the aforementioned gemcitabine. The drug according to claim 1, in terms of the average amount in the bottle (FBE).

4. Local administration into the bladder of the aforementioned patient is 10 mg / day to 50 mg / day of the aforementioned gemcitabine. The drug according to claim 1, in terms of the average amount in the bottle (FBE).

5. Local administration into the bladder of the aforementioned patient is 15 mg / day to 25 mg / day of the aforementioned gemcitabine. The drug according to claim 1, in terms of the average amount in the bottle (FBE).

6. Local administration into the bladder of the aforementioned patient is approximately 20 mg / day of gemcitabine (FBE) The drug according to claim 1, wherein the average amount is ).

7. Local administration into the bladder of the aforementioned patient, continuous over a period of 1 to 30 days, A drug specified in any one of the requests 1 to 6.

8. Local administration into the bladder of the aforementioned patient, intermittently over a period of 1 to 30 days, A drug specified in any one of the requests 1 to 6.

9. Local administration into the bladder of the aforementioned patient, intermittently over a period of 1 to 14 days. The drug according to any one of claims 1 to 6, wherein the drug is continuous.

10. The claim is to administer the substance locally into the bladder of the aforementioned patient over a period of 1 to 7 days. A drug listed in any one of items 1 to 6.

11. The gemcitabine continuously delivers the gemcitabine into the urine in the bladder over a sustained period of time. Any one of claims 1 to 6, delivered into the bladder from an intravesical drug delivery device that releases drugs precisely. The drugs listed in item 1.

12. The intravesical drug delivery device delivers gemcitabine to the bladder over a period of 1 to 14 days. The drug according to claim 11, which is continuously released into the urine in the vesicle.

13. The intravesical drug delivery device contains and controlsly releases gemcitabine, The retaining shape is configured to hold the device in the patient's bladder, and the device is to be held in the patient Claim 12, comprising a housing that is elastically deformable between a configuration for passing through the urethra and a corresponding configuration. The drugs listed.

14. The drug according to claim 13, wherein the gemcitabine contained in the housing is in a non-liquid state. Agent.

15. The non-liquid state is a tablet, granule, semi-solid preparation, capsule, or a combination thereof. The agent according to claim 14, selected from the group.

16. The gemcitabine is delivered into the bladder from the coating material applied to the bladder, and the The coating substance releases gemcitabine into the urine in the bladder over a sustained period of time. The drug according to any one of claims 1 to 6.

17. The agent according to claim 16, wherein the coating substance comprises a mucosal adhesion preparation.

18. Local administration into the bladder of the aforementioned patient, continuous over a period of 1 to 14 days, The drug described in item 17.

19. The claim is to administer the substance locally into the bladder of the aforementioned patient over a period of 1 to 7 days. The drugs listed in item 17.

20. The aforementioned local administration is performed via a urethral catheter or suprabibular catheter placed in the bladder. Claims 1 to 6 include pumping the liquid gemcitabine into the bladder through a pipe. A drug listed in any one of the items.

21. Local administration into the bladder of the aforementioned patient, continuous over a period of 1 to 7 days or The drug according to claim 20, which is intermittent.

22. A drug delivery device comprising the drug described in any one of the prior claims, The device is configured to release gemcitabine when inserted into the bladder. , the aforementioned device.

23. A method of administering drugs to patients requiring treatment for bladder cancer, Gemcitabine is administered intravesically into the bladder of the patient to obtain a therapeutically effective concentration in the bladder tissue. To produce the gemcitabine, a sustained concentration of the gemcitabine is given to the bladder. The method, which includes obtaining it in the urine.

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

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

26. Urea or another solubility modifier is used to improve the solubilization of gemcitabine or other Claim 23 further comprises administering into the bladder in an amount effective for changing the form. The method.

27. The urea or other solubility modifier is released from the intrabladder device that releases gemcitabine. The method according to claim 26, which is released.

28. A housing configured for intravesical insertion, and Dosage forms containing gemcitabine Equipped with, The housing holds the dosage form and contains gemcitabine in a therapeutically effective amount for treating bladder conditions. It is configured to be released into the bladder. Gemcitabine is administered to the bladder at the average dose of gemcitabine described above, ranging from 1 mg / day to approximately 300 mg / day. A drug delivery device configured to release a drug.

29. The housing releases gemcitabine by diffusion through a drug-permeable polymer wall material. The device according to claim 28.

30. The housing releases gemcitabine without having a pre-set release opening. The device according to claim 28.

31. The housing contains (i) a thickening agent, (ii) an osmotic agent, or (iii) a thickening agent and an osmotic agent. The combination includes a release port that communicates with a drug reservoir containing gemcitabine. The device according to claim 28.

32. The gemcitabine is supplied to a first region comprising one or more tablets, and the osmotic agent and / or a thickener is supplied to a second region comprising one or more tablets, and the first and second The device according to claim 31, wherein the region is a separate space within the drug storage section.

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