Patent Application
20150360012
This disclosure is generally in the field of implantable medical devices and methods, including but not limited to drug delivery devices deployable within the urinary bladder.
Targeted delivery of drug to the local or regional tissue sites where the drug is needed continues to have room for improvement in a variety of diseases and conditions in humans and other mammals. This is particularly true for tissue sites that are not readily accessible to the physician, where controlled release of drug is needed over an extended period, where a sufficient amount of drug can be stored on-board an implantable device having a relatively small volume, and/or where device is deployable with minimally invasive systems and methods and provides minimal patient discomfort. The devices should be relatively simple in their construction and operation, to provide a robust device, reliable drug delivery, and cost effective device construction and assembly.
Implantable medical devices are described in patent application publications US 2010/0331770, US 2011/0152839, US 2012/0089122, and US 2012/0203203, which are incorporated herein by reference. Some of the devices described have one or more apertures, or orifices, through which drug is released from the device. It would be desirable to have alternative and/or improved devices and methods that use release orifices in the course of providing controlled release of drug in vivo. For example, it would be desirable to reduce or avoid the manufacturing cost associated with laser drilling microscale orifices in silicone tubing.
In some drug delivery devices that rely on diffusion, osmosis or a combination thereof, it may be difficult for the device to dispense the entire drug from the reservoir. This problem may be magnified where the drug, such as some anti-cancer drugs, are extremely expensive to produce. Accordingly, it would be desirable to make sure that all or most of the drug provided in the device actually is released from the device during a treatment period.
In one aspect, a drug delivery device is provided which includes a device body that includes an elongated drug reservoir lumen and a retention frame lumen; a drug positioned in the drug reservoir lumen; a retention frame positioned at least partly in the retention frame lumen; and at least one end plug positioned at an end of the device body. The retention frame is or includes an elastic wire, and the end plug includes a cavity configured to receive an end portion of the elastic wire. The end plug optionally may include an aperture extending therethrough.
In another aspect, a drug delivery device is provided for insertion into the bladder of a patient. The device includes a device body that includes an elongated drug reservoir lumen; a drug positioned in the drug reservoir lumen; and at least one polymeric end plug positioned at an end of the device body. The end plug includes an aperture therethough, and the device is configured to release the drug from the drug reservoir lumen through the aperture.
In still another aspect, a drug delivery device is provided that includes a device body comprising an elongated drug reservoir lumen; a drug positioned in the drug reservoir lumen; and at least one end plug positioned at an end of the device body, the end plug comprising an aperture therethough, wherein the aperture is defined by a bioerodible material configured to degrade in vivo such that the opening of the aperture effective for drug release increases as drug is released. For example, the aperture has a cross-sectional open area (perpendicular to the direction of flow through the aperture) that enlarges over the course of drug release. In addition or in the alternative, the length of the aperture (in the direction of flow through the aperture) may decrease over the course of drug release.
The devices, systems, and methods disclosed herein build upon those described in the following patent application publications: US 2012/0203203 (Lee et al.); US 2012/0089122 (Lee et al.); US 2012/0089121 (Lee et al.); US 2011/0218488 (Boyko et al.); US 2011/0202036 (Boyko et al.); US 2011/0152839 (Cima et al.); US 2011/0060309 (Lee et al.); US 2010/0331770 (Lee et al.); US 2010/0330149 (Daniel et al.); US 2010/0003297 (Tobias et al.); US 2009/0149833 (Cima et al.); and US 2007/0202151 (Lee et al.), which are incorporated by reference herein. The improvements and developments are described below and illustrated in the attached figures.
An embodiment of a drug delivery device 100 is illustrated in
For the purposes of this disclosure, terms such as “relatively expanded shape,” “relatively higher-profile shape,” or “retention shape” generally denote any shape suited for retaining the device in the intended insertion location, including but not limited to the pretzel shape shown in
In the illustrated embodiment, the drug reservoir and retention frame portions 102, 104 of the drug delivery device 100 are longitudinally aligned and are coupled to each other along their length, although other configurations are possible. For example, the drug reservoir portion 102 may be attached to the retention frame portion 104 at discrete points but otherwise may be separate or spaced apart from the retention frame portion 104.
The drug delivery device 100 includes an elastic or flexible device body 106 that defines a drug reservoir lumen 108 and a retention frame lumen 110. The drug reservoir lumen 108 is designed to house a drug formulation, such as a number of solid drug units 112, to form the drug reservoir portion 102. The retention frame lumen 110 is designed to house a retention frame 114 to form the retention frame portion 104. The illustrated lumens 108, 110 are discrete from each other, although other configurations are possible.
As shown in the cross-sectional view of
As shown in
Once the drug units 112 are loaded, end plugs 120 block the entry 130 and exit 132. The end plugs 120 may be cylindrical plugs inserted into the entry 130 and the exit 132. In some instances, each of the end plugs 120 may have a slightly larger outer diameter than an inner diameter of the drug reservoir lumen 108 so that the plugs substantially enclose the entry 130 and exit 132 and are snugly retained in position. In other instances, the end plugs 120 may have an outer diameter that is the same as or slightly smaller than an inner diameter of the drug reservoir lumen 108. Such a configuration may provide tolerances for the end plugs 120 to swell. For example, the end plugs 120 may swell in vivo when in contact with bodily fluid, such as urine in the bladder. In other instances, the end plugs 120 may be secured within the drug reservoir lumen 108 by an adhesive. In still other instances, the end plugs 120 may be secured within the drug reservoir lumen 108 by an external clamp disposed about the drug reservoir lumen 108. The end plugs 120 may be secured within the drug reservoir lumen 108 by any means disclosed herein or a combination thereof.
One or both of the end plugs 120 includes an aperture 118 to provide a passageway for releasing drug (from the drug units) from the drug reservoir lumen 108 as discussed in greater detail below. In some instances, the dimensions of the aperture in the end plugs 120, such as the diameter or length, may change during the use of the drug delivery device 100. For example, the diameter of the aperture in the end plugs 120 may increase over time, or the length of the aperture may decrease over time, for example due to dissolution or bioerosion of the material defining the aperture.
In certain embodiments, each of the end plugs 120 may include a cavity for receiving an end portion of the retention frame 114 as discussed in greater detail below. In some cases, a number of end plugs 120 can be positioned in the entry 130 or the exit 132. The end plugs 120 may be silicone plugs. In embodiments where one of the end plugs 120 is omitted, the entry 130 or exit 132 without the end plug 120 may be closed with any other suitable biocompatible material. In one example, the material is an adhesive substance that is placed in the drug reservoir lumen 108 in workable form and cures therein.
The retention frame lumen 110 is loaded with the retention frame 114, which may be an elastic wire. The retention frame 110 may be configured to spontaneously return to a retention shape, such as the illustrated example “pretzel” shape or another coiled shape, such as those disclosed in the patent publications described above. In particular, the retention frame 114 may serve to retain the device 100 in the body of a patient, such as in the bladder. For example, the retention frame 114 may have an elastic limit and modulus that allows the device 100 to be introduced into the body in a relatively lower-profile shape, permits the device 100 to return the relatively expanded shape once inside the body, and impedes the device from assuming the relatively lower-profile shape within the body in response to expected forces, such as the hydrodynamic forces associated with contraction of the detrusor muscle and urination. Thus, the device 100 may be retained in the body once inserted, limiting or prevent accidental expulsion.
The material used to form the device body 106 may be elastic or flexible to permit moving the device 100 between deployment and retention shapes. When the device is in the retention shape, the retention frame portion 104 may tend to lie inside the drug reservoir portion 102 as shown, although the retention frame portion 104 can be positioned inside, outside, above, or below the drug reservoir portion 102 in other cases. The material used to form the device body 106 also may be water permeable or porous so that solubilizing fluid (e.g., urine or other bodily fluid) can enter the drug reservoir portion 102 to solubilize the drug units 112 once the device is inserted. For example, silicone or another biocompatible elastomeric material may be used.
In one embodiment, in which the drug delivery device 100 is designed to be inserted in the bladder, the drug delivery device 100 is designed to be inserted into (and optionally retrieved from) the bladder through the urethra cystoscopically. Thus, the device may be sized and shaped to fit through a narrow tubular path of a deployment instrument, such as a catheter or cystoscope.
The exact configuration and shape of the intravesical drug delivery device may be selected depending upon a variety of factors including the specific site of deployment/insertion, route of insertion, drug, dosage regimen, and therapeutic application of the device. The design of the device may minimize the patient's pain and discomfort, while locally delivering a therapeutically effective dose of the drug to a tissue site (e.g., urothelial tissue) in a patient.
The Drug Reservoir Portion
In one embodiment, the drug reservoir portion of the device includes an elongated tube. An interior of the tube may define one or more drug reservoirs, and a drug formulation may be housed in the drug reservoir(s). In another embodiment, the drug reservoir portion is in a form other than a tube.
The release rate of the drug from the drug reservoir portion generally is controlled by the design of the combination of the device components, including but not limited to the materials, dimensions, surface area, and one or more apertures of the drug reservoir portion and/or the end plugs, as well as the particular drug formulation and total mass of drug load, among others.
An example of such a drug reservoir portion is shown in
In one embodiment, the drug reservoir portion operates as an osmotic pump. In such embodiments, the tube may be formed from a water permeable material, such as a silicone, or tube may have a porous structure, or both. Following insertion of the device into the patient, water or urine permeates through the wall of the tube, one or more apertures formed through the end plug and/or the tube wall, or one or more passing pores formed through a porous tube. The water enters the reservoir, and is imbibed by the drug formulation. In some instances, solubilized drug is dispensed at a controlled rate out of the reservoir through the one or more apertures associated with the end plugs, driven by osmotic pressure in the reservoir. The delivery rate and overall performance of the osmotic pump is affected by device parameters, such as the surface area of the tube; the permeability to liquid of the material used to form the tube; the shape, size, number and placement of the apertures in the end plugs; and the drug formulation dissolution profile, among other factors. In some embodiments, the device may initially exhibit a zero-order release rate and subsequently may exhibit a reduced, non-zero-order release rate, in which case the overall drug release profile may be determined by the initial zero-order release rate and the total payload. Representative examples of osmotic pump designs, and equations for selecting such designs, are described in U.S. Patent Publication No. 2009/0149833.
In an alternative embodiment, the device may operate essentially by diffusion of the drug from the tube through the one or more discrete apertures or passing pores formed in the end plugs. In one embodiment, the drug diffuses only through one or more apertures in the end plug(s). In another embodiment, the drug diffuses both through one or more apertures in the end plug(s) and also through the sidewall of the tube defining the drug reservoir, or through an aperture defined in the sidewall.
In still other embodiments, the device may operate by a combination of osmosis and diffusion. For example, where release of a first portion of the drug is predominantly or exclusively driven by osmotic pressure, and release of a second portion of the drug is predominantly or exclusively driven by diffusion.
The drug reservoir portion may be formed from an elastomeric material, which may permit elastically deforming the device for its insertion into a patient, e.g., during its deployment through deployment instrument such as a cystoscope or catheter. For example, the tube may be elastically deformed along with the retention frame for intravesical insertion, as described in further detail below.
In a preferred embodiment, the drug reservoir portion is formed from a material that is both elastomeric and water permeable. One material that is both elastomeric and water permeable is silicone, although other biocompatible materials may be used.
The length, diameter, and thickness of the tube may be selected based on the volume of drug formulation to be contained, the desired rate of delivery of the drug from the tube, the intended site of insertion of the device within the body, the desired mechanical integrity for the device, the desired release rate or permeability to water and urine, the desired induction time before onset of initial release, and the desired method or route of insertion into the body, among others. The tube wall thickness may 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.
In one embodiment, the device body is non-resorbable. It may be formed of medical grade silicone tubing, as known in the art. Other suitable non-resorbable materials may be used. In some embodiments, the device body is bioerodible. In one embodiment of a bioerodible device, the tube of the body is formed of a biodegradable or bioresorbable polymer. Any suitable polymers may be used.
The tube of a drug reservoir portion tube may be substantially linear and in some cases may be substantially cylindrical with a circular cross-section, although polygonal cross-sectional shapes can be used, among others.
In one embodiment, the tube has multiple reservoirs. Each reservoir may be defined by a portion of the tube inner surface and at least one partition structure inserted into the tube. The partition structure may have a larger cross-section than the tube, securing the partition structure in place and segregating adjacent reservoirs. The partition may be non-porous or semi-porous, non-resorbable or resorbable and may be formed of a material described herein with reference to the end plug 120. The partition also may be formed in the tube, such as by molding. For example, one or more webs may extend through the tube along its length to segregate axial reservoirs that extend along the length of the tube. The partition also may be a structure that joins two different tubes that serve as separate reservoirs.
The multiple reservoirs permit segregating two or more different drug formulations in different reservoirs, delivering a single drug from different reservoirs at different rates or times following insertion, or combinations thereof. For example, two different reservoirs may have different configurations, such as different materials, different permeabilities, different numbers or placements of apertures (or the absence of apertures), different timing membranes in the apertures, among others or combinations thereof. The two different reservoirs also may house the same or different drug formulations in the same or different forms (such as liquid, semi-solid, and solid), or combinations thereof. The two different reservoirs further may be configured to release drug via different release mechanisms, such as via osmosis through an aperture and by diffusion through a drug reservoir wall that may lack an aperture completely. Coatings or sheaths also may be provided along different portions of a single drug reservoir or along different drug reservoirs housing the same or different drug formulations. These embodiments can be combined and varied to achieve the desired release profile of the desired drug.
For example, the onset of release of two doses in different reservoirs can be staged by configuring the device accordingly, such as by using different materials for portions of the tube defining different reservoirs, by associating the aperture(s) of different reservoirs with different timing membranes, by placing drugs with different solubilities in the reservoirs, or by placing drugs with different forms in the reservoirs, such as a liquid form for immediate release and a solid form to be solubilized prior to release. Thus, the device may release some drug relatively quickly after insertion while other drug may experience an induction time before beginning release.
In one embodiment, the total volume of the reservoir (or combined reservoirs) is sufficient to contain all of the drug needed for local delivery over the course of a single treatment, reducing the number of procedures needed to treat a particular condition.
The term “drug” as used herein encompasses any suitable pharmaceutically active ingredient. The drug may be small molecule, macromolecule, biologic, or metabolite, among other forms/types of active ingredients. The drug described herein includes its alternative forms, such as salt forms, free acid forms, free base forms, and hydrates. The drug may be formulated with one or more pharmaceutically acceptable excipients known in the art. Non-limiting examples of the drug include gemcitabine, oxaliplatin, and/or another chemotherapeutic agent; trospium and/or another antimuscarinic agent; and/or lidocaine and/or another anesthetic agent. In one embodiment, the first compartment may be loaded with two or more types of drug tablets (e.g., different drugs), so that a combination of drugs may be delivered.
In embodiments, the drug is one used to treat pain. A variety of anesthetic agents, analgesic agents, and combinations thereof may be used. In one embodiment, the drug is an anesthetic agent. The anesthetic agent may be a cocaine analogue. The anesthetic agent may be an aminoamide, an aminoester, or combinations thereof. Representative examples of aminoamides or amide-class anesthetics include articaine, bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocalne, ropivacaine, and trimecaine. Representative examples of aminoesters or ester-class anesthetics include amylocalne, benzocaine, butacaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine, hexylcaine, larocaine, meprylcaine, metabutoxycaine, orthocaine, piperocaine, procaine, proparacaine, propoxycaine, proxymetacaine, risocaine, and tetracaine. The drug also can be an antimuscarinic compound that exhibits an anesthetic effect, such as oxybutynin or propiverine. In embodiments, the analgesic agent includes an opioid. Representative examples of opioid agonists include alfentanil, allylprodine, alphaprodine, anileridine, benzyl morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, di methylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. Other opioid drugs, such as mu, kappa, delta, and nociception opioid receptor agonists, are contemplated. Representative examples of other suitable pain relieving agents include such agents as salicyl alcohol, phenazopyridine hydrochloride, acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen; indomethacin, naproxen.
In certain embodiments, the drug is one used to treat inflammatory conditions such as interstitial cystitis, radiation cystitis, painful bladder syndrome, prostatitis, urethritis, post-surgical pain, and kidney stones. Non-limiting examples of drugs for these conditions include lidocaine, glycosaminoglycans (e.g., chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, or a combination thereof. Other non-limiting examples of drugs that may be used in the treatment of IC include nerve growth factor monoclonal antibody (MAB) antagonists, such as Tanezumab, and calcium channel alpha-2-delta modulators, such as PD-299685 or gabepentin.
In certain embodiments, the drug is one used to treat urinary incontinence, frequency, or urgency, including urge incontinence and neurogenic incontinence, as well as trigonitis. Drugs that may be used include anticholinergic agents, antispasmodic agents, anti-muscarinic 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 suitable drugs for the treatment of incontinence include oxybutynin, S-oxybutylin, emepronium, verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine, clenbuterol, darifenacin, terodiline, trospium, hyoscyamin, propiverine, desmopressin, vamicamide, clidinium bromide, dicyclomine HCl, glycopyrrolate aminoalcohol ester, 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), Z D-6169 (Zeneca Co., United Kingdom), and stilonium iodide.
In certain embodiments, the drug is one used to treat urinary tract cancer, such as bladder cancer and prostate cancer. Drugs that may be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or a combination thereof. Representative examples of drugs which may be suitable for the treatment of urinary tract cancer include Bacillus Calmette Guerin (BCG) vaccine, cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall-DNA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin, fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide, a selective estrogen receptor modulators (i.e. a SERM, such as tamoxifen), botulinum toxins, and cyclophosphamide. The drug may be a biologic, and it may comprise a monoclonal antibody, a TNF inhibitor, an anti-leukin, or the like. The drug also may be an immunomodulator, such as a TLR agonist, including imiquimod or another TLR7 agonist. The drug also may 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 mitogen-activated protein kinase (MAPK) inhibitor, among others or combinations thereof. Other examples include celecoxib, erolotinib, gefitinib, paclitaxel, polyphenon E, valrubicin, neocarzinostatin, apaziquone, Belinostat, Ingenol mebutate, Urocidin (MCC), Proxinium (VB 4845), BC 819 (BioCancell Therapeutics), Keyhole limpet haemocyanin, LOR 2040 (Lorus Therapeutics), urocanic acid, OGX 427 (OncoGenex), and SCH 721015 (Schering-Plough). Other intravesical cancer treatments include small molecules, such as Apaziquone, adriamycin, AD-32, doxorubicin, doxetaxel, epirubicin, gemcitabine, HTI-286 (hemiasterlin analogue), idarubicin, γ-linolenic acid, mitozantrone, meglumine, and thiotepa; large molecules, such as Activated macrophages, activated T cells, EGF-dextran, HPC-doxorubicin, IL-12, IFN-α2b, IFN-γ, α-lactalbumin, p53 adenovector, TNFα; combinations, such as Epirubicin+BCG, IFN+farmarubicin, Doxorubicin+5-FU (oral), BCG+IFN, and Pertussis toxin+cystectomy; activated cells, such as macrophages and T cells; intravesical infusions such as IL-2 and Doxorubicin; chemosensitizers, such as BCG+antifirinolytics (paramethylbenzoic acid or aminocaproic acid) and Doxorubicin+verapimil; diagnostic/imaging agents, such as Hexylaminolevulinate, 5-aminolevulinic acid, Iododexyuridine, HMFG1 Mab+Tc99m; and agents for the management of local toxicity, such as Formaline (hemorrhagic cystitis).
In certain embodiments, the drug is one used to treat infections involving the bladder, the prostate, and the urethra. Antibiotics, antibacterial, antifungal, antiprotozoal, antiseptic, antiviral and other antiinfective agents can be administered for treatment of such infections. Representative examples of drugs for the treatment of infections include mitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, sulfonamides trimethoprimsulfamethoxazole, erythromycin, doxycycline, metronidazole, tetracycline, kanamycin, penicillins, cephalosporins, and aminoglycosides.
In certain embodiments, the drug is one 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.
In certain embodiments, the drug is one used to treat neurogenic bladder. Representative examples of such drugs include analgesics or anaesthetics, such as lidocaine, bupivacaine, mepivacaine, prilocalne, articaine, and ropivacaine; anticholinergics; antimuscarinics such as oxybutynin or propiverine; a vanilloid, such as capsaicin or resiniferatoxin; antimuscarinics such as ones that act on the M3 muscarinic acetylcholine receptor (mAChRs); antispasmodics including GABAB agonists such as baclofen; botulinum toxins; capsaicins; α-adrenergic antagonists; anticonvulsants; serotonin reuptake inhibitors such as amitriptyline; and nerve growth factor antagonists. In various embodiments, the drug may be one that acts on bladder afferents or one that acts on the efferent cholinergic transmission, as described in Reitz et al., Spinal Cord 42:267-72 (2004).
In certain embodiments, the drug is one used to treat incontinence due to neurologic detrusor overactivity and/or low compliant detrusor. Examples of these types of drugs include bladder relaxant drugs (e.g., oxybutynin (antimuscarinic agent with a pronounced muscle relaxant activity and local anesthetic activity), propiverine, impratroprium, tiotropium, trospium, terodiline, tolterodine, propantheline, oxyphencyclimine, flavoxate, and tricyclic antidepressants; drugs for blocking nerves innervating the bladder and urethra (e.g., vanilloids (capsaicin, resiniferatoxin), botulinum-A toxin); or drugs that modulate detrusor contraction strength, micturition reflex, detrusor sphincter dyssynergia (e.g., GABAb agonists (baclofen), benzodiazapines). In another embodiment, the drug is selected from those known for the treatment of incontinence due to neurologic sphincter deficiency. Examples of these drugs include α-adrenergic agonists, estrogens, β-adrenergic agonists, tricyclic antidepressants (imipramine, amitriptyline). In still another embodiment, the drug is selected from those known for facilitating bladder emptying (e.g., α-adrenergic antagonists (phentolamitie) or cholinergics). In yet another embodiment, the drug is selected from among anticholinergic drugs (e.g., dicyclomine), calcium channel blockers (e.g., verapamil) tropane alkaloids (e.g., atropine, scopolamine), nociceptin/orphanin FQ, and bethanechol (e.g., M3 muscarinic agonist, choline ester).
End Plugs
The end plugs, or plug components, may have any shape suited to wholly or partially plug or close the tube end, such as a cylinder 120 as shown in
In a preferred embodiment, the drug units 112 are disposed flush with the end plugs 120. That is, at least one of the drug units is immediately adjacent to the interior end of the end plug. This may advantageously minimize the lag time before drug release begins following insertion into the patient. In an alternative embodiment, the drug units 112 are spaced apart from the end plugs 120. Similarly, the drug units 112 may be disposed flush with other drug units 112 or spaced apart from other drug units 112. The less space between the drug units 112 and/or the end plugs 120 reduces lag time before drug release begins.
The end plug may be formed from biocompatible material, including a metal such as stainless steel, a polymer such as silicone, a ceramic, sapphire, or adhesive, among others or combinations thereof. The material may be biodegradable or bioerodible. In a preferred embodiment, the plug is formed of a relatively stiff thermoplastic polymer, such as polyethylene.
As depicted in
In another embodiment, the end plugs 120 may be secured within the drug reservoir lumen 108 mechanically. That is, in one embodiment, the end plugs 120 may be secured within the drug reservoir lumen 108 by an external clamp 408 disposed about the tube 122. For example, the end plugs 120 may be positioned within the end portions of the drug reservoir lumen 108, such as entry 130 and/or exit 132, and a clamping means, such as clamp 408, may be disposed about the tube 122. In one embodiment, the clamp is a heat-shrunk polymeric tube or sheath. In this manner, the clamp 408 may be configured to apply a clamping force about a portion of the drug reservoir lumen 108 such that the end plugs 120 within the entry 130 and/or exit 132 of the drug reservoir lumen 108 are secured in place. Although various example embodiments have been described for securing the end plugs 120 in place, the end plugs 120 may be secured via any means, such as press fitting, adhesive, mechanically, a combination thereof, or the like.
In certain embodiments, each of the end plugs 120 may include an aperture 118 therethrough to provide a passageway for releasing solubilized drug from the drug reservoir lumen 108. The aperture 118 may extend through a center portion of the end plugs 120, or the aperture 118 may extend through any portion of the end plugs 120. That is, the aperture 118 may be off-center. Moreover, the aperture 118 may extend through the end plugs 120 parallel to a center line of the end plugs 120 or at an angle offset therefrom. In some instances, a number of apertures 118 may be used. That is, two or more apertures 118 may extend through the end plugs 120. In other instances, only one of the end plugs 120 may include an aperture 118. The aperture 118 may be formed using any manufacturing techniques, including drilling, laser ablation, punch, molding, or the like. In some instances, the aperture 118 may include a constant diameter along its length. In other instances, the aperture 118 may include varying diameter along its length, such as an hour glass shape or the like. The aperture 118 may be circular, although other shapes are possible and envisioned, with the shape typically depending on manufacturing considerations. The aperture 118 may slightly taper from an exterior to an interior of the tube, and the aperture 118 may be created either before or after the drug is loaded into the tube 122. In some instances, the aperture 118 may include a diameter ranging from about 200 μm to about 1200 μm, although other diameters are possible and envisioned. In other instances, the aperture 118 may include a length ranging from about 5 mm to about 15 mm, although other lengths are possible and envisioned.
In some embodiments, the aperture 118 associated with the end plugs 120 is the only passageway for releasing drug from the drug reservoir lumen 108. However, in another embodiment, the device may include both an aperture 118 associated with one or each of the end plugs 120 and an aperture through a sidewall of the elastomeric tube defining the drug reservoir lumen 108.
In a particular embodiment, as depicted in
In some embodiments, the distal portion 504 of the end plugs 120 also includes a cavity, such as lumen 508, for receiving an end portion of the retention frame 114. In this manner, the lumen 508 encompass the end portion of the retention frame 114 to secure the end portion of the retention frame 114 within the lumen 508 and thereby shielding the pointed tip end of the retention frame 114 and thereby preventing or limiting its ability to damage tissue in vivo or damage the drug reservoir lumen. For example, when the proximal portion 502 of the end plug 120 is inserted into the end portion of the tube 122, as indicated by arrow A, the lumen 508 may abut with the end portion of the retention frame lumen 110 to form a continuous lumen for housing the retention frame 114 therein.
With this embodiment, a metal retention frame wire, such as a nitinol wire, advantageously can be provided without a plasma ball on the end (which is used to provide a blunt end for further lowering the risk of having the wire end puncture tissue or the device) and consequently enables one to temporarily insert a thin, straight tube into the retention frame lumen (and over the retention frame wire) to keep the drug reservoir lumen straight during the process of filling the drug reservoir lumen with drug units.
In some instances, the ends of the distal portion 504 may be rounded or bullet nosed. That is, the ends of the distal portion 504 may be smooth or devoid of edges that may damage tissue. Such configurations may also advantageously facilitate ease of insertion of the device through a deployment instrument and into the bladder or other body lumen of the patient. In
As depicted in
For example, the aperture 618 in the end plugs 600 may increase over time as indicated by the dashed lines and corresponding arrows. In some instances, as depicted in
The dynamic aspects of the aperture 618 may facilitate the controlled release of drug from the drug reservoir lumen 108. For example, the end plugs 600 may be erodible, and the release of the drug formulation may be controlled at least in part by the degradation or erosion of the end plugs 600. In some instances, the end plugs 600 partially or wholly degrades over the life of the device. In one instance, the end plugs erode uniformly, such as a straight channel. In another instance, the end plugs erode in an irregular shape, such as open cell foam. The change in the aperture 618 may be gradual or abrupt. In one embodiment, the end plugs 600 includes a degradable polymer, such as poly (D, L-lactic-co-glycolic acid (PLGA) or poly(d,L-lactic acid). The change in the aperture 618 dimensions may be affected by both inner and/or outer pH levels, such as the pH levels within and/or outside of the drug reservoir lumen 108.
Various changing-orifice embodiments of end plugs (also herein called orifice components or degradable components) are illustrated in
In one embodiment, drug release may be facilitated by a combination of osmosis and diffusion. In this manner, in certain embodiments, as the diameter of the aperture becomes larger, diffusion may become the predominant or sole driving mechanism of drug release.
The Retention Frame Portion
The drug delivery device may include a retention frame portion. The retention frame portion is associated with the drug reservoir portion and permits retaining the drug reservoir portion in the body, such as in the bladder. The retention frame portion may include a retention frame that is deformable between a relatively expanded shape and a relatively lower-profile shape. For example, the retention frame may naturally assume the relatively expanded shape, may be manipulated into the relatively lower-profile shape for insertion into the body, and may spontaneously return to the relatively expanded shape upon insertion into the body. The retention frame in the relatively expanded shape is shaped for retention in a body cavity, and the retention frame in the relatively lower-profile shape is shaped for insertion into the body through the working channel of a deployment instrument such as a catheter or cystoscope. To achieve such a result, the retention frame may have an elastic limit, modulus, and/or spring constant selected to impede the device from assuming the relatively lower-profile shape once inserted. Such a configuration may limit or prevent accidental expulsion of the device from the body under expected forces. For example, the device may be retained in the bladder during urination or contraction of the detrusor muscle.
In embodiments, the retention frame includes or consists of an elastic wire. In one embodiment, the elastic wire is formed of a relatively low modulus elastomer, which may be relatively less likely to irritate or cause ulcer within the bladder or other insertion site and may be biodegradable so that the device need not be removed. In another embodiment, the elastic wire is formed of a superelastic alloy, such as nitinol.
In the embodiment shown in
In some embodiments, the retention frame lumen 110 may include the retention frame 114 and a filling material, such as a polymer filling. An example filling material is a silicone adhesive, such as MED3-4213 by Nusil Technology LLC, although other filling materials may be used. The filling material may fill the void in the retention frame lumen 110 about the retention frame 114. For example, the filling material may be poured into the retention frame lumen 110 about the retention frame 114 and may cure therein. The filling material may reduce the tendency of the drug reservoir lumen 108 to stretch along, or twist or rotate about, the retention frame 114, while maintaining the drug reservoir lumen 108 in a selected orientation with reference to the retention frame 114. The filling material is not necessary, however, and may be omitted.
When the retention frame is in the relatively expanded shape, such as the coiled shapes shown in
A retention frame that assumes a pretzel shape may be relatively resistant to compressive forces. The pretzel shape essentially comprises two sub-circles, each having its own smaller arch and sharing a common larger arch. When the pretzel shape is first compressed, the larger arch absorbs the majority of the compressive force and begins deforming, but with continued compression the smaller arches overlap, and subsequently, all three of the arches resist the compressive force. The resistance to compression of the device as a whole increases once the two sub-circles overlap, impeding collapse and voiding of the device as the bladder contracts during urination.
In embodiments in which the retention frame comprises a shape-memory material, the material used to form the frame may “memorize” and spontaneously assume the relatively expanded shape upon the application of heat to the device, such as when exposed to body temperatures upon entering the bladder.
The retention frame may be in a form having a high enough spring constant to retain the device within a body cavity, such as the bladder. A high modulus material or a low modulus material may be used. Especially when a low-modulus material is used, the retention frame may have a diameter and/or shape that provides a spring constant without which the frame would significantly deform under the forces of urination. For example, the retention frame may include one or more windings, coils, spirals, or combinations thereof, specifically designed to achieve a desirable spring constant, such as in the range of about 3 N/m to about 60 N/m, or more particularly, in the range of about 3.6 N/m to about 3.8 N/m. Such a spring constant may be achieved with one or more of the following techniques: increasing the diameter of the elastic wire used to form the frame, increasing the curvature of one or more windings of the elastic wire, and adding additional windings to the elastic wire. The windings, coils, or spirals of the frame may have a number of configurations. For example, the frame may be in a curl configuration comprising one or more loops, curls or sub-circles. The ends of the elastic wire may be adapted to avoid tissue irritation and scarring, such as by being soft, blunt, inwardly directed, joined together, or a combination thereof.
The retention frame may have a two-dimensional structure that is confined to a plane, a three-dimensional structure, such as a structure that occupies the interior of a spheroid, or some combination thereof. Examples of alternative configurations are described in the U.S. patent applications incorporated by reference herein.
In embodiments, the device is inserted in a patient's body cavity or lumen and subsequently releases one or more drugs for the treatment of one or more conditions. The drug is released locally to one or more tissues at the deployment site and/or regionally to other tissues distal from the deployment site. The release may be controlled over an extended period.
In one example, the device is inserted into the body by passing the drug delivery device through a deployment instrument and releasing the device from the deployment instrument into the body. In one embodiment, the device is inserted into a body cavity such as the bladder, and the device assumes a retention shape, such as an expanded or higher profile shape, once the device emerges from the deployment instrument into the cavity. An example is illustrated in
Once inserted, the device releases the drug. The device may provide extended, continuous, intermittent, or periodic release of a desired quantity of drug over a desired, predetermined period. In 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 and total amount of drug delivered from the device can be selected depending upon the particular drug and the disease or condition being treated.
In embodiments in which the device comprises a drug in a solid form, elution of drug from the device occurs following dissolution of the drug within the device. Bodily fluid enters the device, contacts the drug and solubilizes the drug, and thereafter the dissolved drug diffuses from the device or flows from the device under osmotic pressure and/or via diffusion. For example, the drug may be solubilized upon contact with urine in cases in which the device is inserted in the bladder.
Subsequently, the device may be retrieved from the body, such as in cases in which the device is non-resorbable, non-collapsible, or otherwise needs to be removed. In some cases, the device does not need to be retrieved, for example, if the device is resorbed, excreted, or some combination thereof.
The device also may be configured to be completely or partially bioresorbable, such that retrieval is unnecessary. In one case, the device is resorbed or sufficiently degraded that it can be expelled from the bladder during urination. In particular embodiments, the device include biodegradable links such that the device can collapse into a shape that permits passage through the urethra during urination, as described in U.S. Patent Application Publication No. 2012/0089122. In one embodiment, the device is retrieved or resorbed after a portion of the drug, or preferably most or all of the drug, has been released.
The device may be deployed into the bladder of a patient in an independent procedure or in conjunction with another urological or other procedure or surgery, either before, during, or after the other procedure. The device may release one or more drugs that are delivered to local and/or regional tissues for therapy or prophylaxis, either peri-operatively, post-operatively, or both.
In one embodiment, the medical device, with a self-contained drug payload, is deployed wholly within the bladder to provide sustained delivery of at least one drug to the bladder in an amount that is therapeutically effective for the target tissue in need of treatment. It may be the bladder itself or regionally proximate to the bladder. Such regional delivery may provide an alternative to systemic administration, which may entail undesirable side effects or result in insufficient bioavailability of the drug. Following in vivo deployment of the device, at least a portion of the payload of drug is released from the device substantially continually over an extended period, to the urothelium and possibly to nearby tissues, in an amount effective to provide treatment or to improve bladder function in the patient. In a preferred embodiment, the device resides in the bladder releasing the drug over a predetermined period, such as two weeks, three weeks, four weeks, a month, or more.
In such cases, the device may be used to treat interstitial cystitis, radiation cystitis, pelvic pain, overactive bladder syndrome, bladder cancer, neurogenic bladder, neuropathic or non-neuropathic bladder-sphincter dysfunction, infection, post-surgical pain or other diseases, disorders, and conditions treated with drugs delivered to the bladder. The device may 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 that have other effects, or combinations thereof. The bladder-deployed device also may deliver a therapeutically effective amount of one or more drugs to other genitourinary sites within the body, such as other locations within urological or reproductive systems of the body, including 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 ovaries, or one or both of the fallopian tubes, among others or combinations thereof. For example, the intravesical drug delivery device may be used in the treatment of kidney stones or fibrosis, erectile dysfunction, among other diseases, disorders, and conditions.
In one embodiment, the intravesical drug delivery device is inserted into a bladder to locally deliver lidocaine or another anesthetic agent for management of pain arising from any source, such as a disease or disorder in genitourinary tissues, or pain stemming from any bladder procedure, such as surgery, catheterization, ablation, medical device implantation/insertion, or stone or foreign object removal, among others.
The present invention may be further understood with reference to the following non-limiting examples.
Devices were made from silicone tubing housing lidocaine HCl tablets with the dose of 400 mg lidocaine free base equivalent (FBE). In a subset of the devices, the tubing sidewall had a single laser-drilled orifice and the ends were sealed with silicone spacers and adhesive. In the remaining devices, the tubing sidewall had no apertures, and the ends were plugged at one or both ends with custom made silicone orifice end plugs, 5 mm or 15 mm in length. The end plugs, all of which were 2.16 mm OD, were provided with 206 μm, 302 μm, 496 μm, 737 μm, or 1016 μm diameter orifices. Unplugged ends were sealed with a silicone spacer and adhesive. A subset of the devices were loaded with lidocaine HCl tablets with the dose of 450 mg lidocaine free base equivalent (FBE) and sealed at one end with a 5 mm long end plug having a 302 μm diameter orifice.
Each device was then placed in a jar containing aqueous liquid and samples of the liquid were tested for lidocaine periodically over 14 days to determine the cumulative amount of the drug released. The device structures are shown in
An end plug having a single orifice was made from PLGA (50:50) (Sigma-Aldrich, 719897, acid terminated, MW 7,000-17,000). The end plug was 1 mm in length, and the orifice was about 280 μm in diameter. It was made by melting PLGA and then casting it within a silicone tube while a wire having an outer diameter of about 280 μm was into the opening of the silicone tube and through the molten PLGA, while the PLGA cooled. Next, the wire was removed, and the PLGA plug was removed from the silicone tube.
Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.
This application claims priority to and benefit of U.S. Provisional Application No. 61/772,751, filed Mar. 5, 2013, which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2014/020703 | 3/5/2014 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 61772751 | Mar 2013 | US |
