The cysteinyl leukotrienes are primarily endogenous mediators of inflammation and play an integral role in the pathophysiology of asthma. Activation of leukotriene receptor has numerous effects in the lungs, including increased bronchial hyper responsiveness, increased mucus secretion, increased venopermeability, and promotion of eosinophil migration into airway mucosa. Effects of the cysteinyl leukotriene can be blocked by leukotriene receptor antagonists. Leukotriene receptor antagonists inhibit bronchoconstriction and prevent many types of asthmatic responses, including allergen-induced, exercise- induced, cold-air-hyperventilation-induced, and aspirin-induced asthma (Wright et al 1998). Therefore, these antagonists represent a new class of drugs for the treatment of asthma. Montelukast is a potent and selective antagonist of the cysteinyl leukotriene receptor. It has been approved for the treatment of asthma in children 6 months and older (Skoner 2001). Studies have compared montelukast with other asthma treatments. In studies compared montelukast with inhaled corticosteroids in asthmatic patients, researchers concluded that evidence was not convincing for the use of leukotriene receptor antagonist as first-line monotherapy in mild-to-moderate asthma (Ng et al 2004), as patients on antileukotrienes are more likely to suffer an exacerbation requiring systemic steroids and to exhibit a lesser improvement in lung function. Therefore, substitution of montelukast for low-dose inhaled corticosteroid is not recommended. In a pediatric study comparing montelukast with long-acting b2-agonists (LABA), researchers concluded that addition of montelukast to low-dose steroid was more effective than the addition of LABAs (Miraglia et al 2007). More pediatric studies are needed to further compare montelukast with LABA as add-on therapy to inhaled corticosteroid in persistent asthma. In order to provide an oral dosage form of montelukast with comparable efficacy and improved tolerability profile, and as a more preferred choice by children and caregivers compared with the existing oral dosage forms, Galaxy Bio developed NAL6336 montelukast ODF that is intended for daily use. Based on the innovative and proprietary Bio-FX Oral Dissolving DDS technology, NAL6336 ODF was formulated by incorporating the drug together with Bio-FX oral cavity absorption enhancers, polymer carriers, taste-masking agents and other excipients, and display many advantages including fast onset and improved bioavailability, as well as less GI tract and liver side effects. Data from preliminary studies showed a desirable dissolution profile and satisfactory stability results, which suggest that the NAL6336 ODF may be an ideal system for oral delivery of montelukast in children. The formulation of NAL6336 has been well developed. In the proposed study, we will compare the pharmacokinetics profile of NAL6336 ODF and montelukast oral suspension in rats, and assess the irritation and safety of NAL6336 ODF by buccal oral mucosal irritation studies in rabbits and hamsters. The irritation study will be conducted in juvenile animals as differences between mature and immature systems introduce the possibility of drug toxicity, or resistance to toxicity in immature systems that are not observed in mature systems, therefore, data from juvenile animal studies can better contribute to the assessment of drug effects in the pediatric population. Upon completion of the PK and irritation studies, we will file IND to initiate the phase I clinical trial to prove safety and detrmine best dose for NAL6336 ODF.

Public Health Relevance

Asthma is the most common chronic disease of childhood and its prevalence has substantially increased worldwide, particularly in pre-school children. Montelukast, a cysteinyl leukotriene receptor antagonist (LTRA) which has been extensively studied in children since 1990s (Jones et al 1995), has been approved for the treatment of asthma in children 6 months and older (Skoner 2001). Comparative studies in pediatric patients have confirmed the therapeutic efficacy of montelukast. In this study, we are presenting a montelukast oral dissolving film, NAL6336 ODF, which contains 5mg montelukast, and provides comparable efficacy and improved compliance by younger patients, and a more preferred choice by patients and caregivers.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-ETTN-M (50))
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Giacoia, George
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Galaxy Bio, Inc.
Monmouth Junction
United States
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