Patent Application
20080065002
The foregoing summary and the following detailed description are better understood when read in conjunction with the accompanying drawings, which are included by way of example, and not by way of limitation.
The round window membrane separating the middle and inner ear is permeable to many drugs. Drugs delivered to the round window will diffuse through the membrane and reach the inner tissues. Catheters according to certain embodiments are designed to transfer fluids into and out of the inner ear through the round window membrane and are useful for delivering drugs to treat inner (and middle) ear conditions. Notably, therapeutics can be delivered on a temporary basis to the middle ear and/or to the round window niche to treat disease (e.g., an infection), to treat injury, or for other therapeutic purposes. For example, catheters according to certain embodiments can be used to treat tinnitus or sudden sensorineural hearing loss, as well as for the administration of neuroprotective drugs following acoustic trauma. Diagnostic drugs can also be delivered to a specific location so as to allow a physician to determine if a particular therapy will be helpful. Additional examples of ear and hearing-related conditions that can be treated with (or as part of) various embodiments are described below. The invention is not limited to use for treatment of conditions specifically identified, however.
Indeed, embodiments of the invention can be used for treatment of conditions affecting regions of the human body other than the middle or inner ear. Although the following description will in many instances refer to placement of components in a round window niche, this is only for purposes of illustration. Additional embodiments include devices such as are described below for round window drug delivery, but that have components sized or otherwise configured for placement into other body regions. Such other body regions include, but are not limited to, an auditory nerve, an optic nerve, an eye, a pituitary gland, an adrenal gland, a thymus gland, an ovary, a testis, a heart, a pancreas, a liver, a spleen, a brain (surface or implanted) or a spinal cord.
In addition to the devices described herein, further embodiments include use of these and other devices for delivery of drugs and/or electrical stimulation to treat any of various conditions.
Examples of drugs that can be used in (or in conjunction with) various embodiments include, but are not limited to, antibiotics (e.g., an aminoglycoside, an ansamycin, a carbacephem, a carbapenum, a cephalosporin, a glycopeptide, a macrolide, a monobactam, a penicillin), anti-viral drugs (e.g., an antisense inhibitor, a ribozyme, fomiversen, lamivudine, pleconaril, amantadine, rimantadine, an anti-idotype antibody, a nucleoside analog), anti-inflammatory steroids (e.g., dexamethasone, triamcinolone acetonide, methyl prednisolone), a neurologically active drug (e.g., ketamine, caroverine, gacyclidine, memantine, lidocaine, traxoprodil, an NMDA receptor antagonist, a calcium channel blocker, a GABAA agonist, an α2δ agonist, a cholinergic, an anticholinergic), anti-cancer drugs (e.g., abarelix, aldesleukin, alemtuzamab, alitretinoin, allopurinol, altretamine, amifostine, anastrolzole, azacitidine, bevacuzimab, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carmustine, cisplatin, cyclophosphamide, darbepoetin, daunorubicin, docetaxel, doxorubicine, epirubicin, epoetin, etoposide, fluorouracil, gemicitabine, hydroxyurea, idarubicin, imatinib, interferon, letrozole, methotrexate, mitomycin C, oxaliplatin, paclitaxel, tamoxifen, topothecan, vinblastine, vincristine, zoledronate), or a fungicide (e.g., azaconazole, a benzimidazole, captafol, diclobutrazol, etaconazole, kasugamycin, or metiram). Analogs of the above-identified specific drugs (and other drugs) could also be used.
The catheter end fittings in the embodiments of
Catheters of the embodiments shown in
Fluoropolymers, in particular polytetrafluoroethylene (PTFE), do not exhibit high affinity for hydrophobic drugs such as gacyclidine. PTFE is not thrombogenic and will not promote stenosis (the narrowing of a cavity, such as the auditory canal). Catheters fabricated from fluoropolymers thus will have advantages over catheters fabricated from other materials. In particular, drug delivery will be more efficient due to lower binding of hydrophobic drugs with the catheter, less diffusion of drug through catheter walls, less potential for occlusion by blood clots, and less potential for stenosis. Fluoropolymers that can be used in catheters in at least some embodiments include PTFE, hexafluoropropylene (HFP), tetrafluoroethylene (TFE), fluorinated ethylene-propylene (FEP, a copolymer of TFE and HFP), perfluoroalkoxy polymers (PFA, a copolymer of TFE and PPVE), ethylene tetrafluoroethylene (ETFE, a copolymer of TFE and ethylene), MFA (a copolymer of TFE and perfluoromethylvinyl ether (PMVE)), polychlorotrifluoroethylene (PCTFE), polyvinylidene difluoride (PVDF), polyvinyl fluoride (PVF), ethylene chloro-trifluoroethylene (ECTFE), THV (terpolymer of TFE, HFP and vinylidene fluoride (VF2)) and other known fluoropolymers (as listed by, e.g., J. George Drobny in Technology of Fluoropolymers, pages 1-3 (CRC Press, Boca Raton 2001)).
In some embodiments, the tubing and catheter end fitting are formed entirely from one or more fluoropolymers. In other embodiments, the tubing, the end fitting, and/or other components of the catheter may be formed from non-fluoropolymer materials and then coated or coextruded so that fluid-contacting regions (e.g., inner surfaces of lumens and of the fluid chamber) are covered with a fluoropolymer to maintain a low affinity for drug substances. Fabrication of a bulb (or other end fitting) from a fluoropolymer (or other biocompatible and drug compatible polymer) may also help prevent blood clot attachment to the end fitting.
As seen in
In some embodiments the end fitting can be squeezed with tweezers or forceps during implantation to make the insertion into the round window niche easier. As indicated above, and for embodiments designed for delivery of drugs to the round window membrane, the size of the end fitting is designed to comfortably fit in the round window niche. After implantation the squeezed end fitting will return to the original form and fit tightly in the round window niche. In other embodiments the end fitting is hard and not easily compressed with tweezers. In this case the catheter placement in the round window niche can be directed with tweezers holding the assembly on the neck just behind the end fitting and placing the hard end fitting in the correct position.
In some embodiments catheters are similar to those described above, but are configured for placement of the end fitting into a different anatomical region. In such embodiments, the end-fitting is appropriately sized based on the desired use of the catheter. In yet other embodiments, the end fitting of the catheter is removable, allowing a physician to replace it with an end fitting better suited for a particular therapy.
As indicated above, drugs can be actively released from an end fitting as part of a mobile phase flow from a pump or other device supplying a drug-laden liquid. In some cases, drugs exit the catheter passively (with or without fluid flow) through holes in the end fitting or by diffusion through a porous membrane in the end fitting. In particular, the chamber in the end fitting is filled with drug-laden fluid, but the fluid source does not actively pump additional fluid into the chamber and the outflow lumen is closed (e.g., via a valve). A combined approach can also be used (i.e., passive drug delivery can be employed when an active device such as a pump is turned off or removed).
Liquid used for delivery of drug through the catheter can be supplied in various ways.
Examples include a syringe, a syringe pump, a mechanical pump, an osmotic pump, a MEMS pump or a piezoelectric pump. The delivery liquid can be, e.g., a homogeneous liquid-drug formulation, a particulate suspension containing drug (e.g., a nanoparticulate formulation), or a liquid passing through a solid drug eluting component, as described in any of commonly-owned U.S. patent applications Ser. No. 11/414,543 (titled “Apparatus and Method for Delivery of Therapeutic and Other Types of Agents” and filed May 1, 2006), Ser. No. 11/759,387 (titled “Flow-Induced Delivery from a Drug Mass” and filed Jun. 7, 2007), Ser. No. 11/780,853 (titled “Devices, Systems and Methods for Ophthalmic Drug Delivery” and filed Jul. 20, 2007) and/or Ser. No. 11/831,230 (titled “Nanoparticle Drug Formulations” and filed Jul. 31, 2007), all of which applications are incorporated by reference herein. As indicated above, a return flow path away from the treated region (e.g., the outflow lumens in
In some embodiments the catheter tubing may include suture anchoring elements.
In addition to delivery of drugs, catheters according to some embodiments include electrodes to provide electrical stimulation to tissue. For example, electrical stimulation of the cochlear round window, the promontory, or the external ear has been known to suppress tinnitus in some patients. As with embodiments in which the catheter is only used for drug delivery, a combined electrical stimulation/drug delivery catheter system can be implanted in the round window niche positioned towards the round window. One or more electrodes in (or near) the end fitting can be coupled to an electronics package and used to stimulate the nerves of the cochlea, the nerves running through and near the middle ear, the round window and/or the promontory area adjacent to the round window. The electrode(s) are designed to deliver a reliable electrical charge/potential as directed by the electronics package. In some embodiments, one or more electrodes is on the catheter end fitting and a ground electrode is placed where it is needed. The electronics package may be placed external to the patient's middle ear and the auditory canal for convenience (e.g., behind the ear or as part of the pumping system). The electronics can be battery operated and have an on/off switch, or can be powered via radio frequency transmission or use some other wireless electronic stimulator which will not require a battery.
A ground electrode may be outside the ear, or may be in the middle ear away from the round window membrane.
A combined electrical stimulation/drug delivery catheter can also be used with an implanted pump or port for tinnitus suppression or other treatments. Therapeutic fluid may be delivered via an osmotic pump or may be introduced through a subcutaneous port. Examples of such ports and pumps are described in the commonly-owned U.S. patent applications incorporated by reference above.
As discussed above, various embodiments include a bladder to provide a more secure fit of the end fitting in a round window niche. In other embodiments, an end fitting can include a collar in combination with (or as an alternative to) a bladder. As with a bladder, a collar can help to keep the end fitting (and thus, the catheter system) in place. Specifically, the collar will adhere to the osseus border of the round window niche and allow a more secure fit of the end fitting in the niche. In some embodiments, a collar is flexible and has a cylindrical shape and can be compressed during implantation with tweezers or forceps. After positioning in the round window niche, the compressed collar will return to the original shape, thereby providing frictional engagement with the wall of the round window niche. In some embodiments, the outer surface of the collar can include surface features (e.g., bumps) to help increase such frictional engagement. Materials for a collar can include flexible biocompatible materials such as silicone or polyurethane. In certain embodiments a collar includes a stent-like expandable ring around the catheter tip which will secure the catheter in the round window niche.
In still other embodiments not shown in the drawings, a skirt-type cover member is located at the end of a catheter to be positioned in the round window niche, and is used to form a fluid-receiving zone. The cover member is positioned above the round window membrane in the round window niche to form a fluid receiving zone adjacent to the round window membrane. Drug-containing fluid is delivered through the catheter and the cover member into the fluid receiving zone. The drug-laden fluid will pass through the round window membrane by diffusion, active transport or osmosis, thereby moving into the inner ear for treatment. Any remaining residual fluid in the fluid-receiving zone can be withdrawn from the patient. Extraction of the residual fluids is accomplished by applying light suction on a second end of a fluid extraction lumen. Alternatively, the device can be removed and the residual fluid will remain in the middle ear or be swallowed.
While catheters according to some embodiments release drug in the round window niche for diffusional passage through (or, in some selected cases, active transport across) the round window membrane, other embodiments can be used for injection of medications across the round window and into the cochlea. One such embodiment is shown in
In some embodiments an outlet pressure sensor and pressure valve are coupled to the outflow lumen of tubing 251 so as to maintain physiologic intracochlear pressure (e.g., 0.5 to 1.5 mm Hg) independent of the rate of flow used for medication delivery. Alternatively, the outflow lumen can remain fully open, such that there is little or no pressure buildup during delivery of medication. The cochlear pressure can be maintained at the desirable level by appropriate use of the return pressure regulating outlet valve.
In some embodiments needle-equipped catheters such as catheter 250 may also include one or more electrodes for stimulation of the inner ear or promontory. In some such embodiments, such as catheter 310 shown in
In at least some embodiments employing needles to pierce the round window membrane and deliver drugs, an antibacterial filter is employed to help ensure the sterility of drug-laden fluid delivered to the cochlea. Such an antibacterial filter can be located in any of various locations in the fluid path between a source of drug-laden fluid and an outlet of the catheter delivering drug to the cochlea.
For at least some treatments, it is known that the ionic composition and osmolality of medication in a liquid delivery vehicle should match that of perilymph. This can be of greater importance when two needles are employed to give faster infusion rates, resulting in more efficient exchange of intracochlear fluid. One example of a suitable vehicle is Ringer's solution at an osmolality of 290 to 310 mOsm. At the injection flow rates that can be accomplished with a single needle, distribution of drug in the cochlea is dominated by diffusion. However, at the higher infusion flow rates that are possible with two needles (a drug delivery needle and an outlet needle), delivery of drug to the cochlea can be achieved more rapidly by fluid exchange.
Several experiments were performed to prove the advantages and drug compatibility of the fluoropolymers to be used in round window catheters according to at least some embodiments. The experiments were performed using a solution of gacyclidine (also known as GK11), a drug that is soluble in its acid form, water insoluble and lypophilic in its basic form. Its water soluble form has affinity for hydrophobic surfaces, such as would be formed by many polymers used to fabricate conventional catheters. As such, it serves as a model indicator and predictor for drug loss that might be encountered due to binding (adsorption and absorption) to surfaces of materials used in catheter fabrication.
The low adsorption/absorption characteristics of fluoropolymer tubing versus other materials is shown in Table 1. The following tubing materials were evaluated: PTFE (polytetrafluoroethylene), FEP (fluorinated-ethylene-propylene), PVC, trilaminar coaxial tubing and three different types of silicone tubing. Four pieces of each type of tubing material were cut into ½ inch lengths. All the pieces were washed using isopropyl alcohol. The pieces of tubing were then soaked for 20 hours at room temperature in vials containing 100 μM gacyclidine in Ringer's Lactate at pH 6.0. The tubing pieces were placed in glass sample vials, two pieces of tubing in each vial. One milliliter of 100 μM gacyclidine in Ringer's Lactate at pH 6.0 was placed in each vial. The concentration of gacyclidine was determined by spectrophotometry at 234 nm and by HPLC. The FEP and PTFE tubing pieces showed very low retention of gacyclidine. PVC demonstrated high retention with around 20% adsorbed and/or absorbed. The silicones had high adsorption and/or absorption ranging from 27 to 58%. Results for specific tubing pieces are shown in Table 1.
The compatibility of gacyclidine in Ringer's Lactate (pH 6.0) in PTFE tubing at room temperature and at 37° C. was evaluated. Three sets of six segments each of PTFE tubing were used. Six samples were collected at each of three time intervals (6 hr, 23 hr and 72 hr). For each set of samples collected, three were incubated at ambient temperature and three were incubated at 37° C. A 16.5 ft. long segment of PTFE tubing (0.010″ ID, 0.018″ OD) was filled with 100 μM gacyclidine in Ringer's Lactate solution (pH 6.0) by use of a glass syringe. The two ends of the tubing were sealed with a paraffin wax vapor barrier. After incubating at room temperature or 37° C. for a specified time, the solution was pumped directly into a glass HPLC autosampler vial insert using an air-filled syringe. The PTFE tubing drug loss in 72 hours at room temperature was 1.3% and at 37° C. was 7.9%. These results were not corrected for decomposition. The expected amount of decomposition expected in 72 hours at 37° C. is 8.0%. As such, there is no apparent loss due to adsorption or absorption of gacyclidine to the PTFE tubing.
Six 120 cm lengths of tubing containing thermoplastic polyurethane were filled with 350 μL of 3 mM gacyclidine in Ringer's solution (pH 5.5) and incubated at room temperature. Two tubing lengths were emptied for each time point (1 hr, 8 hr and 24 hr) and collected in an acid-washed autosampler vial. A 1:50 dilution in Ringer's solution was prepared from the collected samples. Concentrations of gacyclidine in the diluted samples were determined spectrophotometrically at 234 nm. There was an increase in gacyclidine concentration, presumably due to loss of water by evaporation through the tube walls. This was confirmed by a corresponding increase in solution osmolality as determined by use of a freezing point osmometer. The percentage increase in gacyclidine concentration corresponds quantitatively with the percentage increase in osmolality.
Fluoropolymer-lined (single-lumen) catheters were tested for drug compatibility with 100 μM gacyclidine in Ringer's Solution (pH 5.5). The lumens of the single-lumen catheters were filled with 200 μL of 100 μM gacyclidine in Ringer's solution and allowed to sit at room temperature. The ends of the devices were covered with paraffin wax vapor barrier to prevent evaporation. All three catheters were emptied after 48 hours into acid-washed HPLC autosampler vials. The concentration of gacyclidine was determined spectrophotometrically at 234 nm. The average overall percentage loss from experiments with three devices using 100 μM gacyclidine was 3.1% (1-5%, see Table 2).
In some embodiments, materials used in fabricating electrodes should be chosen to have low affinity for drug substances, to not be thrombogenic, and to not promote stenosis. While titanium has low affinity for hydrophobic drugs, such as gacyclidine, titanium is known to be thrombogenic, as are steel, tungsten and platinum. As such, if titanium is employed to provide contact for electrical stimulation, it may optionally be positioned inside the catheter (as shown in
Disorders of the middle and inner ear that can be treated by use of the drug delivery system described herein include: autoimmune inner ear disorder (AIED), Meniere's disease (idiopathic endolymphic hydrops), disorders of the inner ear associated with metabolic imbalances, infections, allergic or neurogenic factors, blast injury, noise-induced hearing loss, drug-induced hearing loss, tinnitus, presbycusis, barotrauma, otitis media (acute, chronic or serious), infectious mastoiditis, infectious myringitis, sensorineural hearing loss, conductive hearing loss, vestibular neuronitis, labyrinthitis, post-traumatic vertigo, perilymph fistula, cervical vertigo, ototoxicity, Mal de Debarquement Syndrome (MDDS), acoustic neuroma, migraine associated vertigo (MAV), benign paroxysmal positional vertigo (BPPV), eustachian tube dysfunction, cancers of the middle or inner ear, and bacterial, viral or fungal infections of the middle or inner ear. Cancers, bacterial, viral or fungal infections or endocrine, metabolic, neurological or immune disorders in other locations could also be treated by use of catheters similar in design to those described herein.
As previously indicated, devices similar to those described above for round window drug delivery can be sized or otherwise configured for placement into different regions of a patient's body for treating other conditions. For example, embodiments include catheters configured to deliver therapeutic substances to the vicinity of the auditory, optic, or other sensory nerves; to the eye, cochlea or other sensory organ for treating sensory disorders; to specific regions within the skin for local therapy; to the vicinity of the pituitary, adrenal, thymus, ovary, testis, or other gland for specific endocrine effects; to a region of the heart, pancreas, liver, spleen or other organ for organ-specific effects; and/or to specific regions of the brain or spinal cord for selective effects on the central nervous system. Embodiments also include methods employing such catheters, as well as methods employing catheters configured for round window drug delivery.
Numerous characteristics, advantages and embodiments of the invention have been described in detail in the foregoing description with reference to the accompanying drawings. However, the above description and drawings are illustrative only. The invention is not limited to the illustrated embodiments, and all embodiments of the invention need not necessarily achieve all of the advantages or purposes, or possess all characteristics, identified herein. Various changes and modifications may be effected by one skilled in the art without departing from the scope or spirit of the invention. Although example materials and dimensions have been provided, the invention is not limited to such materials or dimensions unless specifically required by the language of a claim. The elements and uses of the above-described embodiments can be rearranged and combined in manners other than specifically described above, with any and all permutations within the scope of the invention. As used herein (including the claims), “in fluid communication” means that fluid can flow from one component or region to another component or region; such flow may be by way of one or more intermediate (and not specifically mentioned) other components or region; and such flow may or may not be selectively interruptible (e.g., with a valve). As also used herein (including the claims), “coupled” includes two components that are attached (movably or fixedly) by one or more intermediate components.
This application claims the benefit of U.S. Provisional Application Ser. No. 60/824,895, filed Sep. 7, 2006 and titled “Catheter for Localized Drug Delivery and Electrical Stimulation,” hereby incorporated by reference herein.
| Number | Date | Country | |
|---|---|---|---|
| 60824895 | Sep 2006 | US |
