Pulmonary and Nasal Anti-Inflammatory and Anti-Allergy Inhalation Aerosol Delivery Systems

Transcription

1 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, 10, Pulmonary and Nasal Anti-Inflammatory and Anti-Allergy Inhalation Aerosol Delivery Systems Xiao Wu, reoluwa. Adedoyin and eidi M. Mansour * Department of Pharmaceutical Sciences-Drug Development Division, University of Kentucky College of Pharmacy, 789 South Limestone Street, Lexington, KY , USA Abstract: Most respiratory infections, diseases and allergic reactions have varying degrees of inflammation. Inflammation is a natural immunodefensive response to the presence of allergens or foreign particles that come into contact or affect the cells and tissues within the respiratory tract. The three main types of therapeutic drug classes available for anti-inflammatory and anti-allergy effects are corticosteroids, antihistamines and decongestants. Corticosteroid drugs for pulmonary inhalation and/or nasal delivery include beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Antihistamine drugs for nasal delivery include azelastine and olopatadine. Two common decongestants available are oxymetazoline and phenylephrine. Another therapeutic class, the anticholinergic agents, such as ipratropium bromide and tiotropium bromide, are used in pulmonary delivery in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease. The mast cell stabilizer therapeutic class, cromolyn sodium, can be used to prevent and relieve nasal allergic symptoms. Additionally cromolyn sodium was the first dry powder inhaler product for pulmonary drug delivery several decades ago and currently is on the market as a pressurized metered dose inhaler for pulmonary inhalation delivery. Based on the devices used in pulmonary drug delivery, this route can be subdivided into three categories; namely nebulizers, pressurized metered dose inhalers, and dry powder inhalers. Nasal delivery of anti-inflammatory and antiallergy drugs is most commonly available commercially in an aqueous spray form. This article comprehensively reviews and discusses different kinds of drugs used for anti-inflammatory and anti-allergic effects via the pulmonary and nasal delivery route, as well as their mechanisms of action, marketed products, disease state indications while highlighting drug delivery and therapeutic aspects. Keywords: Pulmonary drug delivery, aerosol, nasal spray, anti-inflammatory, anti-allergy, corticosteroids, antihistamines, decongestants, rhinitis, anti-cholinergics, mast cell stabilizers, beta agonists, short-acting, long-acting. 1. INTRDUCTIN T PULMNARY DELIVERY SYSTEMS Pulmonary drug delivery to or via the lungs, is one of the most ancient yet still advancing fields in the world of drug development and delivery. Traditionally, therapy via inhalation is targeted at treatment of localized lung diseases [1]. It has numerous advantages including rapid onset of action, drug confinement to target organ, circumvention of first pass effect, avoidance of drug degradation by the gastrointestinal tract, large lung surface area of low metabolic activity, and lower dosage thus minimizing adverse reactions [2, 3]. There are three major categories of aerosol devices used in pulmonary drug delivery and the device type, together with the nature of the aerosol droplet emitted, will determine the deposition characteristics and location within the respiratory tract [4]. The three main classes are the nebulizers, pressurized metered dose inhalers (pmdis), and dry powder inhalers (DPI). These three main categories differ in their mode of operation, degree of dependency on the patient's inspiratory flow to create the aerosol, particle characteristics, compatible drug formulations and portability. Certain features are expected of aerosol devices for performance and *Address correspondence to this author at the University of Kentucky, College of Pharmacy, Department of Pharmaceutical Sciences-Drug Development Division, 789 South Limestone Street, Lexington, KY , USA; Tel: (859) ; heidi.mansour@uky.edu therapeutic efficacy which include the ability to generate aerosol particles of suitable aerodynamic size for pulmonary inhalation deposition, provide reproducible drug dosing, ease of use, convenient, inexpensive, and portable [4, 5]. Choosing an appropriate pulmonary inhalation device and patient education are important in order to achieve the desired clinical outcomes [6]. Nebulizers are the first commercially marketed pulmonary inhalation devices and the aerosol generated does not depend on the patient's inspiratory flow. They are used most often in in-patient settings and for patients (e.g. neonates, young children, the acutely ill, the elderly, and those with restricted dexterity in coordinating inhalation and device actuation) who may not be able to achieve adequate therapy using the pmdi or DPI device [7, 8]. Nebulizers (which can be jet or ultrasonic) are able to deliver pulmonary drugs in solution while also allowing for dosing adjustments [1]. The jet nebulizers are particularly well suited for administration of aqueous and mixed aqueous/alcohol (i.e. water and solvent) solutions. Nebulization can exhibit variability in lung deposition patterns between patients, a wide range in the aerosol particle size distribution in a given aerosol plume, sterility problems, requires an external power source and a relatively long administration time, and can be relatively high cost [1, 5, 9]. owever, advancement in technology has yielded more portable and smaller hand-held battery-operated nebulizers, can provide the ability to time aerosol delivery and patients inspiration with improved lung

2 216 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No. 3 Wu et al. deposition and decreased aerosol waste to the environment [1]. Nebulizer delivery is generally reserved clinically for acute care, inpatient settings, and select patient populations (e.g. some pediatric and geriatric patients). To circumvent the problems posed by nebulizers, pmdis were developed. pmdis have been the mainstay of asthma inhalation therapy for the past several decades and are more portable than nebulizers [9]. The key components of the formulation are a propellant, the drug (or two drugs), cosolvent mixture, and surfactant [4]. owever, the requirement by the Montreal Protocol to significantly reduce and gradually phase out the use of chlorofluorocarbon propellants due to its depleting effect on the zone layer necessitated the use of alternative propellants/propellant systems such as the hydrofluroalkanes (FA) in pmdis [4, 8]. pmdis have numerous advantages such as their portability, affordability, and ease of use. owever, the presence of the propellant/ cosolvent mixture limits the range of drug substances that can be delivered (due to solubility limits and/or drug degradation problems in solution) and also can have an aftertaste that patients may dislike. Furthermore, there is a need for patients to coordinate actuation and inspiration for enhanced lung deposition [9]. In addition, due to the introduction of new alternative propellants and propellant systems, new issues associated with solubility of active drug entities, stability, aerosol behavior and excipient compatibility have arisen; and as such, extensive research is being devoted to re-formulation of conventional CFC-based pmdis [1]. DPIs are the fastest growing sector of approved pulmonary inhalation products, due in large part to their many advantages. The drug is formulated as an inhalable dry powder [8], and thus, is in the solid state which affords greater drug stability and higher dose delivery than nebulizers and pmdis. DPI devices can be classified as either passive (i.e. aerosol dispersion depends on the patient's inspiratory flow) or active (i.e. aerosol dispersion does not depend on the patient s inspiratory effort) [8]. Exubera, approved by the FDA in 2006, was the first marketed pulmonary product with an active dispersion DPI device; all other currently approved marketed products utilize passive devices [4]. In contrast to pmdis, DPIs are more environmentally friendly and do not cause patient aftertaste due to the absence of propellant. ther advantages include the versatility to deliver a wide range of drugs, portability, and a reduced need of synchronization of actuation and patient inspiration [1, 8, 9]. n the other hand, dry powders can have high oro-pharyngeal deposition if the powder is highly cohesive (i.e. aggregated) and there is drug-inhaler device specificity for each DPI commercial product [1, 5, 6]. It is important to note that the physicochemical properties (e.g. particle size, particle size distribution, particle morphology, surface roughness, crystallinity, ternary/fine component, surface impurities, hygroscopicity, and electrostatic charge) of drugs formulated as respirable dry powders significantly affect the aerosolization performance of DPIs as they directly influence the powder interparticulate forces and particle aggregation/deaggregation [10]. ptimization of these properties is essential in the formulation, stabilization and performance enhancement of dry powders for inhalation delivery Pathogenesis of Inflammation Most respiratory infections and diseases have within their pathogenesis the existence of varying degrees of inflammation. This inflammation is a defensive response to the presence of allergens or foreign particles that come in contact with or affect the cells and tissues within the respiratory tract. Several cell types (including mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines, prostaglandins, and the complement system) are involved in allergic and non-allergic-mediated inflammation [11, 12]. When the pulmonary system senses the presence of allergens, there is a profuse release of these inflammatory mediators which results in smooth muscle contraction, production/secretion of mucus and a cascade of other inflammatory responses, in addition to wheezing, chest tightness, coughing and shortness of breath that is often experienced by patients with pre-existing pulmonary disease (e.g. asthma, chronic obstructive pulmonary disease, etc). The inflammatory response can be prevented or controlled by corticosteroids, which can be natural or synthetic. Corticosteroids act by supressing the formation, release and activity of these endogenous inflammatory cells and mediators thus modifying the body s immune system [11]. Cortisol (also known as hydrocortisone) is the naturally occurring glucocorticoid hormone that is a potent anti-inflammatory Pulmonary Diseases Treated with Anti-Inflammatory Drugs Anti-inflammatory agents such as corticosteroids, leukotriene antagonists, and mast cell stabilizers are used in treatment of many pulmonary diseases having varying degrees of inflammation, including Chronic bstructive Pulmonary Disease (CPD), asthma, bronchitis, mesothelioma, and lung cancer. Asthma is a chronic inflammatory airway disease characterized by airway obstruction that is usually episodic and often reversible with symptoms such as cough, shortness of breath, wheezing, and chest tightness [12, 13]. The goal of asthma treatment is to improve lung function, symptoms, and the ability to perform daily activities, and reduce the risk of exacerbations [14]. Successful treatment of asthma entails the use of inhaled corticosteroids and -2 adrenoceptor agonists as the cornerstone of successful therapy and this combination therapy has been found to be more effective at controlling symptoms, improving lung function and preventing worsening of the symptoms [13]. Corticosteroids however have a wide range of inhibitory activities against different cell types and inflammatory mediators thus, are efficacious in treatment of asthma [15]. Chronic obstructive pulmonary disease (CPD) is a complex chronic inflammatory disease of the lungs (usually characterized by emphysema and bronchitis) that involves different inflammatory cells and mediators. Corticosteroids are a very important drug class used in CPD and asthma therapy to reduce inflammation in the airways thus preventing airway narrowing, reduce edema, reduce secretion of mucus into the airway, and reduce lung damage caused by inflammation [16]. Corticosteroids for respiratory diseases can be taken orally or via inhalation. Common examples of

3 Pulmonary and Nasal Inhalation Aerosol Delivery Systems Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No Table 1. Marketed Anti-Inflammatory Inhalation Prescription (Rx) Products and Common Brand Names in the United States Drug Name Drug Class Common Brand Name Beclomethasone Dipropionate Budesonide Fluticasone Propionate Corticosteroid Corticosteroid Corticosteroid Beclovent pmdi (GlaxoSmithKline); Qvar pmdi (3M Pharmaceuticals); Vanceril pmdi (Schering Plough) Pulmicort (AstraZeneca); Pulmicort Turbuhaler DPI (AstraZeneca); Pulmicort Flexhaler DPI (AstraZeneca); Pulmicort Respules (AstraZeneca); Symbicort Budesonide/formoterol (AstraZeneca) Flovent FA Inhalation Aerosol (GlaxoSmithKline); Flovent Diskus Inhalation Powder (GlaxoSmithKline); Flovent (GlaxoSmithKline); Flovent Nebules /inhalation suspension (GlaxoSmithKline); Flovent Rotadisk DPI (GlaxoSmithKline); Advair Diskus DPI (+salmeterol xinafoate) (GlaxoSmithKline); Advair pmdi (GlaxoSmithKline); Advair FA pmdi (GlaxoSmithKline) Ciclesonide Corticosteroid Alvesco inhalation aerosol pmdi (Sepracor) Flunisolide Corticosteroid Aerobid Inhalation Solution pmdi (Forest Pharmaceuticals); Aerobid-M pmdi (Forest Pharmaceuticals) Mometasone Furoate Corticosteroid Asmanex Twisthaler inhalation powder (Schering-Plough) Triamcinolone Acetonide Corticosteroid Azmacort inhalation aerosol pmdi (Abbott Laboratories, USA; Discontinued in 2009) Table 2. Marketed Inhalation Prescription (Rx) Products and Common Brand Names Indicated for Use in Inflammatory Pulmonary Diseases such as Asthma and/or Chronic bstructive Pulmonary Disease (CPD) Drug Name Drug Class Common Brand Name Cromolyn Sodium Mast Cell Inhibitor Intal Inhaler pmdi (Aventis); DPI (Fisons) Ipratropium Bromide Anti-cholinergic Atrovent inhalation aerosol (Boehringer Ingelheim); Atrovent FA pmdi; Combivent pmdi (Boehringer Ingelheim) Tiotropium Bromide Anti-cholinergic Spiriva andihaler DPI (Boehringer Ingelheim) inhaled corticosteroids used in reducing inflammation in the airways include fluticasone propionate, budesonide, mometasone and beclomethasone dipropionate. Several studies [17-23] have shown the benefits of combination treatment in the successful management and treatment of many lung diseases (asthma, bronchitis, lung cancer, CPD) due to the fact that multiple etiologies and cell receptors are involved in producing these symptoms. Thus, treatment is often initiated using multiple drug classes (anti inflammatory, -2 adrenoceptor agonists, anticholinergics, anti-infectives) having different modes of action and different targets. Common examples of United States and European marketed anti-inflammatory and antiallergy agents are listed in Tables 1 and ANTI-INFLAMMATRY DRUGS DELIVERED BY PULMNARY INALATIN 2.1. Beclomethasone Dipropionate Beclomethasone dipropionate is a prodrug that undergoes hydrolysis to its active form Beclomethasone -17 monopropionate which has high affinity for the human glucocorticoid receptor. Beclomethasone dipropionate is synthetically related to dexamethasone with the difference being the presence of a chlorine instead of a fluorine at the 9-alpha carbon and having a 16 beta-methyl group instead of a 16 alpha-methyl group. It is a creamy white odorless powder having a molecular formula of C Cl 7 and molecular weight of g/mol [24]. For many decades, nebulized beclomethasone dipropionate has been in use therapeutically showing great clinical efficacy and tolerability in patients with chronic and persistent asthma [7]. It is also delivered as a pmdi. QVAR (beclomethasone dipropionate) can deliver smaller-particle-sized medication to the large, intermediate and small airways [24]. Interestingly, the replacement of CFC with hydrofluoroalkanes (FA) can provide the opportunity to specifically target certain corticosteroids directly to all inflammatory sites that exist in both the upper and lower airways [25]. This commercial product is indicated for use in maintenance treatment of asthma as prophylactic therapy in patients 5 years of age and older. Lipworth et al. (1999) compared the pharmacokinetic profile of Beclazone TM (beclomethasone dipropionate) in its CFC-based vs. FA-based formulations [26]. They found the T max occurred significantly (P<0.05) earlier and the plasma concentrations were significantly higher with formulations containing FA rather than CFC. In addition, the geometric mean values for the AUC were significantly greater and the C max values were significantly greater for the FA-containing formulation compared to the CFC formulation after drug inhalation in healthy volunteers Budesonide Budesonide is a corticosteroid for inhalation use that marketed both as liquid and solid-state formulations. Budesonide is a corticosteroid with potent anti-inflammatory properties. Studies have shown that addition of a long-acting

4 218 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No. 3 Wu et al. -2 agonist (formoterol) to budesonide was more beneficial in controlling asthma, and improving lung function and symptoms [27-29]. Symbicort is a combination drug aerosol pmdi marketed pharmaceutical product indicated for treatment of asthma, inflammation, bronchoconstriction and for maintenance treatment of CPD [15, 30]. It contains the antiinflammatory drug budesonide and formoterol fumarate dihydrate, a long-acting bronchodilator that exerts agonistic effects on -2 adrenergic receptors of the bronchial smooth muscles Fluticasone Propionate Fluticasone propionate is a highly hydrophobic synthetic trifluorinated fatty acid-conjugated corticosteroid used as a long-acting anti inflammatory agent in treatment and management of allergic rhinitis, asthma, and other respiratory diseases. It is delivered as a nasal spray, pmdi, and DPI. It is a white powder with an empirical formula of C F 3 5 S and molecular weight of 500.6g/mol [31]. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol. Comparative effectiveness of certain corticosteroids using the McKenzie vasoconstrictor assay demonstrated that fluticasone propionate is a potent agonist of the human glucocorticoid receptor with activity 18 times greater than dexamethasone and about two times greater than of beclomethasone-17-pripionate and about 3 times greater than that of budesonide. owever, even though the McKenzie assay is the standard in vivo method for comparing topical potency and bioequivalence of steroids based on the degree of vasoconstriction, certain studies have shown that the degree of topical potency of corticosteroids does not necessarily correlate to their efficacy when used as an inhaled anti inflammatory agent [31-33]. Nevertheless, Frois et al. (2009) conducted a review comparing the clinical effectiveness and tolerability of certain corticosteroids in use in asthma therapy, and concluded that fluticasone was reported to have significantly greater improvement in lung function and better asthma symptom control than budesonide [34]. Fluticasone propionate pmdi consists of an FA propellant (1,1,1,2-tetrafluoroethane) and a micronized microcrystalline suspension of the drug. No other excipients are included in the formulation [31]. n the other hand, Flovent Diskus is a specially designed for DPI delivery having a specific multi-unit dose delivery device (i.e. the diskus) and contains individual double-foil blister strips consisting of microfine fluticasone propionate and large lactose carrier particles [35]. In clinical trials comparing the efficacy of inhaled powder and orally administered tablets of fluticasone propionate, the inhaled powder demonstrated far greater clinical efficacy in maintaining asthma stability and improving lung function compared to oral tablets and placebo; thus demonstrating that the anti inflammatory effect of fluticasone propionate is due to direct local effect on the lung cells rather than systemic [35]. In DPIs containing physical blends of micronized flutihydrate carrier particles, it was experimentally demonstrated that the hydrophobicity of FP (fluorinated corticosteroid having a conjugated propionate moiety) may strongly influence the interfacial properties favoring aggregation, thereby resulting in a subsequent decrease in aerosolization of the drug [36]. Advair Diskus is a marketed combination drug multiunit-dose DPI containing the long-acting corticosteroid fluticasone propionate and salmeterol xinofoate (a long-acting beta-adrenergic receptor agonist) [37, 38]. It is used in treatment of asthma and CPD. This drug combination is supplied both as a DPI and pmdi. Rojas et al. (2007) compared the effect of a salmeterol xinofoate/fluticasone propionate combination treatment vs. fluticasone propionate alone on the maintenance treatment of moderate persistent asthma being treated only with inhaled short-acting -2 agonists [39]. They concluded that significantly more patients attained better control of their asthma during treatment with the combination drug therapy (46%) compared with fluticasone propionate alone (32%) Ciclesonide Ciclesonide is a non-halogenated glucocorticoid with a molecular formula of C and a molecular weight of 540.7g/mol [40]. It is a white to yellow-white powder and is formulated and delivered as a nasal spray (e.g. mnaris ) for the treatment of allergic rhinitis or as an inhalation aerosol in maintenance therapy of asthma as prophylactic therapy (Alvesco ) [41]. Alvesco inhalation aerosol contains ciclesonide in a solution mixture of propellant FA-134a (1,1,1,2 tetrafluoroethane) and ethanol. It is a novel, safe and highly efficacious aerosol metered dose inhaler formulation due to the fact that it is lung targeted, lung activated and lung limited [41, 42]. Ciclesonide demonstrates about 99% protein binding in serum thus implying the presence of very little amounts of des-ciclesonide systemically. This suggests a very low potential for occurrence of systemic adverse effects after inhalation of ciclesonide [43]. In addition, due to the very high affinity desciclesonide has for glucocorticoid receptors in the lungs, Alvesco demonstrates improved efficacy, low systemic bioavailablity, fewer occurrence of adverse effects, and enhanced safety profile [41]. When compared with other corticosteroids like budesonide and fluticasone, several studies have indicated the similarity of all three drugs in improving lung function and asthma symptoms however, ciclesonide was shown to demonstrate a better safety profile with less cortisol suppression [41, 44, 45]. Ciclesonide has been shown to be as effective as other inhaled corticosteroids at initiating, maintaining, and controlling asthma symptoms with a positive safety profile and is well tolerated [46] Flunisolide Flunisolide is a corticosteroid indicated in maintenance treatment of asthma as prophylactic therapy and for asthma patients requiring systemic corticosteroid administration. It is a white to creamy white crystalline powder with a molecular weight of g/mol [47].

5 Pulmonary and Nasal Inhalation Aerosol Delivery Systems Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No Aerobid TM /Aerobid-M Inhaler is a pmdi containing a microcrystalline suspension of flunisolide hemihydrate in a mixture of propellants, a dispersing/suspending agent (sorbitan trioleate), and in the case of Aerobid-M, the addition of a flavoring agent (menthol) [48]. Newman et al. (1996) conducted a comparative evalution of deposition pattern and efficacy of flunisolide by different devices and demonstrated that use of a multidose hand-held nebulizer (Respimat Soft mist inhaler TM ) which delivered an ethanolic solution of flunisolide had much higher whole lung deposition than the pmdi or pmdi-spacer combination [49]. As described earlier due to the Montreal Protocol, other flunisolide formulations without the CFC propellants have been developed. For example, Tzou et al. (1999) invented an aerosol formulation comprised of flunisolide, an FA propellant comprising 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3, 3-heptafluoropropane, and a mixture thereof, and sufficient ethanol to solubilize the drug [48]. This FA formulation eliminates problems of increased particle size, rapid flocculation, irreversible particle aggregation and bulk separation; thus resulting in a higher respirable fraction of drug vs. the CFC based propellants [48] Mometasone Furoate Mometasone furoate is a synthetic corticosteroid with an empirical formula of C C l2 6, a molecular weight of g/mol, and is used as an anti-inflammatory agent [11]. Mometasone furoate shows in vitro binding affinity for the human glucocorticoid receptor about 12 times that of dexamethasone, 7 times that of triamcinolone, 5 times that of budesonide, and 1.5 times greater than that of fluticasone, though the clinical significance of this is unknown [11]. Asmanex Twisthaler is a cap-activated multidose DPI containing micronized respirable mometasone furoate as its active ingredient physically blended with large non-respirable lactose carrier particles. It is indicated for the maintenance treatment of asthma as prophylactic therapy [11]. It uses a stabilized agglomerate formulation to measure and deliver accurate drug doses over a range of inspiratory flow rates [50]. Mometasone furoate delivered via dry powder inhaler for once daily maintenance treatment of asthma was found to be both safe and efficacious in both adults and children [14]. Furthermore, mometasone furoate shows comparative efficacy with budesonide, beclomethasone dipropionate and fluticasone and has been shown to be superior in improving lung function, controlling asthma symptoms and improving quality of life in persistent asthmatics being treated with short-acting -2 agonists or twice daily maintenance therapy with certain inhaled corticosteroids [51] Triamcinolone Acetonide Triamcinolone acetonide is a potent corticosteroid derivative of triamcinolone, with a chemical formula of C F 6 and a molecular weight of 434.5g/mol [52]. It is formulated and delivered as cream, ointment, dental paste, injection, nasal spray, and inhaler. Triamcinolone is about 1 or 2 times more potent than prednisolone but triamcinolone acetonide is about 8 times more potent than prednisolone [53]. Azmacort Inhalation Aerosol is a metered-dose pmdi that contains a microcrystalline suspension of triamcinolone acetonide in the propellant dichlorodifluoromethane and dehydrated alcohol USP 1% w/w [53]. It is indicated in the maintenance treatment of asthma as prophylactic therapy, and for asthma patients that need systemic corticosteroid administration, where adding Azmacort may reduce or eliminate the need for the systemic corticosteroids [53]. owever, it was voluntarily withdrawn from the market in 2009 by the manufacturer and not reformulated with an FA propellant [54]. 3. TER DRUGS DELIVERED BY TE PULMNARY RUTE FR TE TREATMENT F ASTMA AND CPD 3.1. Cromolyn Sodium Cromolyn sodium is the disodium salt of 5,5'-[(2- hydroxytrimethylene) dioxy]bis [4-oxo-4-1-benzopyran-2- carboxylate] with molecular formula C Na 2 11 and molecular weight of g/mol [55]. Cromolyn sodium (disodium cromoglycate) is a mast cell stabilizer which prevents release of inflammatory mediators such as histamine and SRS-A (slow reacting substance of anaphylaxis) from mast cells thus preventing bronchoconstriction that manifests in response to exposure to an antigen [55]. Cromolyn sodium is supplied as nasal spray (allergic rhinitis), inhalation solution (asthma prophylaxis), ophthalmic solution (keratitis, vernal conjunctivitis, vernal keratoconjunctivitis) and oral solution (systemic mast cell disease) [55]. In the management of asthma today, cromolyn sodium is delivered via nebulizer or pmdi. Interestingly, it was the first dry powder inhaler (DPI) ever marketed many decades ago but is not available as a DPI currently. Blends of disodium cromoglycate (DSCG) and lactose monohydrate have been shown to demonstrate superior aerosol performance (increased fine particle fraction) and this phenomenon is attributed to the ability of DSCG to reduce the high interfacial interactions occurring between particles [56]. Intal inhaler is a pressurized metered dose inhaler used to deliver cromolyn sodium via inhalation. It contains two propellants CFC-12 (dichlorodifluoromethane) and CFC-114 (dichlorotetrafluoroethane) but has been discontinued by the manufacturer due to the ozone layer depletion effects of CFCs [57]. owever, despite this, cromolyn sodium nebulizer solution and FA-containing propellants are still available for use by asthma suffers Ipratropium Bromide Ipratropium bromide is an anti-cholinergic drug formulated and supplied as a nasal spray, pmdi, and nebulized inhalation solution. It is a cholinergic antagonist of acetylcholine at the cholinergic receptors, and suppresses the increase of of cyclic guanosine monophosphate (cyclic GMP) levels due to the interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle [58, 59]. Inhalation aerosol delivery to the lungs by pmdi or nebulized solution is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with

6 220 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No. 3 Wu et al. CPD pulmonary disease, including chronic bronchitis and emphysema [58, 59]. In addition, combination drug delivery of albuterol and ipratropium bromide (Combivent ) have been formulated, as a pmdi and nebulized solution, for treatment of severe bronchospasm in patients with CPD. This is a combination of a short-acting beta-adrenergic bronchodilator (albuterol) and an anticholinergic agent (ipratropium bromide) to widen the air passages and help the asthmatic patient breathe more easily [60]. Analyses of the influence of physical blends of different lactose monohydrate carrier batches with ipratropium bromide indicate that there is no significant difference in the carrier influence on the fluidization and entrainment properties of ipratropium bromide formulation aerosols [36] Tiotropium Bromide Tiotropium bromide is a long-acting anti-cholinergic agent which exerts its pharmacological activity by inhibiting the M3-receptors of the smooth muscles leading to bronchodilation [61]. Like ipratropium bromide, it is an anticholinergic drug but tiotropium is long-acting. It is indicated for long-term once a day maintenance treatment of bronchospasm associated with CPD [62]. It has a molecular weight of 490.4g/mol and a molecular formula of C N 4 S 2 Br 2 [63]. Spiriva andialer consists of individual capsules containing a dry powder formulation of tiotropium bromide monohydrate blended with lactose monohydrate that the patient must actively load into the unitdose inhaler device, the andialer [62, 63]. F S Cl F F Beclomethasone dipropionate Budesonide Fluticasone propionate F Cl Cl S F F Mometasone furoate Ciclesonide Fluticasone furoate Cl N N N F N Triamcinolone acetonide Azelastine lopatadine N N N xymetazoline Phenylephrine Fig. (1). Chemical structures of corticosteroids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide), antihistamines (azelastine and olopatadine) and decongestants (oxymetazoline and phenylephrine) available in the nasal sprays or drops for prevention or relief of nasal allergy and inflammation

7 Pulmonary and Nasal Inhalation Aerosol Delivery Systems Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No NASAL DELIVERY F ANTI-INFLAMMATRY AND ANTI-ALLERGY DRUGS 4.1. Introduction Nasal delivery of anti-inflammatory and anti-allergy drugs is available most commonly and commercially as pharmaceutical products in two forms; namely, as a pressurized aerosol and as a spray pump (aqueous) [64]. The pressurized aerosol form delivers a predetermined dose of dry medication when activated. The more commonly used pump delivers a water-based spray, which may provide some moisturizing and soothing effect as well as antiinflammatory action. Patients who feel that the drip in their nose and throat increases when using the aqueous spray pump form may prefer the aerosol. In contrast, the spray is favored if the pressurized aerosol causes irritation or excessive drying of the nasal membranes. The nasal delivery devices include nasal inhalers, nasal sprays, and nebulizers. They can be classified into single and multi-use intranasal delivery devices for both liquid and powder formulations. A nasal spray is usually in an aqueous medium and delivered by instilling a fine mist into the nostril by action of a hand-operated pump mechanism. It contains a drug or drugs for either locally or generally alleviation of inflammation or allergy symptoms, including sinusitis [65, 66], rhinosinusitis [67-70], rhinitis [71-74], rhinopharyngitis [75] and hay fever [76]. Inflammation often occurs as a result of an allergic reaction, and people who suffer from nasal allergies, such as hay fever, dust mite and pet allergies, tend to experience a variety of symptoms due to this inflammation [77]. Inflammation of the nasal passage forces fluid out of the nasal tissues, resulting in a runny and blocked nose. ther symptoms include sneezing, and watery, itchy eyes. The three main types of drugs available for antiinflammatory and anti-allergy effect are corticosteroids [78-92], antihistamines [73, 93-97] and decongestants. Corticosteroid drugs include beclomethasone dipropionate [68, ], budesonide [ ], ciclesonide [74, ], fluticasone furoate [71, 111, 112], fluticasone propionate [ ], mometasone furoate [ ] and triamcinolone acetonide [ ]. Antihistamine drugs include azelastine [94, 126] and olopatadine [127]. Two common decongestants available in the nasal sprays or drops form are oxymetazoline and phenylephrine. Their chemical structures and names are shown in Fig. (1) and Table 3, respectively Nasal Steroid Sprays Corticosteroid medicines are derivatives of corticosteroid hormones that are produced naturally by the adrenal glands. The corticosteroids have potent anti-inflammatory effects and are very effective in treating allergic inflammation in the nose. The best therapeutic efficacy could be obtained when the sprays are used on a regular preventative basis. With seasonal allergies, daily use of these sprays should begin one to two weeks before the allergy season and continue throughout the season. In year round or perennial allergic rhinitis, particularly if unresponsive to treatments, daily use of intranasal steroids has been found very effective in controlling symptoms, particularly nasal congestion. Nasal steroids may also help improving the sense of smell, which is frequently diminished in allergic rhinitis. The medication may work by reducing swelling high up in the nose, where the area for smell is located. Decreasing the swelling allows more air containing the odors to reach the nerves that are responsible for the sense of smell [128]. Table 3. Popular Anti-Inflammatory and Anti-Allergy Drugs Incorporated in the Marketed Nasal Sprays and their Chemical Names Drugs Beclomethasone dipropionate Budesonide Ciclesonide Fluticasone furoate Fluticasone propionate Mometasone furoate monohydrate Triamcinolone acetonide Azelastine hydrochloride lopatadine hydrochloride xymetazoline hydrochloride Phenylephrine Ipratropium bromide monohydrate Cromolyn sodium Chemical Names 9-chloro-11,17,21-trihydroxy-16 -methylpregna-1,4-diene-3,20-dione 17,21-dipropionate (RS)-11-beta, 16-alpha, 17, 21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16, 17-acetal with butyraldehyde pregna-1,4-diene-3,20-dione, 16,17-[[R-cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)- (11,16 ) (6, 11, 16, 17 )-6,9-difluoro-17-{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4- dien-17-yl 2-furancarboxylate S-(fluoromethyl) 6,9-difluoro dihydroxy-16 -methyl-3-oxoandrosta-1,4-diene-17 -carbothioate, 17- propionate 9,21-Dichloro-11ß,17-dihydroxy-16a-methylpregna-1,4-diene-3,20-dione 17-(2 furoate) monohydrate 9-Fluoro-11ß,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone (±)-1-(2)-phthalazinone,4-[(4-chlorophenyl) methyl]-2-(hexahydro-1-methyl-1-azepin-4-yl)-, monohydrochloride (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride 3-(4,5-dihydro-1-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol hydrochloride (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol 8-azoniabicyclo (3.2.1) octane,3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide, monohydrate (endo,syn)-, (±) disodium 5, 5'-[(2-hydroxytrimethylene)dioxy]bis[4-oxo-4-1-benzopyran-2-carboxylate]

8 222 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No. 3 Wu et al Antihistamines Excessive histamine function is the primary cause of allergic reaction in people. istamine is a chemical released from allergic cells in the body, such as mast cells and basophils, usually in response to an allergen. When histamine is released by allergic cells in the nose, it can cause sneezing, runny nose, itching nose, nasal congestion and post-nasal drip. These are the symptoms of hay fever, also known allergic rhinitis. istamine works by attaching itself to the histamine receptors on the surface of cells and thereby causing its effects. uman cells have three different types of histamine receptors, including 1, 2 and 3. It is mainly through the 1 receptor that histamine causes symptoms of allergy. Antihistamine drugs compete with histamine for 1 histamine receptor sites. By occupying the histamine receptor sites, they prevent histamine from binding to them and causing allergic symptoms [73, 129, 130]. Antihistamines are most effective when taken continuously during the allergy season. They usually begin working between 30 to 60 minutes after being taken [94]. owever, histamine is only one of the many chemicals involved in the allergic reaction, which explains why relief from antihistamines is usually only partial. Astelin Nasal Spray (azelastine hydrochloride), Astepro Nasal Spray 0.1% (azelastine hydrochloride), Astepro Nasal Spray 0.15% (azelastine hydrochloride) and Patanase Nasal Spray (olopatadine hydrochloride) are the local antihistamines available in the market. They have gained popularity with sufferers of allergic rhinitis Nasal Decongestants Allergies can cause a congested or stuffy nose. This congestion results when membranes lining the nose become swollen. Topical decongestants are medications used to relieve nasal congestion after applied directly to the nasal cavity. These drugs act on alpha-adrenergic receptors in the mucosa of the respiratory tract to produce vasoconstriction of the blood vessels in the nose and paranasal sinuses, which temporarily reduces the swelling associated with inflammation of the mucous membranes lining the nasal passages [129]. Commonly used decongestant nasal sprays often contain oxymetazoline (Afrin and other brands) and phenylephrine (Neosynephrine and other brands), which are direct agonists, acting directly on the adrenergic receptor system. Topical nasal sprays work more quickly than oral decongestants (a few minutes compared to thirty minutes). More, they are safer by reducing the side-effects associated with systemically-acting decongestants, such as high blood pressure, heart palpitations, sleeplessness, nervousness and dizziness. The most common side effects from decongestant nasal sprays and nose drops are sneezing and temporary burning, stinging, or dryness. These effects are usually temporary and do not need medical attention. It is important, however, not to use these topical agents for longer than 3 to 5 days, because rebound congestion may occur after repeated doses over a short period of time. When this happens, the nose remains stuffy or gets worse with every dose. The only way to stop the cycle is to stop using the drug. The stuffiness should then go away within about a week. If the cycle is not membranes, which lead to a condition known as rhinitis medicamentosa [131]. Rhinitis medicamentosa refers to an inflammation in the nose that is caused by the use of medications. Symptoms include severe stuffiness, burning, bleeding, and dryness of the nose ther Nasal Sprays Ipratropium Bromide Nasal Spray Ipratropium bromide is an anticholinergic agent [ ]. Its structural formula is shown in Fig. (2). Ipratropium bromide inhibits vagally-mediated reflexes by antagonizing the action of acetylcholine at the cholinergic receptor [132, 136]. Acetylcholine is a chemical that signals the mucous glands in the nose to produce mucous. Allergic reactions can trigger excessive acetylcholine activity on the mucous glands. In humans, ipratropium bromide has anti-secretory properties and, when applied intranasally, occupies the same receptor on the glands as does acetylcholine and in this way reduces watery hypersecretion from mucosal glands in the nose [ ]. C 3 C(C 3 ) 2 N + C C C C 2 Fig. (2). Chemical structure of ipratropium bromide. Side effects of ipratropium bromide are infrequent, because it minimally crosses the nasal and gastrointestinal membrane and the blood-brain barrier, resulting in a reducetion of the systemic anticholinergic effects (e.g., neurologic, ophthalmic, cardiovascular and gastrointestinal effects) that are seen with tertiary anticholinergic amines. owever, there are still adverse events reported by a small percentage of the patients receiving ipratropium bromide. These adverse effects include dry nose, dry mouth, nasal irritation, nose bleeding, dizziness, ocular irritation, blurred vision, conjunctivitis, hoarseness, cough, and taste perversion [134] Cromolyn Sodium Nasal Spray The chemical structure of cromolyn sodium is shown in Fig. (3). It works to reduce nasal inflammation as the noncorticosteroid treatment of choice. Many of the symptoms and signs of allergic reactions are caused by chemicals such as histamine that are released from mast cells, a type of cell that is found in the lungs, nose and eyelids. Cromolyn sodium acts on mast cells to stabilize them, thereby preventing the release of histamine and other mediators that would normally attract inflammatory cells [137]. Cromolyn sodium was approved by the FDA in In 1997, the FDA approved over-the-counter status for the nasal solution to treat seasonal allergic rhinitis. Since cromolyn sodium is strictly a controller medication, rather than a reliever medication, it must be taken before allergic exposure, usually at least 2 weeks prior, due to its slow onset of effectiveness [138, 139]. The drug tends Br -

9 Pulmonary and Nasal Inhalation Aerosol Delivery Systems Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No to be more effective in younger people with higher levels of lge. It is a particularly well tolerated medication with minimal side effects (e.g., sneezing, nasal irritation, or stinging). Rare cases of nasal bleeding or residual bad taste are reported. These are no systemic or body-wide side effects. NaC 2 C 2 C C Fig. (3). Chemical structure of cromolyn sodium. CNa 5. CURRENT NASAL SPRAYS AVAILABLE N TE MARKET A summary of marketed pharmaceutical products of nasal anti-inflammatory and anti-allergy sprays is shown in Table Beconase AQ Nasal Spray The active component of Beconase AQ Nasal Sprat is beclomethasone dipropionate, Beconase AQ Nasal Spray is a metered-dose, manual pump spray unit containing a microcrystalline suspension of beclomethasone dipropionate, monohydrate equivalent to 42 mcg of beclomethasone dipropionate, calculated on the dried basis, in an aqueous medium containing microcrystalline cellulose, carboxymethylcellulose sodium, dextrose, benzalkonium chloride, polysorbate 80, and 0.25% v/w phenylethyl alcohol. The p through expiry is 5.0 to 6.8. Following topical administration, beclomethasone dipropionate produces anti-inflammatory and vasoconstrictor effects. Beconase AQ Nasal Spray is indicated for the relief of the symptoms of seasonal or perennial allergic and nonallergic (vasomotor) rhinitis [ ] and also for the prevention of recurrence of nasal polyps following surgical removal [140]. The mechanisms responsible for the anti-inflammatory action of beclomethasone dipropionate are unknown. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic mediated inflammation. The direct relationship of these findings to the effects of beclomethasone dipropionate on allergic rhinitis symptoms is not known Rhinocort Aqua Nasal Spray The active component of Rhinocort Aqua Nasal Spray is budesonide, an anti-inflammatory synthetic corticosteroid. Rhinocort Aqua is an unscented, metered-dose, manualpump spray formulation containing a micronized suspension Table 4. Marketed Pharmaceutical Products of Nasal Anti-Inflammatory and Anti-Allergy Sprays Drug classes Drugs Brand names Manufacturers Disease state indications Rx vs. TC Corticosteroids Antihistamines Decongestants Anticholinergic agent Mast cell stabilizer Beclometasone dipropionate Budesonide Beconase AQ GlaxoSmithKline Relieve the symptoms of hay fever, prevent regrowth of nasal polyps following surgical removal Rhinocort Aqua Astrazeneca Treat seasonal or perennial allergic rhinitis Rx Ciclesonide mnaris Sepracor Inc. Treat seasonal or perennial allergic rhinitis Rx Fluticasone furoate Veramyst GlaxoSmithKline Treat seasonal or year-round allergy symptoms Rx Fluticasone propionate Mometasone furoate monohydrate Triamcinolone acetonide Azelastine hydrochloride lopatadine hydrochloride xymetazoline hydrochloride Flonase Nasonex Nasacort AQ Astepro Patanase Afrin GlaxoSmithKline Schering Corporation Sanofi-aventis U.S. LLC Meda Pharmaceuticals Inc. Alcon laboratories, Inc. Schering-Plough Treat seasonal or perennial allergic rhinitis, nonallergic rhinitis Treat seasonal and perennial nasal allergy symptoms, prevent most seasonal nasal allergy symptoms, treat nasal polyps Treat seasonal or perennial allergic rhinitis Treat seasonal or perennial allergic rhinitis Treat seasonal allergic rhinitis Relieve congestion associated with allergies, hay fever and sinus irritation Phenylephrine Sinex Vicks Relieve sinus congestion TC Ipratropium bromide monohydrate Atrovent Boehringer Ingelheim Pharmaceuticals, Inc. Cromolyn sodium NasalCrom BlackSmith Brands Relief of rhinorrhea associated with allergic and nonallergic perennial rhinitis Prevents and relieves nasal allergy symptoms like runny/itchy nose, sneezing and allergic stuffy nose without drowsiness Rx Rx Rx Rx Rx Rx TC Rx TC

10 224 Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry, 2011, Vol. 10, No. 3 Wu et al. of budesonide in an aqueous medium. Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, and purified water are contained in this medium; hydrochloric acid is added to adjust the p to a target of 4.5 [141]. Rhinocort Aqua Nasal Spray is indicated for the management of nasal symptoms of seasonal or perennial allergic rhinitis [104, 142]. The precise mechanism of corticosteroid actions in seasonal and perennial allergic rhinitis is not known mnaris Nasal Spray mnaris Nasal Spray delivers the corticosteroid ciclesonide as a hypotonic aqueous spray via a metered-dose manual pump. mnaris Nasal Spray also contains microcrystalline cellulose, carboxymethylcellulose sodium, hypromellose, potassium sorbate and edetate sodium; and hydrochloric acid to adjust the p to 4.5 [143]. Like Rhinocort Aqua Nasal Spray, mnaris Nasal Spray is also indicated for the management of nasal symptoms of seasonal or perennial allergic rhinitis [74, 92, ]. In well designed trials, intranasal ciclesonide 200 μg once daily was more effective than placebo in terms of reducing nasal symptoms in adolescents and adults with moderate to severe seasonal allergic rhinitis or moderately severe perennial allergic rhinitis [108]. Systemic exposure to ciclesonide and its active metabolite desisobutyryl-ciclesonides is low after intranasal administration. igh protein binding (~ 99%) and rapid first-pass clearance further reduce systemic exposure to the drug Veramyst Nasal Spray The active component of Veramyst Nasal Spray is fluticasone furoate, a synthetic corticosteroid derived from fluticasone. It is marketed by GlaxoSmithKline for the treatment of seasonal and year-round allergy symptoms in adults and children 2 years old and older [71, 111, 112]. Inactive ingredients in Veramyst Nasal Spray include 0.015% w/w benzalkonium chloride, dextrose anhydrous, edetate disodium, microcrystalline cellulose, carboxymethylcellulose sodium, polysorbate 80, and purified water [144] Flonase Nasal Spray The active component of Flonase Nasal Spray is fluticasone propionate. Flonase Nasal Spray is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump. Flonase Nasal Spray also contains microcrystalline cellulose and carboxymethyl-cellulose sodium, dextrose, 0.02% w/w benzalkonium chloride, polysorbate 80, and 0.25% w/w phenylethyl alcohol, and has a p between 5 and 7 [145]. Flonase Nasal Spray is indicated for the management of the nasal symptoms of seasonal and perennial allergic [114, 146, 147] and nonallergic rhinitis in adults and pediatric patients [148] 4 years of age and older Nasonex Nasal Spray Nasonex Nasal Spray contains the active ingredient a metered-dose, manual pump spray unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate calculated on the anhydrous basis; in an aqueous medium containing glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, sodium citrate, citric acid, benzalkonium chloride, and polysorbate 80 [149]. The p is between 4.3 and 4.9. Mometasone furoate works by stopping the cells in the nasal lining from producing various inflammation-causing chemicals that are normally released when the body reacts to allergens or irritation. These include prostaglandins and various other inflammatory substances. By preventing these inflammatory chemicals from being released in the nose, mometasone furoate reduces the inflammation and relieves its related symptoms. The nasal spray delivers mometasone directly to the area where it is needed, which reduces the chance of side effects occurring elsewhere in the body. Nasonex Nasal Spray treats the nasal symptoms of seasonal allergic [118, 119, 150, 151] and perennial allergic rhinitis [118, 152, 153], in adults and pediatric patients [ ] 2 years of age or older. It can also be used to prevent the nasal symptoms of seasonal allergic rhinitis in adult and adolescent patients 12 years and older. Treatment should be start 2 to 4 weeks prior to the anticipated start of the pollen season for this purpose. Moreover, Nasonex Nasal Spray is indicated for the treatment of nasal polyps in patients 18 years of age and older [158, 159] Nasacort AQ Nasal Spray The active ingredient of Nasacort AQ Nasal Spray is triamcinolone acetonide. Nasacort AQ Nasal Spray is a thixotropic, water-based metered-dose pump spray formulation unit containing a microcrystalline suspension of triamcinolone acetonide in an aqueous medium. Microcrystalline cellulose, carboxymethylcellulose sodium, polysorbate 80, dextrose, benzalkonium chloride, and edentate disodium are contained in this aqueous medium; hydrochloric acid or sodium hydroxide may be added to adjust the p to a target of 5.0 within range of 4.5 and 6.0 [160]. Nasacort AQ Nasal Spray treats nasal symptoms of seasonal and perennial allergic rhinitis in adults and children 2 years of age and older [ ] Astepro Nasal Spray Astepro Nasal Spray is an antihistamine formulated as a metered-spray solution for intranasal administration. The active ingredient is azelastine hydrochloride, a white, almost odorless, crystalline powder with a bitter taste. It has a molecular weight of It is sparingly soluble in water, methanol, and propylene glycol and slightly soluble in ethanol, octanol, and glycerine. It has a melting point of about 225 C and the p of a saturated solution is between 5.0 and 5.4. Astepro Nasal Spray also contains sorbitol, sucralose, hypromellose, sodium citrate, edetate disodium and benzalkonium chloride in an isotonic aqueous solution [3]. It provides relief from seasonal allergic rhinitis and perennial allergic rhinitis symptoms including nasal congestion without added decongestants like pseudoephedrine [73, 126, 161, 162].