Review Article

Evolution of Montelukast medicine.

Originally written as - Montelukast medicines of today and tomorrow: from molecular
pharmaceutics to technological formulations
Abstract - Montelukast sodium is a well-known leukotriene antagonist medicine of
growing interest as a suitable replacement therapy for asthma across different age
groups due to its Broncho-protective, and anti-allergic properties. Currently,
montelukast is accepted only in oral solid dosage forms, which are the favourite of
adult patients but may pose challenges in medication to young children or patients
suffering from dysphagia. This review presents a comprehensive and practical
revision of scientific reports and patents on emerging methods for the delivery of
montelukast. A common objective of this report is pursue of an enhanced montelukast
performance, by increasing its bioavailability and physio-chemical stability. A
wide variety of strategies can be found, from the formation of supramolecular
adducts with cyclodextrins to encapsulation in nanoparticles and liposomes. The new
dosage constituents for montelukast are designed for non-enteric absorption, some
for absorption in the oral cavity and another two being for local action in the
nasal mucosa or some in the pulmonary epithelium. This review describes the
emerging delivery strategies to pursue beyond the current limitations to the use of
montelukast that are expected to ultimately lead to the development of more
patient-compliant and beneficial dosage forms.
Introduction - The discovery in 1979 of the implication of leukotrienes in the
etiology of respiratory diseases and the elucidation of their structure triggered
the search for novel compounds able to block leukotrienes as new treatments for
asthma. For over a decade, the company Merck Frosst developed two research programs
on the topic, one to find an inhibitor of the key biosynthesizing enzyme, 5-
lipoxygenase, and the other to find a selective and efficient blocker of the
Leukotriene D-4 receptor. These projects yielded six compounds, which were brought
into human clinical trials and ultimately led to the release of montelukast (as
shown in the picture) under the tradename Singulair. Today, montelukast treats
millions of patients worldwide with market sales estimated around 5 billion US
dollars per year.
Asthma, a chronic illness also known as shortness of breath, wheeze and chest
tightness, is a global public health concern and an emergency call to action. World
Allergy Organ J Global Initiative for Asthma (GINA), Global Strategy for Asthma is
raising awareness and concerns in public health due to the increase in the number
of cases over the last decades. Asthma is now one of the major health concerns
across the globe. The respiratory airways present hyper responsiveness (AHR) to
external stimulus and bronchoconstriction due to subepithelial fibrosis and smooth
muscle hypertrophy and hyperplasia, which reduce the ventilation capacity of these
airways (Lemanske & Busse, Lemanske RF, Jr., Busse WW. (2003). 6. Asthma. J Allergy
Clin Immunol; Adcock et al., Adcock IM, Caramori G, Chung KF. (2008). New targets
for drug development in asthma. Lancet 372:1073�87, Kudoet Kudo M, Ishigatsubo Y,
Aoki I. Pathology of asthma. Front Microbiol 4:16. Global Initiative for Asthma
(GINA), Global Strategy for Asthma Management and Prevention, Global Initiative for
Asthma (GINA) 2015.
Montelukast is generally well tolerated by patients and it is suitable for
incorporation into oral dosage forms this approach was a major improvement in drug
administration when compared to the classic medicines for asthma treatment such as
corticosteroids and bronchodilating agents, available only as inhalables.
Presently, montelukast sodium is available from a variety of pharmaceutical
companies, either under the tradename Singulair or as a generic API. The
formulations are to be taken orally and comprise only solid dosage forms, namely
tablets, chewable tablets and oral granules
Uses and limitations
The most important limitations to the use and formulation of montelukast are
associated with its physico-chemical properties. Montelukast, both in the neutral
and the salt form, is sensitive to light, temperature, humidity and oxidation
Effect of light and heat on the stability of montelukast in solution and in its
solid state al, DiMaso M, Lobenberg R. (2008). Dynamic dissolution testing in order
to establish and sustain in vitro/in vivo correlations for montelukast sodium, a
poorly soluble drug. In this context, the presently available dosage forms are
designed to minimize exposure to light and humidity, which clearly explains why
liquid formulations are not marketed to date.
Administration of montelukast to small babies is still a challenge. The available
formulation is the granules with guaranteed compatibility only for mixtures with
the mother�s milk or milk formulas, after which they should be quickly
administered.
Adverse reactions & drug interactions
Montelukast is generally well tolerated, although adverse reactions were reported,
with stronger incidence in infants: headache, diarrhea, abdominal pain, nausea,
fever and cough .Montelukast for chronic asthma in 6 to 14 year old children.
Clinical safety and tolerability of montelukast, in controlled clinical trials was
tested over patients older than 6 years. Safety, tolerability, and exploratory and
efficiency of montelukast in 6 to 24 month old patients with asthma. In adults,
cases of hypersensitivity have been reported, leading to autoimmune vasculitis,
hepatic eosinophilic infiltration and even anaphylaxis Montelukast-induced adverse
drug reactions.
Orally disintegrating tablets
Orodispersible tablets (ODTs), also known as Orally disintegrating tablets are
designed to disintegrate in the mouth before swallowing. Initially defined as �a
solid dosage form containing medicinal substances which disintegrates very rapidly,
usually within a matter of seconds, when placed upon the tongue�, there is still no
consensus on the maximum disintegrating time. USP�s guidelines recommend a maximum
of 30?seconds (Center for Drug Evaluation and Research (CDER), Nomenclature
Standards Committee, 1998. While many other sources cite 1?min as the only limit
for disintegration. The preparation of ODTs relies chiefly on the use of an
adequate dispersing agent. These excipients are strongly hydrophilic and receive
the common name of �super disintegrant� since they are able to ensure
disintegration occurs within a very short period of time. Chrono-therapeutic
approaches
Resulting from a combination of chronobiology and pharmaceutics,
chronopharmaceutics is devoted to the design and evaluation of drug delivery
systems that release an API at a rhythm that ideally matches the biological
requirement of a given disease therapy. The chronotherapeutic approaches take into
account the circadian fluctuations associated with chronic diseases, namely
diabetes, arthritis, ulcers and asthma. In asthmatic patients, the airway
resistance increases progressively during the night and the lung function reaches a
low point in the early morning. Conclusion
This review illustrates how the work performed by various research groups spread
throughout the world constitutes a solid foundation to engineer, in the near
future, innovative formulations and delivery systems for montelukast, which may
bring significant improvements to two main weaknesses: the bioavailability and the
instability of this API.

A number of these drug delivery approaches are devoted to the improvement of the
bioavailability, based mainly on oral delivery in order to increase pre-gastric
absorption and thus avoid loss of drug due to the hepatic-first pass metabolism.
This metabolic action is responsible for the reductions of 30�40% of the plasmic
concentration of montelukast. The proposed new delivery strategies include
orodispersible tablets and fast-dissolving thin films for quick release and onset
of action. Nevertheless, the most promising dosage form for absorption in the oral
cavity is, in our opinion, the buco adhesive patches, which were shown to provide a
prolonged action, avoiding bronchoconstrition for a period of up to 6?h.
Nano-encapsulation techniques bring a two-in-one solution for montelukast delivery,
as they protect it from degradation and simultaneously offer dramatic increases in
bioavailability � providing that the nanoparticles have the right size to elude
liver uptake, that is, between 120 and 200?nm.
Encapsulation into nanoparticles - Polymeric nanoparticles for pulmonary delivery.
The pulmonary route for drug delivery allows a reduction of the amount of drug
administered to the patients, a decrease of the side effects and avoidance of the
hepatic first pass metabolism. A handful studies have focused on the development of
aerosol forms for the delivery of montelukast, using nanoparticles of chitosan or
poly-lactic acid (PLA).

The inclusion of montelukast into chemically modified CDs in aqueous solution was
first demonstrated in 2006, using heptakis-(2,6-di-O-methyl)-�-cyclodextrin (DIMEB)
as the host (Duran Meras et al., 2007Duran Meras I, Espinosa-Mansilla A, Rodriguez
DA. (2007). Complexation study of cinalukast and montelukast with cyclodextrines.
Nevertheless, only in 2015 a stable aqueous oral solution of montelukast was
achieved.
Conclusion
This review illustrates how the work performed by several esteemed research groups
spread across the globe constitutes a solid foundation. In the near future,
innovative formulations and delivery systems for montelukast which may bring
significant improvements to two main weaknesses namely the bioavailability and the
instability of this API.
A number of these drug delivery approaches are dedicated to the betterment of the
bioavailability, emphasised mainly on oral delivery in order to increase pre-
gastric absorption and thus avoid loss of drug due to the hepatic-first pass
metabolism. This metabolic action is responsible for the reductions of 30�40% of
the plasmic concentration of montelukast.In order to save the above mentioned loss,
this approach is proven to be significant. The proposed new delivery strategies
include orodispersible tablets and fast-dissolving thin films for quick release and
onset of action. Nevertheless, the most promising dosage form for absorption in the
oral cavity is, in our opinion, the bucoadhesive patches, which were shown to
provide a prolonged action, avoiding bronchoconstrition for a period of up to 6?h.

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Journals we have approached � We have communicated our paper with Associated Asia
Research Foundation (AARF). Their information is provided below �