Abstract:
Apparatus and methods deliver treatment agents simultaneously with capnic gases. The capnic gases can enhance the effectiveness of the treatment agent for treating rhinitis, lower the dosage of drug or concentration of agent necessary to achieve a therapeutic result, or both. Exemplary capnic gases include carbon dioxide, nitric oxide, nitrous oxide, and dilute acid gases.

Description:
[0001]    This application is a continuation of U.S. patent application Ser. No. 11/459,798, filed Jul. 25, 2006; which is a continuation-in-part of U.S. patent application Ser. No. 11/192,852, filed Jul. 29, 2005; which is a continuation-in-part of U.S. patent application Ser. No. 09/708,186, filed Nov. 7, 2000 (now U.S. Pat. No. 6,959,708); which claimed the benefit of U.S. Provisional Patent Application Nos. 60/185,495, filed Feb. 28, 2000, and 60/164,125, filed Nov. 8, 1999. The contents of the above-identified applications are incorporated herein by reference in their entirety 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    1. Field of the Invention 
         [0003]    The present invention relates to drug delivery. More particularly, the present invention relates to methods and apparatus for delivering agents to mucosal and other tissue surfaces, in the presence of capnic gases, particularly for the treatment of rhinitis. 
         [0004]    Drug delivery to mucosal surfaces, such as the mucosa of the nose, is well known. While in some cases drugs delivered to the nose and other mucosal surfaces are intended to have local effect, more often such transmucosal drug delivery is intended for systemic administration. In either case, penetration of the drug into or through the mucosa is limited by the ability of the particular drug to pass into or through the mucosal cell structure. Such resistance from the mucosal cell structure can result in slowing of the delivery, the need to use higher dosages of the drug, or in the case of larger molecules, the inability to deliver via a nasal or other mucosal route. 
         [0005]    A walk through the cold and allergy section of any pharmacy quickly reveals that there is wide spread interest in remedies for relieving symptoms commonly associated with allergies, colds, asthma, and other common ailments which have symptoms of rhinitis e.g., runny noses and watery eyes. The commonly available therapies include oral medicines, nasal sprays, oral inhalers, nasal inhalers, eye drops, and nose drops, and probably other devices and approaches that have been developed over the years. Still more possible therapies are available from the pharmacy with a prescription from a patient&#39;s doctor (e.g., injectables, inhalables). Despite the very large number of therapies which are available, no one therapy meets all patient needs, and many of the therapies suffer from very significant shortcomings. For example, present day therapies are slow-acting, may have numerous adverse side effects (e.g., drowsiness, rebound congestion from decongestant overuse, dizziness, sedation, addiction, and numerous others), have low efficacy, and are contraindicated for a large portion of patients (e.g., those with hypertension, coronary artery disease, cerebrovascular disease, peptic ulcers, pregnancy, concurrent medications that would interact, children, elderly, and others). Suffice it to say that there is a continuing interest in providing improved methods and apparatus for treating such common symptoms and ailments. 
         [0006]    Very recently, the use of carbon dioxide and other capnic gases alone and in combination with other gases has been proposed for the treatment of rhinitis and other conditions. The carbon dioxide is preferably delivered to nasal or other mucosa without inhalation. It is believed that the carbon dioxide may cause an intracellular acidosis which inhibits the release of calcitonin gene-related peptide (CGRP) and other neuropeptides which in turn reduces nasal symptoms of rhinitis. It has also been found that the onset of relief with carbon dioxide is usually much more rapid than that achieved with antihistamines, intranasal corticosteroids, leukotriene antagonists, and other drug therapies. 
         [0007]    Despite the promise of conventional drug therapies and the newer delivery of capnic gases, neither therapy is effective in all individuals and neither therapy is entirely effective in relieving rhinitis and associated symptoms in all circumstances. It would thus be desirable to provide improved methods and systems for treating rhinitis. In particular, it would be desirable to provide treatments which are more effective, more rapid, more long-lasting, and/or which have other benefits when compared to the administration of either known rhinitis drugs or capnic gases alone. 
         [0008]    2. Description of Background Art 
         [0009]    Inhalation devices, systems and methods for delivering carbon dioxide and other gases and aerosols to patients, with and without co-delivery of a drug are described in U.S. Pat. Nos. 3,776,227; 3,513,843; 3,974,830; 4,137,914; 4,554,916; 5,262,180; 5,485,827; 5,570,683, 6,581,539; and 6,652,479. While some methods and devices provide for co-delivery of a drug and carbon dioxide or other gases, the purpose is usually not potentiation. For example, carbon dioxide may be used as a safe propellant, as shown in Wetterlin, U.S. Pat. No. 4,137,914. See also copending application Ser. Nos. 09/614,389, 10/666,947, and 10/666,562; the full disclosures of which are incorporated herein by reference. 
         [0010]    Additional background art may be found in the following references: Guyton A C, Hall J E.  Textbook of Medical Physiology . Ninth Ed., W.B. Saunders Co., Philadelphia, 1996; Tang A, Rayner M, Nadel J. “Effect of CO 2  on serotonin-induced contraction of isolated smooth muscle,”  Clin Research  20:243, 1972; Qi S, Yang Z, He B. “An experimental study of reversed pulmonary hypertension with inhaled nitric oxide on smoke inhalation injury,”  Chung Hua Wai Ko Tsa Chih  35(1):56-8, January 1997; Loh E, Lankford E B, Polidori D J, Doering-Lubit E B, Hanson C W, Acker M A. “Cardiovascular effects of inhaled nitric oxide in a canine model of cardiomyopathy,”  Ann Thorac Surg  67(5): 13 80-5, May 1999; Pagano D, Townend J N, Horton R, Smith C, Clutton-Brock T, Bonser R S . “A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation,”  Eur J Cardiothorac Surg  10(12):1120-6, 1996; and Sterling G, et al. “Effect of CO2 and pH on bronchoconstriction caused by serotonin vs. acetylcholine,”  J of Appl Physiology , vol. 22, 1972. 
       SUMMARY OF THE INVENTION 
       [0011]    The present invention provides methods and apparatus for treating patients, particularly patients suffering or at risk of suffering from rhinitis, by administering a treatment agent to the patient and simultaneously delivering a capnic gas to a nasal, oral, auricular, or ocular membrane of the patient. By “simultaneously,” it is meant that the treatment agent will be administered and the capnic gas delivered at the same time or within a very short time of each other, typically within 60 minutes, preferably within 30 minutes, and more preferably within 10 minutes. In some instances, it may be desirable to deliver the treatment agent together with the capnic gas, e.g., where the capnic gas can act as a carrier for the treatment agent. It will be more common to deliver the treatment agent separately in a separate dosage form, such as any of the dosage forms which are commonly available for the particular treatment agents described below. While the treatment agent will often be delivered systemically, in other cases it may be delivered orally to the target mucosa and have a local effect in the mucosal tissue. 
         [0012]    In preferred protocols, at the onset of a rhinitis attack, the patient would take a dose of the treatment agent and substantially simultaneously initiate delivery of the capnic gas to the target membrane. The capnic gas would provide a rapid onset of action, possibly by inhibiting the release of CGRP as described above, in order to interrupt or delay progression of the rhinitis attack. At the same time, the treatment agent would begin to function by its particular mode of action. The patient would experience a more effective treatment in one of several ways. As the capnic gas would at least slow the progression of the rhinitis attack, the symptoms would be less intense by the time the treatment agent becomes effective. The magnitude of congestion, runny nose, watery eyes, and associated symptoms experienced by the patient should be lessened at all points during the treatment. In other cases, the patient might benefit by reducing the dosage of the treatment agent and thereby reducing side effects. 
         [0013]    Rhinitis is the medical term describing irritation and inflammation principally of the nose. Symptoms include a runny nose, sneezing, congestion and irritation in the nose, eyes, throat and ears. Rhinitis is related to and often occurs together with other disorders such as asthma and sinusitis. It is chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or irritants. The inflammation results in excessive mucous production producing a runny nose, nasal congestion and postnasal drip. 
         [0014]    Exemplary systemic treatment agents useful in the methods of the present invention include antihistamines; H1 receptor antagonists, such as fexofenadine, cetirizine, loratidine, desloratadine, and azelastine; corticosteroids, such as fluticasone, mometasone, budesonide, triamcinolone, and flunisolide; leukotriene receptor antagonists, such as montelukast; anticholinergics, such as ipratropium; mast cell stabilizers, such as cromolyn; decongestants, such as oxymetazoline, pseudoephedrine and other alpha-adrenergic agonists. 
         [0015]    The treatment agents may be delivered in any conventional form, including oral dosage forms (tablets, gels, capsules, and the like), intranasal forms (in which case they could optionally be combined with delivery of the capnic gases), forms intended for pulmonary delivery, injectable forms, and topical forms (for transcutaneous delivery). 
         [0016]    Preferred capnic treatment gases include carbon dioxide, nitric oxide, nitrous oxide, and dilute acid gases, such as dilute hydrochloric acid and the like. Particularly preferred are carbon dioxide gases having a relatively high concentration, typically greater than 10% by volume, usually greater than 20% by volume, and preferably greater than 25% by volume and often being as great as 80% by volume, 90% by volume, and in many instances being substantially pure. The capnic gases may be used in combinations of one or more adjuvant gases and/or may be combined with physiologically inert gases such as nitrogen, to control concentration of the capnic gases. 
         [0017]    The capnic gas is delivered to a nasal, oral, auricular, or ocular membrane of the patient, typically using a hand-held or other dispenser. Preferably, the capnic gas will be delivered to a nasal or oral mucosa, while the patient refrains from inhaling the capnic gas. In the exemplary embodiments, the capnic gas is infused through a nostril and exits through a nostril and/or the mouth. The patient will refrain from inhaling, typically by holding the velum in the throat closed, while the capnic gas is infused. In other instances, the capnic gas will be infused through the mouth and be allowed to exit through at least one nostril, usually both nostrils. In those instances, the patient will also refrain from inhaling the gas. 
         [0018]    The capnic gases will usually be delivered using a dispenser. Typically, the dispenser includes a pressurized source of the capnic gas and a valve assembly for releasing the gas at a controlled flow rate, typically in the range from 0.5 cc/sec to 30 cc/sec in the case of high concentration of carbon dioxide. Optionally, the treatment agent may be dissolved or suspended in the pressurized capnic gas for simultaneous delivery. Alternatively, the treatment agent may be delivered simultaneously from a separate receptacle, either through the same or a different delivery path. Often, the capnic gas and the treatment agent, even when stored in separate receptacles, will be delivered through a common conduit and nozzle to allow for both simultaneous and sequential delivery. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0019]      FIG. 1  illustrates an exemplary capnic gas infusion device, illustrating a charge/dose and dose rate adjustment features. 
           [0020]      FIG. 2  is a schematic illustration of a delivery system incorporating separate receptacles for the capnic and the treatment agent, where the receptacles are joined through valves into a common delivery conduit. 
           [0021]      FIGS. 3A-3E  show application of the capnic gas optionally in combination with the treatment agent to the nose, mouth, both nostrils, eye, and ear, using a gas dispenser according to the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0022]    An exemplary carbon dioxide dispenser  100  comprising a carbon dioxide cartridge  101  is illustrated in  FIG. 1 . The embodiment of  FIG. 1  is described in greater detail in parent application Ser. No. 09/708,186, now U.S. Pat. No. 6,959,708, the full disclosure of which has previously been incorporated herein by reference. A user delivers a dose of carbon dioxide or other treatment gas, referred to generally as “capnic gases” (optionally carrying the systemic treatment agent to be delivered) by applying the top of the dispenser  608  to the user&#39;s nose or mouth and pushing a button  600  which releases an internal mechanism to allow the CO 2  to flow from the top of the dispenser  608 . The internal mechanism will lower the pressure of CO 2  in the cartridge and will control the flow rate within suitable ranges, typically from 0.5 to 30 cc/sec. The flow rate may be maintained for a suitable time period, typically at least 2 seconds when suffusing the nasal and sinus passages. The device is cocked by rotation as shown by arrow  602  and pushing the button  600  to deliver the dose by an automatic counter-rotation. The user may select the specific carbon dioxide flow rate by setting at a set screw through aperture  609 . 
         [0023]    The dispenser  100  of  FIG. 1  may be used to deliver any of the capnic gases in accordance with the principles of the present invention. The capnic gases may be delivered with or without the systemic treatment agent incorporated in the canister  101 . In cases where the capnic gas is to be delivered by itself, at some suitable concentration, the systemic treatment agent will have to be delivered systemically in some other manner. The systemic treatment agent could be delivered in any of the conventional dosage forms described above or could be delivered to the target mucosa by suffusion or infusion, by placing a liquid, powder, or the like over the tissue surface, by introducing a vapor, mist, or the like using conventional drug delivery vapor sources and misters, or the like. 
         [0024]      FIG. 2  is a schematic illustration showing a system for simultaneous or closely separated sequential delivery of the capnic gas and systemic treatment agent. The capnic gas is held in a separate cartridge or other container  202  while the systemic treatment agent is held in a cartridge or other container  204 . Both the gas and the systemic treatment agent will be in a gaseous, vapor, mist, or other flowable form which permits them to pass through associated valves  206  and  208  respectively, and thereafter through a conduit  210  which receives flow from both valves. The valves will be suitable for controlling both flow rate and pressure of the capnic gas and the systemic treatment agent. It will be appreciated that more complex delivery systems can be provided including flow rate measurement, feedback control, temperature control, timers, and the like. 
         [0025]    Referring now to  FIGS. 3A to 3E , a variety of ways for effecting mucosal infusion with the capnic gas, optionally combined with the systemic treatment agent, are illustrated. The capnic gas is preferably infused at a flow rate in a range from 0.5 cc/sec to 30 cc/sec, depending on the tolerance of the individual being treated. In some instances, the selected drug or other systemic treatment agent can be delivered separately by suffusion, infusion, misting, the application of powder, or the like. As shown in  FIG. 3A-B , the individual P infuses oral and nasal mucous membranes by placing the source of low flow rate CO 2  (or other mixed gas) or other appropriately physiologically active gas or vapor in or around a facial orifice, such as the mouth or nostril, while substantially inhibiting the flow of the CO 2  into the trachea and lungs by limiting inhalation of the CO 2 . If the mouth is infused the gas is allowed to exit from the nostrils. Alternatively, one or both nostrils may be infused either by using the dispenser head shown in  FIG. 3B  or by use of a cup or similar device that covers both nostrils as shown in  FIG. 3E . The gas is allowed to flow from a remaining open orifice, i.e., either the mouth, the uninfused nostril, or both as appropriate. Completely holding the breath is not necessary to substantially prevent inhalation of the CO 2 . With practice, it is possible for the individual to breathe through an uninfused orifice. For example, if one nostril is infused and the gas is allowed to exit though the other nostril, it is possible for the individual to breathe through the mouth without substantial inhalation of the infused gas. The eye or eyes may also be infused using a cup as shown in  FIG. 3C  or merely by holding a hand over the eye and releasing the gas between the hand and the eye. Persons of ordinary skill in the art will appreciate that a double cup could be developed to infuse both eyes simultaneously, and similarly appropriate heads could be developed to infuse the mouth and one nostril. The ear or ears may also be infused as shown in  FIG. 3D . Note that a similar process may be used with the first embodiment to infuse a mixture of a drug and gas into various facial orifices. 
         [0026]    Infusion can be continued to the limit of tolerance or until the desired potentiation effect is realized. Since most individuals develop a temporary increased tolerance after extended applications or repeated applications, it may be possible and desirable to increase the duration of additional infusions after a few applications when all applications occur within a short time of each other, i.e., approximately 1 to 20 minutes between each application. 
         [0027]    While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.