Intravesical drug delivery device

Abstract

To provide a medical device for controlled drug discharge including, but not limited to, a device that can be deployed in a bladder for discharging a drug into the bladder.SOLUTION: An implantable drug delivery device 200 includes: a housing 208 that defines a storage part 204; a first unit 202 inside the storage part; and a second unit 210 inside the storage part. The first unit 202 stores a drug. The second unit 210 stores a functional agent that promotes discharge of the drug. An intravesical drug delivery device 200 includes a housing 208 portion storing a drug preparation and a housing 208 portion storing an excipient, and is configured to discharge the drug according to a first discharge profile and discharge the excipient according to a second discharge profile. A method includes inserting any of these devices 200 to a patient, and discharging a drug from the device 200.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001]

[0001] The present disclosure relates generally to controlled drug delivery to a patient, and more specifically to the delivery of drugs to the bladder Restrictions include, but are not limited to, devices deployable within the bladder for the release of drugs into the bladder. This invention relates to medical devices for controlled drug release. [Background technology]

[0002]

[0002] Various implantable drug delivery devices are known in the art. For example, Lee et al. U.S. Patent Application Publication No. 2007 / 0202151 to Cima et al. Patent Publication No. 2009 / 0149833 discloses a device for minimally invasive deployment within a cavity or lumen within a patient, such as the bladder. The present invention describes a drug delivery device for the treatment of urinary tract ulcers and urinary tract infections. For example, the device must be relatively thin for deployment within the body. The implant may be configured to a narrow profile and, once implanted, may have a relatively expanded profile to promote retention. The device may include a retention frame that can deliver the drug in a defined manner over an extended period of time. In some embodiments, the device can provide a controlled release of The device comprises a permeable tube defining a drug reservoir for containing the drug and a small opening for releasing the drug. and at least one aperture. Osmotic pumping or diffusion allows the drug to be released from the reservoir. This may be the primary mechanism by which highly water-soluble drugs such as lidocaine hydrochloride become therapeutically effective via osmotic pressure. In other embodiments, the device may be primarily The drug may be configured to release poorly soluble or other drugs either selectively or exclusively via diffusion.

[0003] However, it would be desirable to provide improved drug delivery devices and systems. For example, it would be desirable to have a relatively low solubility drug that is osmotically dissolved at a therapeutically useful rate. Thus, devices, systems, and methods are provided that can release the It would be desirable to deliver various active agents with selected release kinetic profiles. To provide an implantable drug delivery device and system that can To improve control of drug release in the body, for example from a device deployed in the bladder. It would also be desirable to provide additional techniques, structures and / or formulations of Summary of the Invention

[0004] In one aspect, a method for manufacturing a liquid ejection system includes: a housing defining a reservoir; and a first unit housed within the reservoir. and a second unit housed in a different location from the first unit in the reservoir. An implantable drug delivery device is provided, comprising a first unit containing a drug and a second unit containing a drug. The unit contains a functional agent that facilitates the internal release of the drug from the housing.

[0005]

[0005] In another aspect, a first housing portion loaded with a drug formulation containing a drug; and a second housing portion loaded with an agent. The device is configured to release the drug according to a first release profile, and configured to release the excipient according to a second release profile different from the first release profile. do.

[0006]

[0006] In yet another aspect, as disclosed herein, a method for drug delivery into a patient is provided. and releasing a drug from the inserted device. A method of administering a drug to a subject is provided. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 is a cross-sectional view of one embodiment of a prior art drug delivery device. [Figure 2] FIG. 1 is a cross-sectional view of an embodiment of a multi-unit drug delivery device. [Figure 3] FIG. 10 is a cross-sectional view of another embodiment of a multi-unit drug delivery device. [Figure 4] FIG. 10 is a cross-sectional view of another embodiment of a multi-unit drug delivery device. [Figure 5] FIG. 1 is a cross-sectional view of an embodiment of a multi-unit drug delivery device. [Figure 6] FIG. 6 is a perspective view of a portion of the multi-unit drug delivery device of FIG. 5. [Figure 7] 1 illustrates an example configuration for a drug delivery device having two or more drug housing portions. [Figure 8] FIG. 1 is a plan view of an embodiment of a drug delivery device having two or more drug housing portions. [Figure 9] 1 is a graph showing percent drug release over time for a single tablet drug delivery device and a two tablet drug delivery device. [Figure 10] 1 is a graph showing the drug release rate over time for a single tablet drug delivery device and a two tablet drug delivery device. [Figure 11] 1 is a graph showing percent drug release over time for drug delivery devices with laser-drilled holes and drug delivery devices with spacer holes. [Figure 12] 1 is a graph showing the drug release rate over time for a drug delivery device with laser-drilled holes and a drug delivery device with spacer holes. [Figure 13]1 is a graph showing percent drug release over time for a drug delivery device containing a powdered drug and an osmotic agent tablet and a drug delivery device containing a drug tablet and an osmotic agent tablet. [Figure 14] 1 is a graph showing drug release rates over time for a drug delivery device containing a powdered drug and an osmotic agent tablet and a drug delivery device containing a drug tablet and an osmotic agent tablet. [Figure 15A] FIG. 1 is a perspective view of one embodiment of a housing for a drug delivery device. [Figure 15B] FIG. 1 is a cross-sectional view of one embodiment of a housing for a drug delivery device. [Figure 16] 1A is a cross-sectional view of an embodiment of a drug delivery device in which a reservoir includes a flow channel regulator. FIG. [Figure 17] FIG. 1 is a cross-sectional view of an embodiment of a multi-unit drug delivery device. [Figure 18] FIG. 1 is a cross-sectional view of an embodiment of a multi-unit drug delivery device. [Figure 19] 1 is a graph showing the amount of drug released over time from drug delivery devices having various housing wall thicknesses and durometer values. [Figure 20] 1 is a graph showing the amount of drug released over time from drug delivery devices having various housing wall thicknesses and durometer values. [Figure 21] 1 is a graph showing the amount of drug released over time from drug delivery devices having housing coatings of various lengths. DETAILED DESCRIPTION OF THE INVENTION

[0008]

[0028] for the purpose of delivering drugs locally or locally around the implantation site A device is provided that can be inserted into a body cavity or lumen. The device contains a unit of drug and a separate unit of a second agent that facilitates drug release. In vitro examples show short-term and long-term efficacy compared to similar single unit devices. Furthermore, these devices show an improvement in both drug release profiles during In addition, it allows for the delivery of low-solubility drugs to patients via osmotic release devices. This is particularly useful for drugs that are difficult to convert into a highly soluble form. In general, drug solubility is significantly dependent on the pH of the release medium, and reducing the pH dependence of drug release is important. This is preferred over diffused release when this is desired.

[0009]

[0029] For purposes of this disclosure, the term "implantation site" generally refers to a site within the body of a human patient or other animal. The implantation site refers to any urogenital site, such as, among other sites: Bladder, urethra, ureters, kidneys, prostate, seminal vesicles, ejaculatory ducts, vas deferens, vagina, uterus, fallopian tubes, ovaries, or It may be anywhere within the urinary tract or reproductive system of the body. The implantation site is the bladder.

[0010]

[0030] In certain embodiments, the device is adapted to be passed through natural orifices and lumens of the body. The device is designed to be deployed in a minimally invasive deployment procedure that utilizes the body's natural The device may also have a deployed configuration suitable for deployment through a lumen of, for example, an implant. Once implanted, the implant can be attached to the body by achieving a retained shape or by being fixed in the body. The device is designed to be retained within the body. In certain embodiments, the device is inserted through the urethra. It can be deployed within the bladder and, once implanted, overcomes the force of urination due to its retention within the bladder. It is possible to do this.

[0011]

[0031] Once implanted, the device releases one or more drugs over an extended period of time. Drugs can be delivered by osmotic pumping through openings in the device or by injecting drugs into the device. by diffusing through the surface of the device or through openings in the device. or a combination thereof. The drug release may be continuous and defined. The release profile of the compound may be as follows:

[0012]

[0032] In certain embodiments, the device comprises one or more drug units and one As used herein, the term "functional agent" refers to a functional agent that is loaded with one or more functional agent units. refers to an agent or excipient that promotes the controlled release of a drug from a device in the body. For example, the functional agent may be an osmotic agent, a drug solubilizer, a drug stabilizer, a permeation enhancer, or any of these. The functional agent may include a combination of the following based on the drug(s) being delivered from the device: For example, the drug to be delivered may be a poorly soluble drug, and the functional agent may be selected to dissolve the drug in water. An osmotic agent may be included to facilitate endosmotic release.

[0013]

[0033] As used herein, the term "poorly soluble" means that the It refers to a drug having a solubility of about 0.001 mg / mL to about 10 mg / mL. As used herein, the term "highly soluble" refers to a solubility of greater than about 10 mg / mL in water at 37°C. The solubility of a drug is affected, at least to some extent, by its form. For example, a drug in the form of a water-soluble salt may have high solubility, while the same drug in the base form may have high solubility. may have low solubility.

[0014]

[0034] In conventional drug delivery devices, highly soluble drugs are generally transported through an osmotic gradient induced by While the drug may be suitable for release according to the method described above, poorly soluble drugs may be released via diffusion through walls or passageways within the drug housing. The devices disclosed herein may be suitable for a variety of release modes and release kinetic profiles. Various drugs can be delivered through the drug profile, improving the control of drug release in the body. Additional techniques, structures and / or formulations for improving the sensitivity of the ion exchange membrane may be provided.

[0015]

[0035] Whether the drug selected has high or low solubility, The product may contain one or more functional agents (e.g., osmotic agents to increase water flux, solubilizers, or Therapeutically effective The drug will be delivered (i.e., released from the delivery device) at a rate of If so, the combination of selected drug solubility and osmotic water flux in the presence or absence of a functional agent. The combination determines the release rate and duration, and such combination determines the release rate and duration. can be configured to be within a therapeutically effective range.

[0016]

[0036] The devices and methods disclosed herein are incorporated by reference in their entirety. No. 2010 / 0331770, U.S. Patent Application Publication No. 2011 / 0152 to Cima et al. 839, and U.S. Patent Application Publication No. 2012 / 0203203 to Lee et al. No. 6,299,499, filed on Oct. 1, 2003, and is incorporated herein by reference.

[0017]

[0037] I. Implantable Drug Delivery Devices

[0018]

[0038] Embodiments of the implantable drug delivery devices disclosed herein generally comprise a reservoir. a housing defining a storage section, and a first unit and a second unit housed within the storage section; For example, the housing may be an elongated annular tube and the reservoir may be the lumen of the annular tube.

[0019]

[0039] The first unit(s) contains the drug or active pharmaceutical ingredient to be delivered to the patient. The second unit(s) contains a functional agent that promotes the release of the drug from the housing in the body. The first unit and the second unit are located at different positions within the reservoir. The first unit and the second unit are different and independent of each other. For example, the first unit and the second unit may be a solid tablet positioned adjacently within the reservoir.

[0020]

[0040] As shown in FIG. 1, a conventional drug delivery device 100 includes a reservoir 104. (For clarity of comparison with other illustrated embodiments, see the accompanying drawings.) For purposes of size and ease, device 100 may be configured in a linear fashion that may be useful during the insertion process into a patient. (Indicated by a solid line.) The tablet 102 contains the drug to be delivered and optionally one or more excipients. When implanted, the device 100 allows osmotic pumping through openings 106 in the device 100. However, the release pattern and kinetics of the drug vary depending on the tablet formulation. and the properties of the materials of construction of the enclosure.

[0021]

[0041] One embodiment of the present disclosure is shown in Figure 2. An implantable drug delivery device 200 includes , includes a housing 208 that defines a reservoir 204. In contrast to device 100, device 2 00 includes a plurality of first units 202 containing a drug and a functional agent contained in a reservoir 204. The first unit and the second unit 202 include a plurality of second units 210 including: 210 are located at different positions within reservoir 204. This arrangement is described in more detail below. This can be particularly advantageous as

[0022]

[0042] The device structure may be combined with a drug and functional agent formulation to provide permeation and / or diffusion The drug and functional agent may be designed to be released via the

[0023]

[0043] FIG. 2 illustrates a device 200 configured to operate as an osmotic pump. The device housing 208 is readily permeable to water but is permeable to the drug and The housing 208 includes a wall that is not permeable to drugs that do not readily diffuse through the wall. That is, the water-permeable portion may be substantially impermeable to the drug in aqueous solution. The portion may define at least a portion of the reservoir 204. After the device is deployed within the patient, Water (or urine if in the bladder) permeates through the wall, enters the reservoir 204, and Alternatively, the water-permeable wall may be formed by solubilizing the first and / or second units 202, 210. In combination with the component, the housing is configured to allow fluid to enter the reservoir within the body. For example, the housing and / or any water-permeable wall portion may include at least one aperture. Polyurethane, thermoplastic polyurethane, ethylene-co-vinyl acetate (EVA), or A combination of the above is also possible.

[0024]

[0044] Injection of several portions of solubilized fluid into the reservoir prior to implantation may be necessary if desired. In certain embodiments, the device may facilitate the hydration process of tablets or formulations thereof. The solution contains at least a portion of the aqueous fluid that is required to solubilize the functional agent and drug prior to implantation. For example, fluid may be introduced into the device reservoir via a needle and syringe. In one embodiment, a portion of the housing is suitable for penetration by a needle or other instrument. For example, the housing may include a low durometer material surrounded by a high durometer material portion. The housing may include a coaxial spacer including a portion of low durometer material. , may include unidirectional hermetic sealing features.

[0025]

[0045] Following implantation, an osmotic pressure gradient is created between the interior and exterior of the device housing 208. Once sufficient pressure is achieved, the solubilized drug is released into at least one of the reservoirs 204 in fluid communication with the reservoir 204. and through another drug release hole 206 at a controlled rate by osmotic pressure within the reservoir 204. Such a mode of release is referred to herein as This may alternatively be referred to as "osmotic delivery" or "osmotic pumping."

[0026]

[0046] As shown in FIG. 2, the drug release hole 206 is located at the end of the tubular housing 208. Such end plugs may also be referred to as "spacer holes." Further details are found in PCT Application No. PCT / US14 / 20703, filed March 5, 2014. FIG. 3 shows a drug release device 306 mounted on the sidewall of the housing 308. 3 illustrates another embodiment of the osmotic device 300 that includes an exit hole 306, which allows the solubilized drug to pass through the The device is configured to allow passage of these.

[0027]

[0047] As shown in FIG. 17, the drug delivery device 1700 includes a tubular housing 1708 at the end thereof. The portion may include a constraining plug 1707. In this embodiment, the constraining plug 1707 , transient flow of one or more microchannels between the elastic portion of the housing 1708 and the restraining plug For example, the osmotic tablet 1710 and the drug tablet 1702 are , between the sealed end 1713 and another portion of the captive plug and the housing (e.g., from an adhesive of the confining plug without inhibiting the transient formation of microchannels within By a captive plug 1707 which may be secured by adhesive 1709 that secures the portion to the housing. Such a constrained plug / microchannel may be contained within a constrained reservoir 1704. Further, PCT Application No. PCT / US14 / 28317, filed March 14, 2014, are described in detail and incorporated herein by reference.

[0028]

[0048] In certain embodiments, the first unit, i.e., the Drug unit, is , drug release hole, drug permeable wall portion, or restraining plug, a second unit, i.e. , are located closer than the functional agent unit. This arrangement is advantageous for certain drugs, such as low-solubility drugs. have been shown to be particularly advantageous with respect to achieving a therapeutically effective rate of release of the drug for It has been done.

[0029]

[0049] If osmotic release is the desired drug release mode, the functional agent in the second unit The formulation may include an osmotic agent that facilitates the osmotic release of the drug. For example, the osmotic agent may be an osmotic agent have a higher solubility than the drug so as to facilitate solubilization and / or subsequent release of the drug. This is typically achieved by using low solubility drugs that are only delivered via diffusion from osmotic delivery devices. This advantageously allows for the delivery of sexual or other drugs.

[0030]

[0050] The device 200 contains a sufficient volume of functional agent and / or agent(s) to achieve an osmotic gradient. Alternatively, the device 200 may exhibit an induction period during which the drug is solubilized. may exhibit a zero-order release rate followed by a decay period that decreases over a non-zero-order release rate The desired delivery rate can be controlled by the surface area and thickness of the water permeable wall, the amount of water used to form the wall, and the amount of water used to form the wall. The water permeability of the material used, the shape, size, number and arrangement of the apertures 206, and the chemical Various parameters of the device, including but not limited to the dissolution profile of the compound and functional agent, This can be achieved by selecting the appropriate data.

[0031]

[0051] The devices described herein also include, alone or in combination with osmotic release. The device may also be configured to release the drug via diffusion. , configured to allow passage through a portion of the housing or one or more apertures therein Good too.

[0032]

[0052] In certain embodiments, the water-permeable wall portion of the housing is also referred to herein as The drug is released through the wall, which is also called "transmural diffusion" in aqueous solution. After the device is implanted, water or urine can penetrate through the wall. The drug then enters the reservoir and solubilizes the functional agent and / or drug. Drug diffusion occurs at a controlled rate directly through the wall due to a drug concentration gradient between the inside and outside. For example, the housing and / or any water or drug permeable wall portions may be made of silicone, thermoplastic polymer, It may be urethane, ethylene-co-vinyl acetate (EVA), or a combination thereof.

[0033]

[0053] In certain embodiments, the housing does not have a release hole and is abutting the reservoir. The drug is released through at least one drug-permeable wall. The permeable wall is secured within the lumen of the tube at or near the end of the tube, optionally with an internal seat. The drug-permeable wall may include a disk sandwiched between the gold and outer washer. This is described in more detail in U.S. patent application Ser. No. 14 / 216,112, filed on the 7th, which is incorporated by reference. In other embodiments, the drug-permeable wall is a It is part of an end plug located at the end of a tubular housing.

[0034]

[0054] Alternatively, or in combination with the water-permeable wall portion, the housing may be configured to allow fluid to be stored in the body. The housing may include at least one aperture configured to allow entry of the housing. Also, one or more apertures or passages configured to allow the solubilized drug to pass through. It may also contain superpores.

[0035]

[0055] As noted above, the device may also be inserted into the body prior to implantation, e.g., via a needle or syringe. to receive at least a portion of the water or fluid required to solubilize the functional agent and drug; may also be configured.

[0036]

[0056] The device exhibits a long-term zero-order emission rate followed by a decreasing Zero-order release occurs when the drug, once solubilized, penetrates the housing wall and does not dissolve. The delivery rate can be relatively rapid, since the drug is immediately available for diffusion through the Among other factors, the surface area and thickness of the wall, its permeability to water and the strength of the material used to form the wall. The drug, drug charge or particle size of the material used, and the dissolution profile of the drug and functional agent In embodiments where the drug is released through one or more open or through pores. In some cases, the number of open or through pores may also affect the overall release rate due to diffusion. Multiple or combinations may be used.

[0037]

[0057] In certain embodiments, the first unit and / or the second unit are For example, as shown in FIG. 4, the first unit 402 is in the form of a powder. In another embodiment, the second unit 410 is in the form of a solid tablet. As shown in Figures 2 and 3, both the first unit and the second unit are solid tablets. In certain embodiments, the solid tablet is in the form of a tablet according to U.S. Pat. No. 6,229,499 to Daniel et al. In embodiments, the tablet is configured as a "mini-tablet" as described in US Pat. No. 8,343,516. As shown in FIG. 5, the device 500 includes a plurality of first units 5 in the form of solid tablets. 02 and a plurality of second units 510 in the form of solid tablets.

[0038]

[0058] In certain embodiments, each drug unit tablet contains a relative amount of drug. For example, each drug tablet contains a therapeutically high weight fraction and a relatively low weight fraction of excipients. 50% by weight, which allows loading of relatively small devices with therapeutically effective amounts of drug The release rate of the drug from the device depends on the combined properties of the functional agent and the drug housing. The housing characteristics, such as its thickness and permeability, as well as the functional agent formulation, can be controlled advantageously by It can be changed by adjusting

[0039]

[0059] The implantable device is adapted to be deployed and retained within a body part, such as the bladder. The device can be designed to allow the device to deform for insertion and still function once implanted. Once inserted, the device is flexible so that it can withstand the force of urination or other forces. In one embodiment, the drug-loaded device may include an adjacent drug unit. Since the solid drug unit and / or functional agent unit may be capable of moving relative to the Although the tablets are filled, they are flexible or deformable. The gaps or crevices between the drug units are similar to those described in U.S. Patent Application Publication No. 2010 / 033 to Lee et al. 1770, while providing a buffer that allows deformation of the device. This allows the individual units to retain their solid form.

[0040]

[0060] As shown in FIG. 4, the powdered units 402 or as shown in FIG. 6, the powdered units 402 are The payload may be formed of individual solid tablets 602, 610 that are movable in unison. Some solid drug and / or functional agent payloads are entirely flexible.

[0041]

[0061] As mentioned above, the device housing is formed at least in part from a water-permeable material. For example, the enclosure may be such that water does not penetrate through its entire length, a portion of it, or one or more of the devices. It may be formed from a water permeable material along both edges to allow diffusion into the drug housing. good.

[0042]

[0062] In certain embodiments, the housing comprises two annular tubes, one permeable and the other impermeable. The tube is in the form of one or more elongated annular tubes that include two wall portions that are water permeable. The configuration is shown in Figures 15A-15B. Here, the annular pipe 1500 has an impermeable wall portion 151 0 and water-permeable wall portion 1520. Upon insertion into a patient, water flows from within lumen 1530 to the wall 1520 and contact the solid drug and / or functional agent payload therein. For example, this structure can be formed by coextrusion. The relative proportions of the two wall sections are as described in U.S. Patent Application Publication No. 2011 / 015283 to Cima et al. 9, e.g., the rate of water permeation (i.e., the surface area available for water permeation). and provide the flexibility / hardness values ​​required for, for example, urethral insertion and bladder retention and tolerance. The thickness may be selected depending on the mechanical properties required to achieve the desired results.

[0043]

[0063] As shown in FIG. 18, the drug delivery device 1800 includes a small tubular housing 1808. At least a portion of the surface may include a water-impermeable coating region 1809. The impermeable wall portion may be formed by coating the housing with an impermeable material. For example, osmotic tablet 1810 and drug tablet 1802 have sealed ends 1813 and release hole protrusions. The lug 1806 may be inserted into the reservoir 1804. , water flows from within the reservoir 1804 through the water-permeable enclosure 1808 (but not through the water-impermeable area 18 09) and contact and solubilize the functional agent and drug tablet payload within it. The water-impermeable region allows for controlled solubilization and release of the drug. Coatings are useful in osmotic delivery devices when the housing material is permeable to the drug. It is possible.

[0044]

[0064] For example, the impermeable coating area is 4 cm to 11 cm along the length of the enclosure. In one particular embodiment, the tube may extend along the length of the housing, for example, 6.5 cm. The case has an inner diameter of 2.64 mm and can accommodate a 6 to 11 cm functional agent tablet and a 2 to 4.5 cm While containing a drug tablet, the device has an impermeable coating that extends the housing length from 4 cm to 11 cm. For example, a water-impermeable parylene coating can be applied to a silicone or other enclosure. may be provided to.

[0045]

[0065] As mentioned above, the walls of the device housing are designed to prevent water from flowing through their surfaces into the reservoir. and / or may have one or more passages that provide a path for the drug to flow from the reservoir. In some embodiments, the wall has one or more through holes formed therein. In other embodiments, the wall may be porous, meaning that it can be drilled, perforated, or otherwise penetrated. In the form of a defined opening formed completely through the wall, such as by a hole or molding. The apertures may be circular or have other shapes. The apertures may be straight apertures extending through the wall. The sidewalls may be curved or tapered.

[0046]

[0066] In some embodiments, the wall is made of a resilient biocompatible polymeric material. The material may be non-resorbable or resorbable. An example non-resorbable material is poly( ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrolidone) ), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(silicone) Poly(tetrafluoroethylene), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers The resorbable polymers of the present invention include synthetic polymers selected from the group consisting of poly(siloxanes), poly(siloxanes), and poly(siloxanes). The materials, specifically biodegradable or bioerodible polymers, include poly(amides), poly(esters), and the like. poly(ester amides), poly(anhydrides), poly(orthoesters), polyphosphite azenes, pseudo-poly(amino acids), poly(glycerol-sebacate), poly(lactic acid), Poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(caprolactone), Poly(caprolactone) (PC) derivatives, amino alcohol-based poly(ester amide) ( Poly(ethylene glycol ether) (PEA) and poly(octanediol citrate) (POC), as well as other curable biomaterials The PC-based polymers include synthetic polymers selected from absorbable elastomers. To obtain the desired properties, lysine diisocyanate or 2,2-bis(ε-caprolactone ( An additional cross-linking agent such as (caprolacton-4-yl)propane may be required. Copolymers, blends, and combinations of the above materials may also be used.

[0047]

[0067] In certain embodiments, the housing is made of a material that is both water permeable and flexible. Silicone, when formed as a thin wall, may be formed from It can act as a flexible and water-permeable membrane, with the permeability determined by the wall thickness. For example, the thin wall of silicone is about 100 μm to about 10 The silicone may have a thickness in the range of 0.5 to 100 μm, although other wall thicknesses may be used. The thin wall of the drug depends, for example, on the porosity of the wall, the size of the drug molecule, its molecular weight, or its charge. and may be permeable to some drugs.

[0048]

[0068] The dimensions of the housing, including the wall thickness, depend on, among other things, the drug and functional agent formulations to be contained. the volume of the drug, the desired rate of delivery of the drug from the tube, the intended site of implantation of the device within the body, the desired mechanical integrity of the device, the desired release rate or permeability to water and urine, the initial release and the desired method or route of insertion into the body. The wall thickness is such that a wall that is too thin may not have sufficient mechanical integrity, while a wall that is too thick may cause damage. may experience an undesirably long induction time for initial drug release from the device and / or or other narrow body lumens, and therefore may not be flexible enough to allow delivery through such narrow body lumens. This can be determined based on the properties and water permeability of the tubing material.

[0049]

[0069] For example, the housing may be an elongated circular tube having an inner diameter of about 2 mm to about 5 mm. The first unit and the second unit have a diameter substantially the same as the inner diameter of the elongated annular tube. One or more of the first unit tablets may be solid tablets having a length of about 1 cm to about 3 cm. The inner cavity of the tube can be filled with one or more of the second unit tablets, and the second unit tablets can be filled with one or more of the second unit tablets, and the second unit tablets can be filled with one or more of the second unit tablets. In one embodiment, the first unit(s) may fill the lumen of a tube up to cm in length. The ratio of the volume to the volume of the second unit(s) is about 0.05 to about 0.5. Other lengths and ratios of the payload are envisioned.

[0050]

[0070] For example, the housing may have a wall thickness of 0.1 to 0.4 mm, such as a wall thickness of 0.2 mm. The housing material may be 25A, 50A, 65A, 70A, or 8A. It may be selected to be a durometer value between 25A and 80A, such as 0A.

[0051]

[0071] In certain embodiments, the device is inserted into the patient's bladder through the patient's urethra. It has a relatively straight shape suitable for insertion into the bladder and a retaining structure suitable for holding the device in the bladder. For example, the device may be resiliently deformable between a holding shape and a holding configuration. The retaining frame may include a retaining frame lumen having a frame. The retaining frame may be a retaining frame as described in U.S. Patent Application Publication No. 2010 to Lee et al. As described in / 0331770, it is made from superelastic alloy or other elastic wire. and is incorporated herein by reference.

[0052]

[0072] An exemplary embodiment is shown in Figure 5, where the device 500 comprises a first unit and a second unit. 5, including a housing 508 that houses the drug housings 502, 510, and a retaining frame 512. 508 is axially aligned with the retaining frame 512, and the device 500 is in the retaining configuration shown in FIG. 3 and a straight, unfolded shape as shown in Figure 3. The "retention shape" generally corresponds to the shape shown in FIG. 5, which is suitable for retaining the device in the bladder. Retaining the device within the intended implantation location, including but not limited to, a Letzel-like shape While the term "deployed configuration" refers to any shape suitable for insertion into the urethra or other natural FIG. 10 is a diagram suitable for deploying a device through a working channel of a deployment instrument positioned within a cavity. 3. Any suitable shape for deploying a drug delivery device into the body, including a straight or elongated shape as shown in FIG. In one embodiment, the device is forced into the deployed configuration. and / or via a deployment device, etc., in the absence of compressive load, The coil is configured to spontaneously assume a shape having a length of 1.0 mm.

[0053]

[0073] In one particular embodiment, as shown in FIG. 16, the storage of device 1600 The storage section 1604 is located between the first and second units 1602 and 1610. For example, the flow regulation channel may be The flow regulation channel may be a channel having a diameter smaller than the channel (i.e., the reservoir). It can serve to restrict the flow of fluid between the sacs (sacs) and the sacs (sacs), thus limiting the ability of the functional agent to contact the drug. In certain embodiments, the release of the drug from the housing is slowed down. The device may be configured with two or more flow regulators for further control over the rate of drug release from the device. It may include a channel.

[0054]

[0074] In certain embodiments, the drug delivery device is loaded with a drug formulation. The first housing portion and the second housing portion are filled with an excipient, and the first release profile is a second release profile different from the first release profile, The housing portion is configured to release the excipients according to a release profile. by having different configurations, by containing different formulations, or by containing different release Different release rates can be achieved by using different release mechanisms, or by a combination of these. The housing portions can be assembled to achieve the desired drug release profile. For example, excipients may be release and / or drug solubilizers, drug stabilizers, or It may also be a functional agent configured to enhance drug delivery, such as a permeation enhancer. Alternatively, the excipient may be in the form of one or more tablets.

[0055]

[0075] For example, the device may be configured to, among other things, provide different loading or time periods before the start of the first release. differences or the drug and excipients may be released at different rates or follow different release curves after the onset of release. or release the drug and excipients for different periods before the payload is substantially depleted. The housing may include housing portions that are different from each other, or a combination thereof. , showing a relatively short initial time difference, then continuing at a relatively constant rate for a long period of time and achieving a desired release profile from the drug delivery device as a whole, such as a release profile that exhibits a release that is consistent with the desired release profile from the drug delivery device. may be combined to achieve a

[0056]

[0076] For example, the drug and excipient may be osmotically pumped or diffused or otherwise transported, as described above. It may be released by some of these combinations. In certain embodiments, The drug leaves the first housing portion primarily via osmotic pressure through the openings in the first housing portion. The excipient is released from the second housing portion by diffusion. The drug diffuses from the first housing portion through a drug-permeable wall within the first housing portion. The excipient is released through the openings in the second housing portion and transported to the second housing portion primarily via osmotic pressure. It is emitted from the housing part.

[0057]

[0077] In certain embodiments, the drug delivery device is associated with a single holding portion. The housing includes at least two separate or discrete housing portions, each of which has a holding portion. The separate reservoir housings or housing portions associated with the holding portion are separate within a single housing associated with the holding portion. FIG. 7 shows an example housing with separate reservoir housings of Examples A to C. FIG. 7 also illustrates the separate regions within a single enclosure of embodiments D-F. 7 also illustrates the housing portion of the example. Housing portions that can have either configuration are also illustrated.

[0058]

[0078] FIG. 8 illustrates a drug delivery device having a housing divided into multiple separate housing portions. 8 is a plan view of another embodiment of a chair 800. These housing portions 802, 804, and 806 are 6 is shown, but any number can be used. Each housing section is a portion of the housing wall. and at least one partition structure 808 that separates the housing portion from adjacent housing portions. The partition structure 808 is fixed due to its size or adhesiveness, among other things. The partition structure 80 may be a plug inserted into the enclosure, such as a cylinder, sphere, or disk. 8 may also be a part of the housing formed directly therein by molding or the like. The webs shown in Examples D-E are partition structures that separate housing sections along the length of the device. is.

[0059]

[0079] A device with at least two separate housing portions may have a corresponding number of reservoirs. at least one drug payload and at least one excipient or functional agent payload from The two separate portions may be suitable for controlled release of the drug. The two different configurations may have the same or different configurations, such as one or any combination of the configurations. The construction of a drug delivery device having a drug portion comprising: This is further described in US Pat. No. 6,299,999.

[0060]

[0080] II. Uses and Applications of Implantable Drug Delivery Devices

[0061]

[0081] The implantable drug delivery devices described herein are useful in a variety of medical applications, particularly In certain embodiments, the present invention may be used in therapeutic and prophylactic treatments for patients. The device is designed to deliver lidocaine, gemcitabine, docetaxel, carboplatin, and cisplatin. drugs such as rivaroxaban, oxaliplatin, trospium, tolterodine, or mitomycin C The device is configured to deliver

[0062]

[0082] In some embodiments, the device provides pain relief to the patient. Anesthetics, analgesics, and combinations thereof may be used. The device delivers one or more local anesthetic agents. The local anesthetic agent may be a cocaine analog. In certain embodiments, the local anesthetic is an aminoamide, an aminoester, or a combination thereof. Representative examples of aminoamide or amide type anesthetics are articaine, bupivacaine, Vacine, carticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine , mepivacaine, prilocaine, ropivacaine, and trimecaine. Representative examples of amine or ester type anesthetics are amylocaine, benzocaine, butacaine, Roroprocaine, cocaine, cyclomethicaine, dimethocaine, hexylcaine, larocaine meprylcaine, metabutoxycaine, orthocaine, piperocaine, procaine , proparacaine, propoxycaine, proxymetacaine, lysocane, and tetracaine These local anesthetics are generally weak bases and are salted with salts such as hydrochlorides to make them water-soluble. Although anesthetics may be formulated as such, the anesthetic may also be used in free base or hydrate form. Other anesthetics, such as lontocaine, may also be used. It may also be an antimuscarinic compound that exhibits anesthetic effects, such as sibutinin or propiverine. The topical anesthetic may also include other drugs described herein, either alone or in combination with the local anesthetic. good.

[0063]

[0083] In certain embodiments, the analgesic agent comprises an opioid. Typical examples of drugs are alfentanil, allylprozin, alphaprozin, and anilelizine. Benzylmorphine, bezitramide, buprenorphine, butorphanol, clonidine Zene, codeine, desomorphine, dextromoramide, dezocine, diampromide, zia Morphone (diamorphone), dihydrocodeine, dihydromorphine, dimenon Xadol, Dimepheptanol, Dimethylthiambutene, Dioxaphetyl butyrate , dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmol Hine, etonitazene fentanyl, heroin Insulin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemide morphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, Putazinol, metazocin, methadone, metopon, morphine, myrophi ne), nalbuphine, narceine, nicomorphine, norlevorphanol, normetad nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone , Papaveretam, Pentazocine, Phenadoxone, Phenomorphan, Phenazocin, Enoperidine, Piminodine, Piritramid, Proheptadine, Promedol, Properidine propiram, propoxyphene, sufentanil, tilidine, tramadol, and mixtures thereof. Other opioid drugs, such as receptor agonists, are contemplated.

[0064]

[0084] Representative examples of other suitable analgesics include salicylic alcohol, phenazopyrrolidin, and phenazopyrrolidin. gin, acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, These include agents such as indoprofen, indomethacin, and naproxen.

[0065]

[0085] In embodiments, the drug delivery device is for use in treating interstitial cystitis, chemical cystitis, , radiation cystitis, radiation and chemotherapy induced hemorrhagic cystitis, ketamine cystitis inflammation (or ketamine bladder syndrome), painful bladder syndrome, prostatitis, urethritis, postoperative pain, and Used to treat inflammatory conditions such as kidney stones. Non-limiting examples include lidocaine, immunosuppressants (e.g., tacrolimus, liposomal tacrolimus, limus), glycosaminoglycans (e.g., chondroitin sulfate, sulodexide), pen Sodium polysulfate (PPS), dimethyl sulfoxide (DMSO), oxybutyric acid steroids, mitomycin C, heparin, flavoxate, ketorolac, or combinations thereof For kidney stones, there are medications to treat pain and / or to aid in stone dissolution. The drug(s) may be selected.

[0066]

[0086] In some embodiments, pain resulting from ureteral stent placement, urinary urgency, Drug delivery devices are used in conjunction with the placement of ureteral stents, such as to treat urinary congestion or frequency. Non-limiting examples of specific drugs for treatment include antimuscarinics, alpha blockers, Anesthesia, and phenazopyridine.

[0067]

[0087] The drug delivery device may be used to treat urinary incontinence, including, for example, urge incontinence and neurogenic incontinence. It can be used to treat urinary incontinence, urgency, and trigonitis. The drugs are anticholinergics, antispasmodics, antimuscarinics, beta-2 agonists, alpha-adrenergics, and anticonvulsants. , norepinephrine absorption inhibitor, serotonin absorption inhibitor, calcium channel blocker, calcium Representative examples of drugs suitable for treating incontinence include: sodium channel openers, and muscle relaxants. Oxybutynin, S-oxybutytin, emepronium, Verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine roxiverine, clenbuterol, darifenacin, terodiline, trospium, hiyo Hyoscyamin, propiverine, desmopressin, vamicamide, odor Clidinium chloride, dicyclomine HCl, glycopyrrolate amino alcohol ester, Ipratropium bromide, mepenzolate bromide, methscopolamine bromide, scopolamine hydrobromide Lamin, iotropium bromide, fesoterodine Fumarate, YM-46303 (Yamanouchi Co., Japan), Lampe Lizon (Nippon Kayaku Co., Japan), Inaperisone, NS-2 1(Nippon Shinyaku Orion, Formenti, Japan / I taly), NC-1800 (Nippon Chemiphar Co., Japan ), ZD-6169 (Zeneca Co., United Kingdom), and Yo Contains stilonium iodide.

[0068]

[0088] In other embodiments, the drug delivery device is for treating cancer of the urinary tract, such as bladder cancer or prostate cancer. Used to treat cancer. Drugs that can be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, and Representative examples of drugs suitable for treating urinary tract cancer include carboplatin, cyclosporine ... Bacillus gracilis-Guérin (BCG) vaccine, docetaxel, oxaliplatin, carboplatin Cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall-D NA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin , fluorouracil, leuprolide, diethylstilbestrol, estramustine, Megestrol acetate, cyproterone, flutamide, selective estrogen receptor modulators (s i.e., SERMs such as tamoxifen), botulinum toxin, histone deacetylase inhibitors drugs (e.g., suberoylanilide hydroxamic acid), and cyclophosphamide The drug may also be a biologic, such as a monoclonal antibody, a TNF inhibitor, or an anti-leukin. etc. The drug may also include TLR agonists, including imiquimod or another TLR7 agonist. The drug may also be an immunomodulatory agent, such as, inter alia, a fibroblast growth factor receptor-3 (FG FR3)-selective tyrosine kinase inhibitor, phosphatidylinositol 3-kinase (P I3K) inhibitors, or mitogen-activated protein kinase (MAPK) inhibitors, or The drug treatment may be a kinase inhibitor such as a combination of these. It may be combined with radiation or surgical treatment.

[0069]

[0089] In yet another embodiment, the device is associated with the bladder, prostate, and urethra. Used to treat infections caused by: Antibiotic, antibacterial, antifungal, antiprotozoal, antiseptic Antiviral and other anti-infective agents may be administered to treat such infections. Representative examples of drugs used to treat infectious diseases include mitomycin, ciprofloxacin, and norfloxacin. cin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin Phosphorus, nafcillin, trimethoprim, sulfonamide trimethoprim sulfamethoxazoline erythromycin, doxycycline, metronidazole, tetracycline, These include namycin, penicillin, cephalosporin, and aminoglycoside.

[0070]

[0090] In other embodiments, the device is used to line a urogenital site, such as the bladder or uterus. A representative example of a drug for the treatment of fibrosis is pentoxufulin (p entoxphylline) (xanthine analogue), anti-TNF, anti-TGF, GnRH Analogs, exogenous progestins, antiprogestins, selective estrogen receptor modulators, Dana These include benzodiazepines, benzodiazepines, and NSAIDs.

[0071]

[0091] The drug delivery device may also be used to treat neurogenic bladder. Representative examples of drugs for the treatment of neurogenic bladder include lidocaine, bupivacaine, and mepivacaine. analgesics or anesthetics such as prilocaine, articaine, and ropivacaine; anticholinergics; antimuscarinics such as oxybutynin or propiverine, capsaicin or resiniferatogenic Vanilloids such as cin act on M3 muscarinic acetylcholine receptors (mAChR) antimuscarinics such as baclofen, and GABA B Antispasmodic drugs containing agonists, botulinum toxin Serotonin-related drugs such as capsaicin, alpha-adrenergic antagonists, anticonvulsants, and amitriptyline In various embodiments, the drug is R In eitz et al., Spinal Cord 42:267-72 (2004) As described, it is not intended to affect bladder afferent nerves or efferent cholinergic transmission. It may also be something like this.

[0072]

[0092] Medications for the treatment of neurogenic bladder fall into one of two general types: It can be used to treat spastic neurogenic bladder and atonic neurogenic bladder. In this form, the drug is used to treat incontinence caused by neurological detrusor overactivity and / or a weak detrusor muscle. Examples include bladder relaxants (e.g., oxybutyric acid, benzodiazepines ... Chinine (an antimuscarinic agent with significant muscle relaxant and local anesthetic activity), propiverine , impratroprium, tiotropium, trospiu terodiline, tolterodine, propantheline, oxyphencyclamine, flavoxamine steroids, and tricyclic antidepressants, bladder and urethra (e.g., vanilloids (capsaicin, Drugs that block nerves that control the immune system (resiniferatoxin), botulinum toxin A, or urination Drugs that regulate muscle contraction strength, micturition reflex, and detrusor-sphincter dyssynergia (e.g., GABA-active drugs) Drugs (baclofen, benzodiazapine) and others In this embodiment, the drug is a known anti-incontinence drug for the treatment of incontinence due to neurological sphincter deficiency. Examples include alpha adrenergic agonists, estrogens, beta adrenergic These include phospholipid agonists and tricyclic antidepressants (imipramine, amitriptyline). In embodiments, the drug is one known to promote urination (e.g., an alpha adrenergic antagonist). In yet another embodiment, the compound is selected from the group consisting of an anti-inflammatory drug (phentolamine) or a cholinergic agonist. Drugs include anticholinergics (e.g., dicyclomine), calcium channel blockers (e.g., tropane alkaloids (e.g., atropine, scopolamine), putin / orphanin FQ, and bethanechol (e.g., m3 muscarinic agonists, cholinergic esters).

[0073]

[0093] In certain embodiments, the functional agent or excipient is an osmotic agent, a drug solubilizer, In particular, functional agents or The excipient may be suitable to facilitate delivery of the drug to the internal release or implantation site. The functional agent may be a poorly soluble drug, and the functional agent may be an osmotic agent such as urea. The release of the drug from the housing is facilitated by osmotic pressure-induced fluid flow. Other examples of functional agents and excipients that may be used include cyclodextrin, glycerol, polyethylene glycol, Contains cholate, citrate, acetate, phosphate, ascorbic acid, and sodium sulfite .

[0074]

[0094] In an embodiment, the first unit(s) contain a high weight percent of drug. and the second unit(s) comprises a high weight percentage of a functional agent or excipient. For example, the first unit may contain at least 50 weight percent of the drug, at least 60 weight percent of the drug, percent drug, at least 75 weight percent drug, about 60 to about 99 weight percent The second unit may contain about 100% or about 75 to about 95 weight percent of the drug. At least 80 weight percent functional agent, at least 85 weight percent functional agent, at least at least 90 weight percent functional agent, about 80 to about 99 weight percent functional agent, or about 8 The remainder of the unit may contain 5 to about 95 weight percent of the functional agent. It may also contain excipients such as a filler or binder, for example, an oily lubricant, PEG, or PVP. The excipient may also include a release retardant, for example, a release retardant that further retards the release of the drug. In order to control It can be provided.

[0075]

[0095] In certain embodiments, the first units comprise at least 75 weight percent the second unit contains at least 85 weight percent of gemcitabine HCl; For example, the first unit contains about 80 weight percent gemcitabine HCl. 1 and the second unit may contain about 90 weight percent urea.

[0076]

[0096] In one embodiment, the housing is water permeable and the first unit contains a low-solubility drug. The second unit includes a first tablet containing a substance, and a second unit releases the drug from the housing by osmotic pressure. In one embodiment, the drug is a gemcitabine. Tabine and the osmotic agent is urea.

[0077]

[0097] The device may be inserted into a body cavity or lumen of a patient. The device may be localized to one or more tissues at the deployment site or to other tissues distal to the deployment site. Either or both may release one or more drugs for the treatment of one or more conditions. Release can be controlled over an extended period of time, after which the device is removed or resorbed. The urinary tract may be ingested, excreted, or a combination thereof.

[0078]

[0098] In certain embodiments, the device is deployed within the patient through a deployment instrument. The device is inserted by passing it through the device holder and releasing it into the body through the deployment tool. The deployment tools, whether commercially available or specially modified for deploying the device, and suitable endoluminal devices such as catheters, urethral catheters, cystoscopes, or combinations thereof. In certain embodiments, the device is implanted into the bladder. The device may have retention characteristics, such as by assuming a retention shape or by being anchored within the bladder. It is retained in the bladder due to the

[0079]

[0099] The device may be used as a standalone procedure or in conjunction with another urinary or other procedure or surgery. The device may be deployed either before, during, or after other procedures. , to local and / or regional tissues, for therapeutic or prophylactic purposes, either intraoperatively, postoperatively, or Both may release one or more drugs.

[0080] [000100] Following deployment in the body, the device releases the drug. This may occur due to an osmotic pressure gradient between the inside and outside of the device, and the drug may be absorbed by the osmotic force. The release also occurs through one or more holes or through-pores in the device. Drug concentration gradients between the device and the exterior may result in drug penetration into one or more pores or This occurs by diffusion through the passage pores and / or through the drug-permeable wall of the device. Combinations of these release modes within a single device are possible, and several In some embodiments, a holistic approach that is not readily achievable from any of the individual modalities is provided. It is suitable for achieving a desired release profile.

[0081] [000101] Following insertion of the device into a patient, water or aqueous bodily fluids from the implantation site may be drawn into the device. For example, a water-permeable barrier or barriers within the wall of the device may be used to solubilize the active ingredient or excipient and drug. For example, functional agents and drugs may enter the device through the bladder when the device is implanted in the bladder. In some cases, the functional agent may be solubilized upon contact with urine. It may be a structured solubilizer.

[0082] [000102] In certain embodiments, at least two payloads (i.e., one The release of the drug payload and one excipient and / or functional agent payload) is immediate and Profiles exhibiting different initial onset of release such as delayed release, short release and extended release or profiles exhibiting different durations of release, such as zero order release or other release rates. may occur according to different release profiles, including profiles exhibiting different release rates Therefore, continuous and prolonged release can be facilitated according to the desired profile. The device may release the functional agent payload relatively rapidly, and the device may release the drug payload may be further released continuously.

[0083] [000103] The device provides long-term, continuous delivery of a desired amount of drug over a desired and predetermined period of time. In various embodiments, the device may provide for continuous, intermittent, or periodic release. The dosage of the drug can be administered over a long period of time, for example, 12 hours, 24 hours, 5 days, 7 days, 10 days , 14 days, or 20, 25, 30, 45, 60, or 90 days or more The rate of delivery and the amount of drug administered will depend on the drug being delivered and the disease or condition being treated. In embodiments, the device may deliver a therapeutically effective amount of a drug for 1 to 30 days. A period of days, for example, 2 to 30 days, 1 to 21 days, 1 to 14 days, 2 to 14 days, or 5 days In certain embodiments, the drug is From the device at zero-order speed, for a period of 1 day to 30 days, e.g., 2 days to 14 days, or 3 days to 7 days It is released over a wide area.

[0084] [000104] The device is then resorbed, e.g., if the device is non-resorbable or otherwise removable. In cases where the patient needs to be removed, the patient can be retrieved from the body. , which are known in the art or may be specially fabricated. Devices may also be used, for example, As described in U.S. Patent Application Publication No. 2012 / 0089122 to ee et al., Will the entire device be resorbed or will the device degrade sufficiently for elimination from the bladder during urination? It is either fully or partially bioabsorbable so that retrieval is unnecessary. The device may contain some or all of the drug. Or it cannot be recovered or reabsorbed until most or all of the drug has been released. If necessary, a new drug-loaded device may be transferred during or following the same procedure as the retrieval. Can be planted.

[0085] [000105] In one embodiment, an implantable device with a self-contained drug payload is The drug is fully deployed in the bladder and delivers an effective amount of at least one drug locally to the bladder. Following deployment of the device in the body, at least part of the drug payload is delivered. a portion of which is administered to the urinary tract in an amount effective to provide treatment or improve bladder function in a patient; The device releases substantially continuously and over an extended period of time into the skin and / or nearby tissues. In a preferred embodiment, the period is determined based on a predetermined period, such as 2 weeks, 3 weeks, 4 weeks, 1 month, or The drug-releasing device remains in the bladder for longer than that. The device is designed to treat interstitial cystitis, chemical cystitis, radiation cystitis, and radiation and chemical cystitis. Therapy-induced hemorrhagic cystitis, ketamine cystitis (or ketamine bladder syndrome), bone Bladder pain, overactive bladder syndrome, bladder cancer, neurogenic bladder, neuropathic or non-neuropathic bladder constriction Muscle deficiency, infection, post-operative pain or other diseases or disorders treated with drugs delivered to the bladder, and The device can be used to treat symptoms such as bladder capacity, compliance, and / or uninhibitedness. Medications to improve bladder function, such as frequency of contractions, pain in the bladder or other nearby areas Drugs that reduce pain and discomfort, or have other effects, or combinations thereof may be delivered.

[0086] [000106] In some embodiments, the drug delivery device comprises one or more proximal urinary The device is deployed in the patient's bladder for localized drug delivery to the genital area. The device may release drugs locally into the bladder and locally into other areas near the bladder. The device also provides a therapeutically effective amount of one or more drugs to one or more of the kidneys, among other tissues. Both, urethra, ureter, or both, penis, testicles, or seminal vesicles, or both, spermatozoa one or both of the ejaculatory ducts, one or both of the prostate, vagina, uterus, and ovaries the urinary tract of the body, including one or both of the ureters, one or both of the fallopian tubes, or a combination thereof Delivery may also be to other urogenital organs within the body, such as other locations within the organs or reproductive system. For example, intravesical The drug delivery device may be used to treat kidney stones or fibrosis, among other diseases, disorders, and conditions. , may be used to treat erectile dysfunction. Such delivery may be accompanied by undesirable side effects or may involve the use of medications. It may provide an alternative to systemic administration, which may result in poor bioavailability of the substance.

[0087] [000107] The present invention may be further understood with reference to the following non-limiting examples. Unless otherwise indicated, all percentages are by weight.

[0088] [000108] Example 1: Single Unit to Many Unit Device

[0089] [000109] The drug delivery device model was constructed using silicone tubing with an inner diameter of 2.64 mm. It was prepared using.

[0090] [000110] A single unit device was prepared according to the device embodiment shown in FIG. The tube was filled with 17.7% gemcitabine hydrochloride (164 mg FBE), 73.6% of urea, 7.8 percent oil-based pharmaceutical lubricant LUBRITAB® (JR S PHARMA, Rosenberg, Germany), and 0.9 percent Polyvinylpyrrolidone (PVP) K29-32 (PLASDONE®) International Specialty Products, New J The tube was filled with tablets containing 100% PEG-1000 (commercially available from Mersey). The tablets were placed in a tube with a diameter substantially equal to the inner diameter of the tube. The tablets were formed to a diameter of 15.2 cm and packed into the tube in a tandem array. The device contained a spacer-type release hole having a length of 5 mm.

[0091] [000111] A multi-unit device was also prepared according to the device embodiment shown in FIG. The tube was filled with 80.0% gemcitabine HCl, 13.3% urea, 4.2 percent PVP K29-32, and 2.5 percent polyethylene glycol ( The drug tablets were filled with multiple drug tablets containing PEG 8000. The drug tablets were 2.8 cm long. and positioned in series adjacent to a spacer-type release hole having a length of 5 mm. The tube also contains 90.0 percent urea and 10.0 percent Lubritab. The functional agent tablets were filled into a 12.0 cm long tube.

[0092] [000112] The overall formulation of the multi-unit device was similar to that of the single-unit device. , 18.9% gemcitabine HCl, 71.8% urea, 7.7% 1.0 percent Lubritab, 1.0 percent PVP K29-32, and 0.6 percent Specifically, the single unit device contained 164.0 mg of PEG 8000. gemcitabine FBE, while the multi-unit device contained 163.8 mg of gemcitabine. Citabine FBE was accommodated.

[0093] [000113] In vitro drug release profiles were analyzed for single unit and multi-unit devices. Both were measured in water. Figures 9 and 10 show the percent drug release and release rate (per day). Figures show gemcitabine FBE (measured in mg) versus time. Overall, higher A multi-unit device that releases a higher percentage of drug and maintains a faster release rate of drug for a longer period of time. As shown in Figure 9, the multi-unit device outperformed the single-unit device. The device released more than 90 percent of the drug payload over a 7-day period, while the single The knitted device released less than 80 percent of the drug payload over the same period. As shown in Figure 1, the multi-unit device also showed that the drug release rate leveled off between days 2 and 4. The drug had a "flatter" release profile that was consistent with the long-term release of the drug. For example, a multi-unit device may be used for continuous release over a period of 5-7 days. It performed significantly better than single unit devices with long-term drug release.

[0094] [000114] Example 2: Laser-drilled emission holes versus spacers in multi-unit devices mold release hole

[0095] [000115] A multi-unit device with spacer-type release holes was fabricated using the device implementation shown in Figure 2. The ejection hole had a length of 5 mm and an inner diameter of 0.3 mm. The nozzle hole was located at one end of the tube.

[0096] [000116] A multi-unit device with laser drilled emission holes was fabricated as shown in Figure 3. The device was prepared according to the device embodiment. The ejection hole had an inner diameter of 0.150 mm and was attached to the housing of the device. Located within the body wall.

[0097] [000117] Each tube was filled with multiple drug tablets and multiple functional agent tablets. The tablets contain 90.0 percent urea and 10.0 percent Lubritab. The drug tablets were packed into 6.0 cm long tubes. l, 13.3 percent urea, 4.2 percent PVP K29-32, and 2.5 percent polyethylene glycol (PEG) 8000 and 2.5 cm long The laser-drilled device contained 141.6 mg of gemcitabine FBE. The spacer pore device contained 140.5 mg of gemcitabine FBE.

[0098] [000118] As shown in Figure 3, within the laser drilled hole device 300, A 2.5 cm drug tablet 302 was placed in the laser drilled hole 306 so that the tablet 302 was centered around the hole. A 3 cm functional agent tablet 310 was placed on each side of the 02. As shown in FIG. Within the pacer hole device 200, 2.5 cm of drug is located adjacent to the spacer hole 206. The tablet 202 is placed, and a functional agent tablet 210 of 6.0 cm is placed adjacent to the drug tablet 202. Ta.

[0099] [000119] In vitro drug release profiles were determined using laser-drilled and spacer hole designs. Both devices were measured in water. Figures 11 and 12 show the percent drug release and release rate. (measured in mg of FBE gemcitabine per day) versus time, respectively. The device delivers up to approximately 70 percent of the drug payload over a seven-day period, essentially zero-times. The drug showed a similar release profile, with approximately 20 mg of the drug released between days 1 and 4. The release rate profiles of the devices were also similar, with a plateau region of FBE / day release. are.

[0100] [000120] Example 3: Powdered Drug vs. Tablet Drug Multi-Unit Device

[0101] [000121] A multi-unit device having a drug tablet and a functional agent tablet is shown in FIG. The functional agent tablets were prepared according to the embodiment. The drug tablets contained 100mg of Lubritab and were packed into 6.0 cm long tubes. 80.0 percent gemcitabine HCl, 13.3 percent urea, 4.2 percent of PVP K29-32, and 2.5 percent polyethylene glycol (PEG) The tablet drug device contained 123.4 mg gemcitabine FBE was contained.

[0102] [000122] The multi-unit device having the functional agent tablet and the powdered drug unit is shown in FIG. The functional agent tablets 410 were prepared according to the device embodiment. 0 percent Lubritab and was filled into a 7.8 cm long tube. Unit 402 is 80 percent gemcitabine HCl and 20 percent urea powder. The powdered drug device contained 124.4 mg of Gemcitabine FBE was accommodated.

[0103] [000123] Each device had an inner diameter of 0.300 mm and a length of 5.0 mm. It includes a spacer-type release hole.

[0104] [000124] In vitro drug release profiles were determined using laser-drilled and spacer hole designs. Both devices were measured in water. Figures 13 and 14 show the percent drug release and release rate. (measured in mg of FBE gemcitabine per day) versus time, respectively. The device delivers up to approximately 85 percent of the drug payload over a seven-day period, essentially zero-times. The drug showed a similar release profile, with approximately 20 mg of the drug released between days 1 and 4. The release rate profiles of the devices were also similar, with a plateau region of FBE / day release. are.

[0105] [000125] As can be seen from the above examples, multiple unit drug delivery devices can be Offers improved both short-term and long-term drug release profiles compared to single-unit devices These devices provide controlled, long-term drug release, e.g., 0-7 days. Additionally, these devices advantageously allow for the osmotic release of low-solubility drugs into the patient. This provides a method for delivering the compound via an injection device, which further modifies the compound into a highly soluble form. These devices are particularly useful for drugs that are difficult to administer. A variety of drugs can be delivered via various mechanisms and release kinetic profiles, e.g., It is possible to provide improved control of drug release in the body from a device deployed in the bladder. can.

[0106] [000126] Example 4: Effect of silicone tubing housing wall thickness and durometer on drug release from device Value Impact

[0107] [000127] The multi-unit device having the drug tablet and the functional agent tablet is shown in FIG. The functional agent tablets were prepared according to the present embodiment. The functional agent tablets were osmotic tablets. The mass and The mass and length of the drug tablet are approximately 400 mg and 6 cm, respectively. The gemcitabine tablet formulation was 85.5 percent Gemcitabine HCl, 5 percent urea, 4.5 percent PVP K30, 2.5 percent Neusilin, and 2.5 percent magnesium stearate. The osmotic tablet formulation was 90 percent urea and 10 percent Lubritab All tablets were made by direct powder compression method.

[0108] [000128] Four different types of extruded silicone tubular housings were used in this example. ) Inner diameter 2.64mm, wall 0.13mm, Shore A hardness 65A (MED-4765, N uSil Technology LLC), 2) 2.64mm inner diameter, 0.1mm wall, Shore A hardness meter value 80A (MED-4780, NuSil Technology LLC) ), 3) Inner diameter 2.64 mm, wall 0.2 mm, Shore A hardness 50A (MED-4750 , NuSil Technology LLC), and 4) 2.64mm inner diameter, 0.4mm wall mm, Shore A hardness meter value 25A (MED-4720, NuSil Technology LLC).

[0109] [000129] In each device, one end of the tube was attached to a silicone tube as shown in Figure 17. Adhesive MED3-4213-1 (NuSil Technology LLC) The other end was sealed with Elvax 760, an ethylene vinyl acetate (EVA) copolymer. The constrained plug was made from EVA support beads (FBK Medical Tubing) containing mer. The plug has an outer diameter of approximately 2.74 mm and a length of 5 mm, and is fitted with a 30-60 degree cut. The cut surface and the cavity created by the silicone tube are shown in Figure 17. As shown in the figure, when the osmotic pressure increased in the silicone tube, a string was inserted to prevent the plug from peeling off. The in vitro release was measured in deionized water. The experiment was carried out at 37°C and the results are shown in Figure 19. The sample size for each group was 2 where error bars indicate the standard deviation (SD) around the mean. Some error bars are As used in the legend, "O" indicates an osmotic tablet, and "A" indicates , indicates the active pharmaceutical ingredient, i.e., drug, tablet.

[0110] [000130] Specifically, Figure 19 shows the results of measurements from devices with various housing wall thicknesses and durometer values. The amount of drug released over time is shown. The ability of gemcitabine release varies with the wall thickness of the silicone tubing. These results were influenced by the wall thickness and hardness of the housing material. The size of the housing, including its rigidity and flexibility, is determined based on the volume of the drug and functional agent formulation to be contained and the length of the tube. This shows that the dosage can be selected based on the desired rate of delivery of the drug.

[0111] [000131] Example 5: Effect of silicone tubing housing wall thickness and durometer on drug release from device Value Impact

[0112] [000132] Another series of experiments was carried out using the device configuration shown in Figure 17. In the examples, three different silicone tubular housings were used: 1) 2.64 mm inner diameter, 1.5 mm wall thickness; 0.2mm, Shore A hardness meter value 50A (MED-4750, NuSil Technol ogy LLC), 2) Inner diameter 2.64 mm, wall 0.2 mm, Shore A hardness 70A (M ED-4770, NuSil Technology LLC), and 3) inner diameter 2.64 mm, wall 0.4 mm, Shore A hardness 25A (MED-4720, NuSil Tec hnology LLC).

[0113] [000133] The tablets were placed side by side in the reservoir as shown in Figure 17. The mass and length of the tablet are approximately 700 mg and 11 cm, respectively. The length was approximately 300 mg and 4.5 cm, respectively. The drug (gemcitabine) tablet formulation was , 85.5% gemcitabine HCl, 5% urea, 4.5% PVP K30, 2.5 percent Neusilin, and 2.5 percent stearic acid The osmotic tablet formulation was 90 percent urea and 10 percent L All tablets were made by direct powder compression. The release was carried out in deionized water at 37°C and the results are shown in Figure 20. The sample size for each group was 2, and the error bars indicate the standard deviation (SD) around the mean. Error bars are not visible if they are smaller than the symbol. As used in the legend, "O" indicates penetration. indicates a tablet and "A" indicates the active pharmaceutical ingredient, i.e., drug, tablet.

[0114] [000134] Specifically, Figure 20 shows the results of measurements from devices with various housing wall thicknesses and durometer values. The amount of drug released over time is shown. The ability of gemcitabine release varies with the wall thickness of the silicone tubing. These results were influenced by wall thickness, length, and housing material. The size of the housing, including the hardness and flexibility of the material, is determined based on the volume of the drug and functional agent formulation to be contained and This shows that the rate at which the drug is delivered from the tube can be selected based on the desired rate of drug delivery from the tube.

[0115] [000135] Example 6: Impermeable Coating of Silicone Tubing Housing on Drug Release from Device Effect of the length of the feeding region

[0116] [000136] The multi-unit device having the drug tablet and the functional agent tablet is shown in FIG. The fabrication method was the same as that of the previous embodiment. Unlike the previous construction, Parylene C (water-impermeable coating) was used. The tube has an inner diameter of 2.64 mm, a wall of 0.2 mm, and a Shore A hardness rating of 50 A (MED -4750, NuSil Technology LLC) on extruded silicone tubing A hole with a diameter of 0.3 mm was placed at one end of the tube. The other end was sealed with silicone adhesive MED3-4213-1. Silicone tube housings of different configurations were tested. 1) Osmotic tablet mass / length: 700 mg / 11cm, drug tablet mass / length: 320mg / 4.5cm, parylene coated Length of area: 6.5cm, 2) Penetration tablet mass / length: 700mg / 11cm, Drug tablet mass Amount / length: 320 mg / 4.5 cm, length of parylene-coated area: 11 cm , and 3) Osmotic tablet mass / length: 400 mg / 6 cm, drug tablet mass / length: 150 mg / 2cm, length of parylene coated area: 4cm.

[0117] [000137] In vitro release was performed in deionized water at 37°C and the results are shown in Figure 21 The sample size for each group was 2, and the error bars represent the standard deviation (SD) around the mean. ) are used in the legend. Some error bars are not visible if they are smaller than the symbols. "O" indicates an osmotic tablet, and "A" indicates an active pharmaceutical ingredient, i.e., a drug, tablet. .

[0118] [000138] Specifically, Figure 21 shows devices with various impermeable coating region lengths. The amount of drug released from the device over time is shown. The ability to release gemcitabine is determined by the permeation and drug Affected by the length of the parylene-coated region relative to the length of the tablet region These results indicate that the length of the water-impermeable region is related to the volume and size of the drug and functional agent formulations contained therein. It is shown that the thickness of the housing coating can be selected based on the desired rate of drug delivery from the tube. This can be useful when the housing material is drug permeable and osmotic release is desired.

[0119] [000139] Publications cited herein and the material for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein are within the scope of the invention as detailed above. From the description, such changes and modifications will become apparent to those skilled in the art. It is intended to fall within the scope of

Claims

1. 80% by weight gemcitabine HCl, urea, Polyvinylpyrrolidone, and Polyethylene glycol (PEG) A solid drug formulation for use in an intravesical drug delivery device, comprising the above.

2. The solid drug preparation according to claim 1, wherein the preparation is a plurality of tablets.

3. The solid drug formulation according to claim 1 or 2, wherein the polyethylene glycol comprises PEG8000.

4. A solid drug preparation according to any one of claims 1 to 3, comprising 13.3% by weight of urea.

5. A solid drug formulation according to any one of claims 1 to 4, comprising 4.2% by weight of polyvinylpyrrolidone.

6. A solid drug formulation according to any one of claims 1 to 5, comprising 2.5% by weight of polyethylene glycol.

7. Each 80% by weight gemcitabine HCl, urea, Polyvinylpyrrolidone, and Polyethylene glycol (PEG) A first set of multiple tablets comprising, Each 90% by weight urea, and 10% by weight of one or more excipients A second set of multiple tablets consisting of A drug preparation containing the above.

8. The drug formulation according to claim 7, wherein the polyethylene glycol comprises PEG8000.

9. The drug formulation according to claim 7 or 8, comprising 13.3% by weight of urea.

10. A drug formulation according to any one of claims 7 to 9, comprising 4.2% by weight of polyvinylpyrrolidone.

11. A drug formulation according to any one of claims 7 to 10, comprising 2.5% by weight of polyethylene glycol.

12. A bladder drug delivery device, A housing that defines a storage section having a first region and a second region, The first area of ​​the storage unit is located 80% by weight gemcitabine HCl, urea, Polyvinylpyrrolidone, and Polyethylene glycol (PEG) A drug preparation comprising, A functional agent preparation containing an osmotic agent or a solubilizer or solubility enhancer is arranged in the second region of the storage unit. Includes, The first region and the second region are in fluid communication with each other. An intravesical drug delivery device wherein the functional agent formulation is configured to allow the drug to be solubilized and released from the housing such that the rate and duration of release are within a therapeutically effective range, by altering the permeable water flow rate and / or drug solubilization.

13. The intravesical drug delivery device according to claim 12, wherein the drug formulation comprises a first plurality of tablets and the functional agent formulation comprises a second plurality of tablets.

14. The intravesical drug delivery device according to claim 12 or 13, wherein the housing includes an elongated annular tube.

15. The intravesical drug delivery device according to claim 14, wherein the elongated annular tube is formed of a water-permeable elastomer material.

16. The intravesical drug delivery device according to any one of claims 12 to 15, wherein the device is elastically deformable between a relatively straight shape suitable for insertion into the patient's bladder through the patient's urethra and a retaining shape suitable for holding the device in the bladder.

17. The intravesical drug delivery device according to any one of claims 12 to 16, wherein the housing further comprises a retaining frame lumen and a retaining frame positioned within the retaining frame lumen.

18. The intravesical drug delivery device according to any one of claims 12 to 17, wherein the functional agent formulation comprises 90% by weight of urea and 10% by weight of one or more excipients.

19. The drug preparation is 80% by weight gemcitabine HCl, 13.3% by weight urea, 4.2% by weight of polyvinylpyrrolidone, and 2.5% by weight polyethylene glycol (PEG) 8000 A bladder drug delivery device according to any one of claims 12 to 17, comprising the above.

20. A bladder drug delivery system, A housing including an elongated annular tube that defines a storage section having two ends and an intermediate section between the two ends, The intermediate portion comprises a plurality of first small tablets containing (i) 80% by weight gemcitabine HCl, (ii) 13.3% by weight urea, (iii) 4.2% by weight polyvinylpyrrolidone, and (iv) 2.5% by weight polyethylene glycol 8000. A second plurality of small tablets, each having two ends and containing 90% by weight of urea, with the remainder being one or more pharmaceutical excipients, The elastic retaining frame comprises a superelastic alloy and is positioned within the lumen of the retaining frame in the housing, biasing the elongated annular tube into a coil shape including a pair of interconnected and overlapping coils. Includes, The intermediate portion and the two ends are in fluid communication with each other. The aforementioned elongated annular tube is formed of a water-permeable silicone material. The drug delivery system is configured to allow the first and second tablets to be solubilized in the body and to release gemcitabine by osmosis through the opening in the elongated annular tube adjacent to the intermediate portion. Intravesical drug delivery system.

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