Intravesical drug delivery device

专利摘要:
MULTI-UNIT DRUG DELIVERY DEVICES AND METHODS. These are implantable drug delivery devices that include a housing defining a reservoir, a first unit within the reservoir, and a second unit within the reservoir. The first unit contains a drug and the second unit contains a functional agent that facilitates drug delivery. Intravesical drug delivery devices include a housing portion that contains a drug formulation and a housing portion that contains an excipient, and are configured to deliver the drug according to a first release profile and the excipient according to a second release profile. Methods include inserting any of these devices into a patient and releasing drug from the device.
公开号:BR112016002646B1
申请号:R112016002646-2
申请日:2014-08-19
公开日:2022-01-25
发明作者:Heejin Lee；Karen Daniel；Matthew Sansone
申请人:Taris Biomedical Llc；
IPC主号:

专利说明:

FIELD OF TECHNIQUE
[001] This disclosure generally refers to the controlled delivery of drug to patients and, more particularly, refers to medical devices for controlled drug delivery, including, but not limited to, devices installable in the urinary bladder to release drug into the bladder. BACKGROUND
[002] Various implantable drug delivery devices are known in the art. For example, U.S. Patent Application Publication No. 2007/0202151 by Lee et al. and U.S. Patent Application Publication No. 2009/0149833 by Cima et al. describe drug delivery devices for minimally invasive placement and retention in a cavity or lumen in a patient, such as the bladder. Devices resist excretion, such as in response to forces associated with urination. For example, the devices may include a retaining frame, which may be configured in a relatively low profile for installation on the body, and once deployed, may assume a relatively expanded profile to facilitate retention. Devices can provide controlled drug delivery over an extended period in a predefined manner. In some embodiments, the devices include a water permeable tube that defines a drug reservoir for housing a drug and at least one groove for releasing the drug. Osmotic pumping or diffusion may be the dominant mechanism by which the drug is released from the reservoir. Highly water-soluble drugs, such as lidocaine hydrochloride, can be released via osmotic pressure at therapeutically useful rates over an extended period. In other embodiments, the device may be configured to release lower solubility or other drugs primarily or exclusively through diffusion.
[003] It would be desirable, however, to provide improved drug delivery devices and systems. For example, it would be desirable to provide devices, systems, and methods in which drugs of relatively lower solubility can be released at therapeutically useful rates by an osmotic pressure medium over an extended period. It would also be desirable to provide implantable drug delivery devices and systems capable of delivering a variety of active agents at a selected release kinetic profile and to provide additional techniques, frameworks, and/or formulations to enhance in vivo drug release control. , for example, by means of a device installed in the bladder. SUMMARY
[0004] In one aspect, an implantable drug delivery device is provided, which includes a housing defining a reservoir, a first unit contained within the reservoir, and a second unit contained within the reservoir in a position distinct from the first unit. The first unit contains a drug and the second unit contains a functional agent that facilitates the in vivo release of the drug from the housing.
[0005] In another aspect, an intravesical drug delivery device is provided, including a first housing portion loaded with a drug formulation that includes a drug, and a second housing portion loaded with an excipient. The device is configured to release the drug according to a first release profile and is configured to release the excipient according to a second release profile that differs from the first release profile.
[0006] In yet another aspect, there is provided a method of administering a drug to a patient, including inserting a drug delivery device as disclosed herein into a patient, and releasing the drug from the inserted device. BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Figure 1 is a cross-sectional view of an embodiment of a prior art drug delivery device;
[0008] Figure 2 is a cross-sectional view of an embodiment of a multi-unit drug delivery device;
[0009] Figure 3 is a cross-sectional view of another embodiment of a multi-unit drug delivery device;
[0010] Figure 4 is a cross-sectional view of another embodiment of a multi-unit drug delivery device;
[0011] Figure 5 is a cross-sectional view of an embodiment of a multi-unit drug delivery device;
[0012] Figure 6 is a perspective view of a portion of the multi-drug unit delivery device of Figure 5.
[0013] Figure 7 illustrates exemplary configurations for drug delivery devices that have more than one drug housing portion.
[0014] Figure 8 is a plan view of an embodiment of a drug delivery device that has more than one drug housing portion.
[0015] Figure 9 is a graph showing the percentage of drug release over time of a single tablet drug delivery device and a two tablet drug delivery device.
[0016] Figure 10 is a graph showing the drug release rate over time of a single tablet drug delivery device and a two tablet drug delivery device.
[0017] Figure 11 is a graph showing the percentage of drug release over time of a drug delivery device that has a laser-pierced hole and a drug delivery device that has a spacer hole.
[0018] Figure 12 is a graph showing the drug release rate over time of a drug delivery device that has a laser-pierced hole and a drug delivery device that has a spacer hole.
[0019] Figure 13 is a graph showing the percentage of drug release over time of a drug delivery device that contains a drug powder and an osmotic agent tablet, and a drug delivery device that contains a drug tablet and an osmotic agent tablet.
[0020] Figure 14 is a graph showing the drug release rate over time of a drug delivery device that contains a drug powder and an osmotic agent tablet, and a drug delivery device that contains a drug tablet and an osmotic agent tablet.
[0021] Figures 15A and 15B are perspective and cross-sectional views, respectively, of an embodiment of housing for a drug delivery device.
[0022] Figure 16 is a cross-sectional view of an embodiment of a drug delivery device in which the reservoir includes a flow channel modulator.
[0023] Figure 17 is a cross-sectional view of an embodiment of a multi-unit drug delivery device;
[0024] Figure 18 is a cross-sectional view of an embodiment of a multi-unit drug delivery device;
[0025] Figure 19 is a graph showing the amount of drug released over time from drug delivery devices that have various wall thicknesses and housing durometers.
[0026] Figure 20 is a graph showing the amount of drug released over time from drug delivery devices that have various wall thicknesses and housing durometers.
[0027] Figure 21 is a graph showing the amount of drug released over time from drug delivery devices that have a housing liner of various lengths. DETAILED DESCRIPTION
[0028] Devices are provided that can be inserted into a body cavity or lumen of a patient for the purpose of delivering drug locally or regionally around a site of implantation. In one embodiment, the devices contain drug units and separate units of a second agent that promotes drug delivery. In vitro examples show improvements in both short-term and long-term drug release profiles compared to comparable single-unit devices. Furthermore, these devices advantageously allow the delivery of low-solubility drugs to patients through osmotic delivery devices. This is especially useful for drugs that are difficult to reformulate into more highly soluble forms. In addition, osmotic delivery is generally preferred over diffusion-based delivery when drug solubility significantly depends on the pH of the delivery media and it is desirable to reduce the pH dependence of drug delivery.
[0029] For the purposes of the present disclosure, the term "place of implantation" generally refers to a place within the body of a human or other animal patient. The site of implantation can be any genitourinary site, such as the bladder, urethra, ureters, kidneys, prostate, seminal vesicles, ejaculatory duct, vas deferens, vagina, uterus, fallopian tubes, ovaries, or any other location within a urological system. or reproductive system of the body, among other places. In particular embodiments, the site of implantation is the bladder.
[0030] In certain embodiments, devices are designed to be installed through natural orifices and body lumens in minimally invasive installation procedures. For example, the devices may have an installation format suitable for installation through a natural lumen of the body. The devices are also designed to be retained in the body once implanted, such as achieving a retention shape upon implantation or by anchoring within the body. In particular embodiments, the devices can be installed through the urethra into the bladder and can overcome urination forces once implanted for bladder retention.
[0031] Once implanted, devices can deliver one or more drugs over an extended period. The drug may be released by osmotic pumping through an opening in the device, diffusing across a surface of the device, diffusing from an opening in the device, or a combination thereof. Drug delivery can be continuous and according to a predefined release profile.
[0032] In certain embodiments, the devices are loaded with one or more drug units and one or more functional agent units. As used herein, the term "functional agent" refers to agents or excipients that facilitate in vivo controlled release of a drug from the device. For example, functional agents can include osmotic agents, drug solubilizing agents, drug stabilizing agents, permeation enhancing agents, or combinations thereof. The functional agent can be selected based on the drug(s) to be delivered from the device. For example, the drug to be delivered may be a drug of low solubility and the functional agent may include an osmotic agent to facilitate in vivo osmotic release of the drug.
[0033] As used herein, the term "low solubility" refers to a drug that has a solubility of about 0.001 mg/ml to about 10 mg/ml of water at 37°C. as used herein, the term "high solubility" refers to a drug that has a solubility above about 10 mg/ml in water at 37°C. Drug solubility may be affected at least in part by its form. For example, a drug in the form of a water-soluble salt may have a high solubility, while the same drug in the base form may have a low solubility.
[0034] With conventional drug delivery devices, drugs of high solubility may generally be suitable for release according to an induced osmotic pressure gradient, while drugs of low solubility may be suitable for release via diffusion through the wall or passageway. in the drug housing. The devices disclosed herein have the capability to deliver a variety of drugs through various delivery modes and release kinetics profiles, and to provide additional techniques, frameworks, and/or formulations to enhance in vivo drug release control. .
[0035] Regardless of whether the selected drug has a high or low solubility, it must be delivered (i.e., released from the delivery device) at a therapeutically effective rate, which may require the addition of one or more functional agents (e.g. , an osmotic agent to increase water flow, solubilizing or solubility agent, pH adjusting agent, or stability enhancing agent). In general, the combination of the solubility of the selected drug in the presence or absence of functional agents, if any, and osmotic water flow will determine the release rate and duration, and such a combination can be configured for the rate and duration to be within a range. therapeutically effective range.
[0036] The devices and methods disclosed herein constructed from those described in the U.S. Patent Application Publication. 2010/0331770 by Lee et al, U.S. Patent Application Publication. 2011/0152839 by Cima et al, and U.S. Patent Application Publication. 2012/0203203 by Lee et al, which are incorporated herein by reference.
[0037] I. IMPLANTABLE DRUG DELIVERY DEVICES
[0038] Embodiments of implantable drug delivery devices disclosed herein generally include a housing defining a reservoir, and first and second units contained within the reservoir. For example, the housing may be an elongate annular tube and the reservoir can be the lumen of the annular tube.
[0039] The first unit(s) include a drug or pharmaceutically active ingredient to be delivered to a patient, and the second unit(s) include a functional agent that facilitates the in vivo release of the drug from the housing. The first and second units are located at different positions within the reservoir. That is, the first and second units are distinct and separate from each other. For example, the first and second units may be solid tablets that are positioned adjacently in the reservoir.
[0040] As shown in Figure 1, a conventional drug delivery device 100 includes multiple identical tablets 102 positioned in a reservoir 104. (For purposes of clarity and ease of comparison with other illustrated embodiments, device 100 is shown in a linear, which may be useful during the process of inserting the device into the patient.) Tablets 102 include the drug to be delivered and, optionally, one or more excipients. Once implanted, the device 100 delivers the drug by osmotic pumping through an opening 106 in the device 100. However, the mode of drug delivery and kinetics are limited by the tablet formulation, as well as the characteristics of the housing materials of construction. .
[0041] An embodiment of the present disclosure is shown in Figure 2. The implantable drug delivery device 200 includes a housing 208, which defines a reservoir 204. In contrast to the device 100, the device 200 includes a plurality of first units 202, which include a drug, and a plurality of second units 210, which include a functional agent, which are contained within reservoir 204. The first and second units 202, 210 are located at distinct positions within reservoir 204. Such an arrangement may be particularly advantageous, as detailed below.
[0042] The device structure, in combination with the drug and functional agent formulations, can be designed to release the drug and functional agent through osmosis and/or diffusion.
[0043] Figure 2 illustrates a device 200 that is configured to operate as an osmotic pump. The device housing 208 includes a wall that is readily permeable to water, but not the drug to be delivered, and a drug that cannot readily diffuse through the wall of housing 208. That is, the water-permeable portion can be substantially impermeable. to the drug in aqueous solution. The water permeable wall portion may define at least part of the reservoir 204. After the device is installed in a patient, water (or urine if in the bladder) permeates through the wall, enters the reservoir 204, and solubilizes the first and /or second units 202, 210. Alternatively, or in combination with a water permeable wall portion, the housing may include at least one groove configured to allow fluid to enter the reservoir in vivo. For example, the housing and/or any water permeable wall portions can be silicone, a thermoplastic polyurethane, ethylene-co-vinyl acetate (EVA), or a combination thereof.
[0044] Injection of some portion of a solubilizing fluid into the reservoir prior to implantation can accelerate the process of hydration of tablets or formulations therein if necessary. In one embodiment, the device is configured to receive at least a portion of the aqueous fluid necessary to solubilize the functional agent and drug prior to implantation. For example, fluid can be delivered to the reservoir device via a needle and syringe. In one embodiment, a portion of the housing includes a low-hardness material suitable for penetration by a needle or other instrument. For example, the housing may include a coaxial spacer that includes a portion of low durometer material surrounded by a portion of high durometer material. In another example, the housing may include a one-way airtight seal feature.
[0045] Following implantation, an osmotic pressure gradient develops between the interior and exterior of the device housing 208, and once sufficient pressure is obtained, solubilized drug is released from the reservoir 204 through at least one release port. drug 206, which is in fluid communication with reservoir 204, at a controlled rate, driven by osmotic pressure in reservoir 204. Such a mode of release may be termed herein as "osmotic release" or "osmotic pumping."
[0046] As shown in Figure 2, drug delivery orifice 206 may be provided in an end plug located at one end of tubular housing 208. Such end plugs, also referred to as "spacer holes", are described in more details in PCT Application No PCT/US 14/20703, filed March 5, 2014, which is incorporated herein by reference. Figure 3 illustrates another embodiment of an osmotic device 300 that includes a drug delivery hole 306 in the side wall of housing 308, the groove configured to allow solubilized drug to pass therebetween.
[0047] As shown in Figure 17, the drug delivery device 1700 may include a restriction plug 1707 at one end of the tubular housing 1708. In this embodiment, the restriction plug 1707 controls the release of the drug by the transient formation of one or more more microchannels between the elastic portion of housing 1708 and the restriction plug. For example, osmotic tablets 1710 and drug tablets 1702 can be contained in the reservoir 1704, which is connected by a sealed end 1713 and the restriction plug 1707, which can be held in place by adhesive 1709, which holds a portion of the restraint to housing prevent transient microchannel formation between another part of the restraint plug and housing (eg, in an area away from the adhesive). Such restriction/microchannel plugs are described in more detail in PCT Application No PCT/US 14/28317, filed March 14, 2014, which is incorporated herein by reference.
[0048] In certain embodiments, the first unit, i.e. the drug unit, is located closer to the drug release port, the drug permeable wall portion, or restriction plug than the second unit, i.e. , the unit functional agent. This arrangement has been shown to be particularly advantageous in terms of achieving therapeutically effective drug release rates for determining drugs, such as low-solubility drugs.
[0049] When osmotic delivery is the desired drug delivery mode, the functional agent in the second units may include an osmotic agent that facilitates osmotic drug delivery. For example, the osmotic agent may have a greater solubility than the drug, so that the osmotic agent accelerates solubilization and/or subsequent drug release. This beneficially allows for the delivery of low solubility or other drugs typically only delivered via diffusion, osmotic delivery based devices.
[0050] Device 200 may exhibit an induction period while a sufficient volume of functional agent and/or drug is solubilized to achieve the osmotic pressure gradient. Subsequently, the device 200 may exhibit a zero-order release rate for an extended period, followed by a reduced non-zero-order release rate during a slump period. A desired delivery rate can be achieved by controlling/selecting various device parameters, including, but not limited to, surface area and water permeable wall thickness; the water permeability of the material used to form the wall; the shape, size, number and placement of slots 206; and the drug and functional agent dissolution profiles.
[0051] The devices described herein may also be configured to deliver drug via diffusion, either alone or in combination with osmotic delivery. The device may be configured to allow the solubilized drug to pass through a portion of the housing or one or more slots therein.
[0052] In certain embodiments, a water-permeable wall portion of the housing is also permeable to drug in aqueous solution, so that solubilized drug is released through the wall portion, also referred to herein as "pass-through diffusion." Wall". After the device is implanted, water or urine permeates through the wall, enters the reservoir, and solubilizes the functional agent and/or drug. The drug then diffuses directly through the wall at a controlled rate, due to a drug concentration gradient between the interior and exterior of the device. For example, the housing and/or any water or drug permeable wall portions can be silicone, a thermoplastic polyurethane, ethylene-co-vinyl acetate (EVA), or a combination thereof.
[0053] In certain embodiments, the housing has no release port and is configured to release the drug through at least one drug permeable wall connecting the reservoir. For example, the drug permeable wall may include a disc stabilized in the lumen of a tube at or near one end of the tube, optionally sandwiched between an inner washer and an outer washer. Drug permeable walls are described in more detail in the U.S. Patent Application. 14/216, 112, filed March 17, 2014, which is incorporated by reference herein. In other embodiments, the drug permeable wall is part of a side wall of a tubular housing, or part of an end plug located at the end of a tubular housing.
[0054] Alternatively, or in combination with a water permeable wall portion, the housing may include at least one groove configured to allow fluid to enter the reservoir in vivo. The housing may also include one or more passageways or pores configured to allow solubilized drug to pass through.
[0055] As described above, the device may also be configured to receive at least a portion of the water or fluid necessary to solubilize the functional agent and drug prior to implantation, for example, via a needle and syringe.
[0056] The device may exhibit a zero order release rate for an extended period followed by a reduced non-zero order release rate during a down period. Zero-order release can begin relatively quickly, as the drug can be immediately available to diffuse through the housing wall once solubilized. Delivery rate is affected by surface area and wall thickness; by the water and drug permeability of the material used to form the wall; by drug charge or particle size; and the drug and functional agent dissolution profile, among other factors. In embodiments in which the drug is released through one or more grooves or passageways, a number or combination of grooves or passageways may be used, which can also affect the overall rate of release attributable to diffusion.
[0057] In certain embodiments, the first unit and/or the second unit is in the form of a solid tablet. For example, as shown in Figure 4, first unit 402 is in powder form, while second units 410 are in solid tablet form. In other modalities, as shown
[0058] In Figures 2 and 3, both the first and second units are in the form of solid tablets. In certain embodiments, solid tablets are configured as "mini-tablets" as described in the U.S. patent document. 8,343,516 by Daniel et al. In embodiments, as shown in Figure 5, the device 500 contains a plurality of solid tablet-shaped first units 502 and a plurality of solid-tablet-shaped second units 510.
[0059] In certain embodiments, each drug unit tablet includes a relatively high weight fraction of drug and a relatively low weight fraction of excipients. For example, each drug tablet can include more than 50% drug by weight, which allows loading a relatively small device with a therapeutically effective amount of drug. The drug release rate from the device can be predominantly controlled by the combined properties of the functional agent and drug housing and can be changed by adjusting the housing characteristics, such as its thickness and permeability, as well as the functional agent formulation. .
[0060] The implantable device may be designed for installation in a portion of the body and retention within it, such as the bladder. The device may be flexible so that the device may be deformed for insertion, yet once implanted the device may resist excretion in response to urination or other forces. In one embodiment, the drug loaded device is flexible or deformable despite being loaded with the solid drug unit and/or tablets of functional agent units, as each drug unit may be allowed to move with reference to the units. of adjacent drugs. In particular, interstices or breaks between individual drug units can form reliefs that allow deformation of the device, while allowing individual units to retain their solid form, as described in the U.S. Patent Application Publication. 2010/0331770 by Lee et al.
[0061] Some solid charges of drug and/or functional agent are flexible in general, including powder units 402, as shown in Figure 4, or charges formed from individual solid tablets 602, 610 that can move in reference to each other, as shown in Figure 6.
[0062] As described above, the housing device may be formed at least partially of a water permeable material. For example, the housing may be formed of a water-permeable material that allows water to diffuse into the drug housing along its entire length, a portion thereof, or at one or both ends of the device.
[0063] In a particular embodiment, the housing is in the form of one or more elongate annular tubes wherein the annular tube includes two wall portions, one of which is permeable to water and the other is impermeable to water. One embodiment of the annular tube is shown in Figures 15A and 15B. Here, the annular tube 1500 includes the water impermeable wall portion 1510 and the water permeable wall portion 1520. Upon insertion into the patient, water permeates into the lumen 1530 through the wall portion 1520, whereupon it would enter into the lumen 1530. contact and would solubilize solid drug and/or functional agent loads therein (not shown). This structure can be formed by coextrusion, for example. The relative proportions of the two wall portions can be selected, for example, depending on the rate of (and thus surface area available for) water permeation and the mechanical properties required, for example, to provide the device with the flexibility values /durometer required for transurethral insertion and bladder retention and tolerance as described for example in the US Patent Application Publication 2011/0152839 by Cima et al.
[0064] As shown in Figure 18, drug delivery device 1800 may include a water impermeable coating region 1809 along at least a portion of tubular housing 1808. That is, a water impermeable wall portion may be formed by coating the housing with a water impermeable material. For example, osmotic tablets 1810 and drug tablets 1802 can be contained in reservoir 1804, which is connected by a sealed end 1813 and a release orifice plug 1806. Upon insertion into the patient, water permeates into the reservoir 1804 through the permeable housing. to water 1808 (but not through water impermeable region 1809), where it contacts and solubilizes the charges of functional agent and drug tablet therein. The water impermeable region allows for controlled solubilization and drug release. In particular, a housing coating may be useful for osmotic delivery devices where the housing material is permeable to the drug.
[0065] For example, a region of water impermeable coating may extend along 4 cm to 11 cm of the housing length, such as 6.5 cm along the housing length. In certain embodiments, a tubular housing has an internal diameter of 2.64 mm, and contains 6 to 11 cm of functional agent tablets and 2 to 4.5 cm of drug tablets, while having an impermeable coating region that extends from 4 cm to 11 cm of the housing length. For example, a water impermeable parylene coating can be provided in a silicone or other housing.
[0066] As mentioned above, the wall of the housing device may have one or more passages through its surface, providing a path for water flow into the reservoir and/or drug flow therefrom. In some embodiments, the wall may be porous, meaning that the wall may have one or more through pores formed therein. In other embodiments, the wall may be in the form of a defined groove formed completely through the wall, such as by drilling, punching or molding. The groove may have a circular shape or another shape. The groove may have a straight side wall or a tapered side wall that extends through the wall.
[0067] In some embodiments, the wall is made of a biocompatible elastic polymeric material. The material may be non-resorbable or resorbable. Exemplary non-resorbable materials include synthetic polymers selected from poly(ethers), poly(acrylates), poly(methacrylates), poly(vinyl pyrolidones), (poly)vinyl acetates, poly(urethanes), celluloses, cellulose acetates, poly( siloxanes), poly(ethylene), poly(tetrafluoroethylene) and other fluorinated polymers, and poly(siloxanes). Exemplary resorbable materials, especially biodegradable or bioerodible polymers, include synthetic polymers selected from poly(amides), poly(esters), (poly)ester amides, poly(anhydrous), poly(orthoesters), polyphosphazenes, pseudo poly(amino acids), poly(glycerol) sebacate, (poly)lactic acids, (poly)lglycolic acids, (poly)lactic-co-glycolic acids, poly(caprolactones), poly(caprolactone) derived from (PC), (poly)ester starches based on amino alcohol (PEA) and (poly)octane-diol citrate (POC), and other curable bioresorbable elastomers. PC-based polymers may require additional cross-linking agents such as lysine diisocyanate or 2,2-bis(e-caprolactone-4-yl)propane to obtain elastomeric properties. Copolymers, blends, and combinations of the above materials can also be used.
[0068] In certain embodiments, the housing may be formed of a material that is both water permeable and flexible. Silicone is an exemplary polymeric material that is flexible and can act as a water permeable membrane when formed as a thin wall, with permeability determined at least in part by wall thickness. For example, a thin wall of silicone can have a thickness in the range of about 100 μm to about 1000 μm, although another wall thickness can be used. In addition, a thin silicone wall may be permeable to some drugs, depending on, for example, the porosity of the wall, the size of the drug molecule, its molecular weight, or its charge.
[0069] Housing size, which includes wall thickness, can be selected based on the volume of drug and functional agent formulations to be contained, the desired rate of drug delivery from the tube, the intended place of device implantation within the body, the desired mechanical integrity of the device, the desired release rate or permeability to water and urine, the desired induction time before the onset of initial release, and the desired method or route of insertion into the body, among others. Tube wall thickness can be determined based on the mechanical properties and water permeability of the tube material, as a tube wall that is too thin may not have sufficient mechanical integrity while a tube wall that is too thick may experience an undesirably long induction time for initial drug release from the device and/or may not have sufficient flexibility to allow delivery through a urethra or other narrow body lumen.
[0070] For example, the housing may be an elongate annular tube having an internal diameter of from about 2 mm to about 5 mm. The first and second units may be solid tablets having a diameter substantially equal to the inner diameter of the elongate annular tube. One or more of the first unit tablets can fill a length of about 1 cm to about 3 cm of the tube lumen, and one or more of the second unit tablets can fill a length of about 10 cm to about 10 cm. 15 cm from the tube lumen. In one embodiment, the volume ratio of the first unit(s) to the volume of the second unit(s) is from about 0.05 to about 0.5. Other tablet load lengths and ratios are provided.
[0071] For example, the housing may be an elongated annular tube having a wall thickness of 0.1 to 0.4 mm, such as a wall thickness of 0.2 mm. the material housing can be selected so that the housing has a durometer from 25A to 80A, such as 25A, 50A, 65A, 70A or 80A.
[0072] In certain embodiments, the device is elastically deformable between a relatively stretched shape suitable for insertion through a patient's urethra and into the patient's bladder and a retention shape suitable for retaining the device within the bladder. For example, the device may include a retaining frame lumen which has a retaining frame positioned therein. The retaining frame may be made of a superelastic alloy or other elastic yarn, as described in the U.S. Patent Application Publication. 2010/0331770 by Lee et al, which is incorporated herein by reference.
[0073] An exemplary embodiment is shown in Figure 5, in which the device 500 includes a housing 508 that houses the first and second units 502, 510, and a retaining frame 512. The drug housing 508 is axially aligned with the retaining frame 512, and is formed of a flexible material, which allows the device 500 to be moved between the retaining shape shown in Figure 5, and a stretched installation format, as shown in Figure 3. The "retaining shape" generally indicates any shape suitable for retaining the device in the intended implantation site, including but not limited to the pretzel-like shape shown in Figure 5 which is suitable for retaining the device in the bladder, while the "fitting shape" generally indicates any shape suitable for installing the drug delivery device in the body, which includes the linear or elongated shape shown in Figure 3 which is suitable for installing the device through a working channel garlic from an installable instrument positioned in the urethra or other natural lumen. In one embodiment, the device is configured to spontaneously assume a shape having an interconnected and overlapping pair of coils, in the absence of a compressive load, such as caused by being forced into an installation format and/or through an installable instrument.
[0074] In certain embodiments, as shown in Figure 16, the reservoir 1604 of the device 1600 includes a flow modulator channel 1642 positioned between the first and second units 1602, 1610. For example, the flow modulator channel may be a passageway which has a diameter smaller than the diameter of the reservoir. The flow modulating channel may serve to limit the flow between channels (i.e., reservoir sections), and thereby delay drug release from the housing by limiting the ability of the functional agent to contact the drug. In certain embodiments, the device may include more than one flow modulator channel for additional control of the drug release rate from the device.
[0075] In certain embodiments, a drug delivery device includes a first housing portion loaded with a drug formulation, and a second housing portion loaded with an excipient, and is configured to deliver the drug according to a first profile. and is configured to release the excipient according to a second release profile that differs from the first release profile. The housing portions can achieve different release rates by having different configurations, housing different formulations, or employing different release mechanisms, among others, or combinations thereof. The housing portions can be combined to achieve a desired drug release profile. For example, the excipient can be a functional agent configured to facilitate drug delivery and/or delivery, such as a drug solubilizing agent, a drug stabilizing agent, or a permeation enhancing agent. The drug formulation and/or the excipient may be in the form of one or more tablets.
[0076] For example, the device may include housing portions that exhibit different induction or delay times before the start of the initial release, that release the drug and excipient at different rates or according to different release curves after the start of the initial release. release, or that release the drug and the excipient for different periods before the loads are substantially depleted, among others or combinations thereof. The disparate housing portions can be combined to achieve a desired release profile from the drug delivery device as a whole, such as a release profile that demonstrates a relatively short initial lag time and then demonstrates continued release at a relatively constant rate. for an extended period.
[0077] For example, drug and excipient may be released by osmotic pumping or diffusion as described above, or some combination thereof. In certain embodiments, the drug is released from the first housing portion through a slot in the first housing portion, primarily by osmotic pressure, and the excipient is released from the second housing portion by diffusion. In another embodiment, the drug is released from the first housing portion by diffusion through a drug permeable wall in the first housing portion, and the excipient is released from the second housing portion, through a slot in the second housing portion, primarily through osmotic pressure.
[0078] In particular embodiments, the drug delivery device includes at least two distinct or segregated housing portions associated with a single retention portion. The housing portions may be separate reservoir housings, each associated with the holding portion, or the housing portions may be separate areas within a single housing that is associated with the holding portion. Figure 7 illustrates exemplary housing portions with separate reservoir housings in Examples A through C. Figure 7 also illustrates exemplary housing portions which are segregated areas within a single housing in Examples D through F. Figure 7 also illustrates housing portions. housing in Examples G to I which could have any configuration depending on materials and construction.
[0079] Figure 8 is a plan view of another embodiment of a drug delivery device 800 that has a housing that is divided into multiple segregated housing portions. Three housing portions 802, 804, and 806 are shown, although any number can be used. Each housing portion is defined by a housing wall portion and at least one partition structure 808, which separates the housing portion from an adjacent housing portion. The partition structure 808 can be a plug inserted into the housing, such as a cylinder, sphere, or disk, among others, which is held in place by its size or with an adhesive. Partition structure 808 may also be a housing portion formed directly therein, such as by molding. For example, the frames shown in Examples D to E of Figure 7 are partition structures that segregate housing portions along the length of the device.
[0080] A device with at least two distinct housing portions may be suitable for controlled release of at least one drug load and at least one load of excipient or functional agent from a corresponding number of reservoirs. The two distinct portions may have the same or different configurations, such as or any combination of the configurations described above with reference to Figures 1 to 6. Configurations of drug delivery devices that have two distinct drug portions are further described in the Publication of order in the US 201 1/0060309 by Lee et al.
[0081] II. USE AND APPLICATIONS OF IMPLANTABLE DRUG DELIVERY DEVICES
[0082] The implantable drug delivery devices described herein can be used in a variety of medical applications, particularly therapeutic and prophylactic treatments for patients. In certain embodiments, the device is configured to deliver a drug such as lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, trospium, tolterodine, or mitomycin C.
[0083] In some embodiments, the devices provide pain relief to the patient. A variety of anesthetic agents, analgesic agents, and combinations thereof can be used. In embodiments, the device delivers one or more local anesthetic agents. The local anesthetic agent may be a cocaine analogue. In particular embodiments, the local anesthetic agent is an aminoamide, an aminoester, or combinations thereof.
[0084] Representative examples of aminoamides or amide class anesthetics include articaine, bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine and trimecaine. Representative examples of aminoesters or ester class anesthetics include amylocaine, benzocaine, butacaine, chloroprocaine, cocaine, cyclometicaine, dimethocaine, hexylcaine, larocaine, meprilcaine, metabutoxycaine, orthocaine, piperocaine, procaine, proparacaine, propoxycaine, proxymetacaine, risocaine and tetracaine. Such local anesthetics are typically weak bases and can be formulated as a salt, such as a hydrochloride salt, to make them water soluble, although anesthetics can also be used in free base or hydrate form. Other anesthetics, such as lontocaine, may also be used. The drug can also be an antimuscarinic compound that exhibits an anesthetic effect, such as oxybutynin or propiverine. The drug may also include other drugs described herein, alone or in combination with a local anesthetic agent.
[0085] In certain embodiments, the analgesic includes an opioid. Representative examples of opioid agonists include alfentanil, allylprodine, alfaprodine, anyleridine, benzylmorphine, bezitramid, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxdol, dimefeptanol, dimethylthiambutene, dioxaphetyl butyrate , dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopone, morphine, myrophine, nalbuphine, nalbuphine nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveret, pentazocine, fenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pyritramide, proheptazine, promedol, properidine, propyram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts of the same, and mixtures thereof. Other opioid drugs, such as mu, kappa, delta, and nociception opioid receptor agonists, are contemplated.
[0086] Representative examples of other suitable pain-relieving agents include such agents as salicyl alcohol, phenazopyridine, phenazopyridine hydrochloride, acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen, indomethacin and naproxen.
[0087] In embodiments, the drug delivery device is used to treat inflammatory conditions such as interstitial cystitis, chemical cystitis, radiation cystitis, chemotherapy- and radiation-induced hemorrhagic cystitis, ketamine cystitis (or ketamine bladder syndrome) , painful bladder syndrome, prostatitis, urethritis, post-surgical pain, and kidney stones. Non-limiting examples of drugs specific to these conditions include lidocaine, immunosuppressive agents (e.g. tacrolimus monohydrate, liposomal tacrolimus monohydrate), glycosaminoglycans (e.g. chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac or a combination thereof. For kidney stones, drug(s) may be selected to treat pain and/or promote stone dissolution.
[0088] In some embodiments, the drug delivery device is used in association with placement of a ureteral stent, such as to treat pain, urinary urgency, or urinary frequency resulting from ureteral stent placement. Non-limiting examples of specific drugs for such treatment include antimuscarinics, α-blockers, narcotics, and phenazopyridine, among others.
[0089] The drug delivery device can be used, for example, to treat urinary incontinence, frequency, or urgency, including stimulus incontinence and neurogenic incontinence, as well as trigonitis. Drugs that may be used include anticholinergic agents, antispasmodic agents, antimuscarinic agents, β-2 agonists, alpha adrenergics, anticonvulsants, norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers, potassium channel openers, and muscle relaxants. Representative examples of drugs suitable for the treatment of incontinence include oxybutynin, S-oxybutytin, emepronium, verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine clenbuterol, darifenacin terodiline trospium, hyoscimine propiverine, desmopressin vamicamide, clidinium bromide, dicilomineHCl, aminoalcohol ester glycopyrolate, ipratropium bromide, mepenzolate bromide, methscopolamine bromide, scopolamine hydrobromide, iotropium bromide, fesoterodine fumarate, YM-46303 (Yamanouchi Co., Japan), lanperisone (Nippon Kayaku Co., Japan), inaperisone NS-21 (Nippon Shinyaku Orion, Formenti, Japan/Italy), NC-1800 (Nippon Chemiphar Co., Japan), ZD-6169 (Zeneca Co., UK), and stylonium iodide.
[0090] In other embodiments, the drug delivery device is used to treat urinary tract cancer, such as bladder cancer or prostate cancer. Drugs that may be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or a combination thereof. Representative examples of drugs that may be suitable for the treatment of urinary tract cancer include Bacillus Calmette-Guérin (BCG) vaccine, docetaxel, oxaliplatin, carboplatin, cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall DNA complex (MCC) , methotrexate, vinblastine, thiotepa, mitomycin, fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide, selective estrogen receptor modulators (i.e. a SERM such as tamoxifen), botulinum toxins, deacetylase inhibitors of histone (eg, suberoylanilide hydroxamic acid) and cyclophosphamide. The drug may be a biologic, and may include a monoclonal antibody, a TNF inhibitor, an anti-leucine, or the like. The drug can also be an immunomodulator, such as a TLR agonist, including imiquimod or another TLR7 agonist. The drug may also be a kinase inhibitor, such as a fibroblast growth factor receptor-3 (FGFR3) selective tyrosine kinase inhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or a protein kinase inhibitor. activated by mitogen (MAPK), among others or combinations thereof. Drug treatment can be coupled with conventional radiation or surgical therapy targeted at the cancerous tissue.
[0091] In still other embodiments, the device is used to treat infections involving the bladder, prostate, and urethra. Antibiotics, antibacterial, antifungal, antiprotozoal, antiseptic, antiviral and other anti-infective agents may be administered to treat such infections. Representative examples of drugs for treating infections include mitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, trimethoprimsulfamethoxazole sulfonamides, erythromycin, doxycycline, metronidazole, tetracycline, kanamycin, penicillins, cephalosporins, and aminoglycosides.
[0092] In other embodiments, the device is used to treat fibrosis of a genitourinary site, such as the bladder or uterus. Representative examples of drugs for the treatment of fibroids include pentoxphylline (xanthine analogue), antiTNF, antiTGF agents, GnRH analogues, exogenous progestins, antiprogestins, selective estrogen receptor modulators, danazol and NSAIDs.
[0093] The drug delivery device can also be used to treat neurogenic bladder. Representative examples of drugs for treating neurogenic bladder include analgesics or anesthetics, such as lidocaine, bupivacaine, mepivacaine, prilocaine, articaine, and ropivacaine; anticholinergics; antimuscarinics such as oxybutynin or propiverine; a vanilloid, such as capsaicin or resiniferatoxin; antimuscarinics such as those that act on the muscarinic M3 acetylcholine receptor (mAChRs); antispasmodics including GABAB agonists such as baclofen; botulinum toxins; capsaicins; alpha-adrenergic antagonists; anticonvulsants; serotonin reuptake inhibitors such as amitriptyline; and nerve growth factor antagonists. In various modalities, the drug may be one that acts on bladder afferents or one that acts on afferent cholinergic transmission, as described in Reitz et al, Spinal Cord 42:267-72 (2004).
[0094] Drugs for the treatment of neurogenic bladder can be categorized into one of two general types: those to treat convulsive neurogenic bladder and those to treat flaccid neurogenic bladder. In embodiments, the drug is selected from those known to treat incontinence due to neurological detrusor overactivity and/or low compliance detrusor. Examples include bladder relaxant drugs (e.g., oxybutynin (an antimuscarinic agent with a pronounced muscle relaxant activity and local anesthetic activity), propiverine, impratropium, tiotropium, trospium, terodiline, tolterodine, propantheline, oxyphencyclimine, flavoxate, and tricyclic antidepressants; to block nerves that innervate the bladder and urethra (eg, vanilloids (capsaicin, resiniferatoxin), botulinum toxin A); or drugs that modulate the force of detrusor contraction, micturition reflex, detrusor sphincter dyssynergia (eg, GABAb agonists (baclofen), benzodiazapines. In other embodiments, the drug is selected from those known to treat incontinence due to neurological sphincter deficiency. Examples include alpha-adrenergic agonists, estrogens, beta-adrenergic agonists, tricyclic antidepressants ( imipramine, amitriptyline). In still other embodiments, the drug is selected from and those known to facilitate bladder emptying (eg, alpha-adrenergic (phentolamine) or cholinergic antagonists). In still other embodiments, the drug is selected from anticholinergic drugs (eg, dicyclomine), calcium channel blockers (eg, verapamil), tropane alkaloids (eg, atropine, scopolamine), nociceptin/orphanine FQ, and bethanechol ( e.g. muscarinic m3 agonist, choline ester).
[0095] In certain embodiments, functional agents or excipients include osmotic agents, drug solubilizing agents, drug stabilizing agents, permeation enhancing agents, or combinations thereof. In particular, functional agents or excipients may be suitable to facilitate in vivo delivery or delivery of the drug to the site of implantation. For example, the drug may be a drug of low solubility and the functional agent may be an osmotic agent, such as urea. Upon solubilization, the osmotic agent can facilitate release of the drug from the housing by osmotic pressure-induced fluid flow. Other examples of functional agents and excipients that can be used include cyclodextrins, glycerol, polyethylene glycol, citrates, acetates, phosphates, ascorbic acid, and sodium sulfide.
[0096] In embodiments, the first unit(s) contain a high weight percentage of drug, and the second unit(s) contain a high weight percentage of functional agent or excipient. For example, the first unit may contain at least 50 weight percent drug, at least 60 weight percent drug, at least 75 weight percent drug, from about 60 to about 99 weight percent drug, or from about 75 to about 95 weight percent drug. The second unit may contain at least 80 weight percent functional agent, at least 85 weight percent functional agent, at least 90 weight percent functional agent, from about 80 to about 99 weight percent functional agent, or from about 85 to about 95 weight percent functional agent. The remainder of the units may include excipients such as pharmaceutical lubricants, stabilizing agents, or binding agents, for example oil, PEG or PVP based lubricants. Excipients may also include a release delaying agent. For example, a release delaying agent could be provided in a portion of the drug units, in a portion of the functional agent units, or in both for further control of drug release.
[0097] In a particular embodiment, the first unit contains at least 75 weight percent gemcitabine HCl and the second unit contains at least 85 weight percent urea. For example, the first unit may contain about 80 weight percent gemcitabine HCl, and the second unit may contain about 90 weight percent urea.
[0098] In one embodiment, the housing is permeable to water, the first unit includes a first tablet that contains a drug of low solubility, and the second unit includes a second tablet that contains an osmotic agent that facilitates release of the drug from the housing. by osmotic pressure. In one embodiment, the drug is gemcitabine and the osmotic agent is urea.
[0099] The device can be inserted into a patient's body cavity or lumen. Once implanted, the device can deliver one or more drugs for the treatment of one or more conditions, either locally to one or more tissues at the site of installation, regionally to other tissues distal to the site of installation, or both. Release can be controlled over an extended period. Thereafter, the device can be removed, reabsorbed, excreted, or a combination thereof.
[0100] In certain embodiments, the device is inserted into a patient by passing the device through an installable instrument and releasing the device from the installable instrument in the body. The installable instrument can be any suitable lumen device, such as a catheter, a urethral catheter, a cystoscope, or a combination thereof, either commercially available or specially adapted to install the present device. In particular embodiments, the device is implanted in the bladder. The device is then retained in the bladder due to the retention feature, such as taking a retention shape or anchoring in the bladder.
[0101] The device may be installed in a standalone procedure or in conjunction with another urological procedure or another procedure or surgery, either before, during, or after the other procedure. The device can deliver one or more drugs that are delivered to site and/or regional tissues for therapy or prophylaxis, either perioperatively, postoperatively, or both.
[0102] Following in vivo installation, the device releases the drug. Release can occur, as described above, due to an osmotic pressure gradient between the inside and outside of the device, with the drug passing through one or more holes or pores in the device under the force of osmotic pressure. Release can also occur by diffusion, in which the drug passes through one or more holes or pores in the device and/or through a drug-permeable wall of the device, due to a drug concentration gradient between the interior and exterior. of the device. Combinations of these delivery modes within a single device are possible, and in some embodiments are preferred in order to achieve an overall drug delivery profile not readily achievable in any individual fashion.
[0103] Upon insertion of the device into the patient, water or aqueous body fluid from the implantation site may enter the device, such as through a water permeable wall or a passage in the device wall, to solubilize the functional agent or excipient and the drug. For example, the functional agent and drug may be solubilized upon contact with urine in cases where the device is implanted in the bladder. The functional agent may be a solubilizing agent configured to facilitate drug solubilization.
[0104] In particular embodiments, the release of at least two payloads (i.e., a drug payload and an excipient and/or functional agent payload) may occur according to different release profiles, which include profiles who exhibit different initial onsets of release, such as immediate or delayed release; profiles that display different release durations, such as quick release and extended release; and profiles that display different release rates, either a zero-order release rate or otherwise. Continuous and extended release is therefore facilitated according to a desired profile. For example, the device can deliver a functional agent payload relatively quickly, and the device can deliver a drug payload more continuously.
[0105] The device can provide extended, continuous, intermittent or periodic release of a desired amount of drug for a predetermined, desired period. In various embodiments, the device can deliver the desired dose of drug over an extended period, such as 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 drug delivery and dosage can be selected depending on the drug that is delivered and the disease or condition that is treated. In embodiments, the device is configured to deliver a therapeutically effective amount of the drug over a period of 1 day to 30 days, such as 2 days to 30 days, 1 day to 21 days, 1 day to 14 days, 2 days days to 14 days, or from 5 days to 7 days, etc. In certain embodiments, drug is released from the device at a zero-order rate over a period of 1 day to 30 days, such as 2 days to 14 days, or 3 days to 7 days.
[0106] Subsequently, the device may be retrieved from the body, such as in cases where the device is non-resorbable or needs to be removed in some other way. Recovery devices for this purpose are known in the art or can be specifically produced. The device may also be completely or partially bioabsorbable, so that recovery is unnecessary as either the entire device is reabsorbed or the device sufficiently degrades for expulsion from the bladder during urination, as described, for example, in the Patent Application Publication. US no. 2012/0089122 to Lee et al, which is incorporated herein by reference. The device may not be recovered or reabsorbed until some of the drug, or preferably most or all of the drug, has been released. If necessary, a new drug loaded device can subsequently be implanted, either during the same procedure as recovery or at a later time.
[0107] In one embodiment, the implantable device, with a one-piece drug payload, is positioned entirely within the bladder to provide local, sustained delivery of at least one drug locally to a bladder in an effective amount. After in vivo positioning of the device, at least a portion of the drug payload is released from the device substantially continuously over an extended period, to the urothelium and possibly to nearby tissues, in an amount effective to provide treatment or improve a bladder function. on the patient. In a preferred embodiment, the device resides in the bladder which releases the drug for a predetermined period, such as two weeks, three weeks, four weeks, one month or longer. In such cases, the device can be used to treat interstitial cystitis, chemical cystitis, radiation cystitis, radiation and chemotherapy-induced hemorrhagic cystitis, ketamine cystitis (or ketamine bladder syndrome), pelvic pain, overactive bladder syndrome, cancer bladder, neurogenic bladder, neuropathic or non-neuropathic bladder sphincter dysfunction, infection, post-surgical pain or other diseases, disorders, and conditions treated with drugs delivered to a bladder. The device can deliver drugs that improve bladder function, such as bladder capacity, compliance, and/or frequency of uninhibited contractions, that reduce pain and discomfort in the bladder or other nearby areas, or have other effects, or combinations. of the same.
[0108] In some embodiments, the drug delivery device is positioned in a patient's bladder for regional drug delivery to one or more nearby genitourinary sites. The device can deliver drug locally to a bladder and regionally to other sites close to a bladder. A bladder positioned device can also deliver a therapeutically effective amount of one or more drugs to other genitourinary sites within the body, such as other locations within the body's urological or reproductive systems, which include one or both of the kidneys, the urethra , one or both of the ureters, the penis, the testes, one or both of the seminal vesicles, one or both of the vas deferens, one or both of the ejaculatory ducts, the prostate, the vagina, the uterus, one or both of the following the ovaries, or one or between the fallopian tubes, among others or combinations thereof. For example, the intravesical drug delivery device can be used in the treatment of kidney stones or fibrosis, erectile dysfunction, among other diseases, disorders and conditions. Such delivery may provide an alternative to systematic administration, which may lead to undesirable side effects or result in drug bioavailability.
[0109] The present invention may be further understood with reference to the following non-limiting examples: Unless otherwise indicated, all percentages are percentages by weight.
[0110] EXAMPLE 1: SINGLE-UNIT DEVICES VERSUS MULTI-UNIT DEVICES
[0111] Drug delivery device models were prepared using silicone production tubes that have an internal diameter of 2.64 mm.
[0112] A single unit device was prepared, according to the device embodiment shown in Figure 1. The tube was loaded with a plurality of tablets containing 17.7 percent gemcitabine hydrochloride (164 mg FBE), 73, 6 percent urea, 7.8 percent LUBRITAB® oil-based pharmaceutical lubricant (commercially available from JRS PHARMA, Rosenberg, Germany), and 0.9 percent polyvinylpyrrolidone (PVP) K29-32 (commercially available as PLASDONE® from International Specialty Products, New Jersey). The tablets were formed to have a diameter substantially equal to the inner diameter of the tube, and were loaded into the tube in a series arrangement. The tablets filled a length of 15.2 cm. The device included a spacer-type release hole with a length of 5 mm.
[0113] A multi-unit device was also prepared, according to the device embodiment shown in Figure 2. The tube was loaded with a plurality of drug tablets containing 80.0 percent gemcitabine HCl, 13.3 percent. urea, 4.2 percent PVP K29-32, and 2.5 percent poly(ethylene glycol) (PEG) 8000. The drug tablets filled a length of 2.8 cm and were positioned in series adjacent to each other. a spacer-type release hole with a length of 5 mm. The tube was also loaded with a plurality of functional agent tablets that contain 90.0 percent urea and 10.0 percent Lubritab. The functional agent tablets filled a 12.0 cm length of tube.
[0114] The total formulation of the multi-unit device was 18.9 percent gemcitabine HCl, 71.8 percent urea, 7.7 percent Lubritab, 1.0 percent PVP K29-32, and 0.6 percent PEG 8000, which was comparable to the total single-unit device formulation. In particular, the single-unit device contained 164.0 mg of gemcitabine FBE, while the multi-unit device contained 163.8 mg of gemcitabine FBE.
[0115] In vitro drug release profiles were measured for both single-unit devices and multi-unit devices in water. Figures 9 and 10 show percent drug release and release rate (measured in gemcitabine FBE mg per day) versus time, respectively. Overall, the multi-unit device performed better than the single-unit device, delivering a higher percentage of the drug, and maintaining a higher rate of drug delivery for a longer period. As shown in Figure 9, the multi-unit device released more than 90 percent of its drug payload in a 7-day period, while the single-unit device released less than 80 percent of its drug payload. drug in the same period. As shown in Figure 10, the multi-unit device also has a "flattening" release profile, in which the drug release rate stabilizes between days 2 and 4. A flat profile is desirable for extended drug delivery. For example, the multi-unit device performed much better than the single-unit device on extended, continuous drug delivery for 5 to 7 days.
[0116] EXAMPLE 2: LASER DRILLED RELEASE HOLES VERSUS SPACE TYPE RELEASE HOLES IN MULTI-UNIT DEVICES
[0117] A multi-unit device that has a spacer-type release hole was prepared, according to the device embodiment shown in Figure 2. The release hole had a length of 5 mm and an inside diameter of 0.3 mm The spacer hole was located at one end of the tube.
[0118] A multi-unit device that has a laser-drilled release hole was prepared, according to the device embodiment shown in Figure 3. The release hole had an internal diameter of 0.150 mm and was located in the housing wall. of the device.
[0119] Each tube was filled with a plurality of drug tablets and a plurality of functional agent tablets. The functional agent tablets contained 90.0 percent urea and 10.0 percent Lubritab, and filled a tube length of 6.0 cm. The drug tablets contained 80.0 percent gemcitabine HCl, 13.3 percent urea, 4.2 percent PVP K29-32, and 2.5 percent poly(ethylene glycol) (PEG) 8000, and filled a tube length of 2.5 cm. The laser-pierced device contained 141.6 µg gemcitabine FBE mg, and the spacer hole device contained 140.5 µg gemcitabine FBE mg).
[0120] As shown in Figure 3, in the laser-pierced hole device 300.3 cm of functional agent tablets 310 were located on each side of 2.5 cm of drug tablets 302, so that drug tablets 302 were centered near the laser-pierced hole 306. As shown in Figure 2, in the spacer hole device 200, 2.5 cm of the drug tablets 202 were located adjacent the spacer hole 206, and 6.0 cm of the functional agent tablets 210 were located adjacent to drug tablets 202.
[0121] In vitro drug release profiles were measured for both laser drilled hole and water spacer hole devices. Figures 11 and 12 show percent drug release and release rate (measured in FBE gemcitabine mg per day) versus time, respectively. Overall, both devices exhibited similar release profiles, releasing more than about 70 percent of the drug payload over 7 days at a substantially zero-order rate. The release rate profiles of the devices are also similar, with a plateau region at about 20 mg FBE/day of release between days 1 to 4.
[0122] EXAMPLE 3: MULTIPLE DRUG UNITS DEVICES OF POWDER VERSUS OF TABLET DRUG
[0123] A multi-unit device that has drug tablets and functional agent tablets was prepared, according to the device embodiment shown in Figure 2. The functional agent tablets contained 90.0 percent urea and 10.0 percent urea. percent of Lubritab and filled a tube length of 6.0 cm. The drug tablets contained 80.0 percent gemcitabine HCl, 13.3 percent urea, 4.2 percent PVP K29-32, and 2.5 percent poly(ethylene glycol) (PEG) 8000, and filled a tube length of 1.5 cm. The tablet drug device contained 123.4 mg of gemcitabine FBE mg.
[0124] A multi-unit device having functional agent tablets and a unit of powdered drug was prepared, according to the device embodiment shown in Figure 4. Functional agent tablets 410 contained 80 percent urea and 20 percent of Lubritab, and filled a tube length of 7.8 cm. Drug powder unit 402 contained 80 percent gemcitabine HCl and 20 percent urea powder, and filled a tube length of 3.4 cm. The powder drug device contained 124.4 mg of gemcitabine FBE mg.
[0125] Each device included a spacer-type release hole that has an inside diameter of 0.300 mm and a length of 5.0 mm.
[0126] In vitro drug release profiles were measured for both laser drilled hole and water spacer hole devices. Figures 13 and 14 show percent drug release and release rate (measured in FBE gemcitabine mg per day) versus time, respectively. Overall, both devices exhibited similar release profiles, releasing more than about 85 percent of the drug payload over 7 days at a substantially zero-order rate. The release rate profiles of the devices are also similar, with a plateau region above 20 mg FBE/day of release between days 1 to 4.
[0127] As can be seen from the Examples above, multi-unit drug delivery devices provide improvements for both short-term and long-term release profiles compared to comparable single-unit devices. These devices advantageously allow controlled extended drug delivery, for example zero-order delivery over 5 to 7 days. Furthermore, these devices provide a means for delivering low-solubility drugs to patients via osmotic delivery devices. This is especially useful for drugs that are difficult to reformulate into more highly soluble forms. Thus, these devices are capable of delivering a variety of drugs through various delivery mechanisms and release kinetics profiles, and provide enhanced control of drug delivery in vivo, for example, from a device installed in the bladder.
[0128] EXAMPLE 4: EFFECT OF WALL THICKNESS AND SILICONE TUBE HOUSING DUROMETER ON DRUG RELEASE FROM THE DEVICE
[0129] A multi-unit device that has drug tablets and functional agent tablets was prepared, according to the device embodiment shown in Figure 17. The functional agent tablets were osmotic tablets. The osmotic tablet mass and length were approximately 400 mg and 6 cm, respectively, and the drug tablet mass and length were approximately 150 mg and 2 cm, respectively. The drug tablet formulation (gemcitabine) 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 the direct powder compaction method.
[0130] Four different types of extruded silicone tubing housings were used in this example: 1) 2.64mm internal diameter, 0.13mm wall, 65A Shore A durometer (MED-4765, NuSil Technology LLC); 2) 2.64 mm internal diameter, 0.1 mm wall, 80A Shore A durometer (MED-4780, NuSil Technology LLC); 3) 2.64 mm internal diameter, 0.2 mm wall, 50A Shore A durometer (MED-4750, NuSil Technology LLC); and 4) 2.64 mm internal diameter, 0.4 mm wall, 25A Shore A durometer (MED-4720, NuSil Technology LLC).
[0131] In each device, as in Figure 17, one end of the tube was sealed by MED3-4213-1 silicone adhesive (NuSil Technology LLC) and the other end included a restriction plug made of EVA support frame ( medical FBK), which comprises Elvax 760, ethylene vinyl acetate (EVA) copolymer. The EVA plug was approximately 2.74 mm in outer diameter and 5 mm in length and a 30 to 60 degree cut was made on one end of the plug. The void created by the cut surface and the silicone tube was filled with silicone adhesive, as shown in Figure 17, which served as a stop to prevent the plug from detaching when osmotic pressure was built up in the silicone tube. In vitro release was performed in deionized water at 37°C and the results are shown in Figure 19. The sample size for each group was 2 and the error bars indicate standard deviation (SD) around the middle. Some error bars are not seen if they are smaller than the symbols. As used in the legend, "O" refers to osmotic tablet and "A" refers to pharmaceutically active ingredient, ie drug, tablet.
[0132] In particular, Figure 19 shows the amount of drug released over time from devices that have various wall thicknesses and housing durometers. Gemcitabine release performance was affected by the wall thickness and durometer of the silicone tube housing. These results indicate that housing size, including wall thickness and the hardness and flexibility of housing material, can be selected based on the volume of drug and functional agent formulations to be contained as well as the desired rate of drug delivery from the drug. pipe.
[0133] EXAMPLE 5: EFFECT OF WALL THICKNESS AND SILICONE TUBE HOUSING DUROMETER ON DRUG RELEASE FROM THE DEVICE
[0134] Another set of experiments was performed using the device configurations shown in Figure 17. In this example, three different silicone tube housings used were: 1) 2.64mm internal diameter, 0.2mm wall, 50A Shore A durometer (MED-4750, NuSil Technology LLC); 2) 2.64 mm internal diameter, 0.2 mm wall, 70A Shore A durometer (MED-4770, NuSil Technology LLC); and 3) 2.64 mm internal diameter, 0.4 mm wall, 25A Shore A durometer (MED-4720, NuSil Technology LLC).
[0135] The tablets were placed next to each other in the reservoir, as in Figure 17. The osmotic tablet mass and length were approximately 700 mg and 11 cm, respectively, and the drug tablet mass and length were approximately 300 mg and 4.5 cm, respectively. The drug tablet formulation (gemcitabine) 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 the direct powder compaction method. In vitro release was performed 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 standard deviation (SD) around the middle. Some error bars are not seen if they are smaller than the symbols. As used in the legend, "O" refers to osmotic tablet and "A" refers to pharmaceutically active ingredient, ie drug, tablet.
[0136] In particular, Figure 20 shows the amount of drug released over time from devices that have various wall thicknesses and housing durometers. Gemcitabine release performance was affected by the wall thickness and durometer of the silicone tube housing. These results indicate that housing size, which includes wall thickness, length, and housing hardness and flexibility, can be selected based on the volume of drug and functional agent formulations to be contained as well as the desired rate. drug delivery tube.
[0137] EXAMPLE 6: EFFECT OF LENGTH OF REGION OF WATERPROOF COATING OF SILICONE TUBE HOUSING ON DRUG RELEASE FROM DEVICE
[0138] A multi-unit device that has drug tablets and functional agent tablets was prepared, according to the device embodiment shown in Figure 18. Unlike previous configurations, Parylene C (a water impermeable coating) was partially coated in extruded silicone tube that has an inside diameter of 2.64 mm, 0.2 mm wall, and 50A Shore A durometer (MED-4750, NuSil Technology LLC). A 0.3 mm diameter hole was placed at one end of the tube while the other end was sealed with MED3-4213-1 silicone adhesive. Three different silicone tube housing configurations were tested: 1) osmotic tablet mass/length: 700 mg/11 cm, drug tablet mass/length: 320 mg/4.5 cm, parylene coated region length: 6.5 cm; 2) mass/length of osmotic tablet: 700 mg/11 cm, mass/length of drug tablet: 320 mg/4.5 cm, length of parylene coated region: 11 cm; and 3) osmotic tablet mass/length: 400 mg/6 cm, drug tablet mass/length: 150 mg/2 cm, parylene coated region length: 4 cm.
[0139] 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 indicate standard deviation (SD) around the middle . Some error bars are not seen if they are smaller than the symbols. As used in the legend, "O" refers to osmotic tablet and "A" refers to pharmaceutically active ingredient, ie drug, tablet.
[0140] In particular, Figure 21 shows the amount of drug released over time from devices that have various lengths of water impermeable coating region. Gemcitabine release performance was affected by the length of the parylene coated region relative to the lengths of the osmotic tablet and drug regions. These results indicate that the length of the water impermeable region can be selected based on the volume of drug and functional agent formulations to be contained as well as the desired rate of drug delivery from the tube. In addition, a housing coating may be useful where the housing material is drug permeable and osmotic release is desired.
[0141] Publications cited herein and the materials in which they are cited are specially incorporated by reference. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to be within the scope of the appended claims.

权利要求:
Claims (28)
[0001]
1. Intravesical drug delivery device, comprising: a housing defining a reservoir; characterized in that it further comprises: a first unit in the form of a solid tablet contained within the reservoir in a first position, the first unit comprising a drug; and a second unit in the form of a solid tablet comprising an osmotic agent and contained within the reservoir in a second position other than the first position, the first and second positions being in fluid communication with each other, wherein the second unit facilitates in vivo release of drug from the housing, and wherein the device is elastically deformable between a relatively straightened shape adapted for insertion through a patient's urethra and into the patient's bladder and a retention shape adapted to retain the device inside the bladder.
[0002]
2. Device according to claim 1, characterized in that the housing comprises a water-permeable wall portion that defines at least part of the reservoir.
[0003]
3. Device according to claim 2, characterized in that either the water-permeable wall portion is impermeable to the drug in aqueous solution or is permeable to the drug in aqueous solution.
[0004]
4. Device according to claim 1, characterized in that the housing comprises at least one groove configured to allow a fluid to enter the reservoir in vivo and/or comprises at least one drug delivery orifice, which is in fluid communication with the reservoir.
[0005]
5. Device according to claim 1, characterized in that the housing comprises an elongated annular tube and the reservoir comprises the lumen of the annular tube.
[0006]
6. Device according to claim 5, characterized in that a drug release orifice is either provided in an end plug located at one end of the tube or on a side wall of the tube.
[0007]
7. Device according to claim 5, characterized in that the housing has no release hole and is configured to release the drug through a drug permeable wall that connects the reservoir.
[0008]
8. Device according to claim 7, characterized in that the drug permeable wall comprises a disc stabilized in the lumen of the tube at or near one end of the tube.
[0009]
9. Device according to claim 7, characterized in that the drug permeable wall is either part of a side wall of the tube or part of an end plug located at one end of the tube.
[0010]
10. Device according to any one of claims 1 to 9, characterized in that the drug is a drug of low solubility.
[0011]
11. Device according to claim 1, characterized in that the device is configured to release a therapeutically effective amount of the drug over a period of 2 days to 30 days.
[0012]
Device according to claim 1, characterized in that the housing comprises an elongate annular tube, the annular tube comprising a water-permeable wall portion and a water-impermeable wall portion.
[0013]
13. Device according to claim 7, characterized in that the first unit is located closer to the drug permeable wall than the second unit.
[0014]
14. Device according to claim 1 or 12, characterized in that the housing has a durometer from 25A to 80A.
[0015]
15. Device according to claim 1 or 12, characterized in that the housing comprises silicone, a thermoplastic polyurethane, ethylene-co-vinyl acetate (EVA), or a combination thereof.
[0016]
16. Device according to any one of claims 1 to 15, characterized in that the drug comprises lidocaine, gemcitabine, do-cetaxel, carboplatin, cisplatin, oxaliplatin, trospium, tolterodine, or mitomycin C.
[0017]
17. Device according to claim 1, characterized in that the drug comprises gemcitabine and the osmotic agent comprises urea.
[0018]
18. Device according to claim 17, characterized in that the first unit comprises at least 75 percent by weight of gemcitabine HCl and the second unit comprises at least 85 percent by weight of urea.
[0019]
Device according to any one of claims 1 to 18, characterized in that it comprises a plurality of first units and a plurality of second units.
[0020]
20. Device according to claim 1, characterized in that: the housing comprises an elongated water-permeable annular tube that has an internal diameter of 2 to 5 mm, the solid tablet of the first unit has a diameter equal to the diameter length of the elongated annular tube, the one or more solid tablets of the first unit filling a 1 cm to 3 cm length of the lumen of the annular tube, and the solid tablet of the second unit having a diameter equal to the internal diameter of the elongated annular tube , with the one or more solid tablets of the second unit filling a length of 10 cm to 15 cm of the lumen of the annular tube.
[0021]
21. Device according to claim 1 or 20, characterized in that a ratio of volume of the first unit to volume of the second unit is from 0.05 to 0.5.
[0022]
22. Device according to claim 1, characterized in that the device is configured to spontaneously assume a shape in the absence of a compressive load, whose shape comprises an interconnected and overlapping pair of coils.
[0023]
Device according to claim 21 or 22, characterized in that the housing additionally comprises a retaining frame lumen and a retaining frame positioned in the retaining frame lumen, wherein the retaining frame comprises superelastic alloy or other elastic yarn.
[0024]
24. Device according to claim 1, characterized in that: the housing is permeable to water, the first unit comprises a drug of low solubility, and the second unit comprises an osmotic agent that facilitates the release of the drug from the housing by osmotic pressure.
[0025]
25. Device according to claim 24, characterized in that the drug comprises gemcitabine and the osmotic agent comprises urea.
[0026]
26. Device according to claim 1, characterized in that the device is configured, following the positioning of the device on a patient, to allow water or urine to enter the reservoir and solubilize the first and second units.
[0027]
27. Device according to claim 1, characterized in that the osmotic agent is configured to accelerate drug solubilization.
[0028]
28. Device according to claim 1, characterized in that the device is configured to release the drug and osmotic agent from the housing.

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3089815A|1951-10-11|1963-05-14|Lieb Hans|Injectable pharmaceutical preparation, and a method of making same|

---

US3854480A|1969-04-01|1974-12-17|Alza Corp|Drug-delivery system|

---

US3948254A|1971-11-08|1976-04-06|Alza Corporation|Novel drug delivery device|

---

US4016251A|1972-08-17|1977-04-05|Alza Corporation|Vaginal drug dispensing device|

---

US3888975A|1972-12-27|1975-06-10|Alza Corp|Erodible intrauterine device|

---

US3901232A|1973-10-26|1975-08-26|Alza Corp|Integrated device for administering beneficial drug at programmed rate|

---

US3935860A|1974-08-21|1976-02-03|Alza Corporation|Intrauterine device with restrictor for maintaining device in uterine cavity|

---

US4111203A|1976-11-22|1978-09-05|Alza Corporation|Osmotic system with means for improving delivery kinetics of system|

---

US4210139A|1979-01-17|1980-07-01|Alza Corporation|Osmotic device with compartment for governing concentration of agent dispensed from device|

---

US4235236A|1979-02-12|1980-11-25|Alza Corporation|Device for dispensing drug by combined diffusional and osmotic operations|

---

US4392848A|1979-06-25|1983-07-12|The Procter & Gamble Company|Catheterization|

---

US4309996A|1980-04-28|1982-01-12|Alza Corporation|System with microporous releasing diffusor|

---

GB2079158B|1980-06-09|1985-01-09|Ahi Operations Ltd|Intra-vaginal devices|

---

US4326522A|1980-06-09|1982-04-27|Pitman-Moore, Inc.|Mesh-covered bolus|

---

US4475916A|1982-03-18|1984-10-09|Merck & Co., Inc.|Osmotic drug delivery system|

---

US5366738A|1982-07-29|1994-11-22|Merck & Co., Inc.|Controlled release drug dispersion delivery device|

---

US4629449A|1982-07-29|1986-12-16|Alza Corporation|Vaginal dispenser for dispensing beneficial hormone|

---

US4681583A|1982-12-20|1987-07-21|Alza Corporation|System for dispersing drug in biological environment|

---

US4578075A|1982-12-20|1986-03-25|Alza Corporation|Delivery system housing a plurality of delivery devices|

---

US4655219A|1983-07-22|1987-04-07|American Hospital Supply Corporation|Multicomponent flexible grasping device|

---

DE3332156A1|1983-09-06|1985-03-21|Peter 6000 Frankfurt Prezelj|Nose clip|

---

GB8328916D0|1983-10-28|1983-11-30|Castex Prod|Pharmaceutical pellet|

---

GB8403138D0|1984-02-07|1984-03-14|Graham N B|Sustained release of active ingredient|

---

NZ207341A|1984-03-01|1988-02-29|Harvey Alex Ind Ltd|Device containing chemical impregnants for insertion into a body cavity of an animal|

---

US4968507A|1984-06-20|1990-11-06|Merck & Co., Inc.|Controlled porosity osmotic pump|

---

CH667209A5|1985-07-02|1988-09-30|Sulzer Ag|MEDICAL DEPOT PROBE.|

---

US5008112A|1985-12-16|1991-04-16|International Minerals & Chem. Corporation|Device for the extended delivery of diffusible agents|

---

US4871542A|1987-04-30|1989-10-03|Ferring Service Center, N.V.|Method and apparatus useful for delivering medicinal compositions into the bladder and urinary tract|

---

US5340590A|1987-06-25|1994-08-23|Alza Corporation|Delivery system with bilayer osmotic engine|

---

US5057318A|1988-12-13|1991-10-15|Alza Corporation|Delivery system for beneficial agent over a broad range of rates|

---

US5545208A|1990-02-28|1996-08-13|Medtronic, Inc.|Intralumenal drug eluting prosthesis|

---

US5324280A|1990-04-02|1994-06-28|Alza Corporation|Osmotic dosage system for delivering a formulation comprising liquid carrier and drug|

---

WO1993006792A1|1991-10-04|1993-04-15|Scimed Life Systems, Inc.|Biodegradable drug delivery vascular stent|

---

ZA927779B|1991-10-10|1993-07-05|Alza Corp|Osmotic drug delivery devices with hydrophobic wall materials.|

---

US5441550A|1992-03-26|1995-08-15|The University Of Tennessee Research Corporation|Post-treatment of laminated nonwoven cellulosic fiber webs|

---

US5499997A|1992-04-10|1996-03-19|Sharpe Endosurgical Corporation|Endoscopic tenaculum surgical instrument|

---

ES2150427T3|1992-06-02|2000-12-01|Bard Inc C R|PROCEDURE AND DEVICE OF IMPLANT FOR THE SUPPLY OF LONG-TERM DRUGS.|

---

US5523092A|1993-04-14|1996-06-04|Emory University|Device for local drug delivery and methods for using the same|

---

US5516522A|1994-03-14|1996-05-14|Board Of Supervisors Of Louisiana State University|Biodegradable porous device for long-term drug delivery with constant rate release and method of making the same|

---

IL116433A|1994-12-19|2002-02-10|Galen Chemicals Ltd|INTRAVAGINAL DRUG DELIVERY DEVICES FOR THE ADMINISTRATION OF 17β-OESTRADIOL PRECURSORS|

---

GB9522403D0|1995-11-01|1996-01-03|Hoechst Roussel Ltd|Intravaginal drug delivery device|

---

IL125596A|1996-02-02|2004-07-25|Alza Corp|Sustained delivery of an active agent using an implantable system|

---

US6171298B1|1996-05-03|2001-01-09|Situs Corporation|Intravesical infuser|

---

US6183461B1|1998-03-11|2001-02-06|Situs Corporation|Method for delivering a medication|

---

GB9610862D0|1996-05-23|1996-07-31|Evans Brian K|Pharmaceutical products|

---

US20070161967A1|1996-06-04|2007-07-12|Vance Products Inc., Dba Cook Urological Inc.|Implantable medical device with pharmacologically active ingredient|

---

US5869081A|1996-06-28|1999-02-09|The Population Council|Progesterone vaginal ring for treatment of infertility|

---

US5797898A|1996-07-02|1998-08-25|Massachusetts Institute Of Technology|Microchip drug delivery devices|

---

US5972372A|1996-07-31|1999-10-26|The Population Council, Inc.|Intravaginal rings with insertable drug-containing core|

---

US6464999B1|1998-06-17|2002-10-15|Galt Incorporated|Bioadhesive medical devices|

---

US5868719A|1997-01-15|1999-02-09|Boston Scientific Corporation|Drug delivery balloon catheter device|

---

US6749617B1|1997-11-04|2004-06-15|Scimed Life Systems, Inc.|Catheter and implants for the delivery of therapeutic agents to tissues|

---

US5830230A|1997-03-07|1998-11-03|Micro Therapeutics, Inc.|Method of intracranial vascular embolotherapy using self anchoring coils|

---

GB2338414B|1997-04-03|2001-12-19|Point Biomedical Corp|Intravesical drug delivery system|

---

TW358031B|1997-04-11|1999-05-11|Akze Nobel N V|Drug delivery system for 2 or more active substances|

---

JP2001524124A|1997-05-07|2001-11-27|ガレン（ケミカルズ）リミティド|Vaginal drug delivery device for administration of testosterone and testosterone precursor|

---

WO1998053758A1|1997-05-28|1998-12-03|Dec International Nz Limited|Intra-vaginal device for pigs|

---

US6197327B1|1997-06-11|2001-03-06|Umd, Inc.|Device and method for treatment of dysmenorrhea|

---

US6039968A|1997-06-24|2000-03-21|Hoechst Marion Roussel|Intravaginal drug delivery device|

---

US6267761B1|1997-09-09|2001-07-31|Sherwood Services Ag|Apparatus and method for sealing and cutting tissue|

---

DE69838223T2|1997-10-10|2008-05-08|Bioniche Life Science, Inc., Belleville|ARRANGEMENT FOR MEDICATION INTRODUCTION|

---

PT1051217E|1997-12-31|2003-12-31|Alza Corp|OSMOTIC CONTROL SYSTEM FOR DRUG ADMINISTRATION|

---

US6482837B1|1998-04-24|2002-11-19|University Of Rochester|Antimuscarinic compounds and methods for treatment of bladder diseases|

---

US6159143A|1998-06-17|2000-12-12|Scimed Life Systems, Inc.|Method and device for delivery of therapeutic agents in conjunction with isotope seed placement|

---

US6168801B1|1998-09-09|2001-01-02|Cardiac Pacemakers, Inc.|Controlled release drug delivery|

---

WO2000040234A1|1999-01-06|2000-07-13|Richard Henry|Topical anesthesia of the urinary bladder|

---

US20050238733A1|2000-01-05|2005-10-27|Richard Henry|Topical anesthesia of the urinary bladder|

---

US6293923B1|1999-03-15|2001-09-25|Innoventions, Inc.|Intravesicular balloon|

---

US6083933A|1999-04-19|2000-07-04|Stellar International Inc.|Treatment of cystitis-like symptoms with chondroitin sulfate following administration of a challenge solution|

---

US7232421B1|2000-05-12|2007-06-19|C. R. Bard, Inc.|Agent delivery systems|

---

US6139535A|1999-05-27|2000-10-31|Situs Corporation|Method and apparatus for placement and activation of a medical device within a body cavity|

---

DE60041825D1|1999-11-17|2009-04-30|Boston Scient Ltd|MINIATURIZED DEVICES FOR DISPENSING MOLECULES IN A CARRIER FLUID|

---

CA2393603C|1999-12-10|2010-09-21|Massachusetts Institute Of Technology|Microchip devices for delivery of molecules and methods of fabrication thereof|

---

US6753011B2|2000-01-14|2004-06-22|Osmotica Corp|Combined diffusion/osmotic pumping drug delivery system|

---

US6379382B1|2000-03-13|2002-04-30|Jun Yang|Stent having cover with drug delivery capability|

---

US6988983B2|2000-04-14|2006-01-24|Solace Therapeutics, Inc.|Implantable self-inflating attenuation device|

---

US6682473B1|2000-04-14|2004-01-27|Solace Therapeutics, Inc.|Devices and methods for attenuation of pressure waves in the body|

---

US6730072B2|2000-05-30|2004-05-04|Massachusetts Institute Of Technology|Methods and devices for sealing microchip reservoir devices|

---

US6398718B1|2000-06-15|2002-06-04|Innoventions, Inc.|Intravesicular device|

---

GB0015617D0|2000-06-26|2000-08-16|Vectura Ltd|Improved preparations for dermal delivery of active substances|

---

WO2002005800A2|2000-07-17|2002-01-24|Guilford Pharmaceuticals, Inc.|Compositions for sustained release of analgesic agents, and methods of making and using the same|

---

AU2001286726B2|2000-08-24|2007-03-22|Sidney Lerner|Non-hormonal vaginal contraceptive|

---

US6752829B2|2001-01-30|2004-06-22|Scimed Life Systems, Inc.|Stent with channel for containing and delivering a biologically active material and method for manufacturing the same|

---

CA2442281C|2001-03-27|2010-06-08|Galen Limited|Intravaginal drug delivery devices for the administration of an antimicrobial agent|

---

US6632217B2|2001-04-19|2003-10-14|Microsolutions, Inc.|Implantable osmotic pump|

---

WO2002096389A1|2001-05-30|2002-12-05|Microchips, Inc.|Conformal coated microchip reservoir devices|

---

AU2002326304A1|2001-05-31|2002-12-16|Massachusetts Institute Of Technology|Microchip devices with improved reservoir opening|

---

US7438701B2|2001-07-26|2008-10-21|Durect Corporation|Local concentration management system|

---

US20030118649A1|2001-10-04|2003-06-26|Jinming Gao|Drug delivery devices and methods|

---

US7722894B2|2001-10-22|2010-05-25|Massachusetts Institute Of Technology|Biodegradable polymer|

---

US7005138B2|2001-12-21|2006-02-28|Duramed Pharmaceuticals, Inc.|Method of systematically delivering SSRIs|

---

US7473273B2|2002-01-22|2009-01-06|Medtronic Vascular, Inc.|Stent assembly with therapeutic agent exterior banding|

---

GB2385273B|2002-02-13|2004-05-26|Deborah Huang|Drug delivery device|

---

US6899890B2|2002-03-20|2005-05-31|Kv Pharmaceutical Company|Bioadhesive drug delivery system|

---

US8685427B2|2002-07-31|2014-04-01|Boston Scientific Scimed, Inc.|Controlled drug delivery|

---

DE10247689A1|2002-10-12|2004-04-22|Martin Rahe|Urinary bladder implants for prolonged prevention and treatment of urinary tract infections, comprising antimicrobial active agent, preferably silver, incorporated in carrier, preferably of shape memory material|

---

US7504387B2|2002-10-16|2009-03-17|Arthrodynamic Technologies, Animal Health Division, Inc.|Glycosaminoglycan composition and method for treatment and prevention of interstitial cystitis|

---

US20040260272A1|2002-10-22|2004-12-23|Friedman Craig D.|Method and system for intravesicular delivery of therapeutic agents|

---

WO2004058105A2|2002-12-16|2004-07-15|The Regents Of The University Of Michigan|Assembly and planar structure for use therein which is expandable into a 3-d structure such as a stent and device for making the planar structure|

---

DE60324194D1|2002-12-23|2008-11-27|Medtronic Inc|CATHETER WITH SEVERAL INFUSION SECTIONS AND RELATED METHODS|

---

US7207982B2|2003-03-31|2007-04-24|Alza Corporation|Osmotic pump with means for dissipating internal pressure|

---

US20050228482A1|2003-09-26|2005-10-13|William Herzog|Stent covered by a layer having a layer opening|

---

AU2005209322B2|2004-01-28|2011-05-19|The Regents Of The University Of California|Novel interstitial therapy for immediate symptom relief and chronic therapy in interstitial cystitis|

---

US20050234431A1|2004-02-10|2005-10-20|Williams Michael S|Intravascular delivery system for therapeutic agents|

---

US7647112B2|2004-02-11|2010-01-12|Ethicon, Inc.|System and method for selectively stimulating different body parts|

---

WO2005115245A1|2004-05-28|2005-12-08|Dynaventions Inc.|Intravesicular device|

---

WO2006079055A2|2005-01-24|2006-07-27|Neurosystec Corporation|Apparatus and method for delivering therapeutic and/or other agents to the inner ear and to other tissues|

---

JP2008536639A|2005-04-20|2008-09-11|クックインコーポレイテッド|Rapid introduction medical device|

---

US7862552B2|2005-05-09|2011-01-04|Boston Scientific Scimed, Inc.|Medical devices for treating urological and uterine conditions|

---

CA2618349C|2005-08-11|2016-05-31|Massachusetts Institute Of Technology|Intravesical drug delivery device and method|

---

US20070172507A1|2006-01-26|2007-07-26|Paul Zupkas|Transluminal drug delivery methods and devices|

---

US20070172508A1|2006-01-26|2007-07-26|Paul Zupkas|Transluminal drug delivery methods and devices|

---

WO2007109247A2|2006-03-20|2007-09-27|Duramed Pharmaceuticals, Inc.|Flexible, compressed intravaginal rings, methods of making and using the same, and apparatus for making the same|

---

EP3449873A1|2006-03-31|2019-03-06|Mati Therapeutics Inc.|Drug delivery structures and compositions for nasolacrimal system|

---

US7824383B2|2006-06-16|2010-11-02|Family Health International|Vaginal drug delivery system and method|

---

US20100076261A1|2006-09-28|2010-03-25|Medvision Inc.|Examination device|

---

US8093261B2|2006-10-24|2012-01-10|The Johns Hopkins University|Rapid release mini-tablets provide analgesia in laboratory animals|

---

CA2687281A1|2007-03-20|2008-09-25|Boston Scientific Limited|Urological medical devices for release of prostatically beneficial therapeutic agents|

---

WO2009003125A1|2007-06-26|2008-12-31|Warner Chilcott Company,Inc.|Intravaginal drug delivery devices for the delivery of macromolecules and water-soluble drugs|

---

WO2009029958A2|2007-08-30|2009-03-05|Sunstorm Research Corporation|Implantable delivery device|

---

PL2231254T3|2007-12-11|2014-10-31|Massachusetts Inst Technology|Implantable drug delivery device|

---

RU2011101459A|2008-06-16|2012-07-27|Аппиан Лабс, Ллк |COMPOSITION AND METHOD FOR PRODUCING EXEMPTION SYSTEMS FOR PERMANENT REMOVAL OF ACTIVE MEANS|

---

WO2010019507A2|2008-08-09|2010-02-18|Massachusetts Institute Of Technology|Implantable drug delivery device and methods of treating male genitourinary and surrounding tissues|

---

ES2838012T3|2009-03-12|2021-07-01|Delpor Inc|Implantable device for a long period of time of drugs|

---

BRPI1014320B1|2009-06-26|2020-04-14|Liris Biomedical Inc|drug dosage form, and implantable drug dispensing device|

---

US9017312B2|2009-09-10|2015-04-28|Taris Biomedical Llc|Implantable device for controlled drug delivery|

---

US8167836B2|2009-12-08|2012-05-01|Taris Biomedical, Inc.|Tissue expander configured for drug delivery|

---

PT2512581T|2009-12-17|2021-04-27|Taris Biomedical Inc|Implantable device with intravesical tolerability and methods of treatment|

---

US20110218488A1|2010-03-05|2011-09-08|Taris Biomedical, Inc.|Systems and Methods for Implanting Devices in the Bladder and Other Genitourinary Sites|

---

WO2012048114A1|2010-10-06|2012-04-12|Taris Biomedical, Inc.|Time-selective bioresorbable or collapsible drug delivery systems and methods|

---

JP2014503554A|2011-01-10|2014-02-13|タリスバイオメディカル，インコーポレイテッド|Lidocaine regimen for the use of continuous treatment of bladder pain and irritating urination|

---

CA2825399A1|2011-02-04|2012-08-09|Taris Biomedical, Inc.|Implantable device for controlled release of low solubility drug|

---

TWI615155B|2011-11-01|2018-02-21|拜耳股份有限公司|Osmotically active vaginal delivery system|

---

MX367070B|2012-08-31|2019-08-05|Taris Biomedical Llc|Drug delivery systems and methods for treatment of prostate disease comprising gemicitabine.|

---

EP2964310A1|2013-03-05|2016-01-13|TARIS Biomedical LLC|Drug delivery devices and methods for controlled drug release through device orifice|

---

BR112015022433A2|2013-03-15|2017-07-18|Taris Biomedical Llc|drug permeable drug delivery devices and methods|

---

WO2014144066A1|2013-03-15|2014-09-18|Taris Biomedical, Inc|Drug delivery devices and methods for drug delivery|

---

MX2016011333A|2014-03-06|2016-12-07|Taris Biomedical Llc|Drug delivery systems and methods for treatment of bladder cancer with gemcitabine.|MX367070B|2012-08-31|2019-08-05|Taris Biomedical Llc|Drug delivery systems and methods for treatment of prostate disease comprising gemicitabine.|

---

CN104640549B|2012-08-31|2018-09-07|塔里斯生物医药公司|Drug delivery system for treating carcinoma of urinary bladder and method|

---

EP2964310A1|2013-03-05|2016-01-13|TARIS Biomedical LLC|Drug delivery devices and methods for controlled drug release through device orifice|

---

WO2014144066A1|2013-03-15|2014-09-18|Taris Biomedical, Inc|Drug delivery devices and methods for drug delivery|

---

MX2016011333A|2014-03-06|2016-12-07|Taris Biomedical Llc|Drug delivery systems and methods for treatment of bladder cancer with gemcitabine.|

---

AU2015259361B2|2014-05-12|2020-11-05|Taris Biomedical Llc|Drug delivery devices and methods|

---

DK3160442T3|2014-06-26|2019-06-11|Taris Biomedical Llc|Devices and methods for intravesical drug delivery comprising drug polymer matrix systems|

---

ES2734394T3|2015-03-30|2019-12-05|Taris Biomedical Llc|Devices for local administration of drugs to the upper urinary tract|

---

EP3285850A1|2015-04-23|2018-02-28|TARIS Biomedical LLC|Drug delivery devices with drug-permeable component and methods|

---

CN105056376A|2015-08-21|2015-11-18|崔尚品|Medical instrument for treating cervicitis and cervix HPV infection|

---

WO2017151983A1|2016-03-02|2017-09-08|Taris Biomedical Llc|Osmotic drug delivery devices and methods of making osmotic drug delivery devices|

---

LT3432970T|2017-02-01|2021-05-10|Taris Biomedical Llc|In vivo drug delivery devices|

---

EP3658153A4|2017-07-25|2021-04-21|TARIS Biomedical LLC|Methods of treating tumor metastasis|

---

CA3081839A1|2017-11-08|2019-05-16|Taris Biomedical Llc|Methods of treatment and maintenance therapy for bladder cancer using gemcitabine|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-04-24| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO POR NAO SE ENQUADRAR NO ART. 229-C DA LPI. |

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2020-03-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-11-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2022-01-25| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/08/2014, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201361867245P| true| 2013-08-19|2013-08-19|

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US61/867,245|2013-08-19|

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US201361877610P| true| 2013-09-13|2013-09-13|

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US61/877,610|2013-09-13|

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PCT/US2014/051672|WO2015026813A1|2013-08-19|2014-08-19|Multi-unit drug delivery devices and methods|

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