Fabricating transdermal film formulations of montelukast sodium with improved chemical stability and extended drug release

Abstract

Montelukast Sodium (MK) is a leukotriene receptor antagonist, an oral drug generally prescribed to control chronic asthma symptoms. This research aims to provide the transdermal delivery of this drug in a controlled release profile as a better mode of drug delivery, specifically for the pediatric and elderly population. Transdermal delivery of the drug not only improves the drug's bioavailability but also maintains the concentration of the drug in the plasma without increasing the frequency of the drug dosage. Transdermal film formulations were developed using sodium alginate (SA) and lignosulphonic acid (LS) as the matrix and PEG-400 or Glycerine (Gly) as the plasticizers. Various physiochemical characteristic evaluations of the formulated films were conducted, revealing that the formulation with Glycerine as the plasticizer had a smooth surface and was flexible. It was observed that this formulation had the highest moisture uptake capacity and the lowest moisture loss capacity when compared with the other two formulations. It was also observed that the barium chloride cross-linked formulation had a higher swelling index when compared with calcium chloride cross-linked films. The surface pH of all the formulations was monitored to be around 7.5. In the in vitro release studies, the cross-linked films showed a controlled release over 36 h compared with the non-cross-linked films. Based on the observations and results, the cross-linked film formulation showed a better-controlled release of the drug and could potentially increase its bioavailability. TGA analysis of the polymeric mixture demonstrated the thermal stability of the SA blends, which enhanced the flexibility of the SALS blend with Glycerine. XRD of samples confirmed the amorphous nature of SALS blends with Gly, which influences the flexibility of the blend. The blends are further investigated for morphology using SEM to test their compatibility with the drug.

1. Introduction

Asthma is a chronic obstructive disease associated with the lung wherein the airflow is obstructed due to bronchoconstriction, increased mucous secretion and infiltration of eosinophil-rich inflammatory cells. Asthma is a widespread disease affecting people of all age groups, i.e., babies to older adults. It is a non-communicable disease which generally commences during childhood but may occur anytime throughout the lifespan. According to World Health Organisation (WHO), 339 million people are affected by asthma [1]. Most deaths are seen in elderly patients.

There is no cure for Asthma, but with the help of medications, the symptoms of Asthma can be controlled. Medications prescribed for Asthma are generally taken at night. Symptoms of Asthma worsen typically during the night. Sleeping posture may contribute to night-time symptoms as sleeping on the back may put pressure on the lungs and chest, making breathing difficult. Sleeping on the back may allow the mucous to drip into the throat. During the night, lung activity reduces, which is a natural process. This may also contribute to the night-time symptoms of Asthma. Allergy-induced asthma is the most common type of Asthma, affecting almost 16 million people worldwide [2]. One of the main symptoms of Asthma is difficulty in breathing, whose underlying mechanism is generally bronchoconstriction [1].

Montelukast sodium (MK) is a medication that is a leukotriene receptor antagonist prescribed to treat symptoms associated with chronic Asthma and seasonal allergic rhinitis in case of children and adults [3]. Chemically, Montelukast Sodium is an organic compound belonging to the linear 1,3- diarylpropanoids. It is a lipophilic, hygroscopic, optically active compound with a melting point of 275.9F. Montelukast Sodium has a half-life of 2.7–5.5 h with a bioavailability of 64% [4]. The commercially available form of Montelukast Sodium is the oral dosage form. 10 mg of this drug is prescribed for adult patients, whereas 4 mg is prescribed in the case of pediatric patients. The lethal dose (LD50) for Montelukast is greater than 5000 mg/kg [5]. Montelukast sodium binds to the leukotriene receptor as it has a high affinity toward the cysteinyl leukotriene receptor type-1, thereby preventing other leukotrienes, such as LTD4, from binding to the receptor. This binding prevents bronchoconstriction [6]. As low as 5 mg of Montelukast Sodium can prevent bronchoconstriction by preventing the LTD4 from binding to the receptor. 2 h post the oral administration of the drug, bronchodilation commences. Montelukast sodium has side effects such as stomach pain, nausea, headache, fever, mild rashes, cold-like symptoms, body aches and swelling in the ear [3]. When compared with conventional drug delivery, modified drug release offers objectives such as the targeted and controlled release of the drug. The drug is protected with the help of polymers so that it cannot be degraded in acidic pH like that of the stomach. Thus, the medicine may not irritate the stomach. Controlled drug release aims to maintain the plasma concentration irrespective of the application site. A sustained release system aims to monitor the drug release from the polymer-based matrix and thus can only be limited to an oral formulation. Still, a controlled release system can include oral and transdermal administration routes [7]. Transdermal drug delivery is a controlled drug delivery wherein the developed formulation is applied to the skin. The formulation acts as a reservoir of the drug. The drug from the formulation penetrates the skin. Once the drug passes through the stratum corneum, it enters the epidermis, followed by the dermis, where the drug becomes available for systemic absorption via dermal micro-circulation. Due to the difference in concentration of the drug, the drug can diffuse from the formulation into the skin. For a drug to be delivered transdermally, the drug must be lipophilic and hydrophilic and have a low molecular weight (less than 1 kDa) [8].

Many biodegradable materials are used for drug delivery applications [9,10]. In particular, it can be used for controlled release; the biodegradable polymers used in this work are SA and LS, which are available naturally. Polymers have many applications, including renewable energy resources [11]. Biodegradable blends of sodium alginate (SA) and lignosulphonic acid (LS) in a ratio of 80:20 is known to work best in the case of controlled drug delivery [12,13]. Polyethylene glycol (PEG) and glycerol are non-toxic, biodegradable, and known to be efficient plasticizers [[13], [14], [15], [16]]. PEGylation, the covalent conjugation of PEG with various drug targets, such as protein and oligonucleotides, improves the drug's pharmacokinetics [17]. These plasticizers are known to increase the mobility of groups in a chain.

Further, different cross-linking agents can be employed to increase the stability of the SA/LS polymeric blends [18]. In this study, transdermal delivery of Montelukast Sodium using Sodium alginate and Lignosulphonic acid polymeric film. The transdermal delivery system is selected to increase the drug's bioavailability and therapeutic effect without increasing the dose frequency [19]. While focusing on pediatric and dysphagic patients, transdermal delivery of Montelukast sodium will be apt, as it is non-invasive and can be easily employed.

Various natural membranes, such as the inner membrane of the eggshell, the middle layer of onions and the outer membrane of tomatoes and peaches, were evaluated as an alternative for human skin to conduct permeation studies in a simulated fluid [15]. Since these membranes are natural and readily available, they can be employed in in vitro permeation studies for controlled drug delivery systems [6,7,15,[20], [21], [22]]. The eggshell membrane is known to have a similar composition compared to the stratum corneum. This system can mimic the in vivo action of the drug [Fig. 1]. The permeation test observations confirm the permeation of the drug through the skin [4].

Fig. 1.

Route of Montelukast Sodium when delivered transdermally.

The aim of our study is to develop a blend containing Montelukast sodium (MK) with improved chemical stability and extended drug release. The oral formulation of the drug has a low bioavailability, which is a significant drawback. Our study uses the transdermal route to administer the medication to increase the drug's bioavailability.

2. Materials and methods

2.1. Materials required

Montelukast sodium (MK), Sodium alginate (SA) (MW = 300000 g/mol) and Lignosulphonic acid (LS) (MW = 50000 g/mol) obtained from Sigma Aldrich (India), Polyethylene glycol (PEG) obtained from S D fine-chem Limited (Mumbai), Glycerine, 2% Barium chloride (BaCl₂), 2% Calcium chloride (CaCl₂), Acetate Buffer (pH 4.6), Hydrochloric acid (HCl) and, Distilled water (18.2 M Ω cm⁻¹) was used in all experiments.

2.2. Methods

2.2.1. Preparation of montelukast sodium loaded polymeric films

4% (w/v) of Sodium alginate (SA) and Lignosulphonic acid (LS) were weighed in the ratio of 80:20, respectively. The weighed polymers were dissolved in the Montelukast sodium (50mg/100 mL) drug solution. The SA/LS mixture was stirred for 30 min to ensure complete dissolution using a magnetic stirrer. Plasticizers, such as PEG-400 and Glycerine, were added at a 45% w/w while the polymeric solution was stirred. After the complete dissolution of the polymer in the drug solution, the polymeric solution was poured onto Petri plates. It was kept in the hot air oven for drying at 60 °C [Fig. 2]. The resultant dried films are shown in Fig. 3 (A-C). The resultant dried films were then cut into smaller films such that the weight of these films was maintained [16].

Fig. 2.

The diagram depicts the preparation steps of the Montelukast Sodium loaded transdermal films.

Fig. 3.

Transdermal drug-loaded film: (A) SALS/MK, (B) SALS/PEG-400/MK (C) SALS/Gly/MK.

2.2.2. Cross-linking of the polymeric films

The drug-loaded films were submerged in a 2% cross-linking agent solution for 10 min. The cross-linking agents used were Barium chloride and Calcium chloride.

2.3. Characterization

2.3.1. Fourier transform infra-red spectroscopy (FT-IR) studies

FT-IR spectra of the different samples representing the variations were investigated for chemical interactions using Shimadzu Fourier Transform Infra-Red Spectrophotometer, IR Spirit- L, Model no.206-31000-58. The samples were prepared by making potassium bromide (KBr) pellets, as shown in Fig. 4. Each graph was obtained after averaging 45 scans, and the resultant spectra were obtained a transmittance percentage vs per centimetre.

Fig. 4.

FT-IR Sample pellets of (A) SA/LS/MK (B) SA/LS/MK/PEG (C) SA/LS/MK/Gly (D) Montelukast Sodium (MK) (E) SA/LS/Gly.

2.3.2. Thermogravimetric analysis

Thermal properties of samples are measured using a Thermogravimetric analyser of make TA, USA -SDT Q600. The Universal V4.5 A software is used to obtain the readings obtained. This instrument measured weight change (TGA) and true differential heat flow (DSC) simultaneously on the same sample up to 1500 °C using an alumina pan. The samples are heated 10 °C/min up to 1000 °C in a nitrogen gas atmosphere.

2.3.3. X-ray diffraction studies

The Rigaku Japan Ultima IV instrument was used to investigate the crystallinity of powdered samples listed in Table 1. The X-ray of wavelengths (1.548 Å) was generated by a primux 3000 source. XRD drive system control and data acquisition software are used to process and analyze the signals obtained due to microstructure and phase transitions. The diffraction angle between 5 and 90° was used to identify the crystal structure and intermolecular distances to investigate the intersegmental movement and cross-linking in samples.

Table 1.

Film formulations and its variations.

S no.	Formulations	Variations
1.	SA, LS and MK	S1- Calcium chloride cross-linked film
		S2- Non-cross-linked film
		S3- Barium chloride cross-linked film
2.	SA, LS, MK and PEG-400	P1- Calcium chloride cross-linked film
		P2- Non-cross-linked film
		P3 -Barium chloride cross-linked film
3.	SA, LS, MK and Glycerine	G1- Calcium chloride cross-linked film
		G2- Non-cross-linked film
		G3- Barium chloride cross-linked film

2.3.4. Scanning electron microscope

Scanning electron microscope (SEM) of Carl Zeiss Germany is fast and convenient method to perform 3D view, imaging with nanometre resolution. With a 3D view an ultramicrotome inside the SEM chamber is repeatedly cut, and image the polymer and tissue samples. The surface morphology and chemical analysis of various samples are investigated.

2.4. Evaluation of the physiochemical characteristics of the drug-loaded film

2.4.1. pH studies

The surface pH of the film was determined by dipping the film in 0.5 mL of distilled water, and the electrode of the pH meter was allowed to touch the film's surface.

2.4.2. Moisture uptake and moisture loss studies

The moisture studies of the film were done using a desiccator. The initial weight (Wi) of the film was noted. The weighed film was stored for 24 h in a desiccator containing anhydrous calcium chloride. The weight (Wl) of the film was then recorded after 24 h to determine the moisture loss capacity of the film. The moisture loss capacity can be determined using the following formula (1)

For 24 h, the same film (Wi) after moisture loss was maintained in a desiccator containing Sodium Chloride (NaCl). The weight (Wf) of the film after 24 h was noted. This was done to determine the Moisture uptake capacity of the film. The moisture uptake capacity can be determined using the following formula (2)

$$Moistureloss\%=\frac{\left(Wi-Wl\right)}{Wl}x100$$ (1)

$$Moistureuptake\%=\frac{\left(\mathrm{W}\mathrm{f}-Wl\right)}{Wl}x100$$ (2)

2.4.3. Swelling studies

Swelling studies were performed using the cross-linked film. The weighted (Wo) cross-linked films were submerged in a beaker containing distilled water. The weight of the film (Ws) is noted after every 1-h interval up to 3 h. The swelling index of the film can be determined using the following formula (3)

$$SwellingIndex\%=\frac{\left(\mathrm{W}\mathrm{s}-Wo\right)}{Wo}x100$$ (3)

2.4.4. Determination of Drug Entrapment Efficiency

It measures the efficiency of the preparation method to incorporate the drug into the carrier system. A non-crosslinked drug-loaded film was completely dissolved in a beaker containing water. The concentration of drug (C₀) in the completely dissolved film solution was determined using UV-spectrometer. Another two drug-loaded films were submerged in a 2% cross-linking agent solution for 10 min. The cross-linking agents used were Barium chloride and Calcium chloride. After 10 min, the now cross-linked films were removed, and the solutions in the beakers were analyzed for the concentration of the drug (C_t), which may have been released while cross-linking, using a UV-spectrometer. The weight of the films was kept constant.

Drug Entrapment Efficiency is calculated using formula (4) where, C₀ is the initial concentration of Montelukast sodium, and C_t is the concentration of free Montelukast sodium in the supernatant.

$$EE\%=\frac{\left(\mathrm{C}0-\mathrm{C}t\right)}{Co}x100$$ (4)

2.5. In-vitro release studies

Five solutions of different concentrations (0.5, 1, 2, 3, 5 mg/ml) of Montelukast Sodium were prepared separately using five different aliquots of the standard working solutions. Each concentration was scanned in a range of 185–400 nm against a blank. The maximum wavelength value was observed to be around 285 nm which can be validated using the existing literature [23]. The absorbance values and the statistical data required to plot the calibration curve have been tabulated [Table 2]. The calibration curve was plotted based on the absorbance values vs the concentration [Fig. 5].

Table 2.

Absorbance values and statistical data of the calibration curve for the estimation of Montelukast Sodium.

S. No.	Concentration (mg/ml)	Absorbance
1	0.5	0.246
2	1	0.443
3	2	0.939
4	3	1.410
5	5	2.331

Fig. 5.

Calibration curve of montelukast sodium.

An in vitro release study was done using an egg membrane. The composition of the egg membrane is similar to the composition of the stratum corneum layer of the human skin. The egg membrane was isolated by dipping the egg in an HCl solution, as shown in Fig. 6a. The egg contents were discarded, and the membrane was washed with distilled water [Fig. 6b]. The film under investigation was kept on the egg membrane, and the membrane was tied around the mouth of a centrifuge tube, as seen in Fig. 7. The centrifuge tube was then dipped into a beaker containing acetate buffer such that the egg membrane came in contact with the buffer of pH 4.6, similar to the skin's pH. At an interval of every 1 h, the buffer solution is collected, and the absorbance of the solution is determined using Shimadzu 2600 UV–Visible Spectrophotometer.

Fig. 6.

Isolation of Egg Membrane: (a) Egg kept in Hydrochloric acid (b) Isolated Egg Membrane.

Fig. 7.

In vitro drug release setup: The diagram depicts the drug release setup, which includes the donor compartment with the opening covered with the polymeric film and the egg membrane. The donor compartment is dipped into the receptor compartment containing acetate buffer.

3. Results and discussions

3.1. FT-IR studies

The FT-IR results of Montelukast Sodium and different polymeric blends are depicted in Fig. 8. The spectra corresponding to SA/LS blend show the presence of an absorbance peak at 1032 cm⁻¹, which describes the elongation of the C–O group functional group, and a peak at 1419 cm⁻¹ depicts the symmetric stretching vibrations of COO groups. A characteristic peak at 1613 cm⁻¹ due to the presence of the –C O functional group in SA can also be observed. This peak can be observed in all the polymeric blends except in the FTIR peaks corresponding to SA/LS/MK, where the intensity of the peak has reduced, resulting in a flattened peak. Thus, it can be inferred that the drug Montelukast Sodium interacts with the blend.

Fig. 8.

Graphs depict the FT-IR studies of the drug and different polymer blend combinations.

The spectra corresponding to the drug Montelukast Sodium indicate the presence of a low-intensity peak at 1710 cm⁻¹, which shows the stretching of the –COOH functional group [24]. This low-intensity peak can also be observed in the spectra corresponding to SA/LS/MK, indicating the drug's presence in the SA/LS polymeric blend. FT-IR Spectrum of SA/LS/PEG-400 depicts a peak at 2865 cm⁻¹, which corresponds to the –CH₃ vibrations in PEG-400 [25]. This peak is absent in SA/LS spectrum. Thus, with this observation, the presence of PEG-400 in SA/LS/PEG can be inferred.

Glycerine shows characteristic FT-IR peaks at 2878 cm⁻¹ and 2934 cm⁻¹ due to C–H stretching. A peak at 1416 cm⁻¹ is seen due to the C–O–H bending [26]. FT-IR peaks of SA/LS also depict a peak at 2934 cm⁻¹ due to C–H stretching. From this observation, the presence of Glycerine can be inferred as the intensity of the 2934 cm⁻¹ peak increased in the spectrum corresponding to SA/LS/Gly. On the other hand, the 2934 cm⁻¹ peak intensity of the SA/LS/Gly/Mont appears to be reduced, implying that the drug may have chemically interacted with the SA/LS/Gly blend [27].

3.2. X-ray diffraction studies

The X-Ray diffraction study is a technique which is used to determine the extent of crystallinity in a polymeric mixture, and it can also be used to study the purity of the samples containing polymeric mixtures. A polymeric mixture with a semicrystalline nature generally shows features such as suppressed and sharp peaks that can be either diffused or overlapped [28]. The typical 2θ angles of various components are tabulated based on existing literature [Table 3].

Table 3.

2θ Angles of various components based on the existing literature.

Components	2θ Angle
Montelukast Sodium	16.9⁰, 17.2⁰, 18.5⁰, 19.6⁰, 20.4⁰, 21.0⁰, 22.2⁰, 22.7⁰, 25.2⁰
Sodium Alginate	14⁰, 19.4⁰, 22.89⁰, 32⁰, 38.6⁰, 42.4⁰, 44.1⁰, 48.4⁰,64.4
PEG	19.3⁰, 22⁰, 23.5⁰
Glycerine	19⁰, 27.5⁰, 36.5⁰, 40.5⁰, 41⁰, 44.8⁰, 48.5⁰, 56⁰

The XRD spectra of various components of the polymeric mixture are depicted in Fig. 9. In the XRD spectrum of the pure sample of drug MK, 2θ angles of 18.3⁰, 19⁰, 20⁰, 22⁰ and 25.4⁰ were interpreted as the prominent peaks of Montelukast Sodium drug as shown in Fig. 9. From the referred literature, it can be inferred that the MK drug used in this experiment corresponds to the A1 form of the drug in the literature, indicating the purity of the sample [29]. The sharp peaks of the drug indicate the crystalline nature of the drug [30,31].

Fig. 9.

Graphs depict the XRD studies of the drug and different polymer blend combinations.

The XRD pattern corresponding to SA/LS indicates a specific 2θ angle of 13.5⁰, 19.4⁰, 22.3⁰ and 38.8⁰ was interpreted as the prominent peak of Sodium alginate [32]. The specific 2θ angles of 22⁰ and 23.4⁰ indicated the presence of PEG in the XRD pattern corresponding to the SA/LS/PEG/MK polymeric mixture [33]. The XRD pattern corresponding to SA/LS/Gly indicates a specific 2θ angle of 18.7⁰, 27.8⁰, 36.7⁰, 41.1⁰ indicating the presence of Glycerine [34,35].

From the diffraction pattern of SA/LS/MK, it can be noted that smaller peaks at 2θ angle of 20.6, 21.2⁰ can be observed, which is absent in the spectra corresponding to SA/LS. These 2θ angles in the SA/LS/MK can be interpreted as the peak of montelukast sodium and thus confirms the presence of the Montelukast Sodium drug in the polymeric mixture of SA/LS/MK. The diminished peaks may be due to the low drug-to-polymer ratio. A similar 2θ angle of 20.6⁰, 21.2⁰ can be observed in the XRD spectra of SA/LS/PEG/MK and SA/LS/Gly/MK as well, thereby confirming the presence of the drug in the polymeric mixtures. From the diffraction pattern of SA/LS/PEG/MK, it can be observed that Montelukast Sodium and PEG peak overlaps in the synthesized polymeric mixture because of the same 2θ angle at 22⁰. The specific 2θ angle of 23.4 indicates the presence of PEG in the polymeric mixture, as this specific peak is absent in SA/LS/MK.

From the diffraction pattern of SA/LS/GLY/MK, a specific 2θ angle of 18.9⁰, 36.5⁰,40.2⁰, 44.7⁰ can be observed, which indicates the presence of Glycerine in the polymeric mixture. The resultant diffraction peaks are in good agreement with the existing literature. These observations indicate that the polymeric mixture used in this study existed in an amorphous state, and the crystalline form of the drug Montelukast Sodium did not alter the properties of the polymeric mixture.

3.3. Thermal properties

The aim of this characterization is to study the thermal degradation behaviour of SALS blend with different polymer compositions of Glycerine, and PEG. Many samples, such as SALS/PEG and SALS/Glycerine compositions with MK drug, are discussed based on weight reduction upon an increase in temperature. In this, the weight reduction was observed to find the stability of SALS/PEG and SALS/Glycerine, subjecting these samples to heating. It was observed that in Fig. 10 (SALS) blends are showing mass loss of 35% in the temperature range of 210–400 °C. Whereas in SALS/PEG and SALS/Gly along with MK drug the weight loss was considerably reduced, showing the blends are stable up to 400 °C.

Fig. 10.

TGA graphs of the drug and different polymer blend combinations. a)SALS b)SALS/MK c)SALSPEGMK d)SALSGLYMK e)SALSGLY

3.3.1. Surface morphology by scanning electron microscope

The shape and surface morphology of MK drugs presence in various SALS blends are demonstrated using a scanning electron microscope (SEM) with a magnification range between 2 and 20 nm (Fig. 11). The image of Figure 11(a) of the MK drug in the MK1 blend, appears to be uniformly distributed, and no sign of agglomeration is observed. Whereas images of MK2 (Fig. 11b)- the SALS blend with PEG grains show a rough surface with a slightly spherical shape [36] and aggregates, indicating partial miscibility, and the appearance of white domains shows the presence of MK drug. The appearance of the rough surface may be caused due to the loosely interlaced polymeric strands [26]. However, the SEM images of MK3 (Fig. 11c) – the smooth surface textures show the Gly domains in the SALS matrix, which appear to be uniformly distributed, indicating complete miscibility; also, at high resolution, the white dots show the presence of MK drug distribution in the blend preventing agglomeration. The complete miscibility and homogeneity of Gly presence in the blend influence the segmental motion as it shows more remarkable plasticity and thereby contributes to the release of the drug from the blend in a controlled manner. This indicates its possible use for transdermal applications.

Fig. 11.

SEM images of a) SALS/MK (MK1). b) SALS/PEG/MK(MK2). c) SALS/Gly/MK (MK3).

3.4. Evaluation of the physiochemical properties of the formulated films

3.4.1. pH of the film

The physicochemical characteristics of the films were evaluated. The surface pH of all the films was observed to be neutral, with a pH 7.5. The neutral surface pH value has physiologically consented, and thus the possibility of skin irritation can be avoided [16]. When the flexibility of the films was examined, it was observed that the formulation of sodium alginate, lignosulphonic acid with Glycerine as the plasticizer was the most flexible and the formulation of sodium alginate, lignosulphonic acid with PEG-400 as the plasticizer was the least flexible. This may be due to the fact that PEG-400 is an external plasticizer, whereas Glycerine is an internal plasticizer [37].

3.4.2. Moisture uptake and moisture loss studies

The experimental data of moisture uptake and moisture loss has been tabulated. [Table 4]. With respect to the Moisture capacity studies, the formulation of sodium alginate, lignosulphonic acid with Glycerine as the plasticizer showed the lowest moisture loss capacity of approximately 0.023% [Fig. 12a]. This may be due to Glycerine, which is a humectant that tends to retain moisture. The formulation of sodium alginate, lignosulphonic acid with PEG-400 as the plasticizer showed a moderate moisture loss capacity of approximately 7.31%, as shown in Fig. 12b, and the formulation of sodium alginate and lignosulphonic acid showed the highest moisture loss capacity of roughly 10.08%.

Table 4.

Film Formulations and their observed Moisture uptake and loss %.

Formulations	Moisture uptake %	Moisture loss %
SA/LS	7.56%	10.08%
SA/LS/PEG	7.31%	7.31%
SA/LS/Glycerine	14.61%	0.023%

Fig. 12.

Moisture uptake and moisture loss studies by formulated films in a desiccator containing: (a) Calcium Chloride for moisture loss studies (b) Sodium Chloride for moisture uptake studies.

The formulation of sodium alginate, lignosulphonic acid with Glycerine as the plasticizer showed the highest moisture uptake capacity of approximately 14.61%. In contrast, the formulation of sodium alginate, lignosulphonic acid, with PEG-400 as the plasticizer showed the least moisture uptake capacity of roughly 7.31%. The formulation of sodium alginate and lignosulphonic acid showed a moderate moisture uptake capacity of approximately 7.56%. The films with a lower moisture uptake capacity tend to be more stable, protect the film from bacterial contamination and reduce the bulkiness of the film [16]. Based on this criterion, the formulation with Glycerine as the plasticizer can be observed as the least stable formation when compared with other formulations, as both the polymers and the plasticizer are hydrophilic, due to which the film has an increased moisture uptake capacity. Due to the humectant nature of the plasticizer, there is a decreased moisture loss capacity.

3.4.3. Swelling studies

The swelling index percentage of the formulated films was studied, as shown in Fig. 13. The experimental data of the swelling studies have been tabulated [Table 5]. It was observed that S2, P2 and G2 formulations disintegrated in water within 1 h of the evaluation. At the end of 3 h the swelling index of the formulations S1, P1 and G1 had reached approximately 31.25%, 107.61% and 20.77%, respectively. At the end of 3 h the swelling index of the formulations S3, P3 and G3 had reached approximately 39.46%, 207.25% and 253.45%, respectively. It was noted that the formulation cross-linked with Barium chloride showed a higher swelling index percentage when compared with the formulations cross-linked with calcium chloride. Post 3 h, a decrease in the readings were observed in the case of all the formulation, which may indicate the erosion of the formulation. Swelling of the film can cause increased porosity, which will increase water uptake. With the increase in water absorption, the drug embedded in the polymeric mixture tends to dissolve. It helps in the release of the drug from the polymeric film. Thus, the swelling index affects the controlled release of the drug from the film [13].

Fig. 13.

Swelling Index studies: (A–C) Calcium Chloride cross-linked films after swelling index studies up to 3 h of S1 film, P1 film and G1 film, respectively. (D–F) Barium Chloride cross-linked films after swelling index studies up to 3 h of S3 film, P3 film and G3 film, respectively.

Table 5.

Film Formulations and their observed swelling index %.

Formulations	Swelling index %
	1 h	2 h	3 h
S1	26.70%	29.54%	31.25%
S3	31.96%	39.28%	39.46%
P1	89.52%	100.00%	107.61%
P3	119.87%	146.05%	207.25%
G1	7.20%	18.28%	20.77%
G3	95.44%	184.58%	253.45%

3.4.4. Determination of drug entrapment efficiency

Drug encapsulation efficiency of the cross-linked films was studied and the experimental data has been tabulated [Table 6]. It was observed that the entrapment efficiency of Barium chloride cross-linked films was greater when compared with Calcium chloride cross-linked films. P3 formulation, i.e., SA/LS/PEG/MK, had the highest entrapment efficiency of approximately 88.13%.

Table 6.

Film formulations and their drug entrapment efficiency %.

Formulations	Drug entrapment efficiency %
S1	62.74%
S3	79.03%
P1	69.28%
P3	88.13%
G1	66.49%
G3	76.54%

3.5. 2.6.In vitro release study

In vitro release studies were performed using the setup shown in Fig. 14. The absorbance of acetate buffer from the receptor compartment every 1 h was measured with the help of a UV–Visible spectrophotometer. Based on the absorbance value obtained from the UV spectra, the graphical representation of % of Montelukast Sodium released vs Time (hours) was constructed.

Fig. 14.

UV Plots for release of MK drug for various intervals (a) Non-cross-linked SA/LS film (b) The CaCl₂ cross-linked SA/LS film (c) The BaCl₂ cross-linked SA/LS film (d) Overall release of MK drug.

The graphical representation in Fig. 14(a–c) depicts the UV spectra of the release of the Montelukast Sodium drug from the SA/LS films. It can be inferred that non-cross-linked SA/LS film (Fig. 14a) that the release of the drug from the film was not in a controlled manner, while the release from the CaCl₂ cross-linked film (Fig. 14b) and BaCl2 cross-linked film (Fig. 14c) was observed to be in a controlled manner. Based on the existing literature, the UV peaks at 285 nm can be validated as the absorbance peak of the Montelukast Sodium drug [23]. From the graphical representation (Fig. 14d), it can be observed that the MK drug was completely released in approximately 3 h, while the cross-linked films show a controlled release of the drug Montelukast Sodium up to 36 h. Release studies of sodium alginate, lignosulphonic acid formulated film revealed that there was 100% release of the drug in approximately 3 h in the case of the non-cross-linked formulation (S2). In the case of the formulation cross-linked with Calcium chloride (S1), about 50% of the drug was released in 36 h, while 100% drug was released in 36 h in the case of formulation cross-linked with Barium chloride (S3).

The graphical representation shown in Fig. 15(a–c) depicts the UV spectra of the release of the Montelukast Sodium drug from the SA/LS/Gly films. It can be inferred that non-cross-linked SA/LS/Gly film (Fig. 15a) that the release of the drug from the film was not in a controlled manner, while the release from the CaCl₂ cross-linked film (Fig. 15b) and BaCl2 cross-linked film (Fig. 15c) was observed to be in a controlled manner [38]. From the graphical representation (Fig. 15d), it can be observed that the MK drug was ultimately released in approximately 5 h while the cross-linked films show a controlled release of the drug Montelukast Sodium up to 36 h. Release studies of sodium alginate, lignosulphonic acid formulated film with Glycerine as the plasticizer revealed that there was 100% release of the drug in approximately 5 h in the case of the non-cross-linked formulation (G2). In the case of the formulation cross-linked with Calcium chloride (G1), about 70% of the drug was released in 36 h, while 60% drug was released in 36 h in the case of formulation cross-linked with Barium chloride (G3).

Fig. 15.

UV Plots of SALS-Gly for MK drug release at various intervals (a) The non-cross-linked film (b) The CaCl₂ cross-linked film (c) The BaCl₂ cross-linked film (d)The graph of the overall release of MK drug.

The graphical representation shown in Fig. 16(a–c) depicts the UV spectra of the release of the Montelukast Sodium drug from the SA/LS/PEG films. It can be inferred that non-cross-linked SA/LS/PEG film (Fig. 16a) that the release of the drug from the film was not in a controlled manner, while the release from the CaCl₂ cross-linked film (Fig. 16b) and BaCl₂ cross-linked film (Fig. 16c) was observed to be in a controlled manner. From the graphical representation (Fig. 16d), it can be observed that the MK drug was completely released in approximately 6 h, while the cross-linked films show a controlled release of the drug Montelukast Sodium up to 36 h. Release studies of sodium alginate, lignosulphonic acid formulated film with PEG-400 as the plasticizer revealed that there was 100% release of the drug in approximately 6 h in the case of the non-cross-linked formulation (P2). In the case of the formulation cross-linked with Calcium chloride (P1), about 50% of the drug was released in 36 h, while 80% drug was released in 36 h in the case of formulation cross-linked with Barium chloride (P3).

Fig. 16.

The UV spectra of the release of the MK drug from SALS-PEG film at various intervals (a) The non-cross-linked film (b) The CaCl₂ cross-linked film (c) The BaCl₂ cross-linked film (d) The graph of the overall release of MK drug from all the SA/LS/Gly film variations.

The reason behind such a difference between the cross-linked films and the non-cross-linked ones can be traced to the fact that cross-linking agents such as barium ions and calcium ions can interact with sodium alginate via ionic interaction such that the stability of the film increases. Due to the cross-linking, the drug is entrapped within the polymeric matrix and released in a controlled manner [18].

4. Conclusion

Transdermal films loaded with Montelukast Sodium drug using sodium alginate and lignosulphonic acid were observed to be a potential candidate for delivering Montelukast Sodium transdermally. The transdermal film serves as a reservoir for the controlled release of the drug. The interaction between different components of the film was confirmed with the help of FTIR results. The objective of the study to improve the chemical stability of the formulation was tackled. The characterisations such as TGA of Gly composite with SALS blend was found to be relatively stable for thermal degradation which indicates improved chemical stability. SEM images show no phase separation in SALS blends with Gly, indicating uniform distribution, which can be an ideal blend to load MK drugs for TDD applications. The primary disadvantage to the SA/LS blends were its weak stability as it was observed that the SA/LS blend easily disintegrated in water. The stability of the formulation was improved by incorporating cross-linking agents such as barium chloride and calcium chloride. Another major disadvantage was the brittle nature of the blend which could have hindered the application of the formulation. This problem was tackled by the formulation with glycerine as the plasticizer which was observed to be the most flexible when compared with the other two formulations. Concerning the stability of the formulation based on the moisture capacity studies, the formulation with PEG-400 as the plasticizer was found to be more stable when compared with the other two formulations. Another objective of the study which aimed at the extended-release of the drug was also successfully achieved which is indicated by the result obtained from the in vitro release studies. In the case of the release studies, formulations with glycerine as the plasticizer released the drug in a more controlled manner when compared with the other two formulations. The non-cross-linked films were only able to release the drug for 3–5 h, whereas the drug was released in a controlled manner for up to 36 h using cross-linked films. It can be concluded that cross-linking agents can affect the drug release from the formulation. The resultant observations suggest the possibility that the formulated transdermal films can increase the bioavailability of the drug as the first pass of hepatic metabolism can be avoided, and also the concentration of the drug can be maintained for a longer period without increasing the dosage frequency of the drug. Based on the results obtained from the study, it can be concluded that by using cross-linking agents such as Barium chloride and Calcium chloride and plasticizers such as Glycerine and PEG-400, the stability and the extended release of the drug from the formulations can be improved. Further, the formulation can be tested for its toxicity following which in-vivo testing can be performed.

5. Limitations

This study has four significant limitations which are mentioned below:

• (i)Montelukast Sodium has not been the subject of much research.
• (ii)The scope and depth of the discussions in the paper may have been hampered on many levels as a result of ongoing research on specific topics that make it challenging to understand outcomes.
• (iii)Since this design is observational and it is impossible to control every aspect of lifestyle, there may be some latent confounding.

Declarations

Author contribution statement

Aashli Mary: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data; Wrote the paper. Giridhar Reddy: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data. Siva Kumar Belliraj, Prashanthi K: Analyzed and interpreted the data; Wrote the paper. H C Ananda Murthy: Analyzed and Wrote the paper.

Data availability statement

Data included in article/supplementary material/referenced in article.

Declaration of interest's statement

The authors declare no conflict of interest.

Funding statement

This research has been carried out with funding grants from Vision Group of Science and Technology, Department of Information Technology, Biotechnology and Science & Technology, Govt. of Karnataka, India, for the GRD- 625 (KSTePS/VGST/RFTT/2016-17/279/1) in 2017 for a period of one year.

Aashli Mary was supported by Vision Group on Science and Technology (KSTePS/VGST/RFTT/2016-17/279/1).