Abstract:
A method for controlling narrowing of at least one airway and associated apparatus are provided. The method includes positioning a needle-less injection assembly in an airway of a patient, and introducing a medication from at least one port of the needle-less injection assembly across an epithelium of a wall of the airway and into collagenous and smooth muscle layers of the airway wall such that the medication controls at least one mechanism of airway narrowing.

Description:
BACKGROUND OF THE INVENTION 
     FIELD OF THE INVENTION 
       [0001]    The present invention relates to apparatus for treating asthma by controlled delivery of neurotoxin 5 using a neurotoxin applicator assembly. 
         [0002]    The lung is made up of progressively smaller bronchial bifurcations stemming downward from the trachea. The trachea and proximal bronchi are lumens consisting of an outer layer of fascia surrounding a U-shaped inner cartilaginous layer, wherein the open portion of the U is spanned by smooth muscle. Inside the cartilaginous layer are a collagenous elastic layer and an innermost epithelial layer. Mucus secreting goblet cells and transport cilial cells are interspersed within these inner layers. 
         [0003]    As the bronchi branch and get smaller, the cartilaginous layer changes from a U-shape to irregular and helical shapes. In addition, the smooth muscle layer becomes helical bands surrounding the entire circumference of the bronchi, the goblet cells gradually decrease in numbers and the ciliated cells get smaller and fewer in number. In the most distal bronchi, the outer cartilaginous layer disappears completely, the smooth muscle layer becomes the outermost layer and goblet cells and ciliated cells disappear completely. 
         [0004]    Asthma is a complex disease of the bronchial tree, characterized by airway hyperresponsiveness to allergens, stress and environmental triggers. Environmental triggers include irritants such as pollutants and non-allergenic triggers such as exposure to cold air. Airway hyperresponsiveness results in acute narrowing of the entire bronchial tree reducing airflow through the lungs, compromising respiration and limiting gas exchange in the alveoli. The narrowing of the bronchial tree is a result of three basic characteristic physiologic responses: (1) smooth muscle contraction; (2) increased mucus production; and (3) edema caused by arterial dilatation and increased arterial permeability. The triggering mechanisms for these physiologic responses are part of the body&#39;s inflammatory response system. 
         [0005]    Chronic uncontrolled asthma can result in structural changes to the bronchial wall itself. Smooth muscle hyperplasia results in thickening of the smooth muscle components of the bronchial wall. Thickening of the subepithelial collagen layer that lies between the airway epithelium and the smooth muscle layer results in progressive stiffening of the wall of the bronchi. Studies have shown that stiffening of the airway wall results in more profound narrowing of the airway for a given asthma attack. This is due to changes in the ability of the mucosal layer to fold in response to the smooth muscle layer contraction. 
         [0006]    Recently, the controlled injection of neurotoxin has become a common procedure for controlling skeletal muscle spasms. A frequently used neurotoxin for this procedure is the botulinum toxin, serotype A, sold commercially by Allergan, Inc. as BOTOX®. BOTOX® neurotoxin blocks the release of neurotransmitter from the nerves that control the contraction of the target muscles. Many applications for BOTOX® neurotoxin have been proposed and/or clinically tested, including cervical dystonia, cosmetic relief of frown lines and tremor associated with cerebral palsy. Recently, BOTOX® neurotoxin has become the subject of clinical study for the relief of hyperhidrosis (profuse sweating) and hypersalivation. These studies indicate that BOTOX® neurotoxin can be used to control the action of cholinergic parasympathetic nerves as well as large skeletal muscle groups. The recent findings open the possibility of using neurotoxins such as BOTOX® neurotoxin to control some of the main mechanisms of airway narrowing in asthmatic attacks, specifically smooth muscle contraction and hypersecretion of mucus from the goblet cells. Additionally, there is evidence that some part of the inflammatory response of asthma is stimulated by the release of the neurotransmitters which BOTOX® neurotoxin inhibits. This opens the possibility that BOTOX® neurotoxin may also work to mitigate the inflammatory cycle itself. 
         [0007]    The use of neurotoxin for the control of asthma is described in U.S. Pat. No. 6,063,768 to First, wherein asthma is included in a list of neurogenic inflammatory disorders that may be controlled through the action of neurotoxins such as BOTOX® neurotoxin. That patent also describes that BOTOX® neurotoxin could be aerosolized and introduced into the lungs. An earlier patent, U.S. Pat. No. 5,766,605 to Sanders, et al. describes the use of BOTOX® neurotoxin to treat asthma and COPD, but does not describe the methods or devices used to do so. Further mention of BOTOX® neurotoxin in connection with asthma is provided in a press release dated Feb. 7, 2003 by the University of Alberta in describing the work of Dr. Redwan Moqbel. The release mentions that Dr. Moqbel and others are researching the possible use of neurotoxins such as tetanus and botulinum toxin to prevent eosinophils from activating and starting the inflammatory cascade that results in an asthma attack. 
         [0008]    While it may be possible to simply aerosolize neurotoxins for introduction into the lungs, introducing it into the patient through traditional inhalation means would expose the mouth, tongue, epiglottis, vocal cords, etc. to the actions of the neurotoxin, with obvious deleterious results. Much more controlled and direct application of the neurotoxin to the desired tissue is required for safe and effective therapy. 
         [0009]    Accordingly, it would be desirable to provide apparatus that enables controlled delivery of a neurotoxin to target treatment areas within a patient&#39;s bronchial airways. 
         [0010]    It also would be desirable to provide an apparatus permitting the controlled injection of neurotoxin into the bronchial wall of a patient. 
         [0011]    It would further be desirable to provide a needle-less injection apparatus to eliminate potential complications related to the presence of needles within a patient&#39;s bronchial airways. 
         [0012]    Additionally, it would be desirable to provide an apparatus permitting the application of neurotoxin onto a target treatment area within a patient&#39;s bronchial airways. 
       BRIEF SUMMARY OF THE INVENTION 
       [0013]    In view of the foregoing, it is an object of the present invention to provide apparatus that enables the controlled delivery of a neurotoxin to target treatment areas within a patient&#39;s bronchial airways. 
         [0014]    It is a further object of the present invention to provide an apparatus permitting the controlled injection of neurotoxin into the bronchial wall of a-patient. 
         [0015]    It is an additional object of the present invention to provide a needle-less injection apparatus to eliminate potential complications related to the presence of needles within a patient&#39;s bronchial airways. 
         [0016]    It is another object of the present. invention to provide an apparatus permitting the application of neurotoxin onto a target treatment area within a patient&#39;s bronchial airways. 
         [0017]    These and other objects of the present invention are accomplished by providing an intrabronchial neurotoxin delivery system for controlled delivery of neurotoxin to a target treatment area within a patient&#39;s bronchial airways to lessen the effects of asthma. The introduction of neurotoxin into the bronchial airways disables the hyperresponsive smooth muscle layer and controls the hypersecretion of mucus. 
         [0018]    The intrabronchial neurotoxin delivery system preferably includes a bronchoscope and neurotoxin applicator assembly. The neurotoxin applicator assembly may be a needle assembly, rotating needle assembly, needle-less injection assembly or a nebulizer assembly. 
         [0019]    In a first illustrative embodiment, the neurotoxin applicator assembly comprises a needle assembly including at least one needle having a lumen in fluid communication with a source of liquid neurotoxin. The needles are preformed to contract radially when disposed within a lumen, such as a lumen of the bronchoscope, but may be extended to penetrate and inject small doses of neurotoxin into the bronchial wall of a patient. 
         [0020]    In an alternative embodiment, the neurotoxin applicator assembly comprises a rotating needle assembly including plural needles disposed along the circumference of a wheel. Again, the needles include lumens in fluid communication with a source of liquid neurotoxin. In operation, the wheel is adapted to be rolled across a target treatment area about a central hub. Optionally, the rotating needle assembly may include a fender to protect a portion of the bronchial wall substantially opposite the target treatment area. 
         [0021]    In another alternative embodiment, the neurotoxin applicator assembly comprises a needle-less injection assembly including a shaft having at least one port in fluid communication with a source of liquid neurotoxin. The needle-less injection assembly can be used to inject neurotoxin into the bronchial wall without needle penetration. Optionally, an inflatable balloon may be provided to help position the at least one port adjacent the target treatment area. 
         [0022]    In yet a further alternative embodiment, the neurotoxin applicator assembly comprises a nebulizer assembly including an atomizer in fluid communication with a source of liquid neurotoxin. The atomizer converts the liquid neurotoxin into a fine spray or mist that is directed onto the target treatment area. The particle size of the mix can be controlled using injection pressure or atomizer head design to access specific portions of the lung adjacent to or downstream of the treatment device. An inflatable balloon optionally may be provided to facilitate positioning the atomizer adjacent the target treatment area. The balloon also serves to isolate the lung segment downstream of the device to prevent reflux of the mist into undesired portions of the airway. In addition, lumens optionally may be disposed between the balloon and atomizer to provide a ventilation system that allows pressure control of the treatment area to prevent over-inflation of the lung, mixing of the atomized fluid, and evacuation of remaining mist at termination of therapy, prior to balloon deflation. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0023]    The above and other objects and advantages of the present invention will be apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout, and in which: 
           [0024]      FIG. 1  is a side view of an intrabronchial neurotoxin delivery system of the present invention; 
           [0025]      FIG. 2  is a perspective view of an illustrative embodiment of a neurotoxin applicator assembly of the present invention; 
           [0026]      FIGS. 3A and 3B  are cross-sectional views of the neurotoxin applicator assembly of  FIG. 2  in retracted  30  and extended positions, respectively; 
           [0027]      FIG. 4  is a perspective view of an alternative embodiment of a neurotoxin applicator assembly of the present invention; 
           [0028]      FIGS. 5A and 5B  are partial cross-sectional views of the neurotoxin applicator assembly of  FIG. 4  in. retracted and extended positions, respectively; 
           [0029]      FIG. 6  is a perspective view, of another alternative embodiment of a neurotoxin applicator assembly of the present invention; 
           [0030]      FIG. 7A and 7B  are partial cross-sectional views of the neurotoxin applicator assembly of  FIG. 6  in retracted and extended positions, respectively; 
           [0031]      FIG. 8  is a perspective view of a yet further alternative embodiment of a neurotoxin applicator assembly of the present invention; 
           [0032]      FIGS. 9A and 9B  are partial cross-sectional views of the neurotoxin applicator assembly of  FIG. 8  in retracted and extended positions, respectively. FIG.  9 AA is a cross-sectional view taken along line  9 AA- 9 AA in  FIG. 9A . 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0033]    Referring to  FIG. 1 , apparatus for controlled delivery of neurotoxin to a target treatment area within a patient&#39;s bronchial airways to lessen the effects of asthma is described. Preferably, the apparatus comprises bronchoscope  10  and neurotoxin applicator assembly  20 . Bronchoscope  10  has proximal end  12 , distal end  13 , and lumen  14 . As is conventional, bronchoscope  10  also includes a light source for illuminating the interior of a patient&#39;s lung and optics, such as a miniature camera, that enables the physician to view the interior of the patient&#39;s lung. Alternatively, bronchoscope  10  may omit the light source and optics, and instead comprise an outer sheath. In this latter case, device  10  and neurotoxin applicator  20  would be observed using a separate conventional bronchoscope. 
         [0034]    In accordance with the principles of the present invention, neurotoxin applicator assembly  20 , of which various illustrative embodiments are described hereinbelow, enables the physician to selectively administer controlled doses of neurotoxin to or within selected treatment sites in the patient&#39;s lung. More specifically, neurotoxin applicator assembly  20  may be selectively advanced through lumen  14  of bronchoscope  10  to deliver a neurotoxin, such as botulinum toxin, serotype A, to a target treatment area. 
         [0035]    Neurotoxin applicator assembly  20  includes shaft  21  coupled to at its proximal end to handle  22 , distal end  23  having neurotoxin applicator  24 , and lumen  25 . Lumen  25  provides fluid communication between proximal end and handle  22  and applicator  24 . Syringe  26  having plunger  27  is coupled to a port on proximal end  22 . Syringe  26  is filled with neurotoxin in liquid form, and applies the neurotoxin to applicator  24  via lumen  25  when plunger  27  is actuated. 
         [0036]    Handle  22  enables the physician to extend and retract applicator  24  from within lumen  14  of bronchoscope  10 , and to manipulate distal end  23  of neurotoxin applicator assembly  20  under direct visual observation using the optics of bronchoscope  10 . The neurotoxin applicator assembly preferably remains retracted within lumen  14  of the bronchoscope during insertion of the catheter into the patient&#39;s bronchial airways, and is deployed once the applicator is in a desired position. Alternatively, applicator  20  may be housed inside of a retaining sheath, and both units can be advanced through lumen  14  together. 
         [0037]    Referring now to  FIGS. 2-3 , a first illustrative embodiment of applicator  24  of neurotoxin applicator assembly  20  constructed in accordance with the principles of the present invention is described. Applicator  241  comprises needle assembly  28  having at least one needle  30  with lumen  31  in fluid communication with lumen  25 . The needles are configured to penetrate the airway epithelium and directly inject small amounts of neurotoxin from the syringe into the collagenous and smooth muscle layers of bronchial wall B. 
         [0038]    In  FIG. 3A , needle assembly  28  is depicted  10  retracted with lumen  14  of bronchoscope  10 . Alternatively, device  10  may comprise an outer sheath that is dimensioned to be slidably accept neurotoxin applicator assembly  20 , and which is selectively retractable to expose needle assembly  28 . In a further embodiment, a retaining sheath housed within lumen  14  and covering applicator  20  is selectably retractable to expose needle assembly  28 . As depicted in  FIG. 3B , needles  30  comprise a material capable of retaining a preformed shape, such as nickel-titanium, and are preformed to deflect radially outward when extended beyond distal end  13  of bronchoscope  10  (or the distal end of the outer sheath, if present). Each needle  30  optionally includes hilt  36  disposed a pre-selected distance from the distal end of the needle to control the depth of penetration of the needle tip into the bronchial wall. 
         [0039]    When needle assembly  30  is deployed, as illustrated in  FIGS. 2 and 3B , needles  30  penetrate target treatment area T of bronchial wall B so that neurotoxin may be injected in the bronchial wall. Syringe  26  may include graduations that enable the physician to inject a pre-determined amount of neurotoxin at each target treatment area. 
         [0040]    Referring now to  FIGS. 4 and 5 , an alternative embodiment of applicator  24  of neurotoxin applicator assembly  20  is described. Applicator  24  in this embodiment comprises rotating needle assembly  38 , including wheel  39  mounted to rotate about hub  40 . While wheel  39  illustratively is round, it alternatively may comprise a ellipse or hexagon or other polygonal shape. Plurality of needles  41  is disposed around the circumference of the wheel, each needle  41  having lumen  42  in fluid communication with lumen  25  via a passageway in hub  40 . Optional fender  45  protects a portion of the bronchial wall substantially opposite the target treatment area. 
         [0041]    In  FIG. 5A , rotating needle assembly  38  is shown retracted within outer sheath  37 . Outer sheath  37  is dimensioned to fit within lumen  14  of bronchoscope  10 , and may be selectively retracted to expose rotating needle assembly  38 . Alternatively, rotating needle assembly  38  extends through lumen  14  and past the tip of bronchoscope  10 . In this embodiment, the wheel is covered by a retractable protection sheath which covers the wheel during insertion of, the system. In  FIGS. 4 and 5B , rotating needle assembly  38  is shown in the extended position. When so deployed, wheel  39  may be rolled across target treatment area T, so that as the wheel rotates needles  41  alternately penetrate and inject neurotoxin into bronchial wall B. 
         [0042]    Suitable needles materials for needle assembly  28  of  FIGS. 2-3  and rotating needle assembly  38  of  FIGS. 4-5  include shape memory alloys such as nickel titanium alloys and spring tempered stainless steel alloys. Advantageously, either needle assembly permits direct injection of neurotoxin into the bronchial wall. This prevents the cilial transport system from trapping the neurotoxin and transporting it to other regions of the respiratory system, e.g., the oropharynx, where potentially unintended targets may be exposed to the neurotoxin, and prevents accidental exhalation of aerosolized neurotoxin. 
         [0043]    Referring now to  FIGS. 6 and 7 , another. alternative embodiment of applicator  24  of the neurotoxin applicator assembly of the present invention is described. Applicator  24  of  FIGS. 6-7  comprises a needle-less injection assembly  46 , which uses pressurized injection to deliver neurotoxin from the proximal controller to target treatment area T. Advantageously, the needle-less injection assembly allows controlled introduction of neurotoxin across the airway epithelium without the potential complications of introducing needles proximate to the delicate bronchial tissues, and may allow a lower profile system. 
         [0044]    Needle-less injection assembly  46  comprises shaft  47  including at least one port  48  in fluid communication with lumen  25 . Inflatable balloon  49  optionally may be coupled to shaft  47 , and used to position the shaft adjacent target treatment area T. Balloon  49  is inflated with a fluid introduced through a lumen of shaft  47 . When the shaft is aligned with the target treatment area, pulses of pressurized gas may be employed to inject predetermined amounts of neurotoxin across the airway wall and into the collagenous and smooth muscle layers. 
         [0045]    In  FIG. 7A , needle-less injection assembly  46 , with balloon  49  deflated, is depicted housed within the lumen  14  of bronchoscope  10  (or a separate outer sheath).  FIGS. 6 and 7B  depict needle-less injection assembly  46  with balloon  49  inflated to place ports  48  in apposition to target treatment area T. Once the physician has confirmed placement of needle-less injection assembly  46 , e.g., by visualization using the optics of bronchoscope  10 , x-ray, fluoroscopy or other suitable means, a controller attached to the proximal end of neurotoxin applicator assembly  20  (instead of syringe  26 ), may be activated to deliver the desired doses of neurotoxin to the bronchial wall. As an alternative to the balloon  49 , the assembly may have  2  or more needle-less injectors arranged to position against opposite walls of the bronchial passage. For instance, they might be spring loaded to expand the sections away from the midline and contact the bronchial wall. As a further alternative, the shaft of the assembly may be pre-curved or actively curved with an activation mechanism to urge the injector against the wall of the bronchial passage. 
         [0046]    With respect to  FIGS. 8 and 9 , a yet further alternative embodiment of applicator  24  of the neurotoxin applicator assembly constructed in accordance with the present invention is described. Applicator  24  comprises nebulizer assembly  50  having shaft  55  with atomizer  51  disposed at its distal end and in fluid communication with central lumen  25 . Atomizer  51  converts the liquid neurotoxin from the syringe into a fine spray or mist. Particle size of the mist can be controlled through nebulizer head design or by varying injection pressure in order to control the depth of penetration of the mist into the target segment. 
         [0047]    Nebulizer assembly  50  may also include optional inflatable balloon  52  disposed on shaft  55  proximal of atomizer  51 . Selective inflation of balloon  52  allows positioning of atomizer  51  so that aerosolized neurotoxin may be directly sprayed onto target treatment area T. Balloon  52  also acts to isolate the treatment area from the rest of the lung, preventing reflux of mist into unintended areas. As for the embodiment of  FIGS. 6-7 , balloon  52 ′ may be inflated using a fluid introduced through an auxiliary lumen in shaft  55 . 
         [0048]    In  FIG. 9A , the nebulizer assembly, including deflated balloon  52 , is disposed within lumen  14  of bronchoscope  10 , or alternatively, in an outer sheath (not shown) that is slidably received in lumen  14 . Alternatively, the nebulizer assembly  50  may be inserted within a separate delivery sheath (not shown), with the bronchoscope  10  inserted separately. In  FIGS. 8 and 9B , nebulizer assembly  50  is depicted deployed from lumen  14  (or the outer sheath, if present), with balloon  52  on shaft  55  inflated. Advantageously, nebulizer assembly  50  can be dimensioned to access very small bronchial passageways, and also may be used to deliver neurotoxin to upstream regions of the lung. 
         [0049]    Still referring to  FIGS. 9A and 9B , shaft  55  which carries balloon  52  may optionally also include an additional auxiliary lumen or lumens  25   a,    25   b  (FIG.  9 AA) coupled to inlet port  53  and outlet port  54  disposed between the balloon  52  and the atomizer  51 . Lumen  25  provides for medicine delivery as in previous embodiments. Inlet port  53  allows the introduction of gas (such as fresh air) near the target treatment area, while outlet port  54  allows air or gas mixed with atomized neurotoxin to be removed. Inlet and outlet ports  53  and  54  therefore provide a ventilation system that shields tissue adjacent and proximal to target treatment area T from being inadvertently exposed to the atomized neurotoxin. Inlet and outlet ports  53  and  54  further serve to either actively inflate and deflate the isolated segment, or simply to normalize pressure within the lung near the target treatment area. The lumens  25 ,  25   a,  and  25   b  may be connected to the neurotoxin source, gas source, and an aspiration source via ports  23   a,    23   b,  and  23   c  in handle  22 . A control unit may be connected to the proximal outlets of ports  53  and  54  to control the introduction and removal of gases from the lung without allowing escape of atomized neurotoxin to the environment or patient. 
         [0050]    Although preferred illustrative embodiments of the present invention are described above, it will be evident to one skilled in the art that various changes and modifications may be made without departing from the invention. It is intended in the appended claims to cover all such changes and modifications that fall within the true spirit and scope of the invention.