CA3003780A1

CA3003780A1 - Delivering osmolytes by nasal cannula

Info

Publication number: CA3003780A1
Application number: CA3003780A
Authority: CA
Inventors: Richard C. Boucher; Michael R. Johnson
Original assignee: Parion Sciences Inc
Current assignee: Parion Sciences Inc
Priority date: 2018-05-03
Filing date: 2018-05-03
Publication date: 2019-11-03

Abstract

The invention described herein is directed to method of treating chronic obstructive pulmonary disease, comprising administering an effective amount of an osmolyte by at least one nasal cannula to a subject in need thereof. Also provided is a nasal cannula system for delivering an osmolyte, comprising a nebulizer and tubing having two ends, where the first end of the tubing is connected to the nebulizer and the second end of the tubing is tapered to fit in the nostril of a subject.

Description

TITLE OF THE INVENTION
DELIVERING OSMOLYTES BY NASAL CANNULA
BACKGROUND_OF.THE_INVENTION
= Field ent"o The present invention relates to the aerosolized delivery of hypertonic saline (HS) and other esmelytes to provide overnight nasal hydration to patients with all forms of chronic obstructive pahrionary disease (COM)) over along period of time, The present invention also relates to a device and apparatus with a sufficient reservoir to accomplish the same, sae_tpliz_ef_the Backstround The mucosal surfaces at the interface between the environment and the body have evolved a number of "innate defenses", i.e., protective mechanisms. A
principal form of such innate defense is to cleanse these surfaces with liquid.
Typically, the quantity of the liquid layer on a mucosal surfaoe reflects the balance between epithelial liquid secretion, often reflecting active anion (C1- and/or HCO3`) secretion coupled with water (and a cation counter-ion), and epithelial liquid absorption, often reflecting ,active Na4- absorption, coupled with water and counter anion (Cl"
and/or HCO3'). Many diseases of mucosal surfaces are caused by too little protective liquid.
on those mucosal surfaces created by an imbalance between secretion (too little) and absorption (relatively too much), The defective salt transport processes that characterize these mucosal dysfuttctions reside itt the epithelial layer of the mucosa!
surface.
One approach to replenish the protective liquid layer on mucosal surfaces is to "re-balance" the system by blOckingNa+ channel and liquid absorption. The , epithelial protein that mediates the tate=limiting step of Nil' and liquid absorption is the epithelial Na' channel (ENaC). ENaC is positioned on the apical surface of the epithelium, i.e. the mucosal surface-environmental interface. Therefore, to inhibit ENaC mediated Na 4 and liquid absorption, an ENaC blocker of the arniloride class (which blocks from the extraceilular domain of ENaC) must be delivered to the mucosal surface and, importantly, be maintained at this site, to achieve therapeutic utility, The present invention describes diseases characterized by too little liquid on mucosal surfaces and "topical" sodium channel blockers designed to exhibit the increased potency, reduced mucosal absorbtion, and slow dissociation ("unbinding"
or detachment) from ENaC required for therapy of these diseases.
Chronic obstructive pulmonary diseases arc characterized by dehydration of airway surfaces and the retention of mucous secretions in the lungs, Examples of such diseases include cystic fibrosis, chronic bronchitis, and primary or secondary ciliary dyskinesia. Such diseases affect approximately 1$ million patients in the United States, and are the sixth leading cause of death. Other airway or pulmonary diseases characterized by the accumulation of retained mucous secretions include sinusitis can inflammation of the para.nasal sinuses associated with upper respiratory infection) and pneumonia.
U.S. patent No, 5,817,028 to Anderson describes a method for the provocation of air passage narrowing (for evaluating susceptibility to asthma) and/or the induction of sputum in subjects via the inhalation of mannitol. It is suggested that the same technique can be used to induce sputum and promote mucociliary clearance.
Substances suggested include osmolytes such as sodium chloride, potassium chloride, mannitol and dextrose.
Chronic bronchitis (CD), including the most common lethal genetic form of chronic bronchitis, cystic fibrosis (CF), a disease that reflects the body's failure to clear mucus normally from the lungs, which ultimately produces chronic airways infection. In the normal lung, the primary defense against chronic intrapulmonary airways infection (chronic bronchitis) is mediated by the continuous clearance of mucus from bronchial airway surfaces, This function in health effectively removes from the lung potentially noxious toxins and pathogens. Recent data indicate that the initiating problem, i.e., the "basic defect," in both CB and CF is the failure to clear mucus from airway surfaces, The failure to clear mucus reflects dehydration of airway surfaces that reflects an imbalance between the amount of liquid and mucirt on airway surfaces. This "airway surface liquid" (ASL) is primarily composed of salt and water in proportions similar to plasma (i.e., isotonic). Mucin macromolecules organize into

2 a well defined "mucus layer" which nortnally traps inhaled bacteria and is transported out of the lung via the actions of cilia which beat in a watery, low viscosity solution termed the "poriciliary liquid" (PCL). In the disease state, there is an imbalance in thc quantities of mucins (too much) and ASL (too little) on airway surfaces that produces airway surface dehydration. This dehydration leads to mucus concentration, reduction in the lubricant activity of the PCL, and a failure to clear mucus via ciliary activity to the mouth, The reduction in mechanical clearance of mucus from the lung leads to chronic airways inflammation and bacterial colonization of mucus adherent to airway surfaces. It is the chronic retention of bacteria, the failure of local antimicrobial substances to kill mucus-entrapped bacteria on a chronic basis, and the consequent chronic inflammatory responses of the body to this type of surface infection, that lead to the destruction of the lung in CB and CF.
The current afflicted population in the U.S. is 12,000,000 patients with the acquired (primarily from cigarette smoke exposure) form of chronic bronchitis and approximately 30,000 patients with the genetic form, cystic fibrosis.
Approximately equal numbers of both populations are present in Rurope, In Asia, there is little CF
but the incidence of CB is high and, like the rest of the world, is increasing.
There is currently a large, unmet medical need for products that specifically treat CB and CF at the level of the basic defect that cause these diseases.
The current therapies for chronic bronchitis and cystic fibrosis focus on treating the symptoms and/or the late effects of these diseases. Thus, for chronic bronchitis, g=agonists, inhaled steroids, anti-cholinergic agents, and oral theophyllines and phosphodiesterase inhibitors are all in development. However, none of these drugs treat effectively the fundamental problem of the failure to clear mucus from the lung. Similarly, in cystic fibrosis, the same spectrum of pharmacologic agents is used, These strategies have been complemented by more recent strategies designed to clear the CF lung of the DNA ("Pulmozyme"; Genentech) that has been deposited in the lung by neutrophils that have futilely attempted to kill the bacteria that grow In adherent mucus masses and through the use of inhaled antibiotics ("T0131") designed to augment the lungs' own killing mechanisms to rid the adherent mucus plaques of bacteria, A
general principle of the body is that if the initiating lesion is not treated, in this case mucus retention/obstruction, bacterial infections became chronic And increasingly refractory to antimicrobial therapy. Thus, a major unmet therapeutic need for both CB and CF
lung diseases is an effective means of re-hydrating airway mucus (i.e,,

3 restoring/expanding the volume of the ASL) and promoting its clearancz, with bacteria, from the lung.
The inhalation of osmolytes/osmolyte solutions, such as hypertonic saline (3.
12% preferred embodiment 7%) has been demonstrated to be a safe and effective treatment for individuals with cystic fibrosis. Inhaled hypertonic saline improves mucus hydration and clearance, and is assoeiatedwith improvements in lung function, as well as, a reduction in the number of infectious exacerbations over one year (Donaldson et al. N. Engl. J. Ivied, 354, 3, January 19, 2006, pp, 241-250) and Elkins et. al. (N. Engl. J. Med, 354, 3, January 19,2006, pp, 229-240). -A limitation of inhaled osmolytes to increase mucosal hydration is tho durability of the therapeutic effect of the osmolytes, In cell based assays, the ability of the mucosa] epithelium to efficiently absorb fluid results in the reversal of osmolyte-induced surface hydration. The relatively short therapeutic benefit of inhaled osmolytes can be overcome by increasing the number of treatments per day.
For example, Donaldson at at. (N. Engl. J Med. 354, 3, January 19, 2006, pp.

250) showed inhaling 7% HS four times daily increased FEV1 by two fold grcater than observed by Elkins et al. (A( Engl. J, Med, 354,3, Sanuary 19, 2006, pp, 240) in CF patients inhaling 7% HS twice daily. However, increasing the dosing frequency of hypertonic saline or other osmolytes is inconvenient for subjects in need thereof, requiring hours of time taking medications during the day, Clearly, what are needed are treatments that are more effective at restoring the clearance of mucus from the lungs of patients with CB/CF. The value of these new therapies will be reflected in improvements in the quality and duration of life for both the CF and the CB populations.
In U.S. patent publication no. 2008090841, R,C, Boucher and M.R.
Johnson describe a method to extend the duration of osmolyte therapy by co-administering a potent sodium channel blockers. The inhibition of epithelial sodium transport prevents the reabsorption of HS osmolytes, and thereby, slows mucosa!, fluid absorption and extends the duration of mucosal hydration. The present invention describes an alternative approach to improving both the therapeutic benefit and convenience to the of inhaled osmolyte. treatements,

4 SinsiMaySE INVENTIQN
The present invention is designed to improve the dosing of an osmolyte (e,g., }IS) delivered to the lungs of subjects in need of airway surface rchydration by delivering the osmelyte to the lung via nasal cannulae. The present invention will permit subjects to be treated for long periods of time (e.g., hours) while sleeping or performing daily fiCtiVitICL
Thus, an object of the present invention is a method of treating chronic obstructive pulmonary disease by administering an effective amount clan aerosolized osololYte to a subject in need thereof with a nebulizer connected to a nasal cannula.
Another object of the present invention is a nasal cannula system for delivering an esmolyte, comprising:
a nebulizer and tubing, whore one end of the tubing is connected to the nebulizer and another end of the tubing is tapered to fit in the nostril of a. subject.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following figure and detailed description, Ligluja.SWIDA, 12_,Mlatgla Figure 1: Example of a nebulizer device capable of delivering osmolytes for extended periods of time. The diagram shows a standard large volume nebulizer (with >100 ml capacity) connected to a nasal cannula with heated tubing.

MAU DESCRIPTION OP Tligjravik,Nnoti Osmolytes are well-known therapeutics in the field of respiratory therapeutics.
These agents are molecules or compounds that are osmotically active are "osmolytes"). "Osmotically active" compounds of the present invention are rnembrane-impenneable (i.e,, essentially non-absorbablc) on the airway or pulmonary epithelial surface, The terms "airway strike" and "pulmonary surface," as used .
herein, include pulmonary airway surfaces such as the bronchi and bronchioles, alveolar surfaces, and nasal and sinus surfaces, Active compounds of the present invention may be ionic osmolytes OA, salts), or may be non-ionic osmolytcs (i.e., sugars, sugar alcohols, and organic osmolytes). It is specifically intended that both raterriic forms of the active compounds that are racerrtic in nature are included in the group of active compounds that are usefµ.11 in the present invention. It is to be noted that all racematess enantiomers, diastereomers, tautomers, polymorphs and psoudopolymorphs and racemic mixtures of the osmotically active compounds are embraced by the present invention.
Active osmolytes uaeful in the present invention that are ionic osmolytes include any salt of a pharmaceutically acceptable anion and a pharmaceutically acceptable cation. Preferably, either (or both) of the anion and cation are non-absorbable (i.e., osmotically active and not subject to rapid active transport) in relation to the airway surfaces to which they are administered. Such compounds include but are not limited to anions and cations that are contained in FDA
approved commercially marketed salts, see, e.g., Remington; The Science and Practice of Pharmacy,V al. II, pg. 1457 (l9' Ed, 1995), incorporated herein by reference, and can be used in any combination including their conventional combinations.
Phamiaceutically acceptable osmotically active anions that can be used to carry out the present invention include, but are not limited to, acetate, benzonesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, citrate, dihydrochloride, edetate, edisylate (1,2-ethanedisulfonate), estolate (lauryl sulfate), esylate (1,2-ethanedisutfonate), fumarate, glueeptate, glueonate, glutamate, glycollylarsanilate (p-glycollarnidophenylarsonate), hexylresorcinate, hydrabamine (N,N'-Di(dehydtoitb(etyl)ethylenedimtint), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitratc, methylsulfate, rnucate, napsylate, nitrate, nitrte, pamoate (embonate), pantothenate, phosphate or diphosphate, potygalacturonate, salieylate, stcarate, subacetate, suceinate, sulfate, tannate, tartrate, tecielate (8-chlorotheophyllinate), triethiodide, bicarbonate, etc.
Particularly preferred anions include chloride sulfate, nitrate, gluconate, iodide, bicarbonate, bromide, and phosphate.
Pharmaceutically acceptable cations that can be used to carry out the present invention include, but are not limited to, organic catione such as benzathine (NIAdibenzyethylenediaminc), chloroprocaine, cholinc, diethanolamine, ethylenediamine, meglumine (N-methyl D-glucamine), procaine, D-lysine, L-lysine, D-arginine, arginine, triethylammonium, N.methyl D-glycerol, and the like. Particularly preferred organic cations are 3-carbon, 4-carbon1 5-carbon and 6-carbon organic cations, Metallic cations useful in the practice of the present invention include but are not limited to aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, iron, ammonium, and the like Particularly preferred cations include sodium, potassium, choline, lithium, meglurnine, D-lysine, ammonium, magnesium, and calcium.
Specific examples of osmotically active salts that may be used with the sodium channel blockers described herein to carry out the present invention include, but are not limited to, sodium chloride, potassium chloride, Moline chloride, eholine iodide, lithium chloride, meglumine chloride, L-lysine chloride, D-lysine chloride, ammonium chloride, potassium sulfate, potassium nitrate, potassium gluconate, potassium iodide, ferric chloride, ferrous chloride, potassium bromide, eta.
Either a single salt or a combination of diffbrent osmotically active salts may be used to carry out the present invention. Combinations of different salts are preferred, When different salts are used, one of the anion or cation may be the same among the differing salts, Osmotically active compounds of the present invention also include non-ionic osmolytes such 25 sugars, sugar-alcohols, and organic osmolytes. Sugars and sugar-alcohols useful in the practice of the present invention include but are not limited to 3-carbon sugars (e.g., glycerol, dihydroxyacctone); 4-carbon sugars (e.g., both the 13 and L forms of erythrose, threose, and erythrulose); 5-carbon sugars (e.g., both the and I., forms of ribose, arabirtose, xylose, lyxose, psicose, fructose, eorbose, and tagatose); and 6-carbon sugars (e.g., both the D. and I.-forms of allose, Mose, glucose, mannose, gulose, idose, galactose, and tatose, and the D- and L-forms of allo-heptulose, allo-hepulose, gluco-heptulose, marmo-heptilose, gulo-heptulose, ido-heptulose, galacto-heptulose, talo-heptalose). Additional sugars useful in the practice of the present invention include raffinose, raffinose series oligosaccharides, and stachyose, Both the 1)- and L-forms of the reduced form of each sugar/sugar alcohol = Useful in the present invention are also active compounds within the scope of the invention, For example, glucose, when reduced, becomes sorbitol; within the scope of the invention, sorbitol and other reduced forms of sugar/sugar alcohols (e.g., marmitol, duicitol, arabitoI) are accordingly active compounds of the present invention, Osmotically active compounds of the present invention additionally include the family of non-lank osmolytes termed "organic osmolytes." The term "organic osmolytes" is generally used to refer to molecules used to control intracellular osmolality in the kidney. See e.g., J. S. Handler et al., Camp. Boehm.
Physiol,117, 301-306 (1997); M. Burg, Am. .1 Physiol. 268, F983,7996 (1995).
Although the inventor does not wish to be bound to any particular theory of the invention, it appears that these organic osmolytes are useful in controlling extracellular volume on the airway/pulmonary surface, Organic osmolytes useful as active compounds in the present invention include but are not limited to three major classes of compounds; polls (polyhydric alcohols), methylatnines, and amino acids. The polyol organic osmolytes considered useful in the practice of this invention include, but are not limited to, inositol, myo-inositol, and sorbitol. The tnethylarnine organic osmolytes uaeful in the practice of the invention include, but are not limited to, choline, betaine, carnitine (L-, D- and DL.forms), phosphorylcholine, lyso-phosphorylcholine, glycerophosphorylcholine, creatine, and creatine phosphate.
The amino acid organic osmolytes of the invention include, but are not limited to, the D- and L-forms of garine, alanine, glutamine, glutamate, aspartate, proline and taurine. Additional osmolytes useful in the practice of the invention include tihulose and sarcosine, Mammalian organic osmolytes are preferred, with human organic 'osmolytes being most preferred. However, certain organic osmolytes are of bacterial, yeast, and marine animal origin, and these compounds are also useful active compounds within the scope of the present invention.
Under certain circumstances, an osmolyte precursor may be administered to the subject. Accordingly, these compounds are also useful in the practice of the invention. The term "osmolyte precursor" as used herein refers to a compound which is converted into an osmolyte by a metabolic step, either catabolic or anabolic. The osmolyte precursors of this invention include, but are not limited to, glucose, glucose polymers, glycerol, choline, phosphatidylcholine, lyso-phosphatidyleholine and inorganic phosphates, which are precursors of polyols and methylamines.
Precursors of amino acid osmolytes within the scope of this invention include proteins, peptides, and. polyamino acids, which are hydrolyzed to yield osmolyte amino acids, and metabolic precursors which can be converted into osmolyte amino acids by a metabolio step such as transamination. For example, a precursor of the amino acid glutamine is poly-L.glutamine, and a precursor of glutamate is poly-L,glutamic acid.
Also included within the scope of this invention are chemically modified ostnolytes or osmolyte precursors. Such chemical modifications involve linking to the osmolyte (or precursor) an additional chemical group which alters or enhances the effect of the osmolyte or osmolyte precursor (e,g,, inhibits degradation of the .
osmolyte molecule). Such chemical modifications have been utilized with drugs or prodrugs and are known in the art. (See, for exantple, U.S. Pat. Nos, 4,479,932 and 4,540,564; Slick, E. et al,, Med. Chem. 19:113-117 (1976); Bodor, N. et al., J.
Pharm, Sci, 67:1045-1050 (1978); Bodin, N. et al., 3 Med. Chem. 26:313-318 (1983);
Bodor, N. et alõ J. Pharrn, Sci, 75:29-35 (1986).
lin general, osmotically active compounds of the present invention (both ionic and non-ionic) that do not promote, armn fact deter or retard bacterial growth, are preferred.
It is an object of the present invention to provide a nebulizer connected to a nasal cannula to deliver aerosolized osmolytes (e.g., HS) to subjects over long time intervals. The nebulizer will have the capacity for a large volume of osmolyte solution (up to 2 liters) and will produce aerosol particles in the respirable range(1 -microns MIvID) at a rate that will produce good lung deposition and will be continuous, i.e. will not require refilling over long time periods (8-24 hrs), An example of such a nebulizer is the Westmed Heart High Output Nebulizer, A
nasal cannula/tubing will be connected to the nebulizerby a. tapered fitting, The dimensions of the tubing will be ¨3-5 min with an inner diameter with a length of 2-, 4 meters. The end of the tubing may end in one or two tapered ends that fit into the nostrils, although face masks are alternatives.

Both nebulizers and nasal cannulas are well-known in the field of respiratory treatment, See Critical Care Medicine (Michael lames Murray, American Society of Critical Care Anesthesiologists, Douglas B. Coursin, Ronald G. Pearl, Donald S.
Prough), pp. 431 and 439-445. However, commercial nebulizers are generally designed to rapidly delivery therapeutic agents via the mouth or mask. Nasal cannulas are generally used to delivery oxygen (gasses) to the lungs through the nose.
Nasal cannulas are preferred for the delivery of gasses as they are comfortable to wear for long periods of time, The adaptation of a nasal cannula on a nebulizer provides a novel meant to deliver inhaled osmolytes that offers the following advantages.
(I) The nasal cannulainebulizer device is comfortable and can be worn for extended periods of time. (2) Thc device can deliver osmolytes for long periods of time, thus, increasing the therapeutic benefit of these treatments, Due to the narrow diameter of oxygen tubing and nasal cannulas, the output from a nebulizer will lead to the deposition of aerosol on the inner surface of the tubing, leading to the "condensation" and accumulation of fluid droplets.
Fluid inside the tubing can occlude the flow of aerosol inside the tubing, as well as, result droplets blowing out the nasal cannula that would "drown" the subject with boluses of liquid.
Several modifications improve the performance of the nasal cannula/nebulizer device to prevent fluid condensation on the inner surface of the tubing and nasal cannula. It is an object of the present invention to heat all the fittings, tubing, and/or the nasal cannula of the device to retard condensation in the tubing. Thus the heated, inner surface coated cannula will ensure that the aerosol generated will be delivered to the nostril as a respirable particle. It is another object of the present invention that the tubing will contain a coating on its inner surface so as to prevent condensation of solution in the lumen, It is anticipated that the subject will use the heated cannulae to receive HS for periods of minutes to daily.
gxamoles The nebulizer system shown in Figure 1 was run for SO minutes with 7%
hypertonic saline. The build-up of fluid within the oxygen tubing was observed with and without heating the oxygen tubing in a water bath, For this system, the tubing became occluded with water droplets within 23 minutes of continuous nebulizer operation. Externally heating the tubing to 60 C allow the nebulizer system to run fbr the full 80 minutes without occlusion from water droplets.

Table]. The effect of heating on fluid condensation within the oxygen tubing.
External Tubing Time to Nebulizer/Cornpressor Tubing Temperature Condensation laari-LC Star with ProNeb Oxygen Tubing with Ambient 23 min' Compressor Adult nasal cannula ¨Pari-LC Star with ProNeb Oxygen Tubing with 60'C No significant __________ Compressor , Adult qua] cannula condensation Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.

Claims

What is claimed is:

1. An apparatus, comprising:
a nasal cannula assembly having a tube portion and a face piece portion, the tube portion configured to be operably coupled to an aerosol preparation mechanism, the face piece portion configured to be removably coupled to a nostril of a subject, the nasal cannula assembly configured to receive, at the tube portion and from the aerosol preparation mechanism, a flow of aerosolized medicament including respirable particles, the nasal cannula assembly configured to convey via the face piece portion the aerosolized medicament to the nostril of the subject, at least a portion of the nasal cannula assembly having an inner diameter greater than three millimeters.

2. The apparatus of claim 1, wherein a length from a first end portion of the nasal cannula assembly to a second end portion of the nasal cannula assembly is less than four meters.

3. The apparatus of claim 1, wherein the nasal cannula assembly is configured to deliver the aerosolized medicament to the subject over a period of 23 to 80 minutes while limiting accumulation of liquid droplets from the flow of aerosolized medicament,

4. The apparatus of claim 1, wherein the nasal cannula assembly is configured to convey the aerosolized medicament continuously over a period of hours,

5, The apparatus of claim 1, further comprising:
an aerosol preparation mechanism configured to receive a flow of gas at a first port, the aerosol preparation mechanism configured to convey the flow of aerosolized medicament from a second port and to the tube portion of the nasal cannula assembly.

6. An apparatus, comprising:
a nasal cannula assembly having a tube portion and a face piece portion, the tube portion configured to be operably coupled to an aerosol preparation mechanism, the face piece portion configured to be removably coupled to a nostril of a subject, the nasal cannula assembly configured to receive, at the tube portion and from the aerosol preparation mechanism, a flow of aerosolized medicament including respirable particles, the nasal cannula assembly configured to convey via the face piece portion the aerosolized medicament to the nostril of the subject a length from a first end portion of the nasal cannula assembly to a second end portion of the nasal cannula assembly being less than four meters.

7. The apparatus of claim 6, wherein the nasal cannula assembly is configured to deliver the aerosolized medicament to the subject over a period of 23 to 80 minutes while limiting accumulation of liquid droplets from the flow of aerosolized medicament.

8. The apparatus of claim 6, wherein at least a portion of the nasal cannula assembly has an inner diameter of greater than three millimeters.

9, The apparatus of claim 6, wherein the nasal cannula assembly is configured to convey the aerosolized medicament continuously over a period of hours,

10. The apparatus of claim 6, further comprising:
an aerosol preparation mechanism configured to receive a flow of gas at a first port, the aerosol preparation mechanism configured to convey the flow of aerosolized medicament from a second port and to the tube portion of the nasal cannula assembly.

11. The apparatus of claim 6, wherein the aerosolized medicament includes a hypertonic saline.