Intravesical drug delivery device

Abstract

To provide a medical device which includes a device deployable intravesically to release drug intravesically but is not restricted by this to perform controlled release of drug.SOLUTION: An implantable drug delivery device 200 includes a housing 208 defining a reservoir 204, a first unit 202 within the reservoir, and a second unit 210 within the reservoir. The first unit 202 contains a drug and the second unit 210 contains a functional agent that facilitates release of the drug. An intravesical drug delivery device includes a housing portion containing a drug formulation and a housing portion containing an excipient, and are configured to release the drug according to a first release profile and the excipient according to a second release profile. A method includes inserting any of these devices into a patient and releasing drug from the device.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 a bladder The present invention relates to a device that can be deployed in 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. 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 administration of urinary excretion and retention. For example, the device is 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 retain the drug in a defined manner over an extended period of time. In some embodiments, the device can provide a controlled release of The drug delivery system includes a permeable tube defining a drug reservoir for receiving the drug and a small amount of water 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 sequentially or exclusively via diffusion.

[0003]

[0003] However, it would be desirable to provide improved drug delivery devices and systems. For example, it would be desirable to have a relatively poorly soluble drug that is osmotically dissolved at a therapeutically useful rate. Thus, the present invention provides a device, system, and method for providing a long-term release of It would be desirable to deliver a variety of active agents with selected release kinetic profiles. To provide an implantable drug delivery device and system capable of 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 crystal display includes the steps of: and a second unit housed in the reservoir at a different location from the first unit. An implantable drug delivery device is provided, comprising a first unit containing a drug and a second unit. The unit contains a functional agent that enhances the internal release of the drug from the housing.

[0005]

[0005] In another embodiment, a first housing portion is loaded with a drug formulation containing a drug, and an excipient. 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] In yet another aspect, a method for delivering a drug into a patient as disclosed herein includes the steps of: and releasing a drug from the inserted device. A method of administering a drug to a subject is provided. [Brief description of the drawings]

[0007] [Figure 1] FIG. 1 is a cross-sectional view of one embodiment of a prior art drug delivery device. [Diagram 2] FIG. 1 is a cross-sectional view of an embodiment of a multi-unit drug delivery device. [Diagram 3] FIG. 13 is a cross-sectional view of another embodiment of a multi-unit drug delivery device. [Figure 4] FIG. 13 is a cross-sectional view of another embodiment of a multi-unit drug delivery device. [Diagram 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. 2 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 drug release rates over time for a single tablet drug delivery device and a two tablet drug delivery device. [Figure 11] 1 is a graph showing the 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 drug release rates over time for drug delivery devices with laser drilled holes and drug delivery devices 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. 2 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. [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 PREFERRED EMBODIMENTS

[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 enhances drug release. In vitro examples show short-term and long-term efficacy compared to similar single unit devices. These devices also show an improvement in both drug release profile and drug delivery. In addition, it allows for the delivery of low solubility drugs to patients via osmotic delivery devices. This is particularly useful for drugs that are difficult to convert into a highly soluble form in the drug. In general, drug solubility is highly dependent on the pH of the release medium, reducing the pH dependence of drug release. This is preferred over diffuse release when more than one ion exchange is desired.

[0009]

[0029] For purposes of this disclosure, the term "implantation site" refers generally 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 inserted 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 a device, e.g. Once implanted, the implant is able to retain its shape or be fixed in place in the body. The device is designed to be retained within the body. In certain embodiments, the device is delivered 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 so.

[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 of these. The drug release may be continuous and defined. The release profile of the formulation 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 The present invention describes 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 combination thereof. The functional agent may include a combination of drugs (including multiple Possible ) based on For example, the drug to be delivered may be a poorly soluble drug, and the functional agent may be selected to selectively bind the drug to the body of the drug. An osmotic agent may be included to facilitate endosmotic release.

[0013]

[0033] As used herein, the term "poorly soluble" refers to a compound that is soluble in water at 37°C. 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 in part, 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 form of a base may have high solubility. may have low solubility.

[0014]

[0034] In conventional drug delivery devices, highly soluble drugs are generally delivered via an osmotic gradient induced While a drug may be suitable for release according to the method of the present invention, a poorly soluble drug may be released via diffusion through walls or passageways within the drug housing. The devices disclosed herein can be adapted for a variety of release modes and release kinetics. 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

[0015]

[0035] Regardless of whether the drug selected has high or low solubility, The material may contain one or more functional agents (e.g., osmotic agents for increasing water flux, solubilizing agents, etc. Additional therapeutically effective agents (such as solubility enhancers, pH adjusters, or stability enhancers) may be required. The drug will be delivered (i.e., released from the delivery device) at a rate of 100 rpm. If so, the combination of selected drug solubility and osmotic water flux in the presence or absence of a functional agent is The combination determines the release rate and duration, and such a combination determines the release rate and duration. may 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, and 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. 6,399,433, filed on Oct. 23, 2003, and which is incorporated herein by reference.

[0017]

[0037] I. Implantable Drug Delivery Devices

[0018]

[0038] The embodiments of the implantable drug delivery device disclosed herein generally comprise a reservoir. A housing defining a storage portion, and a first unit and a second unit housed in the storage portion. For example, the housing may be an elongated circular tube and the reservoir may be the lumen of the circular tube.

[0019]

[0039] The first unit(s) contains the drug or active pharmaceutical ingredient to be delivered to the patient. The second unit(s) comprises a functional agent that facilitates the in vivo release of the drug from the housing. The first unit and the second unit are located at different positions in 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) For purposes of speed and ease, the device 100 may be configured in a straight line that may be useful during the process of insertion into a patient. The tablet 102 contains the drug to be delivered and optionally one or more excipients. When implanted, the device 100 is adapted to receive 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 nature of the materials of construction of the enclosure.

[0021]

[0041] One embodiment of the present disclosure is shown in FIG. , and a housing 208 that defines a reservoir 204. In contrast to device 100, device 2 00 includes a plurality of first units 202 including a drug contained in a reservoir 204 and a functional agent. The first unit and the second unit 202, 210 are located at different positions within the 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 drug and functional agent formulations to provide permeation and / or diffusion The catheter may be designed to release drugs and functional agents via the catheter.

[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 drugs and The walls of the housing 208 include walls that are not permeable to drugs that do not readily diffuse through the walls. That is, the water-permeable portion can 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 enters the first unit. Alternatively, the water-permeable wall may be formed by dissolving the water-permeable wall of the second unit 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 acceptable.

[0024]

[0044] Injection of several portions of the solubilized fluid into the reservoir prior to implantation may be necessary. In certain embodiments, the device may facilitate the hydration process of tablets or formulations thereof. The solution is used to solubilize at least a portion of the aqueous fluid in which the functional agent and drug are required to be solubilized 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. , 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 delivered to at least one of the reservoirs 204 in fluid communication with the reservoir 204. The drug is released by the osmotic pressure in the reservoir 204 at a controlled rate through another drug release hole 206. 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, also called "spacer holes", may be provided in the end plugs. Further details are found in PCT Application No. PCT / US14 / 20703, filed March 5, 2014. FIG. 3 shows a drug release device 306 disposed on a side wall of the housing 308. 3 illustrates another embodiment of an osmotic device 300 that includes an exit hole 306, through which a solubilized drug can pass. The casing is configured to allow passage of the casing.

[0027]

[0047] As shown in FIG. 17, the drug delivery device 1700 includes a tubular housing 1708 at one end. In this embodiment, the constraining plug 1707 is , a transient in 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 which secures a 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 No. 6,393,636, which is 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 constraining plug, a second unit, i.e. , which are located closer to the functional agent unit. This arrangement is advantageous for the identification of certain drugs, such as low solubility drugs. has 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] When osmotic release is the desired drug release mode, the functional agent in the second unit The formulation may include an osmotic agent that enhances the osmotic release of the drug. For example, the osmotic agent may be has a higher solubility than the drug, so as to facilitate solubilization and / or subsequent release of the drug. This may be achieved by administering to a patient a low solubility drug that is typically only delivered via diffusion from an osmotic delivery device. This advantageously enables the delivery of therapeutic 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 decreasing non-zero order release rate over a decay period. 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 permeable material used to form the wall. The water permeability of the material used, the shape, size, number and arrangement of the apertures 206, and the Various parameters of the device, including but not limited to the dissolution profile of the drug 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 at a temperature of 100° C. , 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 In order to release the solubilized drug through the wall, a process called "transwall diffusion" is also known. 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. The drug diffuses at a controlled rate directly through the wall due to the 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 polymers, It may be urethane, ethylene-co-vinyl acetate (EVA), or a combination thereof.

[0033]

[0053] In certain embodiments, the housing does not have an outlet hole and is bounded by the reservoir. The drug is configured to release the drug through at least one drug-permeable wall. The material-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 an outer washer. This is described in further detail in U.S. patent application Ser. No. 14 / 216,112, filed on the 7th, which is hereby incorporated by reference. In another embodiment, the drug permeable wall is a wall of the tubular housing. The housing may be part of an end plug located at the end of the housing or a tubular housing.

[0034]

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

[0035]

[0055] As noted above, the device may also be administered, for example, via a needle or syringe, prior to implantation. 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 period of zero-order emission kinetics followed by a decreasing Zero order release is when the drug, once solubilized, penetrates the wall of the container. The rate of delivery can be relatively rapid since the drug is immediately available for diffusion through the bloodstream. 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 embodiments, the number of open or through pores may also affect the overall release rate that may be 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. 6,399,433 to Daniel et al. In one embodiment, 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 drugs The release rate of the drug from the device depends on the combined properties of the functional agent and the drug housing. The properties of the housing, such as its thickness and permeability, as well as the functional agent formulation, can be advantageously controlled by It can be changed by adjusting.

[0039]

[0059] The implantable device is adapted to be deployed and retained within a portion of the body, such as the bladder. The device can be designed such that the device can be deformed for insertion and still remain functional 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 Although the tablets are filled, they are flexible or deformable. Gaps or crevices between the drug units are disclosed in U.S. Patent Application Publication No. 2010 / 033 to Lee et al. As described in US Pat. No. 5,770, a buffer can be formed to allow deformation of the device, while 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. The payload is formed of individual solid tablets 602, 610 that can be moved in unison. Some solid drug and / or functional agent payloads are entirely flexible.

[0041]

[0061] As mentioned above, the device housing is at least partially formed of a water-permeable material. For example, the enclosure may be configured so 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 that allows diffusion into the drug housing along both edges. good.

[0042]

[0062] In certain embodiments, the housing comprises annular tubes, one permeable and the other impermeable. 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 tube 1500 has an impermeable wall portion 151 During insertion into a patient, water may pass through the lumen 1530 into the wall. 1520 and contacting the solid drug and / or functional agent payload therein. For example, this structure may be formed by coextrusion. The relative proportions of the two wall portions are as described in U.S. Patent Application Publication No. 2011 / 015283 to Cima et al. 9, for example, the rate of water permeation (i.e., the surface area available for water permeation). and, for example, to provide the flexibility / hardness scale values ​​required for urethral insertion and bladder retention and tolerance. The thickness of the conductor 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 of the substrate 1802 may include a water impermeable coating region 1809. The water-impermeable wall portion may be formed by coating the housing with a water-impermeable material. For example, osmotic tablet 1810 and drug tablet 1802 have sealed ends 1813 and release holes. The lug 1806 may be inserted into the reservoir 1804, which may be constrained by the lug 1806. Water flows from within the reservoir 1804 through the water-permeable enclosure 1808 (but not through the water-impermeable area 18 09) and contacts and solubilizes the functional agent and drug tablet payload therein. The water-impermeable region allows for controlled solubilization and release of the drug. Coatings are useful for 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. For example, the tube may extend along the length of the housing of 6.5 cm. The housing 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 The drug tablet is housed in an impermeable coating that extends over the length of the housing from 4 cm to 11 cm. For example, a water impermeable parylene coating may be applied to a silicone or other housing. may be provided to.

[0045]

[0065] As mentioned above, the walls of the device housing are designed to prevent water flowing through their surfaces into the reservoir. and / or 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 walls may be porous, meaning that they can be drilled, perforated, or otherwise pierced. In the form of a defined aperture formed completely through the wall, for example 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 slit may have narrow or tapered side walls.

[0046]

[0066] In some embodiments, the wall is made of a resilient biocompatible polymeric material. The material may be non-resorbable or resorbable. Example non-resorbable materials include synthetic polymers selected from poly(ethers), poly(acrylates), poly(methacrylates), poly(vinylpyrrolidone), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, poly(siloxanes), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, and poly(siloxanes). Exemplary resorbable materials, particularly biodegradable or bioerodible polymers, include poly(amides), poly(esters), poly(ester amides), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo-poly(amino acids), poly(glycerol-sebacate), poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(caprolactone), poly(caprolactone) (PC) derivatives, aminoalcohol-based poly(ester amides) (PEA) and poly(octane-diol citrate) (POC), as well as other curable bioabsorbable polymers. Elastomer The PC-based polymer includes a synthetic polymer selected from the following: Elastomer Additional crosslinking agents such as lysine diisocyanate or 2,2-bis(ε-caprolacton-4-yl)propane may be necessary to obtain the desired properties. Copolymers, mixtures, 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 at least to some extent 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 0.1 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, among other things, on the drug and functional agent formulations to be contained. The volume of the drug in the tube, the desired rate of delivery of the drug from the tube, the intended site of implantation of the device in 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 thickness of the tube wall 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 to the device. may experience undesirably long induction times for initial drug release from the device and / or or other small body lumens, and therefore may not be sufficiently flexible 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 a solid tablet having a length of about 1 cm to about 3 cm. The inner cavity of the tube may be filled with one or more of the second unit tablets, the second unit tablets being about 10 cm to about 15 cm in length. 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. The hardness 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. The device has a relatively straight shape suitable for insertion into the bladder and a retention mechanism suitable for holding the device within 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 US Pat. No. 5,970,413, the wire is made of a superelastic alloy or other elastic wire. and is incorporated herein by reference.

[0052]

[0072] In an exemplary embodiment, the device 500 includes a first unit and a second unit. 5, which includes a housing 508 that houses the drug housings 502, 510, and a retaining frame 512. 508 is axially aligned with the retention frame 512, and the device 500 is in the retention configuration and 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 that is suitable for retaining the device in the bladder. Retains the device within the intended implantation location, including but not limited to a rötzl-like shape While the term "deployed configuration" refers to any shape suitable for insertion into the urethra or other natural FIG. 1 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. In the absence of compressive load, such as via a deployment device, a pair of interconnected overlapping The coil is configured to spontaneously assume a shape having a length of 10 mm.

[0053]

[0073] In one particular embodiment, as shown in FIG. The storage unit 1604 is located between the first and second units 1602 and 1610. For example, the flow regulation channel may be The flow rate regulation channel may be a flow path having a diameter smaller than the channel (i.e., the reservoir). It can serve to restrict the flow of fluid between the internal and external compartments, thus limiting the ability of the functional agent to come into contact with the drug. In certain embodiments, the release of the drug from the housing is slowed down. The device may include two or more flow rate 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 capsule has a first housing portion and a second housing portion filled with an excipient, and has a first release profile. and 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 a desired drug release profile. For example, the excipient may be a release and / or drug solubilizer, drug stabilizer, or Functional agents configured to enhance delivery of the drug, such as permeation enhancers, may also be used. 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, differentiate between different loading or time periods prior to the start of the first release. Differences may be observed between the drug and excipients, which may exhibit different release rates or follow different release curves after the onset of release. or release the drug and excipients for different periods of time before the payload is substantially depleted. The dissimilar housing parts may include housing parts that are , which shows a relatively short initial time difference, then continues at a relatively constant rate for a long period of time. In general, a desired release profile from the drug delivery device, such as a release profile that exhibits a release that is consistent with the desired release profile from the drug delivery device. These may be combined to achieve the same file.

[0056]

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

[0057]

[0077] In certain embodiments, the drug delivery device is associated with a single retention portion. The housing includes at least two separate or separate housing portions, each of which includes a holding portion. The separate reservoir housings or housing portions associated with the holding portion may be 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 implementation of embodiments D-F, which are separate regions within a single housing. FIG. 7 also illustrates the housing portion of the example. Depending on the material and construction of Examples G to I, either 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. FIG. 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 may 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 an adjacent housing portion. 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 housing, such as a cylinder, sphere, or disk. 8 may also be a part of the housing formed directly therein, such as by molding. For example, FIG. The webs shown in Examples D-E are partition structures that separate housing sections along the length of the device. It is.

[0059]

[0079] A device with at least two separate housing parts has a corresponding number of reservoirs. from at least one drug payload and at least one excipient or functional agent payload 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. 6,399,313.

[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 method 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 rifabutin, 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 agents may be cocaine analogs. 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 anesthetics of the amine or ester type are amylocaine, benzocaine, butacaine, and chlorine. Roroprocaine, cocaine, cyclomethycaine, dimethocaine, hexylcaine, larocaine in, meprylcaine, metabutoxycaine, orthocaine, piperocaine, procaine , proparacaine, propoxycaine, proxymetacaine, lysocaine, and tetracaine. These local anesthetics are generally weak bases and are salted with a salt such as hydrochloride to make them water soluble. Although the anesthetic may be formulated as a hydrate, 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. Common examples of drugs are alfentanil, allylprozine, alphaprozine, and anilerizine. Benzylmorphine, bezitramide, buprenorphine, butorphanol, clonidine Zene, Codeine, Desomorphine, Dextromoramide, Dezocine, Diampromide, Diazane Morphone (diamorphone), dihydrocodeine, dihydromorphine, dimenno Xadol, Dimepheptanol, Dimethylthiabutene, Dioxaphetyl butyrate , dipipanone, eptazocine, ethoheptadine, ethyl methyl thiambutene, ethyl mol Hine, etonitazene fentanyl, heroin Insulin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemine don, 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] Other representative examples of suitable analgesics include salicylic alcohol, phenazopyridine hydrochloride, 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 It is 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), penicillin Sodium polysulfate (PPS), dimethyl sulfoxide (DMSO), oxybutyric acid nin, mitomycin C, heparin, flavoxate, ketorolac, or combinations thereof For kidney stones, there are also combinations of The drug(s) may be selected.

[0066]

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

[0067]

[0087] The drug delivery device can be used to treat urinary incontinence, including, for example, urge incontinence and neurogenic incontinence. Drugs that may be used to treat urinary incontinence, urgency, and trigonitis. The drugs are anticholinergics, antispasmodics, antimuscarinics, beta-2 agonists, alpha-adrenergics, and anticonvulsants. , norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers, Representative examples of drugs suitable for treating incontinence include: Oxybutynin, S-oxybutytin, emepronium, Verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine , rociverine, 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 Contains stilonium iodide.

[0068]

[0088] In other embodiments, the drug delivery device is for treating a urinary tract cancer, such as bladder cancer or prostate cancer. Used to treat cancer. Drugs that may be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, and Representative examples of drugs suitable for treating urinary tract cancer include carmectin, serotoninib ... Bacillus Calmette-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 toxins, histone deacetylase inhibitors Drugs (e.g., suberoylanilide hydroxamate), and cyclophosphamide The drug may also be a biologic, such as a monoclonal antibody, a TNF inhibitor, or an anti-leukin. etc. Drugs may also include TLR agonists, including imiquimod or another TLR7 agonist. The drug may also be an immunomodulatory agent, such as an immunosuppressant, such as 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 bacteria. Antibiotic, antibacterial, antifungal, antiprotozoal, antiseptic Antiviral and other anti-infective agents may be administered to treat such infections. Representative examples of drugs for treating infectious diseases are mitomycin, ciprofloxacin, norfloxacin, cin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin Phosphorus, nafcillin, trimethoprim, sulfonamide trimethoprim sulfamethoxazo erythromycin, doxycycline, metronidazole, tetracycline, These include namycin, penicillins, cephalosporins, and aminoglycosides.

[0070]

[0090] In other embodiments, the device is a catheter that is attached to a urogenital site, such as the bladder or uterus. A representative example of a drug for the treatment of fibrosis is pentoxulylin (p entoxphylline) (xanthine analogue), anti-TNF, anti-TGF agents, GnRH Analogues, 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 resiniferatoxin Vanilloids such as cin act on the M3 muscarinic acetylcholine receptor (mAChR) antimuscarinics such as baclofen, GABAB Antispasmodics, including botulinum toxin Serotonin-related drugs such as capsaicin, alpha adrenergic antagonists, anticonvulsants, and amitriptyline In various embodiments, the drug is selected from the group consisting of R In eitz et al., Spinal Cord 42:267-72 (2004) As described, the drug acts on bladder afferent nerves or efferent cholinergic transmission. It may also be something like that.

[0072]

[0092] Medications for the treatment of neurogenic bladder fall into one of two general types: For the treatment of spastic neurogenic bladder and for the treatment of atonic neurogenic bladder. In one embodiment, the drug is used to treat incontinence caused by neurological detrusor overactivity and / or a weakly flexible detrusor muscle. Examples include bladder relaxant drugs (e.g., oxybufinamide, cyclosporine ... Chinine (an antimuscarinic agent with significant muscle relaxant and local anesthetic activity), propiverine , impratroprium, tiotropium, trospiu terodiline, tolterodine, propantheline, oxyphencyclamine, flavoxidine sartans, and tricyclic antidepressants, bladder and urethra (e.g., vanilloids (capsaicin, Resiniferatoxin), a drug that blocks the nerves that control the Drugs that regulate muscle contraction strength, micturition reflex, and detrusor-sphincter dyssynergia (e.g., GABAb-active drugs) Drugs (baclofen, benzodiazapine) etc. In one embodiment, the drug is a known agonist for the treatment of incontinence due to neurological sphincter deficiency. Examples include alpha adrenergic agonists, estrogens, beta adrenergic Antidepressants include phosphodiesterase agonists and tricyclic antidepressants (imipramine, amitriptyline). In embodiments, the drug is one known to promote urination (e.g., alpha adrenergic antagonists). In yet another embodiment, the agonist 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., verapamil), tropane alkaloids (e.g., atropine, scopolamine), nociceptors 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 for facilitating delivery of the drug to the internal release or implantation site. For example, the drug The functional agent may be a poorly soluble drug, and the functional agent may be an osmotic agent such as urea. In this way, the release of the drug from the housing is promoted by osmotically induced fluid flow. Other examples of functional agents and excipients that may be used include cyclodextrin, glycerol, polyethylene glycol, and the like. Contains choline, citrate, acetate, phosphate, ascorbic acid, and sodium sulfite .

[0074]

[0094] In an embodiment, the first unit(s) contains 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 comprise at least 50 weight percent of the drug, at least 60 weight percent of the drug, percent drug, at least 75 percent drug by weight, from about 60 to about 99 percent drug by weight The second unit may contain about 100% by weight of the drug, or about 75 to about 95 weight percent of the drug. At least 80 weight percent of the functional agent, at least 85 weight percent of the functional agent, at least 90 weight percent functional agent, from about 80 to about 99 weight percent functional agent, or from about 8 The remainder of the unit may contain from 5 to about 95 weight percent of the functional agent. It may also contain excipients such as binders, such as oil-based lubricants, PEG, or PVP. The excipient may also include a release retardant. For example, the release retardant may further retard the release of the drug. In order to control may 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 HC urea. 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 is a low solubility drug. The first unit includes a tablet that contains a substance, and the second unit is a device that controls the release of the drug from the housing by osmotic pressure. In one embodiment, the drug is gemcitabine. The drug is tabine and the osmotic agent is urea.

[0077]

[0097] The device may be inserted into a body cavity or lumen of a patient. Once implanted, the device 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 ingested fluid may be ingested, excreted, or a combination thereof.

[0078]

[0098] In certain embodiments, the device is deployed through a deployment instrument in a patient. The device is inserted by passing it through the device vise and releasing it from the deployment tool into the body. The deployment tools may be commercially available or specially modified to deploy the device. The catheter may be a suitable endoluminal device such as a catheter, a urethral catheter, a cystoscope, or a combination thereof. In certain embodiments, the device is implanted into the bladder. The device may provide retention characteristics, such as by assuming a retention shape or by being secured within the bladder. It is retained in the bladder due to its location.

[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 can occur due to an osmotic pressure gradient between the inside of the device and the outside of the device, and the drug is absorbed by the osmotic forces. The release also occurs through one or more holes or through-pores in the device. Due to a drug concentration gradient between the device and the exterior, the drug may penetrate into one or more pores or This occurs by diffusion through the passage pores and / or through the drug permeable walls of the device. Combinations of these release modes within a single device are possible, and several In some embodiments, a holistic therapeutic approach that is not readily achievable from any of the individual modalities is provided. It is suitable to achieve a desired release profile.

[0081] [000101] Following insertion of the device into a patient, water or aqueous bodily fluids from the implantation site may enter the device via the To solubilize the active ingredient or excipient and drug, for example, a water-permeable barrier or permeable membrane within the wall of the device. 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 drug 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 long 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. Thus, continuous and extended release can be facilitated according to a desired profile. For example, The device may release the functional agent payload relatively rapidly, and the device may release the drug payload relatively rapidly. may further be released continuously.

[0083] [000103] The device provides long-term, continuous delivery of a desired amount of a drug for a desired and predetermined period of time. In various embodiments, the device may provide continuous, intermittent, or periodic release. Dosage of the drug 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 an embodiment, the device delivers a therapeutically effective amount of the drug to the patient 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 In certain embodiments, the drug is From the device at zero-order rate, for a period of 1 to 30 days, e.g., 2 to 14 days, or 3 to 7 days It is released over a wide area.

[0084] [000104] The device is then subsequently resorbed, e.g., until the device is non-resorbable or otherwise removable. In cases where the patient needs to be removed, the patient may be retrieved from the body. Retrieval devices for this purpose are , which are known in the art or may be specially manufactured. Devices may also be used, for example, As described in U.S. Patent Application Publication No. 2012 / 0089122 to . Will the entire device be resorbed or will the device degrade sufficiently for removal from the bladder during urination? The composition is either fully or partially bioabsorbable so that retrieval is unnecessary since the composition is either The device may also be used to administer some or all of the drug, which is incorporated herein by reference. Or until most or all of the drug has been released it cannot be retrieved or reabsorbed. If necessary, a new drug-loaded device may be transferred during or following the same procedure as the withdrawal. 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 a portion of the drug payload is delivered. a portion 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 tissue. In a preferred embodiment, the method is carried out after a predetermined period of time, such as 2 weeks, 3 weeks, 4 weeks, 1 month, or The device that releases the drug over a longer period remains in the bladder. 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 that are treated with drugs delivered to the bladder, and The device may be used to treat symptoms such as bladder capacity, compliance, and / or uninhibitedness. Medications to improve bladder function, such as frequency of contractions, pain and discomfort in the bladder or other nearby areas Drugs that reduce pain and discomfort, or have other effects, or combinations of these 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 can 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 organs. Both, urethra, ureter or both, penis, testes, seminal vesicles or both, spermatozoa one or both of the ejaculatory ducts, one or both of the prostate, vagina, uterus, or ovaries the urinary tract of the body, including one or both of the fallopian tubes, one or both of the fallopian tubes, or a combination thereof Delivery may also be to other urogenital organs in 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 require the use of medication. 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 percentages by weight.

[0088] [000108] Example 1: Single Unit vs. Many Unit Devices

[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% 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 multiple tablets containing 100% glycerol (commercially available from Mersey). The tablets were fitted to a tube with a diameter substantially equal to the inner diameter of the tube. The tablets were formed to have a diameter of 15.2 cm and packed into the tube in a line 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 tubes were 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 percent gemcitabine HCl, 71.8 percent urea, 7.7 percent 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, whereas the multi-unit device contained 163.8 mg of gemcitabine FBE. Citabine FBE was accommodated.

[0093] [000113] In vitro drug release profiles were determined 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 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 seven-day period, while The knitted device released less than 80 percent of the drug payload over the same period. As shown in Fig. 1, the multi-unit device also showed that the drug release rate plateaued between days 2 and 4. The flatter release profile 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 to 7 days. It performed significantly better than single unit devices with extended 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 having spacer-type release holes was fabricated using the device embodiment shown in FIG. 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 FIG. The device was prepared according to the device embodiment. The ejection hole had an inner diameter of 0.150 mm and was fitted 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 in 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 is 2.5 cm long. The laser-drilled device was filled with 141.6 mg of gemcitabine FBE. The spacer hole device contained 140.5 mg of gemcitabine FBE.

[0098] [000118] As shown in FIG. 3, within the laser drilled hole device 300, 2.5 cm pharmaceutical tablet 302 is placed in a laser drilled hole 306 so that the tablet 302 is centered around the hole. A 3 cm functional agent tablet 310 was placed on each side of the suction cup 02. As shown in FIG. Within the pacer hole device 200, adjacent to the spacer hole 206, 2.5 cm of drug The tablet 202 is placed, and the 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 delineators. The percent drug release and release rate were measured in both devices. (measured in mg of FBE gemcitabine per day) versus time, respectively. The device delivers up to 70 percent of its drug payload at virtually zero dose over a seven-day period. The drug showed a similar release profile with approximately 20 mg of morphine released between days 1 and 4. The release rate profiles of the devices were also similar, with a plateau region of FBE / day release. is.

[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 100% of Lubritab and were packed into 6.0 cm long tubes. 80.0 percent gemcitabine HCl, 13.3 percent urea, 4.2 percent 100% PVP K29-32, and 2.5% polyethylene glycol (PEG) 8000 and packed into a 1.5 cm long tube. The tablet drug device contained 123.4 mg gemcitabine FBE.

[0102] [000122] A multi-unit device having a functional agent tablet and a powdered drug unit is shown in FIG. The functional agent tablet 410 was prepared according to the device embodiment. 0 percent Lubritab and was packaged in 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 has an inner diameter of 0.300 mm and a length of 5.0 mm. The spacer-type release hole is included.

[0104] [000124] In vitro drug release profiles were determined using laser drilled and spacer hole delineators. The drug release percentage and release rate were measured in both devices. (measured in mg of FBE gemcitabine per day) versus time, respectively. The device delivers up to 85 percent of its drug payload virtually zero-tolerance over a seven-day period. The drug showed a similar release profile with approximately 20 mg of morphine released between days 1 and 4. The release rate profiles of the devices were also similar, with a plateau region of FBE / day release. is.

[0105] [000125] As can be seen from the above examples, the multiple unit drug delivery device can be Offers improvements in both short-term and long-term drug release profiles compared to one-unit devices These devices provide controlled, long-term drug release, e.g., from 0 to 10 mg / kg for 5 to 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 is further modified to 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 in vivo drug release from a device deployed in the bladder. can.

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

[0107] [000127] A multi-unit device having a drug tablet and a functional agent tablet is shown in FIG. The functional agent tablet was an osmotic tablet. The mass and The mass and length of the drug tablet are approximately 400 mg and 6 cm, respectively, and the mass and length of the drug tablet are approximately 1 The gemcitabine tablet formulation was administered in 85.5 percent of patients. 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) 2.64 mm inner diameter, 0.4 mm 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 FIG. Adhesive MED3-4213-1 (NuSil Technology LLC) The other end was sealed with Elvax760, an ethylene vinyl acetate (EVA) copolymer. The constraining 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 stretching agent was added to prevent the plug from peeling off. The in vitro release was measured in deionized water and filled with silicone adhesive, which served as a cap. 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, FIG. 19 shows the results of measurements taken from devices having 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 size of the tube. This shows that the dosage form can be selected based on the desired rate of delivery of the drug.

[0111] [000131] Example 5: Effect of silicone tubing wall thickness and hardness tester on drug release from the 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, 1.0 mm wall 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 The company was hnology LLC.

[0113] [000133] The tablets were placed side-by-side in the reservoir as shown in FIG. 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 percent gemcitabine HCl, 5 percent urea, 4.5 percent 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 method. The release was carried out in deionized water at 37° C. and the results are shown in FIG. The sample size for each group was 2, and error bars indicate the standard deviation (SD) around the mean. The error bars are not visible if they are smaller than the symbol. As used in the legend, "O" stands for penetration. The "A" indicates the active pharmaceutical ingredient, i.e., drug, tablet.

[0114] [000134] Specifically, FIG. 20 shows the results of measurements taken from devices having 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 It is shown that the rate at which the drug is delivered from the tube can be selected based on the desired rate of delivery of the drug from the tube.

[0115] [000135] Example 6: Effect of impermeable coating of silicone tubing on drug release from device Effect of the length of the feeding region

[0116] [000136] A multi-unit device having a drug tablet and a functional agent tablet is shown in FIG. The fabric was prepared according to the embodiment of the present invention. Unlike the previous configuration, Parylene C (water-impermeable coating) was used. The gage has an inner diameter of 2.64 mm, a wall of 0.2 mm, and a Shore A hardness rating of 50A (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) Permeation tablet mass / length: 700mg / 11cm, Drug tablet mass Amount / length: 320mg / 4.5cm, length of parylene coated area: 11cm , 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 error bars represent the standard deviation (SD) around the mean. 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, FIG. 21 shows devices having various impermeable coating region lengths. The amount of drug released from the tablet over time is shown in Fig. 1. 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 mass of the drug and functional agent formulation 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 permeable to the drug and osmotic release is desired.

[0119] [000139] The publications cited herein and the material cited therein are specifically incorporated by reference. Modifications and variations of the methods and devices described herein are within the scope of the appended claims. From the description, it will be apparent to those skilled in the art. Such modifications and variations are within the scope of the appended claims. It is intended that the invention fall within the scope of the following:

Claims

1. at least 75 weight percent gemcitabine HCl; Urea and Polyvinylpyrrolidone, At least one pharmaceutical lubricant comprising polyethylene glycol (PEG); 16. A mini-tablet for drug delivery via an intravesical drug delivery device comprising:

2. 2. The mini-tablet of claim 1, wherein the PEG comprises PEG 8000.

3. 3. The mini-tablet of claim 2, comprising about 2.5 weight percent PEG 8000 and about 4 weight percent polyvinylpyrrolidone.

4. The mini-tablet according to any one of claims 1 to 3, comprising about 13 percent by weight of urea.

5. The mini-tablet of any one of claims 1 to 4, comprising about 80 weight percent of gemcitabine HCl.

6. A plurality of mini-tablets according to any one of claims 1 to 5; Contains at least 85 weight percent urea; the remainder being one or more pharmaceutical excipients; Functional tablets and Including, A drug delivery formulation for use in an intravesical drug delivery device.

7. 7. The drug delivery formulation of claim 6, wherein the functional agent tablet comprises about 90 percent by weight of urea.

8. The drug delivery formulation of claim 6 or 7, wherein the one or more pharmaceutical excipients of the functional agent tablet include a pharmaceutical lubricant.

9. 9. The drug delivery formulation of claim 8, wherein the pharmaceutical lubricant comprises magnesium stearate.

10. The drug delivery formulation of claim 8 , wherein the pharmaceutical lubricant comprises glycerol.

11. The drug delivery formulation according to any one of claims 6 to 10, wherein the functional agent tablet is in the form of a mini-tablet.

12. 1. An intravesical drug delivery device comprising: a housing defining a reservoir having a first region and a second region; A mini-tablet according to any one of claims 1 to 5, located in a first region of the reservoir; one or more functional agents in solid form disposed in a second region of the reservoir; Including, the first region and the second region are in fluid communication with each other; the one or more functional agents are configured to modify osmotic water flux and / or solubilization of gemcitabine, thereby allowing gemcitabine from the mini-tablet to be solubilized and released from the housing at a rate and for a duration within a therapeutically effective range; The drug delivery device, wherein the one or more functional agents are an osmotic agent, or a solubilizing or solubility enhancing agent.

13. The device of claim 12 , configured to release solubilized gemcitabine through apertures in the housing.

14. The device of claim 13 , wherein the one or more functional agents comprises an osmotic agent.

15. The device according to any one of claims 12 to 14, comprising a plurality of said mini-tablets.

16. The device of any one of claims 12 to 15, wherein the solid form of the one or more functional agents is in the form of a plurality of tablets.

17. 17. The device of claim 16, wherein the plurality of tablets of the solid form of the one or more functional agents are mini-tablets comprising at least 85 percent by weight of urea.

18. The device of any one of claims 12 to 17, wherein the housing comprises an elongated annular tube.

19. The device of claim 18 , wherein the elongated annular tube is formed of a water-permeable elastomeric material.

20. 20. A device as claimed in any one of claims 12 to 19, which is elastically deformable between a relatively straight shape suitable for insertion through the patient's urethra and into the patient's bladder, and a retained shape suitable for retaining the device within the bladder.

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