Abstract:
Apparatus and methods deliver vasoconstrictive agents simultaneously with capnic gases. The capnic gases can enhance the effectiveness of the vasoconstrictive agent, 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:
This application is a continuation of U.S. application Ser. No. 11/340,410, filed Jan. 25, 2006, now abandoned; which is a continuation-in-part of U.S. application Ser. No. 11/192,852, filed Jul. 29, 2005, now abandoned; which is a continuation-in-part of U.S. application Ser. No. 09/708,186, filed Nov. 7, 2000, now U.S. Pat. No. 6,959,708, issued Nov. 1, 2005; which claims the benefit of U.S. Provisional Patent Application Nos. 60/164,125, filed Nov. 8, 1999 and 60/185,495, filed Feb. 28, 2000. The contents of the above-identified applications are incorporated herein by reference in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to drug delivery. More particularly, the present invention relates to methods and apparatus for delivering agents that cause vasoconstriction to mucosal and other tissue surfaces in the presence of capnic gases, particularly for the treatment of migraine headaches. 
     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. 
     Migraine headaches are a form of severe headache that tends to recur in susceptible patients. Migraine headaches may be accompanied by associated symptoms, such as nausea, vomiting, hypersensitivity to light, sound and odor. Patients suffering from migraines often must remain immobile since even small movements can exacerbate the pain. In “classic” migraine etiology, the patient often experiences an aura some ten to thirty minutes before the onset of the migraine. The aura may include a perception of flashing lights, zigzag lines, or in some instances may even cause temporary vision impairment. So-called “common” migraines are not preceded by such an aura. Both types of migraines may occur as often as several times a week or as rarely as once every few years. 
     Migraines are most often treated using drugs that cause vasoconstriction. For years, ergotamines was the primary drug available for treating severe migraine pain. More recently, triptan drugs have become available for treating all forms of migraine. 
     While drug therapy using triptans and ergotamines are often effective, the drugs can require one to two hours to reach effective plasma concentrations. Even so-called quick acting forms, such as quick-melt tablets, intra-nasal sprays, injectable forms of the drugs, and topical forms of the drug, still have significant lag times before they become effective. Moreover, not all individuals benefit from triptans, ergotamines, or other drug therapies for migraines. 
     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 migraine headaches 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 acidosis which inhibits the release of calcitonin gene-related peptide (CGRP) which in turn reduces the pain and associated symptoms resulting from the migraine. It has also been found that the onset of relief is usually much more rapid than that achieved with triptans, ergotamines, and other systemic drug therapies. 
     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 all migraine pain and associated symptoms in all circumstances. It would thus be desirable to provide improved methods and systems for treating migraine headaches. 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 systemic drugs or capnic gases alone. 
     2. Description of Background Art 
     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. 
     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 CO 2  and pH on bronchoconstriction caused by serotonin vs. acetylcholine,”  J of Appl Physiology , vol. 22, 1972. 
     SUMMARY OF THE INVENTION 
     The present invention provides methods and apparatus for treating patients, particularly patients suffering or at risk of suffering from migraine headaches, by administering a vasoconstrictive 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 vasoconstrictive agent will be administered and the capnic 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 vasoconstrictive agent together with the capnic gas, e.g., where the capnic gas can act as a carrier for the vasoconstrictive agent. It will be more common to deliver the vasoconstrictive agent separately in a separate dosage form, such as any of the dosage forms which are commonly available for the particular vasoconstrictive agents described below. 
     In preferred protocols, at the onset of a migraine headache, the patient would take a dose of the vasoconstrictive 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 migraine episode. At the same time, the circulating plasma levels of the vasoconstrictive agent would increase, resulting in constriction of the cranial blood vessels. 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 migraine, the migraine would be less intense at the time effective plasma levels of the vasoconstrictive agent have been achieved. The magnitude of pain 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 vasoconstrictive agent and thereby reducing side effects. 
     Exemplary vasoconstrictive agents useful in the methods of the present invention include both triptans and ergotamines. The use of triptans is preferred, and common triptans include sumatriptan, zolmitriptan, rizatriptan, almotriptan, naratriptan, eletriptan, and frovatriptan. Common ergotamines include ergotamine tartrate (Cafergot®, Wigraine®, Ergostat®), and dihydroergotamine DHE-45 (Migranal®). 
     In addition to vasoconstrictive agents, in some instances, the methods of the present invention could combine the delivery of capnic gases with other known treatments for migraines, including certain anticonvulsants, such as carbamazepine and topiramate. 
     The vasoconstrictive agents will be delivered systemically, and may be delivered in any conventional systemic 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). In particular for the delivery of triptans, presently available dosage forms include tablets, orally dissolving tablets (also known as quick-melts or rapi-melts), intranasal sprays, and subcutaneous injection. 
     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. 
     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. 
     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 vasoconstrictive agent may be dissolved or suspended in the pressurized capnic gas for simultaneous delivery. Alternatively, the vasoconstrictive agent may be delivered simultaneously from a separate receptacle, either through the same or a different delivery path. Often, the capnic gas and the vasoconstrictive 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 
         FIG. 1  illustrates an exemplary capnic gas infusion device, illustrating a charge/dose and dose rate adjustment features. 
         FIG. 2  is a schematic illustration of a delivery system incorporating separate receptacles for the capnic and the physiologically active agent, where the receptacles are joined through valves into a common delivery conduit. 
         FIGS. 3A-3E  show application of the capnic gas optionally in combination with the physiologically active agent to the nose, mouth, both nostrils, eye, and ear, using a gas dispenser according to the present invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     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 vasoconstrictive 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 . 
     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 vasoconstrictive agent incorporated in the canister  101 . In cases where the capnic gas is to be delivered by itself, at some suitable concentration, the vasoconstrictive agent will have to be delivered systemically in some other manner. The vasoconstrictive 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. 
       FIG. 2  is a schematic illustration showing a system for simultaneous or closely separated sequential delivery of the capnic gas and vasoconstrictive agent. The capnic gas is held in a separate cartridge or other container  202  while the vasoconstrictive agent is held in a cartridge or other container  204 . Both the gas and the vasoconstrictive 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 vasoconstrictive 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. 
     Referring now to  FIGS. 3A to 3E , a variety of ways for effecting mucosal infusion with the capnic gas, optionally combined with the vasoconstrictive 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 vasoconstrictive agent can be delivered separately by suffusion, infusion, misting, the application of powder, or the like. As shown in  FIGS. 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 infue 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. 
     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. 
     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.