Patent Grant
9649477
The present invention relates generally to medical devices and methods and more particularly to substance delivering implants and methods for treating a broad range of disorders including but not limited to sinusitis and other ear, nose and throat disorders.
The paranasal sinuses require adequate ventilation to prevent microbial chronic infection within the sinus cavities. Normally, ventilation is provided through the small natural openings, known as ostia, through which the sinus cavities open into the nose. In addition to ventilation, the natural ostia serve as drainage channels as ciliated cells lining the interior of the sinus cavity continually direct a flow of mucus toward the ostia. Thus, when the natural ostia become narrowed or blocked, ventilation and drainage from the sinus cavity is impaired. The resultant hypoxia, pH changes and mucus stasis within the sinus cavity gives rise to an environment in which some types of microbial growth can flourish. Such microbial infection can, in itself, result in further mucosal inflammation and even further constriction or blockage of the natural sinus ostium.
Techniques for Improving Ventilation and Drainage of Paranasal Sinuses
Functional endoscopic sinus surgery (FESS) is a common type of surgery wherein an endoscope is inserted into the nose and, under visualization through the endoscope, the surgeon may remove diseased or hypertrophic tissue or bone and may surgically enlarge the ostia of the sinuses to restore normal ventilation and drainage of the sinuses.
As an alternative to incisional surgery, in some patients, a balloon catheter may be advanced into the constricted sinus ostium and used to dilate the ostium, thereby eliminating the need for cutting or removing tissue surrounding the ostium (Balloon Sinuplasty™ technology, Acclarent, Inc., Menlo Park, Calif.). Examples of such balloon dilation procedures are described in United States Patent Application Publications No. 2006/0004286, now U.S. Pat. No. 7,720,521, issued May 18, 2010, 2006/0063973, 2006/0210605, now U.S. Pat. 7,803,150, issued Sep. 28, 2010, 2007/0129751, now U.S. Pat. No. 8,894,614, issued Nov. 25, 2014, 2007/0135789, now U.S. Pat. No. 8,858,586, issued Oct. 14, 2014, 2007/0167682, 2007/0208252, 2007/0208301, now U.S. Pat. No. 8,951,225, issued Feb. 10, 2015, and 2007/0293727, now U.S. Pat. No. 9,265,407, issued Feb. 23, 2016, the entire disclosure of each such patent application being expressly incorporated herein by reference.
Implantation of Stents and Space Occupying Materials to Deter Re-Occlusion Following Surgery
In cases where tissue adjacent to the ostium has been surgically removed or incised, post-operative scar tissue, fibrosis, polyposis or tissue ingrowth can result in re-occlusion of the sinus ostium. To deter such re-occlusion of frontal and sphenoid sinuses following surgery, small tubular stents have been placed in the surgically altered sinus ostium or outflow tract for a limited time period following surgery.
One example of a commercially available frontal sinus stent is the Freeman™ Frontal Sinus Stent (InHealth Technologies, Inc., Carpinteria, Calif. The Freeman™ stent comprises a silicon tube that has flanges on either end to retain the stent within the frontal outflow tract for a desired period of time following surgery. Other commercially available frontal sinus stents include the Jasin Frontal Sinus Stent (Medtronic Xomed, Inc., Jacksonville, Fla.), and the Salman FES Stent (Boston Medical Products, Westborough, Mass.).
A sphenoid sinus stent is described in U.S. Pat. No. 7,235,099 (Duncavage, et al.). This stent comprises a soft compressible plastic tube having a generally hemispherical hollow dome on one end. The diameter of the dome is greater than the predetermined diameter of the plastic tube. The stent further includes an annular flange located a predetermined distance from the hemispherical dome. The device is designed to be fitted through a surgically enlarged ostium of the sphenoid sinus such that the dome resides within the sinus cavity and the flange abuts the bony wall surrounding the ostium. This stent serves maintain patency of the surgically altered ostium during the postoperative period and allows irrigation/suctioning through the lumen of the stent. This sphenoid sinus stent is also commercially available as the SP-82020 Sphenoid Sinus Stent (Micromedics, Inc., St. Paul, Minn.).
The above-described frontal and sphenoid sinus stents do not deliver therapeutic substances. Thus, they are frequently used concurrently with orally administered drugs (e.g., corticosteroids) and/or topical nasal sprays.
In some cases, in lieu of a stent, surgeons may place gel-like materials within the surgically altered ostium or outflow tract to prevent ingrowth of scar tissue during the post-surgical period. One example of such material is the MeroPack™ Bioresorbable Nasal Dressing and Sinus Stent available from Medtronic ENT, Inc., Jacksonville, Fla. The MeroPack™ material consists of 80 percent esterified hyaluronic acid and 20 percent collagen. This material is inserted while in its dry state and, upon hydration, swells to 1.0 cm diameter in about six seconds. When in its hydrated state, this material is a biocompatible, muco-adhesive gel.
Local Drug Delivery in the Treatment of Sinus Disease
Various drug delivery implants have been proposed for use in or around the paranasal sinuses to treat sinusitis and/or to deter re-occlusion of surgically altered outflow tracts or ostia following surgery.
For example, United States Patent Application Publication No. 20050043706 (Eaton et al.), now U.S. Pat. No. 7,544,192, issued Jun. 9, 2009, describes biodegradable implants for treating sinusitis, such implants having a size, shape, density, viscosity, and/or mucoadhesiveness that prevents them from being substantially cleared by the mucociliary lining of the sinuses during the intended treatment period. These biodegradable implants deliver therapeutic agents such as antibiotics, steroids or both. These biodegradable implants may be in various forms such as rods, pellets, beads, strips, or microparticles, and may be delivered into a sinus in various pharmaceutically acceptable carriers.
Also, United States Patent Application Publication No. 20070005094 (Eaton et al.), now U.S. Pat. No. 8,025,635, issued Sep. 27, 2011, describes implantable devices useable for the treatment of paranasal sinus conditions. The devices include cavity members that have a first collapsed configuration that permits the device to pass through a sinus ostium and a second expanded configuration after placement into the sinus cavity. In addition to a cavity member, the devices may include a nasal portion and an ostial member that is configured to reside within the sinus ostium. The cavity member is attached to the distal end of the ostial member. The nasal portion is attached to the proximal end of the ostial member and lies within the nasal passage. The active agent may be incorporated into all portions of the device or only included in the expandable cavity member, the ostial member, or nasal portion.
Some investigators have proposed adding drug delivery capability to frontal sinus stents to deliver controlled amounts of drug to the surgically altered outflow tract following frontal sinus surgery. For example, United States Patent Application Publication 2004/0116958A1 (Gopferich et al.), now U.S. Pat. No. 8,740,929, issued Jun. 3, 2014, describes a tubular sheath or “spacer” formed of biodegradable or non-biodegradable polymer that, prior to insertion in the frontal outflow tract, is loaded with a controlled amount of an active substance, such as a corticosteroid or anti-proliferative agent. After surgery to create a fenestration in a frontal sinus as been performed, the sheath (which has been preloaded with the active substance) is inserted into the surgically created fenestration where it a) deters closure of the surgically created fenestration, b) serves as a conduit to facilitate drainage from the sinus and c) delivers the active substance. In some embodiments, the sheath is formed of multiple layers of polymeric material, one or more of which is/are loaded with the active substance and one or more of which is/are free of the active substance. In other embodiments, the sheath has a “hollow body” which forms a reservoir system wherein the active substance is contained and a membrane which controls the release of the active substance from the reservoir. In some embodiments, the sheath may be anchored by causing the end of the sheath that extends into the sinus to swell or otherwise enlarge. Also, United States Patent Application Publication No. 2005/0245906 (Makower et al.), now U.S. Pat. No. 7,361,168, issued Apr. 22, 2008, describes a biodegradable polymeric device that comprises a spacer positionable within a sinus ostium. The spacer has a plurality of substance-eluting struts. The device may be implanted such that the struts are substantially parallel to the cilial flow of mucus along the sinus cavity walls so that normal mucociliary transport is not interrupted.
Additionally, various other types of implantable drug delivery devices have been proposed for use in the nose and/or paranasal sinuses. For example, U.S. Pat. No. 3,948,254 (Zaffaroni) describes implantable drug delivery reservoirs having microporous walls. The reservoir may be formed of a solid drug carrier that is permeable to passage of the drug and the rate of passage of the drug through the microporous wall may be slower than the rate at which the drug passes through the solid drug carrier that forms the reservoir. Zaffaroni also describes a number of applications for the implantable drug delivery devices including placement in a nasal passage. Specifically, Zaffaroni claims a nasal delivery device for dispensing a drug within a nasal passage at a controlled rate wherein the nasal device is comprised of (a) a wall defining the device dimensioned for insertion and placement within a nasal passage, with the wall formed of a nasal acceptable microporous material, (b) a reservoir surrounded by the wall and comprised of a solid carrier permeable to drug and containing drug in an amount sufficient for the device to meter it at a continuous and controlled rate for a prolonged period of time from the device, (c) a liquid medium permeable to the passage of drug by diffusion charged in the micropores, and (d) wherein the device releases drug when in a nasal environment by passage of drug from the carrier and through the liquid to the exterior of the device to produce a useful result. The entire disclosure of U.S. Pat. No. 3,948,254 (Zaffaroni) is expressly incorporated herein by reference.
Other publications have also reported that introduction of drugs directly into the paranasal sinuses is effective in the treatment of sinusitis. See, Tarasov, D. I., et al., Application of Drugs Based on Polymers in the Treatment of Acute and Chronic Maxillary Sinusitis, Vestn Otorinolaringol. Vol. 6, Pages 45-7 (1978). Also, R. Deutschmann, et al., A Contribution to the Topical Treatment of [Maxillary] Sinusitis Preliminary Communication, Stomat. DDR 26 (1976), 585-592 describes the placement of a resorbable drug delivery depot within the maxillary sinus for the purposes of eluting drugs, specifically Chloramphenicol. In this clinical series a water soluble gelatin was used as carrier and was mixed with the drug prior to application and introduced as a mass into the sinus. Since the substance had little mechanical integrity and dissolved in a relatively short timeframe, to achieve a therapeutic effect, the author suggested that it must be instilled every 2 to 3 days. An alternative to gelatin could be a sponge loaded with the therapeutic substance as suggested in U.S. Pat. No. 6,398,758 (Jacobsen, et al.). In this patent directed at delivering a sustained release device against the wall of a blood vessel, a hollow cylindrical sponge is loaded with drug and pressed against the wall. This allows the drug to contact the wall while sustaining blood flow within the center of the lumen. Further, a skin is provided to direct the drug into the walls of the blood vessel and prevent drug from flowing into the lumen. While sponges loaded with drug at the time of their application do permit some degree of sustained release, the time required to load them also correlates closely the time over which they will elute substance. Thus, if delivery is required for a longer period of time additional mechanisms must be employed to regulate their release.
There are also several examples in the patent literature where various sustained release mechanisms have generally been proposed using systems with drugs pre-incorporated into matrices or polymers. These include U.S. Pat. No. 3,948,254 (Zaffaroni), US 2003/0185872A2 (Kochinke), now U.S. Pat. No. 7,074,426, issued Jul. 11, 2006, WO 92/15286 (Shikani), and U.S. Pat. No. 5,512,055 (Domb, et al.). In general, these references discuss various materials and structures that may be used to construct sustained drug delivery vehicles and provide a good overview of the state of sustained drug delivery art. While helpful in laying out certain materials and schemes for creating sustained release systems for drugs, these references do not, however, describe specific methods, means or structures which would permit them to be easily adapted for intended uses that are targeted in the present application.
Other examples of implantable drug delivery devices include those described in U.S. Pat. Nos. 3,993,073; 4,217,898; 5,304,123; 6,042,561; 6,183,461; 6,780,168 and 6,783,522, the entire disclosure of each such patent being expressly incorporated herein by reference.
Techniques for Treatment of Ethmoid Disease
To date, the use of stents and spacers in relation to nose and sinus surgery has been largely limited to placement in the frontal outflow tract or sphenoid sinus ostium following surgery wherein tissue and bone have been cut away or removed. However, as new devices and methods become available for the treatment of other types of nasal and sinus disorders, there will likely be a need for intranasal or sinus spacers and stents (with or without drug eluting capabilities) suitable for placement at various locations lot limited to the frontal outflow tract.
In the prior art, diseased ethmoid air cells have sometimes been treated by a procedure known as an ethmoidectomy wherein a man made passageway is formed between the interiors of the ethmoid air cells and the nasal cavity. Stenting and/or delivery of drugs or other therapeutic substances into these manmade ethmoidectomy passageways has been, in at least some cases, desirable. To accomplish this, strips of gauze soaked with medication may be pushed into the manmade opening and later extracted. Also, in this regard, U.S. Pat. No. 6,543,452 (Lavigne) describes a nasal intubation device that comprises a flexible tube having a flanged distal tip whereon the flanges generally from an arrow shape. The distal tip of this device is capable of penetrating through tissue (e.g., through the ethmoid bulla) to a desired position (e.g., within the ethmoid air cells). Openings are formed in a distal portion of the intubation device so that medication (e.g., a typical steroid) injected through the flexible tube will flow out of the tube into contact with the adjacent area (e.g., the diseased ethmoid air cells). In some cases, a cannula-trocar may be initially inserted and the nasal intubation device may then be advanced through that cannula-trocar. Also, European Patent Publication EP0624349 (Milewski) describes a balloon-tipped catheter having an anatomically shaped balloon which may be inserted through a surgically created opening into a body cavity (e.g., frontal sinus or ethmoid cell) and inflated to create a tamponade by being shaped to suit the anatomical shape of the cavity.
Techniques for Treating the Frontal Sinus
Various of the above challenges are also specifically relevant to the treatment of the frontal sinuses. Additionally, due to the unique anatomy of the frontal sinuses, there are additional challenges. That is, accessing the frontal sinuses can require specialized instrumentality. Moreover, it has been found that conventional FESS procedures on the frontal sinuses have a higher tendency of scarring. Such scarring can lead to a relapse of insufficient drainage and ventilation.
Although corticosteroids have been found to be effective in reducing reactive scarring in the frontal sinuses, there remains a number of key limitations. Nasal sprays and ointments generally do not reach critical areas around the frontal sinus outflow tract. Also, it can be difficult to deliver interventional devices deep within the frontal sinus cavity and there are challenges associated with the retention of interventional instruments in the frontal outflow tract.
Accordingly, there remains a need for the development of new devices and methods for delivering drugs and other therapeutic or diagnostic substances over a sustained period of time into paranasal sinuses, Eustachian tubes, middle ear and/or other locations within the body for the treatment of sinusitis, otitis or other diseases and disorders. In particular, there is a need for an approach to conveniently and effectively access and treat the sinuses such as the frontal sinus.
The present disclosure address these and other needs.
The present invention provides substance delivering spacer devices and methods including expandable reservoirs that are implantable in paranasal sinuses and other cavities, openings and passageways of the body to maintain patency and/or to provide sustained local delivery of a therapeutic or diagnostic substance. Also provided are sinus penetrator devices, systems and methods for creating ethmoidotomy openings or other openings in the walls of paranasal sinuses or other anatomical structures.
In one particular approach, a system and method have been developed to specifically treat the frontal sinuses. The system can include an elongate shapeable tube or sheath adapted to navigate patient anatomy and to present structure for accessing the frontal sinuses. Various approaches to substance delivery spacers with retention structure have also been developed. In this way, compensations can be made for variations in patient anatomy. Also, in one aspect, the spacer device can additionally include an atraumatic tip such as that formed by a soft polymer.
One embodiment of a substance delivery spacer adapted to treat a frontal sinus includes a shaft and an expandable reservoir attached to a distal portion of the shaft. The reservoir can be introduced within a patient in a collapsed configuration, mounted to the frontal sinuses and then expanded. To expand the reservoir, a substance such as a drug or other therapeutic substance can be loaded within the reservoir. Additionally, the reservoir can embody openings through which the drug or therapeutic substance can elute to thereby treat the frontal sinuses. Moreover, the shaft can be cut to length as desired when leaving the spacer at the interventional site. The spacer can further include retention structure configured to facilitate securing the spacer at or within the frontal sinuses. In this regard, one or more retention wings extending along various portions of the reservoir are contemplated. Such wings can assume a compressed configuration for delivery to the interventional site and expanded configurations for securing the spacer within anatomy.
One embodiment of a device and method for treating ethmoid sinusitis involves a penetrator device that has a distal tip and a stopping mark or member located a spaced distance proximal to its distal tip. The distance between the stopping mark or member and the distal tip is less than the distance between the ethmoid bulla and the ipsalateral sphenoid sinus. An ethmoidotomy channel is formed by advancing the penetrator through the ethmoid bulla in a direction that is non-perpendicular to the skull base and generally directed toward the ipsalateral sphenoid sinus. Advancement of the penetrator is stopped when the stopping mark or member is approximately flush with the ethmoid bulla. Thereafter, the penetrator is removed. Optionally, a stent, spacer or substance delivering spacer device may then be placed in the ethmoidotomy channel for a period of time to maintain patency of the channel and/or to effect local delivery of a therapeutic substance.
According to one embodiment, a sinus penetrator device and method may be used to form an ethmoidotomy channel or other opening in a paranasal sinus wall or other body structure. Such device comprises an elongate penetrator member and a handle coupled with the penetrator member at or near its proximal end. A sighting member is disposed along the handle or the elongate member at a location to make it visible from an extracorporeal vantage point when the distal end of the elongate member is inserted into the patient. Such sighting member is useable by a user of the device to generally aim the distal end of the penetrator in a desired direction within the patient's body. In some embodiments, the sighting member may comprise a fin. The sighting member may extend in a plane that is substantially parallel to a plane in which the elongate the penetrator extends from the handle and, optionally may include another member (e.g., a cross member) that is substantially normal to the plane in which the elongate penetrator extends from the handle. In some embodiments, the elongate penetrator may have a curve formed therein and at least a portion of the sighting member may be parallel to the portion of the elongate penetrator that is distal to the curve, thereby providing an indication of the direction or trajectory on which the distal portion of the elongate penetrator is being advanced.
Still further in accordance with the invention, there is provided a substance delivering spacer device and method. In one embodiment, the substance delivering spacer device comprises a shaft and an expandable reservoir located on the shaft. The reservoir may be introduced into a body cavity or opening (e.g., a paranasal sinus, ethmoidotomy channel, frontal sinus outflow tract, or other body cavity, opening, passageway) while in a collapsed configuration. Thereafter, a therapeutic substance may be loaded into the reservoir, causing the reservoir to expand in situ. The shaft may be severed or cut at a desired location and the proximal portion of the shaft may be removed after the reservoir has been loaded. The reservoir is designed such that the substance will elute from the reservoir over a period of time. The reservoir may have a side wall and tapered ends, with openings being formed in the sidewall and tapered ends such that a therapeutic substance loaded into the reservoir will elute through the openings and out of the reservoir. In some embodiments, the device may be equipped with apparatus for holding the reservoir in a desired position within the body (e.g., retention wings, projections, suture loops, etc.) for holding the reservoir in a desired position within the body.
Still further in accordance with the invention, there is provided a method and system wherein a substance delivering spacer device of the above-described character is used in combination with a sinus penetrator (e.g., the ethmoidotomy device described above or any other penetrator) and a sheath. The sheath is initially disposed over the sinus penetrator and the penetrator/sheath combination is advanced through a wall of a paranasal sinus or air cell. The penetrator is then removed, leaving the sheath in place. The substance delivering spacer device is advanced into the sheath. The sheath is then removed, leaving the substance delivering spacer device in place within the sinus or air cell. A diagnostic or therapeutic substance is then loaded into the reservoir such that the substance will thereafter elute from the reservoir into the paranasal sinus or air cell.
Still further in accordance with the invention, there is provided an embodiment of a method for treating sinusitis where an implantable device having a substance eluting reservoir is positioned within a paranasal sinus or within the ostium or outflow tract of a paranasal sinus. Thereafter, a steroid is introduced into the substance eluting reservoir so that the steroid elutes from the reservoir in an amount that is effective to treat the sinusitis.
Still further aspects and details of the present invention will be understood upon reading of the detailed description and examples set forth below.
The following detailed description and the accompanying drawings are intended to describe some, but not necessarily all, examples or embodiments of the invention. The contents of this detailed description do not limit the scope of the invention in any way.
An expandable reservoir 14 is mounted in a collapsed configuration on the distal shaft portion 12b near its distal end and expands to an expanded configuration as it is filled. Details of one embodiment of such reservoir 14 are seen in
As described in further below, this embodiment of the reservoir 14 may be inserted, in a collapsed configuration, into a body opening, passageway or cavity (such as, for example, a frontal sinus outflow tract, paranasal sinus ostium, antrostomy, ethmoidotomy opening, or other location within the ear, nose or throat of a subject) and, thereafter, the reservoir may be loaded with the desired substance, causing the reservoir to transition to an expanded state. For example, for applications intended to treat inflammation of a paranasal sinus using the particular reservoir 14 described above with the opening size/pattern seen in
Also, the reservoir 14 need not be used to deliver a therapeutic substance in all applications. It may, in fact, be used as a space occupying device (e.g., instead of a sinus stent). In such applications, the reservoir 14 may be loaded in situ with saline solution of other inert liquid causing the reservoir 14 to expand and frictionally engage or contact adjacent anatomical structure(s), thereby providing a degree of retention at the desired implantation location. This aspect of the reservoir 14 may be further facilitated by the provision of surface projections on the reservoir. In cases where it is intended for the reservoir 14 to function
The reservoir 14 may be relatively small in diameter when in its collapsed configuration, thus allowing it to be introduced or removed easily. In embodiments where the reservoir 14 is formed of non-compliant or semi-compliant material, the reservoir 14 will not undergo substantial elastic deformation in the filling process and thus will not exert pressure on its contents in order to expel the desired substance through openings 31. Rather, the substance in the reservoir 14 will be carried out through the openings 31 by gravity or by being in contact with the mucus or blood that is continually moved along by the ciliary action in the sinuses. This non-pressurized delivery allows for the slow release of the desired substance over several days. In some other embodiments, the reservoir 14 may be formed of compliant or elastic material with small openings 31 such that the material of which the balloon 14 is formed will contract as substance passes out of the openings 31, thereby maintaining pressure within the balloon. In cases where the reservoir 14 is intended to be inserted into a sinus ostium, outflow tract, antrostomy opening or ethmoidectomy/ethmoidotomy opening and used to deliver an aqueous suspension containing 40 mg/ml of Triamcinolone Acetonide Injectable Suspension, USP (Kenalog®-40, Bristol-Myers Squibb, Somerville, N.J.) or another substance of similar consistency, the reservoir 14 may have approximately 2200 laser cut openings 31 approximately 20 to 40 microns in diameter formed in the sidewall of the reservoir 14. As seen in
In the particular example shown, the distal shaft portion 12b may be made of Nylon 12 and may have an outer diameter of 0.028 inches, an inner diameter of 0.020 inches and length of 17 mm. An aperture 28 as seen in
Optionally, a distal radiopaque marker 24 and proximal radiopaque marker 22 may be provided to facilitate the desired positioning of the reservoir 14 within a subject's body. Each of these markers 22, 24 may be made of a ring of radiopaque material and may be mounted on the shaft 12 in alignment with each end of the reservoir's cylindrical sidewall 14a. In this particular example each marker 22, 24 comprises a band of Platinum-Iridium alloy having outer diameter 0.034 inches and inner diameter 0.030 inches. These markers are visible under various imaging techniques including fluoroscopy and CT scanning.
In the example shown, the proximal shaft portion 12a may be made of polyimide tubing of outer diameter 0.0618 inches and inner diameter 0.052 inches and length 20 cm. A hub 16 comprising a female Luer connector made of clear polycarbonate (Part No. 41519, Qosina, Edgewood, N.Y.) is attached to the proximal end of shaft 12. As seen in
Additionally, in the example shown, the device incorporates two types of position retaining apparatus, namely a suture loop 20 as well as a pair of projections in the nature of retention wings 18. The retention wings 18 are located at diametrically opposed locations on the shaft 12, proximal to the reservoir 14 to help retain the reservoir 14 at a desired position within the body, as will be explained in substantial detail below. In this example, each retention wing 18 comprises a preformed loop of nickel-titanium (nitinol) wire of diameter 0.0086 inches. Each retention wing 18 may be flexed or compressed to a collapsed position where it lies substantially flat against the outer surface of the shaft 12. However, these retention wings 18 are biased to a preformed configuration such that, when unconstrained, each retention wing 18 will resiliently spring outwardly to an extended position wherein it extends at an angle of from about 65 to 90 degrees relative to the longitudinal axis of the shaft 12. Such pre-forming of these wings 18 may be accomplished by heat treating the nitinol wire loop at 520° C. for 20 minutes to produce an austenite finish temperature (Af) of 20° C. Various alternatives to these retention wings 18 may be used. For example,
The suture loop 20 (e.g., an eyelet or ring) may be formed of supple, flexible, resilient, elastic or superelastic material such as suture thread or nickel-titanium alloy (Nitinol) wire. In the particular embodiment shown, the suture loop is formed of black monofilament Nylon non-absorbable surgical suture material having a diameter of 0.0075 inches. The suture loop 20 may be collapsed against the outer surface of shaft 12. The suture loop 20 may be affixed to the outer surface of shaft 12 by winding the wire or other material around the shaft and securing the wire to the shaft using a suitable adhesive such as cyanoacrylate, epoxy or UV curable adhesive and/or by mounting a polymeric sleeve or heat shrinkable member about the portions of wire that are wound around the shaft 12. In some embodiments, the suture loop may be colored so as to be visually distinguishable from blood and the red-pink color of the intra-nasal mucosa. For example, the suture loop 20 may be black, bright blue or green in color so as to be easily locatable by the surgeon. This suture loop 20 may be sutured to the adjacent tissue to anchor the distal portion of the device 10 in place.
As seen in
Although the particular examples of the spacer device 10 described above include a reservoir 14 formed of a single layer balloon, in some embodiments, the reservoir may comprise a balloon having multiple layers with different sized openings in each layer. The substance may then be selectively introduced between the particular layers that will facilitate the desired delivery of that particular substance at the desired rate. In this regard, by way of example,
As will be described in more detail below, the substance delivering spacer device 10, 610 may be implanted in any suitable part or location of the body of a human or animal subject to perform a spacing function (e.g., to prevent tissue ingrowth, scarring, fibrosis, adhesion formation, etc.) and/or to deliver any desired therapeutic substance. For example, in ear, nose and throat applications the device 10, 610 may be implanted in a natural ostium or man-made opening formed in any paranasal sinus or air cell or in any other natural, surgically modified or surgically created opening or passageway, such as the outflow tract of a frontal sinus, the inferior, superior or medial meatus, etc.
The sheath 40 may be formed of a biocompatible polymer such as PEBAX and comprises a proximal sheath body 42 of a first diameter, a distal sheath body 44 of a second diameter (smaller than the first diameter) and a tapered step-down segment 54 between the proximal sheath body 42 and the distal sheath body 44. A flared region 46 is located at the proximal end PE of the sheath 40. A visual marker band 50 is optionally provided on the proximal sheath body 42 near its proximal end PE. A second visual marker band 48 is optionally located on the distal shaft portion 44 approximately 17 mm from the distal end DE. Also optionally, radiopaque markers 52, 56 may be provided at spaced apart locations on the distal sheath body 44. In the particular example shown, the distal radiopaque marker 56 is located approximately 1.5 mm from the distal end and the proximal radiopaque marker 52 is located approximately 17 mm from the distal end DE and beneath the distal edge of visual marker 48. Additionally, in some embodiments, optional wing members 53 may extend laterally from the distal sheath body 44 in the region of visual marker 48. These optional wing members 53 may be constructed in substantially the same manner as the retention wings 18 of the substance delivering spacer device 10 described above and, when extended, each wing member 53 may have a length of about 2 cm. These optional wing members 53 will abut against adjacent an adjacent anatomical structure to limit the distance through which the sheath 40 may be advanced through an opening or channel within the body. This sheath 40 may be used to facilitate insertion of the above-described substance delivering spacer device 10 or this sheath 40 may be used alone to facilitate suctioning of matter or for delivery of therapeutic or diagnostic substances.
In the embodiment shown in
The handpiece 64 comprises a sighting member such as a fin 66, a top elongate member 70 and a bottom elongate member 68 that is attached to and substantially parallel to the top elongate member. The handpiece may also comprise a distal grip portion 72. All or part of the handpiece 64 may be coated with an elastomeric material and/or may be provided with grooves, ridges or surface configurations that facilitate firm grasping of the handpiece 64 by the operator.
The sighting fin 66 extends from the handpiece in a plane that is parallel to the plane of the needle curve 65, thereby providing to the operator a visual indication of the lateral direction in which the distal portion of the needle body 62 is advancing even when the distal end of the needle body 62 is within the subject's body and out of direct sight of the operator. Additionally, the top edge 67 of the vertical sighting fin 66 is parallel to and in substantial alignment with the distal portion of the needle body 62, thereby providing to the operator a visual indication of the vertical tilt or trajectory on which the needle tip 63 is advancing even when the distal end of the needle body 62 is within the subject's body and out of direct sight of the operator.
U.S. Pat. No. 5,314,417 entitled “Safety Trocar” and U.S. Pat. No. 5,267,965 entitled “Safety Trocar”, the entire disclosures of which are incorporated herein by reference, disclose safety mechanisms that may optionally be used in combination with the sinus needle device 60 and sheath 40.
As an alternative to a needle body 63 having a sharp tip such as a trocar tip 63, the sinus needle may comprise any other suitable tissue penetrating apparatus capable of forming the desired penetration through the intended tissue (e.g., for ethmoid applications, through mucosal tissue and bone). These other suitable tissue penetrating apparatus include but are not limited to rotating drills, burs, bipolar or monopolar radiofrequency or electrocautery probes, laser probes, etc.
In other alternative embodiments where the needle 62 is replaced by a laser probe, a fiber optic laser waveguide may extend through the probe and a suitable type of laser light may be delivered through the wave guide and out of the distal end of the probe to penetrate through the desired anatomical structure. For penetration through the ethmoid bulla or other soft tissue or bony paranasal structures one suitable type of laser is a holmium:YAG laser. See, Metson, Ralph; Holmium:YAG Laser Endoscopic Sinus Surgery: A Randomized, Controlled Study; Laryngoscope; 106(1) Supplement 77:1-18 (January 1996).
Treatment of Ethmoid Sinusitis by Needle Ethmoidotomy and Implantation of Substance Delivering Spacer Device with Sustained Corticosteroid Delivery
Initially, as seen in
The subject is anesthetized or appropriate analgesia/sedation is administered. As shown in
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Prior to insertion of the substance delivering spacer device 10, the physician may optionally retract the constraining sheath 30 to expose suture loop 20, and a length of 2-0 or 3-0 suture material 17 having a straight or curved needle 19 may be passed through suture loop and doubled over. The constraining sheath 30 may then be moved to its advanced position, and the opposite ends of the doubled over suture 17 will be caused to protrude out of the proximal end of the constraining sheath 30 as shown in
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Thereafter, as seen in
As seen in
In this ethmoid example, the sinus needle sheath 40 has a distal shaft portion 44 made of Nylon having an outer diameter of 0.087 inches and inner diameter of 0.075 inches and length of 25 mm. Intermediate tapered region 54 is about 5 mm in length and is tapered from an outer diameter of 0.104 inches and an inner diameter of 0.088 inches at its proximal end, to an outer diameter of 0.092 inches and an inner diameter of 0.075 inches at its distal end. Proximal shaft portion 42 is made of Nylon 12 and has an outer diameter of 0.102 inches and inner diameter of 0.088 inches and length of 3.5 inches. Distal and proximal sheath markers 44 are made of rings of a Pt—Ir alloy with an outer diameter of 0.087 inches and an inner diameter of 0.085 inches. The distal shaft marker 44 is located 1 mm from the distal end DE of needle sheath 134. Proximal shaft marker 148 is located 18 mm from the distal end of needle sheath 40. The total length of needle sheath 40 is 115 mm.
Although the example of
The implantable device 10 can be used to preferably deliver fluids or suspensions with a low surface tension. Fluids with low surface tension easily spread across a surface. This is especially useful to deliver substances over a large surface area, especially in anatomical regions such as ethmoid sinuses that have complicated 3-D geometries. In one embodiment, the low surface tension fluid comprises a surfactant. In one method embodiment, a low surface tension irrigating fluid containing one or more substances is delivered to the ethmoid sinuses. In some embodiments, a substantially inert fluid such as saline solution may be delivered to moisten the surrounding tissues and the device may perform a spacing and/or drainage/ventilation function. In other embodiments, an active substance such as a therapeutic or diagnostic substance may be delivered in addition to the spacing and/or drainage/ventilation function of the implanted device 10.
In some applications, the substance delivering spacer device 10 may be implanted within openings (e.g., natural ostia, surgically altered ostia, other man-made openings) of paranasal sinuses to facilitate the treatment of a disease or disorder affecting the paranasal sinus. In such applications, the opening of the paranasal sinus may be enlarged (e.g., dilated) before or after placement of a device 10, 104 of the present invention within such opening. One such procedure is balloon dilation of sinus cavity ostia. In such procedure, a guide catheter having a substantially fixed shape is inserted through the nose and advanced to a position where the distal end of the guide catheter is adjacent to the ostium of a paranasal sinus. A guidewire is then advanced through the guide catheter (e.g., Relieva™ Guide Catheter, Acclarent, Inc., Menlo Park, Calif.) and into the paranasal sinus. Thereafter, a balloon catheter (e.g., Relieva™ Balloon Catheter, Acclarent, Inc., Menlo Park, Calif.) is advanced over the guidewire and is used to dilate the ostium of the paranasal sinus, thereby improving drainage from and/or ventilation of that paranasal sinus. Examples of such devices and procedures for balloon dilation of a paranasal sinus ostium are described in U.S. patent application Ser. No. 10/829,917, now U.S. Pat. No. 7,654,997, issued Feb. 2, 2010, entitled “Devices, Systems and Methods for Diagnosing and Treating Sinusitis and Other Disorders of the Ears, Nose and/or Throat;” Ser. No. 10/944,270, published as U.S. Pub. No. 2006/0004323 on Jan. 5, 2006, entitled “Apparatus and Methods for Dilating and Modifying Ostia of Paranasal Sinuses and Other Intranasal or Paranasal Structures;” Ser. No. 11/116,118, now U.S. Pat. No. 7,720,521, issued May 18, 2010, entitled “Methods and Devices for Performing Procedures Within the Ear, Nose, Throat and Paranasal Sinuses;” Ser. No. 11/150,847, now U.S. Pat. No. 7,803,150, issued Sep. 28, 2010, entitled “Devices, Systems And Methods Useable For Treating Sinusitus” and Ser. No. 11/234,395, now U.S. Pat. No. 7,410,480, issued Aug. 12, 2008, entitled “Devices and Methods for Delivering Therapeutic Substances for the Treatment of Sinusitis and Other Disorders,” the entire disclosure of each such patent application being expressly incorporated herein by reference.
Treatment of Frontal Sinusitis by Balloon Dilation of Frontal Outflow Tract and Implantation of Spacer Device with Sustained Corticosteroid Delivery
In this procedure, the endoscope 400 is inserted and, optionally, a C-arm fluoroscope (not shown) may also be positioned to provide fluoroscopic images of the procedure when desired. Although, for clarity and visual simplicity, the endoscope 400 is shown only in
Under endoscopic visualization, a frontal sinus guide catheter 500 (e.g., the Relieva® 70 Degree Sinus Guide Catheter; Acclarent, Inc., Menlo Park, Calif.) is inserted through the nostril and advanced to a position where its distal end is within or aligned with the frontal sinus ostium FSO. Such positioning of the guide catheter 500 may be verified by endoscopic visualization and/or fluoroscopy.
Thereafter, a guidewire GW (Relieva® Sinus Guidewire; Acclarent, Inc., Menlo park, Calif.) is advanced through the guide catheter 500 and into the frontal sinus FS, as shown in
Thereafter, as shown in
Thereafter, the substance delivering spacer device 10 is prepared and advanced through the guide catheter 500 and into the frontal sinus FS. Prior to insertion of the device 10 into the guide catheter 500, the constraining tube 42 may be removed and the retention wings 18 may be manually folded forward (i.e., in the distal direction) using finger pressure as the spacer device 10 is inserted into the proximal end of the guide catheter 500. As the distal end of the spacer device emerges out of the distal end of the guide catheter 500, the retention wings 18 will spring outwardly and will engage the frontal sinus ostium FSO as shown in
Thereafter, as shown in
Thereafter, as shown in
Thereafter, a proximal portion of the shaft 12 of spacer device 10 may be cut away, leaving a short length of the shaft 12 hanging within the nose. The suture 17 with straight needle 19 is used to suture the suture tab 20 of the spacer device 10 to tissue within the nose, thereby helping to retain the implanted portion of the spacer device 10 in its desired position for a desired time period following the procedure. Some of the substance will remain in the remaining segment of shaft 12 distal to the cut and may leak into the nasal cavity subsequent to the procedure, thereby providing medication to other structures within the nasal cavity as well.
Treatment of Frontal Sinusitis by Implantation of Spacer Device with Sustained Corticosteroid Delivery
In this example,
Thereafter, a guidewire GW (Relieva® Sinus Guidewire; Acclarent, Inc., Menlo park, Calif.) is advanced through the guide catheter 500 and into the frontal sinus FS, as shown in
With reference to
Thereafter, the substance spacer device 10 is prepared as described above and the constraining tube 30 is placed in its advanced position so as to constrain and cover the suture loop 20, retention wings 18 and reservoir 14 in their collapsed positions. The device 10 is advanced into the previously inserted sheath 40 in substantially the same manner as described above and shown in
Thereafter, the sheath 40 and constraining tube 30 are retracted and a syringe containing 0.31 cc to 0.35 cc of Triamcinolone Acetonide injectable suspension (Kenalog® 40, Brystol-Myers Squibb Company, Princeton, N.J.) is attached to the proximal Luer connector of the sinus spacer device 10 and the Triamcinolone Acetonide injectable suspension is injected, thereby causing the reservoir 14 to expand within the frontal sinus FS, as previously described above. Successful expansion of the reservoir 14a may be verified by CT scan if desired.
Thereafter, the proximal end of the sinus spacer device 10 is cut off, and the sheath 40 and constraining tube 30 are retracted proximally and removed in the same manner as described above and shown in
Thereafter, a proximal portion of the shaft 12 of spacer device 10 may be cut away, leaving a short length of the shaft 12 hanging within the nose. The suture 17 with straight needle 19 is used to suture the suture tab 20 of the spacer device 10 to tissue within the nose, thereby helping to retain the implanted portion of the spacer device 10 in its desired position for a desired time period following the procedure as seen in
Alternative Approach to Frontal Sinusitis Treatment
The sinus spacer 511 generally includes the distal shaft portion 512b, an expandable reservoir 514 mounted on the distal shaft portion 512b near its distal end, collapsible retention members 518 for retaining the spacer 511 in the sinus, and a suture loop 517 allowing a physician the option of attaching the spacer 511 to mucosal tissue to further ensure that the spacer 511 stays in a desired, implanted location. In general, the sinus spacer 511 may have any suitable dimensions, features, number of reservoir holes/apertures, sizes and shapes and numbers of retention members 518 and the like. Many of these features and details have been described above and thus will not be repeated here. Several differences between the frontal sinus spacer 511 and the spacers described above for ethmoid sinuses are as follows. The wing span of the retention members 518, measured from tip to tip in the expanded configuration, is approximately 13-16 mm for the frontal spacer device 511, versus approximately 9-12 mm for the ethmoid spacers. Each retention member 518 has an angle, in its expanded configuration and relative to the shaft 512, of about 70 degrees, versus about 80 degrees in the ethmoid spacers. Additionally, the overall length of the frontal sinus spacer 511 (i.e., the clear distal shaft portion 512b) is approximately 65 mm+/−3 mm, versus approximately 50 mm+/−3 mm in the ethmoid spacers. Of course, these features describe but one embodiment of the frontal sinus spacer 511, and various alternative embodiments may have different dimensions.
The reservoir 514 assumes an expanded configuration as it is filled. Here, the reservoir 514 may be formed of any suitable biocompatible material and, in some embodiments, may comprise a balloon formed of non-compliant or semi-compliant material such as Nylon 12. The reservoir can include a plurality of openings and can be configured as shown in
As described below, the reservoir 514 may be inserted in a collapsed configuration into a frontal sinus ostia or outflow tract and, thereafter, the reservoir may be loaded with the desired substance, causing the reservoir to transition to an expanded state.
In some embodiments, the reservoir 514 need not be used to deliver a therapeutic substance. It may, in fact, be used as a space occupying device. In such applications, the reservoir 514 may be loaded in situ with saline solution or other inert liquid, causing the reservoir 514 to expand and frictionally engage or contact adjacent anatomical structure(s), thereby providing a degree of retention at the desired implantation location. This aspect of the reservoir 514 may be further facilitated by the provision of surface projections on the reservoir.
The reservoir 514 may be relatively small in diameter when in its collapsed configuration, thus allowing it to be introduced or removed easily. In embodiments where the reservoir 514 is formed of non-compliant or semi-compliant material, the reservoir 514 will not undergo substantial elastic deformation in the filling process and thus will not exert pressure on its contents in order to expel the desired substance through openings 531. Rather, the substance in the reservoir 514 will elute through the openings 531 by gravity and/or by the passage of mucus through the sinus via ciliary action. This non-pressurized delivery allows for the slow release of the desired substance over several days. In some other embodiments, the reservoir 514 may be formed of compliant or elastic material with small openings 531 such that the material of which the balloon 514 is formed will contract as substance passes out of the openings 531, thereby maintaining pressure within the balloon. Also, in this example, the reservoir has a cylindrical side wall 514a which defines the working length of the reservoir, a distal taper 514b which transitions from the cylindrical side wall 514a to the distal shaft 512b (distal to the reservoir) and a proximal taper 514c that transitions from the cylindrical side wall 514a to the distal shaft 512b (proximal to the reservoir), and the openings 531 extend onto the proximal and distal tapers 514b, 514c, as shown. The reservoir 514 may have dimensions, openings, and overall configuration as described previously with reference to other embodiments.
The distal shaft portion 512b may be made of Nylon 12 in one embodiment. As mentioned above, in one embodiment the full length of sinus spacer 511, from the distal tip to the proximal end of the distal shaft portion 512b, may be about 65 mm+/.+−0.3 mm. An aperture is formed in the catheter shaft 512 to facilitate filling of the reservoir 514. A valve can also be provided to allow the substance (or component(s) of the substance) to flow from the lumen of the catheter shaft 12 into the reservoir 514 and prevent substantial backflow from the reservoir 514 into the lumen 513. The valve may comprise any suitable type of one way valve.
Also, a distal radiopaque marker 524 and proximal radiopaque marker 522 may be provided to facilitate the desired positioning of the reservoir 514 within a subject's body. Each of these markers 522, 524 may be made of a ring of radiopaque material and may be mounted on the shaft 512 in alignment with each end of the reservoir's cylindrical sidewall 514a. For example, each marker 522, 524 can embody a band of Platinum-Iridium alloy. These markers are visible under various imaging techniques including fluoroscopy and CT scanning.
The proximal shaft portion 512a may be made of polyimide tubing in one embodiment. A hub 516 comprising a female Luer connector made of clear polycarbonate can be attached to the proximal end of shaft 512. Proximal shaft portion 512a and distal shaft portion 512b may, in general, have any of the dimensions, features, materials and the like of similar catheter shafts described in reference to other embodiments above. In one embodiment, the proximal shaft portion 512a may include a shaft marker 513. The shaft marker 513 may be positioned along the shaft 512 such that when a distal end of the shaft marker 513 reaches a proximal end of the stop member 531 on the sheath 530 during advancement (described in greater detail below), then the distal end of the sinus spacer 511 is adjacent the distal end of the guide device 540. When the proximal end of the shaft marker 513 reaches the proximal end of the stop member 531, then the sinus spacer 511 has been advanced out of the distal end of the guide 540. Use of the shaft marker during a sinus spacer placement procedure is described more fully below in reference to
Additionally, the implantable substance delivery device or spacer 510 can include a pair of retention wings 518. It is to be recognized that the spacer 510 can alternatively include three or four or more such wings. The retention wings 518 are located at diametrically opposed locations on the shaft 512, and extend distally about the reservoir 514. Each retention wing 518 can embody a preformed loop of nickel-titanium (nitinol) wire. Each retention wing 518 may be flexed or compressed to a collapsed position where it lies substantially flat against the outer surface of the reservoir 514. However, the retention wings 518 are biased to a preformed configuration such that, when unconstrained, each retention wing 518 will resiliently spring outwardly to an extended position wherein it extends at an angle of from about 20 degrees to about 90 degrees relative to the longitudinal axis of the shaft 512, and more ideally from about 50 degrees to about 80 degrees, and in one embodiment about 70 degrees. In various embodiments, the wings 518 may define a wing span of about 9 mm to about 20 mm or more, and more ideally from about 13 mm to about 16 mm, and in one embodiment about 15 mm. In one embodiment, the distal end of the spacer device 511 may be provided with an atraumatic tip formed from a soft polymer. Further, in some embodiments, the geometry and positioning of the wings 518 may be selected so that drug housed in the reservoir 514 can elute out of openings 531 both proximal and distal to the wings 518. In an alternative embodiment, wings 518 may be positioned along the shaft 512 such that all of the openings 531 are disposed distal to the wings 518.
As seen in
In one embodiment, the sheath 530 includes a proximal stop member 541. The stop member 541 is configured to abut a proximal luer on the guide device 540 as the sheath 530 and the substance delivery device 510 are advanced into the guide 540. Thus, as the sheath 530 and substance delivery device 510 are advanced, the stop member 541 stops advancement of the sheath 530, and the substance delivery device 510 continues to be advanced, so that the sinus spacer exits out of the distal end of the guide 540. In other words, the sheath 530 with stop member 541 allows the wings 518 of the sinus spacer 511 to be constrained before and during advancement into the patient, until the spacer 511 is advanced out of the distal end of the guide 540.
The sheath 530 may also include a slanted or bevelled distal tip 532. This slanted distal tip 532 shape may facilitate pulling the sinus spacer 511 back into the sheath 530 if that is necessary during a procedure. The tip 532 may also facilitate advancement of the sheath 530 through the guide 540.
Further alternative embodiments of an implantable substance delivery device are shown in
Turning now to
In some embodiments, the sheath or guide 540 may have a shapeable (bendable, malleable, etc.) distal portion or tip that can be adjusted to fit a patient's anatomy. The tip may be preshaped with a given curve but may be adjusted by the user as necessary. The material of such a tip may be a bendable or malleable tubing that may retain its shape and may also be repeatedly shaped as needed. For example, in one embodiment, the material may be a type of plastic with braided wires 527 (See
With reference now to
In some embodiments, the substance delivery device 510 may be prepared as described above, and the constraining sheath 530 may be placed in its advanced position to constrain and cover the retention wings 518 and reservoir 514 in their collapsed positions. In alternative embodiments, the sheath 530 and substance delivery device 510 may be provided in a configuration ready to be used.
As shown in
As shown in
Thereafter, as shown in
Next, as shown in
The sinus spacer 511 may contain any suitable substance or combination of substances, such as but not limited to any of the substances listed in the present application. The sinus spacer 511 may be left in the frontal sinus for any length of time, such as from one day to one year, and more ideally from about 7 days to about 90 days, and even more ideally from about 14 days to about one month. In some embodiments, substance may only be delivered to a frontal paranasal sinus using the frontal sinus spacer 511. Alternatively, substance may be delivered to the frontal sinus and the frontal recess or outflow tract and in some cases even farther proximally within the nasal cavity. Oftentimes, the delivered substance will be chosen to have a beneficial effect not only within a sinus but in any other location in the nasal cavity to which it might be delivered.
As with the embodiments described above, the method just described may be performed after the frontal sinus ostium and/or frontal outflow tract is expanded using a Balloon Sinuplasty™ sinus dilation procedure. Alternatively, the method may be performed on a “native,” non-operated frontal paranasal sinus. Whether a prior Balloon Sinuplasty™ sinus dilation procedure is performed may sometimes depend on how wide the frontal sinus ostium and/or the frontal outflow tract are.
Referring now to
Although the accompanying drawings and above-described examples have specifically shown techniques for implanting the substance delivering spacer device 510 in the frontal sinus, similar techniques may be employed to implant the device in other sinuses. Of course, various other approaches and delivery equipment may be required to accomplish the same.
Stability of Triamcinolone Acetonide within Spacer Device Following Implantation
A study was performed to confirm that the Triamcinolone Acetonide injectable suspension (Kenalog® 40, Brystol-Myers Squibb Company, Princeton, N.J.), when loaded into the reservoir 14 of the substance delivering spacer device 10, remains intact and capable of pharmacologic activity for at least 30 days following implantation of the device. In this study, the reservoir 14 of one device 10 was loaded by injecting 0.31 cc of the Triamcinolone Acetonide injectable suspension as described above (hereinafter referred to as “Triamcinolone Acetonide loaded reservoir”). The reservoir 14 of a second device 10 was loaded with saline (hereinafter referred to as “placebo loaded reservoir”) and the reservoir of a third device remained empty (hereinafter referred to as “blank reservoir”) All three devices were maintained under ICH stability conditions (40°±2° C./75% RH±5% RH) in Caron Model 6030 Environmental Stability Chamber. High Performance Liquid Chromatography (HPLC) was performed on aliquots of the contents of each reservoir at day 0 and day 30. The results of this study are summarized in Table 1 below:
The Triamcinolone Acetonide potency of samples obtained from the Triamcinolone Acetonide loaded reservoir at days 0 and day 30, respectively, was confirmed by HPLC. In this study, the levels of impurities rose within acceptable ranges and the potency of Triamcinolone Acetonide present in the Triamcinolone Acetonide reservoir remained sufficient to cause the intended local anti-inflammatory effect for at least 30 days.
Efficacy of Triamcinolone Acetonide Delivered Using Substance Delivering Spacer Device 10
Use of topical corticosteroid therapy to treat chronic sinus inflammatory conditions is based on the rationale that more effective drug concentrations can be achieved at local receptor sites in the nasal mucosa, with minimal risk of systemic adverse effects. Triamcinolone Acetonide (TA) is a second generation synthetic corticosteroid of which there are currently six compounds approved for intranasal use. All six corticosteroids appear to be relatively equal with regard to potency and effectiveness. TA was chosen for use in the Ethmoid Sinus Spacer as the compound with the longest safety record and for its availability in a concentrated solution suitable for use in this device. Specifically, Kenalog-40 was used as it is one of the approved and marketed formulations of Triamcinolone Acetonide.
It has been established that intranasal and/or inhaled doses of Triamcinolone Acetonide do not cause hypothalamo-pituitary-adrenal (HPA) suppression even when drug is delivered for up to three years. See, Klossek J M et al., Local Safety Of Intranasal Triamcinolone Acetonide Clinical And Histological Aspects Of Nasal Mucosa In The Long-Term Treatment Of Perennial Allergic Rhinitis, Rhinology, 39(1):17-22 (2001); Lund, V J., Maximal Medical Therapy for Chronic Rhinosinusitis, Otolaryngol Clin N Am 38, 1301-1310 (2005) and Laliberte F et al., Clinical And Pathologic Methods To Assess The Long-Term Safety Or Nasal Corticosteroids, Allergy 55(8): 718-722 (2000).
Locally administered TA has been demonstrated to provide a reduction in the severity of both early and late phase reaction to allergens, reduced sensitivity of local nasal irritant receptors and reduced local inflammation and a decreased likelihood for secondary rhinovirus infections. Even long term local delivery of TA to the nasal sinus does not appear to damage nasal mucosa.
The volume of vehicle in the substance delivering spacer device 10 used in this study has a reservoir 14 that will hold 0.1 ml. when loaded to maximum capacity. If loaded to maximum capacity with the Kenalog-40, the reservoir will contain 4 mg of TA. This amount of TA is roughly equivalent in potency to the 35-40 mg of cortisol produced daily by normal human adrenal glands. Thus, a total 4 mg TA, even if released all at once, would not be expected to adversely affect adrenal corticoid activity.
As explained above, the openings 31 in the reservoir 14 of the substance delivering spacer device 10 may be designed to limit diffusion of TA from the reservoir so that only a small daily dose of drug is delivered over the course of two weeks. In this manner, the dose delivered locally into the ethmoids or other paranasal sinuses may be less than the recommended dose of TA delivered with commercially available nasal inhalers (e.g., Nasacort® Inhaler, Sanofi-Aventis, Bridgewater, N.J.).
Thirteen human subjects suffering from ethmoid sinusitis were treated by performance of a needle ethmoidotomy with post operative delivery of TA by implantation of a substance delivering spacer device 10 substantially as described above and shown in
Post-Operative Follow-Up and Data Collection
Subject Nos. 1-10:
Blood levels of TA were determined in subjects 1-10 prior to the administration of anesthesia and at 1, 2 and 4 hours following implantation and loading of the substance delivering spacer device 10. If the particular subject stayed overnight at the treatment facility, a blood sample was taken at 23 hours or just prior to discharge. Additional blood samples were collected in subjects 1-10 at 3, 7, 10 and 14 days after the procedure and immediately prior to explant and removal of the substance delivering spacer device 10.
In addition to collection of blood samples as noted above, the patient was asked to fill out a Sino-Nasal Outcomes Test (SNOT-20) questionnaire. (SNOT-20—Piccirillo, J F et al., Psychometric and clinimetric validity of the 20-Item Sino-Nasal Outcome Test (SNOT-20), Copyright© 1996 by Jay F. Piccirillo M. D., Washington University, St. Louis, Mo.) at baseline and at 1, 2 and 6 weeks following explant and removal of the substance delivering spacer device 10. Additionally, the patient was asked to fill out a questionnaire specific to the tolerability of the substance delivering spacer device 10. The device was removed during an office visit at day 14 following implantation. Quantification of residual drug in the device provided additional information relevant to the elution of triamcinolone acetonide from the Ethmoid Sinus Spacer during the implantation of the device.
Investigators provided post-operative care as required except no steroid nasal sprays and nasal rinses were administered. Post-operative antibiotic treatment was administered at the discretion of the Investigator, as needed. This was to minimize the effects of concomitant medications on the study outcome.
A final CT scan of the ethmoid sinuses was taken at eight weeks to assess the condition of the ethmoid sinuses and when compared to baseline, the degree of improvement.
Subject Nos. 11-13:
Subjects Nos. 11 through 13 received the same post-operative care and blood sample collection as Subject Nos. 1-10, with the following exceptions:
Following the baseline blood sample taken prior to the administration of anesthesia, blood was drawn at 4 hours following device implantation on the day of the procedure and days 1, (optional) 3, 7, 14, 21 and 28, prior to explant and removal of the substance delivering spacer device 10.
Six follow-up visits were scheduled throughout the study, at days 3, 7, 14, 21 and 28 and a final visit 10 weeks following the procedure. In addition to collection of blood samples as noted above, the patient was asked to fill out a SNOT-20 Quality of Life (QOL) questionnaire at baseline, and at 1, 2, and 6 weeks following explant. Additionally, the patient was asked to fill out a questionnaire specific to the tolerability of the Ethmoid Sinus Spacer. The device was removed during an office visit at day 28 following implantation.
Investigators provided post-operative care as required except no steroid nasal sprays were administered. Post-operative antibiotic treatment was administered at the discretion of the Investigator, as needed. This was to minimize the effects of concomitant medications on the study outcome.
A final CT scan of the ethmoid sinuses was taken at ten weeks (six weeks post explant) to assess the condition of the ethmoid sinuses and when compared to baseline, the degree of improvement.
Subject No. 14:
Subject No. 14 was the one who was treated for frontal sinusitis rather than ethmoid disease. Subject No. 14 received post-operative follow-up and data collection (e.g., blood samples and SNOT-20 questionnaires) in substantially the same manner as Subject Nos. 1-10.
CT Scan Results
The CT scans were read and improvement in the affected sinuses was scored by the Lund McKay scoring method. These Lund McKay Scores are shown graphically in
SNOT-20 and Questionnaire Results
Symptom improvement was also documented in the Patient Questionnaire administered at one, two and six weeks post procedure. All patients reported they were significantly improved or improved six weeks following the procedure, no patients reported feeling worse. At six weeks a majority of patients were satisfied with the results and stated that if given this treatment choice again, they would agree to have the surgery.
Statistical Analysis of Results
The SNOT-20 results were recorded during 5 post-procedural evaluation visits. The null and alternative hypotheses evaluated based on this endpoint are as follows:
Ho: μ(Day 42 minus baseline)=0
Ha: μ(Day 42 minus baseline)≠0
Univariate analysis results from comparing the change in the SNOT-20 scores from baseline were analyzed using a paired-difference t-test. The results from this analysis revealed a significant reduction in the SNOT-20 scores within 7 days of the procedure. A consistent reduction was observed during all successive post-procedure evaluation visits. At the time enrollment was stopped, 13 of the 14 patients (92.9%) had completed the 42-day post-procedure evaluation visit. The reduction from baseline 42 days post-procedure was −22.08 points on the SNOT-20 scale, with a standard deviation of 14.69 and a probability value <0.001. The effect size of this result is 1.50, which is reflective of a very strong treatment effect.
Lund-McKay Scores (CT Scan)
CT scans were performed at baseline and 42 days following the procedure to derive the LMK score. The null and alternative hypotheses evaluated based on this endpoint are as follows:
Ho: μ(Day 42 minus baseline)=0
Ha: μ(Day 42 minus baseline)≠0
Univariate analysis results from comparing the change in the LMK scores from baseline were analyzed using a paired-difference t-test. The results from this analysis revealed a significant reduction in the LMK scores 42 days after the procedure. The reduction for baseline was 6.50 points on the LMK scale, with a standard deviation of 3.96, and a probability value <0.001. The effect size from this result is 1.64, which is reflective of a very strong treatment effect.
A subset analysis was performed comparing the change in the LMK scores from the ethmoid sinuses. The results from this analysis also revealed a significant reduction in the LMK scores 42 days after the procedure. The reduction for baseline was 2.21 points on the LMK scale, with a standard deviation 1.53, and a probability value <0.001. The effect size of this result is 1.44, which is reflective of a very strong treatment effect.
The primary efficacy endpoint was examined using inferential statistics. Based on the performance success of the 14 patients enrolled (100%), the lower 95% exact binomial confidence interval was 76.84%.
Blood Plasma Analysis
To assess the secondary endpoint of the ability of TA to elute from the substance delivering spacer device 10 to over time, TA concentrations were determined in blood plasma from each of the collected blood samples. These data are summarized in Table 2 below.
Low (i.e., not systemically active) but detectable TA levels were determined in the subjects' blood plasma as far out as 28 days following implantation and loading of the substance delivering spacer device 10.
Locally effective doses of TA were delivered from the substance delivering spacer device 10 for up to 28 days post-procedure. The CT scans indicated significant reduction in sinus inflammation. The subjects also realized substantial improvement in sinusitis symptoms on the basis of the SNOT 20 and patient questionnaire results.
The term substance as used herein is to be broadly construed to include any feasible drugs, prodrugs, proteins, gene therapy preparations, cells, diagnostic agents, contrast or imaging agents, biologicals, etc. Such substances may be in bound or free form, liquid or solid, colloid or other suspension, solution or may be in the form of a gas or other fluid or non-fluid. For example, in some applications where it is desired to treat or prevent a microbial infection, the substance delivered may comprise a pharmaceutically acceptable salt or dosage form of an antimicrobial agent (e.g., antibiotic, antiviral, antiparasitic, antifungal, etc.), a corticosteroid or other anti-inflammatory (e.g., an NSAID), a decongestant (e.g., vasoconstrictor), a mucous thinning agent (e.g., an expectorant or mucolytic), an agent that prevents of modifies an allergic response (e.g., an antihistamine, cytokine inhibitor, leucotriene inhibitor, IgE inhibitor, immunomodulator), an anesthetic agent with or without a vasoconstriction agents (e.g. Xylocalne with or without Epinephrine), an analgesic agent, an allergen or another substance that causes secretion of mucous by tissues, hemostatic agents to stop bleeding, anti-proliferative agents, cytotoxic agents e.g. alcohol, biological agents such as protein molecules, stem cells, genes or gene therapy preparations, viral vectors carrying proteins or nucleic acids such as DNA or mRNA coding for important therapeutic functions or substances, cauterizing agents e.g. silver nitrate, etc.
Some non-limiting examples of antimicrobial agents that may be used in this invention include acyclovir, amantadine, rimantadine, oseltamivir, zanamivir, aminoglycosides (e.g., amikacin, gentamicin and tobramycin), amoxicillin, amoxicillin/clavulanate, amphotericin B, ampicillin, ampicillin/sulbactam, atovaquone, azithromycin, cefazolin, cefepime, cefotaxime, cefotetan, cefpodoxime, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, cefuroxime axetil, cephalexin, chloramphenicol, clotrimazole, ciprofloxacin, clarithromycin, clindamycin, dapsone, dicloxacillin, doxycycline, erythromycin, fluconazole, foscarnet, ganciclovir, atifloxacin, imipenem/cilastatin, isoniazid, itraconazole, ketoconazole, metronidazole, nafcillin, nafcillin, nystatin, penicillins including penicillin G, pentamidine, piperacillin/tazobactam, rifampin, quinupristin-dalfopristin, ticarcillin/clavulanate, trimethoprim/sulfamethoxazole, valacyclovir, vancomycin, mafenide, silver sulfadiazine, mupirocin, nystatin, triamcinolone/nystatin, clotrimazole/betamethasone, clotrimazole, ketoconazole, butoconazole, miconazole, tioconazole, detergent-like chemicals that disrupt or disable microbes (e.g., nonoxynol-9, octoxynol-9, benzalkonium chloride, menfegol, and N-docasanol); chemicals that block microbial attachment to target cells and/or inhibits entry of infectious pathogens (e.g., sulphated and sulponated polymers such as PC-515 (carrageenan), Pro-2000, and Dextrin 2 Sulphate); antiretroviral agents (e.g., PMPA gel) that prevent retroviruses from replicating in the cells; genetically engineered or naturally occurring antibodies that combat pathogens such as anti-viral antibodies genetically engineered from plants known as “plantibodies;” agents which change the condition of the tissue to make it hostile to the pathogen (such as substances which alter mucosal pH (e.g., Buffer Gel and Acidform); non-pathogenic or “friendly” microbes that cause the production of hydrogen peroxide or other substances that kill or inhibit the growth of pathogenic microbes (e.g., lactobacillus); antimicrobial proteins or peptides such as those described in U.S. Pat. No. 6,716,813 (Lin et al.) which is expressly incorporated herein by reference or antimicrobial metals (e.g., colloidal silver).
Additionally or alternatively, in some applications where it is desired to treat or prevent inflammation the substances delivered in this invention may include various steroids or other anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory agents or NSAIDs), analgesic agents or antipyretic agents. For example, corticosteroids that have previously administered by intranasal administration may be used, such as beclomethasone (Vancenase® or Beconase®, flunisolide (Nasalide®), fluticasone proprionate (Flonase®), triamcinolone acetonide (Nasacort®), budesonide (Rhinocort Aqua®), loterednol etabonate (Locort) and mometasone (Nasonex®). Other salt forms of the aforementioned corticosteroids may also be used. Also, other non-limiting examples of steroids that may be useable in the present invention include but are not limited to aclometasone, desonide, hydrocortisone, betamethasone, clocortolone, desoximetasone, fluocinolone, flurandrenolide, mometasone, prednicarbate; amcinonide, desoximetasone, diflorasone, fluocinolone, fluocinonide, halcinonide, clobetasol, augmented betamethasone, diflorasone, halobetasol, prednisone, dexamethasone and methylprednisolone. Other anti-inflammatory, analgesic or antipyretic agents that may be used include the nonselective COX inhibitors (e.g., salicylic acid derivatives, aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen and oxaprozin; anthranilic acids (fenamates) such as mefenamic acid and meloxicam; enolic acids such as the oxicams (piroxicam, meloxicam) and alkanones such as nabumetone) and Selective COX-2 Inhibitors (e.g., diaryl-substituted furanones such as rofecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide).
Additionally or alternatively, in some applications, such as those where it is desired to treat or prevent an allergic or immune response and/or cellular proliferation, the substances delivered in this invention may include a) various cytokine inhibitors such as humanized anti-cytokine antibodies, anti-cytokine receptor antibodies, recombinant (new cell resulting from genetic recombination) antagonists, or soluble receptors; b) various leucotriene modifiers such as zafirlukast, montelukast and zileuton; c) immunoglobulin E (IgE) inhibitors such as Omalizumab (an anti-IgE monoclonal antibody formerly called rhu Mab-E25) and secretory leukocyte protease inhibitor).
Additionally or alternatively, in some applications, such as those where it is desired to shrink mucosal tissue, cause decongestion or effect hemostasis, the substances delivered in this invention may include various vasoconstrictors for decongestant and or hemostatic purposes including but not limited to pseudoephedrine, xylometazoline, oxymetazoline, phenylephrine, epinephrine, etc.
Additionally or alternatively, in some applications, such as those where it is desired to facilitate the flow of mucous, the substances delivered in this invention may include various mucolytics or other agents that modify the viscosity or consistency of mucous or mucoid secretions, including but not limited to acetylcysteine (Mucomyst™, Mucosil™) and guaifenesin.
Additionally or alternatively, in some applications such as those where it is desired to prevent or deter histamine release, the substances delivered in this invention may include various mast cell stabilizers or drugs which prevent the release of histamine such as cromolyn (e.g., Nasal Chrom®) and nedocromil.
Additionally or alternatively, in some applications such as those where it is desired to prevent or inhibit the effect of histamine, the substances delivered in this invention may include various antihistamines such as azelastine (e.g., Astylin®), diphenhydramine, loratidine, etc.
Additionally or alternatively, in some embodiments such as those where it is desired to dissolve, degrade, cut, break or remodel bone or cartilage, the substances delivered in this invention may include substances that weaken or modify bone and/or cartilage to facilitate other procedures of this invention wherein bone or cartilage is remodeled, reshaped, broken or removed. One example of such an agent would be a calcium chelator such as EDTA that could be injected or delivered in a substance delivery implant next to a region of bone that is to be remodeled or modified. Another example would be a preparation consisting of or containing bone degrading cells such as osteoclasts. Other examples would include various enzymes of material that may soften or break down components of bone or cartilage such as collagenase (CGN), trypsin, trypsin/EDTA, hyaluronidase, and tosyllysylchloromethane (TLCM).
Additionally or alternatively, in some applications, the substances delivered in this invention may include other classes of substances that are used to treat rhinitis, nasal polyps, nasal inflammation, and other disorders of the ear, nose and throat including but not limited to anti-cholinergic agents that tend to dry up nasal secretions such as ipratropium (Atrovent Nasal®), as well as other agents not listed here.
Additionally or alternatively, in some applications such as those where it is desired to draw fluid from polyps or edematous tissue, the substances delivered in this invention may include locally or topically acting diuretics such as furosemide and/or hyperosmolar agents such as sodium chloride gel or other salt preparations that draw water from tissue or substances that directly or indirectly change the osmolar content of the mucous to cause more water to exit the tissue to shrink the polyps directly at their site.
Additionally or alternatively, in some applications such as those wherein it is desired to treat a tumor or cancerous lesion, the substances delivered in this invention may include antitumor agents (e.g., cancer chemotherapeutic agents, biological response modifiers, vascularization inhibitors, hormone receptor blockers, cryotherapeutic agents or other agents that destroy or inhibit neoplasia or tumorigenesis) such as; alkylating agents or other agents which directly kill cancer cells by attacking their DNA (e.g., cyclophosphamide, isophosphamide), nitrosoureas or other agents which kill cancer cells by inhibiting changes necessary for cellular DNA repair (e.g., carmustine (BCNU) and lomustine (CCNU)), antimetabolites and other agents that block cancer cell growth by interfering with certain cell functions, usually DNA synthesis (e.g., 6 mercaptopurine and 5-fluorouracil (5FU), antitumor antibiotics and other compounds that act by binding or intercalating DNA and preventing RNA synthesis (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C and bleomycin) plant (vinca) alkaloids and other anti-tumor agents derived from plants (e.g., vincristine and vinblastine), steroid hormones, hormone inhibitors, hormone receptor antagonists and other agents which affect the growth of hormone-responsive cancers (e.g., tamoxifen, herceptin, aromatase inhibitors such as aminoglutethamide and formestane, triazole inhibitors such as letrozole and anastrazole, steroidal inhibitors such as exemestane), anti-angiogenic proteins, small molecules, gene therapies and/or other agents that inhibit angiogenesis or vascularization of tumors (e.g., meth-1, meth-2, thalidomide), bevacizumab (Avastin), squalamine, endostatin, angiostatin, Angiozyme, AE-941 (Neovastat), CC-5013 (Revimid), medi-522 (Vitaxin), 2-methoxyestradiol (2ME2, Panzem), carboxyamidotriazole (CAI), combretastatin A4 prodrug (CA4P), SU6668, SU11248, BMS-275291, COL-3, EMD 121974, IMC-1C11, IM862, TNP-470, celecoxib (Celebrex), rofecoxib (Vioxx), interferon alpha, interleukin-12 (IL-12) or any of the compounds identified in Science Vol. 289, Pages 1197-1201 (Aug. 17, 2000) which is expressly incorporated herein by reference, biological response modifiers (e.g., interferon, bacillus calmette-guerin (BCG), monoclonal antibodies, interluken 2, granulocyte colony stimulating factor (GCSF), etc.), PGDF receptor antagonists, herceptin, asparaginase, busulphan, carboplatin, cisplatin, carmustine, cchlorambucil, cytarabine, dacarbazine, etoposide, flucarbazine, fluorouracil, gemcitabine, hydroxyurea, ifosphamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, thioguanine, thiotepa, tomudex, topotecan, treosulfan, vinblastine, vincristine, mitoazitrone, oxaliplatin, procarbazine, streptocin, taxol, taxotere, analogs/congeners and derivatives of such compounds as well as other antitumor agents not listed here.
Additionally or alternatively, in some applications such as those where it is desired to grow new cells or to modify existing cells, the substances delivered in this invention may include cells (mucosal cells, fibroblasts, stem cells or genetically engineered cells) as well as genes and gene delivery vehicles like plasmids, adenoviral vectors or naked DNA, mRNA, etc. injected with genes that code for anti-inflammatory substances, etc., and, as mentioned above, osteoclasts that modify or soften bone when so desired.
Any of the devices and methods described herein may also be used to deliver substances to the brain or alter the functioning of the olfactory system. Such examples include, the delivery of energy or the deposition of devices and/or substances and/or substance delivering implant(s) to occlude or alter olfactory perception, to suppress appetite or otherwise treat obesity, epilepsy (e.g., barbiturates such as phenobarbital or mephoobarbital; iminostilbenes such as carbamazepine and oxcarbazepine; succinimides such as ethylsuximide; valproic acid; benzodiazepines such as clonazepam, clorazepate, diazepam and lorazepam, gabapentin, lamotrigine, acetazolamide, felbamate, levetiraceam, tiagabine, topiramate, zonisamide, etc.), personality or mental disorders (e.g., antidepressants, antianxiety agents, antipsychotics, etc.), chronic pain, Parkinson's disease (e.g., dopamine receptor agonists such as bromocriptine, pergolide, ropinitrol and pramipexole; dopamine precursors such as levodopa; COMT inhibitors such as tolcapone and entacapone; selegiline; muscarinic receptor antagonists such as trihexyphenidyl, benztropine and diphenhydramine) and Alzheimer's disease, Huntington's disease or other dementias, disorders of cognition or chronic degenerative diseases (e.g. tacrine, donepezil, rivastigmine, galantamine, fluoxetine, carbamazepine, clozapine, clonazepam and proteins or genetic therapies that inhibit the formation of beta-amyloid plaques), etc.
The devices and methods disclosed herein may be used to deliver several combinations of two or more substances disclosed herein to a suitable target anatomical region. In one particular embodiment, the devices and methods disclosed herein are used to deliver a combination of an anti-inflammatory agent (e.g. a steroid or an NSAID) and a mucolytic agent.
The devices and methods disclosed herein may be used to deliver gels or viscous liquids comprising one or more substances to anatomical regions such as paranasal sinuses. Such gels or viscous liquids may coat and adhere to a mucous membrane and thus provide sustained delivery of one or more substances to the mucous membrane. In one embodiment, a plasticized hydrocarbon gel comprising gelatin, pectin and sodium carboxymethylcellulose and a suitable substance may be delivered to a mucous membrane such as the mucous membrane of a paranasal sinus. Such gels can be used for sustained delivery of the suitable substance to the mucous membrane.
One or more of the substance reservoirs disclosed herein may comprise multiple compartments such that each compartment stores a particular substance formulation. The multiple compartments prevent mixing of multiple substance formulations before substance formulations are delivered to the anatomy.
One or more of the substance reservoirs comprising holes or pores may be filled with a suitable substance at a sufficiently high pressure to cause a portion of the substance to squirt out of the holes or pores. This process may be used to deliver an initial bolus of the substance to the surrounding anatomy.
One or more of the substance reservoirs disclosed herein may be filled with a suitable substance after the substance reservoir is introduced in an anatomical region. Alternatively, one or more of the substance reservoirs disclosed herein may be filled with a suitable substance before the substance reservoir is introduced in an anatomical region. Alternatively, one or more of the substance reservoirs disclosed herein may be pre-filled with a solid, lyophilized or concentrated substance. The solid, lyophilized or concentrated substance is converted to an active form by introducing a solvent into the substance reservoir. This may be done just before or after the substance reservoir is introduced in an anatomical region. Alternatively, one or more of the substance reservoirs disclosed herein may be pre-filled with an inactive form of a substance. The inactive form of the substance is converted to an active form by introducing an activating agent into the substance reservoir. This may be done just before or after the substance reservoir is introduced in an anatomical region.
It is to be further appreciated that, as described herein, the implantable portion of a substance delivering spacer device 10 may include a through lumen that may function as a vent and/or drain when such implantable portion device is in a paranasal sinus, air cell, Eustachian tube, opening formed in the tympanum or any other location within the body.
The devices and methods disclosed herein may be used to mark an anatomical region with a suitable imagable marker. For example, the devices and methods disclosed herein may be used to deliver a radio opaque marker such as a radio opaque contrast agent to an ostium of a paranasal sinus. This enables a user to image the ostium of the paranasal sinus using X-rays or fluoroscopy.
One or more of the substance delivery devices disclosed herein may comprise a curved, bent or angled region to enable the drug delivery devices to navigate through the anatomy.
The distal-most regions of one or more substance delivery devices disclosed herein may comprise an atraumatic tip. The atraumatic tip is used to prevent or reduce damage to the anatomy by the distal-most regions of the one or more substance delivery devices.
The outer surface of one of more substance delivery devices disclosed herein may comprise a coating that reduces or eliminates the risk of encrusting of the outer surface by a biological material. In one embodiment, the coating comprises a material that absorbs water to form a gel. Examples of such materials include, but are not limited to hyaluronic acid, etc.
One or more of the substance delivery devices disclosed herein may be designed to be easily removable from the anatomy after completion of a treatment.
One or more of the substance delivery devices disclosed herein may be refilled after a significant volume of substance filled in a substance reservoir has been delivered to the anatomy.
One or more of the substance delivery devices disclosed herein may comprise one or more markers to enable a user to locate and/or navigate the substance delivery devices through the anatomy. For example, the substance delivery devices may comprise visual markers to enable the user to determine the depth of insertion of the substance delivery devices into the anatomy. In another example, the substance delivery devices may comprise imaging markers to enable the user to locate and/or navigate the substance delivery devices using imaging modalities such as X-rays, MRI, etc.
As used herein, the term “opening of a paranasal sinus” shall include any opening in a paranasal sinus or air cell such as natural ostia, surgically altered natural ostia, surgically created openings, antrostomy openings, ostiotomy openings, burr holes, drilled holes, ethmoidotomy openings, ethmoidectomy openings, natural or man made passageways, etc.
As used herein, the term “implantable” shall include any device that is maintained in the body of a human or animal for a period ranging from 30 minutes to 60 days.
In each of the above-described examples wherein an endoscope 400 is employed, the endoscope 400 is shown as being inserted separately form the other devices. However, in any applications or embodiments of the invention where feasible, an endoscope may be attached to or integrated with one or more of the other devices used during the procedure as described in parent applications.
It is to be appreciated that Examples 2 and 3 above describe techniques which may be used for introducing the spacer device 10 into frontal sinuses which may or may not have been previously altered by surgery or prior balloon dilations. In some cases, such as where the frontal outflow tract has been previously dilated or modified by surgery so that the frontal sinus FS is relatively easy to access, the operator may simply deliver the spacer device 10 through the constraining tube 42 (or sinus sheath 40, 40a) and into the frontal sinus, with or without the use of forceps or other operative instruments, thereby eliminating the need for the use of a guide catheter, guidewire, dilator or other devices for guiding or facilitating advancement of the spacer device 10 into the frontal sinus as described in Examples 2 and 3.
It is to be further appreciated that, although Examples 1, 2 and 3 above describe Triamcinolone Acetonide injectable suspension (Kenalog® 40, Brystol-Myers Squibb Company, Princeton, N.J.) as the therapeutic agent that is loaded into and elutes from the reservoir, various other therapeutic agents may be used in addition to, or as an alternative to, this Triamcinolone Acetonideq injectable suspension. In some cases where it is desired to use the implanted spacer device 10a to deliver a steroid, the steroid may be prepared as a solution rather than a suspension. In such cases, the steroid will be dissolved in a suitable, biologically compatible solvent. For example, Cyclodextrins have been described as suitable solvents for dissolution of at least some steroids. Khomutov, S. M., Dovbnya, D. V. and Donova, M. V., Dissolution of a Mixture of Steroids in Cyclodextrin Solutions: a Model Description; Pharmaceutical Chemistry Journal; Vol. 35, No. 1i, pp. 627-629 (November, 2001).
In some instances, the devices of the present invention may be used to deliver steroids or other substances in formulations that are commercially available as, or otherwise suitable for, intra-nasal delivery to the nasal mucosa as nasal drops or sprays (i.e., nasal solutions). In at least some cases, such nasal solutions are prepared so that they are similar to nasal secretions and, thus, do not interfere with normal ciliary action. Such nasal solutions usually are isotonic and slightly buffered to a pH of 5.5 to 6.5. In addition, antimicrobial preservatives, similar to those used in ophthalmic preparations, and appropriate drug stabilizers, if required, may be included in the formulation. Various commercial nasal preparations are known and include, for example, antibiotics, steroids, antihistamines, decongestants and ipitropium bromide.
Where possible and appropriate, any of the substances delivered by devices of the present invention may be in the form of liposomes or nanoparticles (e.g., nanocapsules). The formation and use of liposomes is generally known to those of skill in the art. Liposomes are formed from phospholipids dispersed in an aqueous medium such that they spontaneously form multilamellar concentric bilayer vesicles sometimes referred to as multilamellar vesicles (MLVs). MLVs are typically from 25 nm to 4 μm in diameter. When sonicated, MLVs form small unilamellar vesicles (SUVs) of about 200 to 500 angstroms in diameters having cores which contain the aqueous solution. In general, when dispersed in an aqueous medium, phospholipids can form various structures other than liposomes, depending on the molar ratio of lipid to water. At low molar lipid to water ratios, liposomes will form. The physical characteristics of liposomes depend on pH, tonicity and the presence or non-presence of divalent cations. Liposomes can interact with cells by different mechanisms, including 1) endocytosis (e.g., phagocytosis of the liposome by cells such as macrophages and neutrophils), adsorption to the cell surface, 2) interaction with cell-surface components, 3) fusion with the plasma cell membrane by insertion of the lipid bilayer of the liposome into the plasma membrane or 4) transfer of liposomal lipids to cellular or subcellular membranes, or vice versa. Varying the liposome formulation can alter which mechanism(s) by which the lyposomes will interact with cells in the paranasal sinus, nasal mucosa, etc.
A nanocapsule is any nanoparticle that consists of a shell and a space, in which desired substances may be placed. Techniques for forming nanocapsules are known in the art. Polymeric nanocapsules can be made in specific sizes and shapes. They can be produced as monodisperse particles which have precisely defined physical and chemical properties and, thus, can be tailored to facilitate release of the therapeutic or diagnostic substance in response to particular bimolecular triggering mechanisms, such as pH, mucous flow or other conditions present within the paranasal sinus or other area in the ear, nose or throat where the device is implanted. Nanocapsules can be used in the present invention as “smart drugs” which have specific chemical receptors or binding sites that will bind to specific target cells (e.g., cancer cells associated with sinus or nasal tumors or cells associated with inflammatory conditions.
It is to be appreciated that the invention has been described hereabove with reference to certain examples or embodiments of the invention but that various additions, deletions, alterations and modifications may be made to those examples and embodiments without departing from the intended spirit and scope of the invention. For example, any element or attribute of one embodiment or example may be incorporated into or used with another embodiment or example, unless otherwise specified of if to do so would render the embodiment or example unsuitable for its intended use. Also, where the steps of a method or process have been described or listed in a particular order, the order of such steps may be changed unless otherwise specified or unless doing so would render the method or process unworkable for its intended purpose. All reasonable additions, deletions, modifications and alterations are to be considered equivalents of the described examples and embodiments and are to be included within the scope of the following claims.
This patent application is a continuation of U.S. patent application Ser. No. 14/266,002 entitled “Frontal Sinus Spacer” filed on Dec. 22, 2008, now U.S. Pat. No. 8,764,729, which is a continuation-in-part of copending U.S. patent application Ser. No. 12/100,361 entitled “Ethmoidotomy System And Implantable Spacer Devices Having Therapeutic Substance Delivery Capability For Treatment Of Paranasal Sinusitis” filed on Apr. 9, 2008, 1), now U.S. Pat. No. 8,864,787, issued Oct. 21, 2014, which is a continuation-in-part of U.S. patent application Ser. No. 11/544,009 entitled “Implantable Devices and Methods for Treating Sinusitis and Other Disorders” filed on Oct. 4, 2006, now U.S. Pat. No. 7,419,497, which is a continuation-in-part of Ser. No. 11/234,395 entitled “Devices and Methods for Delivering Therapeutic Substances for the Treatment of Sinusitis and Other Disorders” filed on Sep. 23, 2005, now U.S. Pat. No. 7,410,480, which is a continuation-in-part of Ser. No. 10/829,917 entitled “Devices, Systems and Methods for Diagnosing and Treating Sinusitis and Other Disorders of the Ears, Nose and/or Throat” filed on Apr. 21, 2004, now U.S. Pat. No. 7,654,997, and of Ser. No. 10/912,578 entitled “Implantable Device and Methods for Delivering Drugs and Other Substances to Treat Sinusitis and Other Disorders” filed on Aug. 4, 2004, now U.S. Pat. No. 7,361,168, and 2) which is a continuation-in-part of Ser. No. 11/037,548 entitled “Devices, Systems and Methods for Treating Disorders of the Ear, Nose and Throat” filed on Jan. 17, 2005, now U.S. Pat. No. 7,462,175, the entire disclosure of each such application being expressly incorporated herein by reference.
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| Number | Date | Country | |
|---|---|---|---|
| 20140336575 A1 | Nov 2014 | US |
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| Parent | 12341602 | Dec 2008 | US |
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