Montelukast-project-10th-smester.docx

Montelukast project 10th smester: No;1 Abstract Montelukast sodium is a leukotriene antagonist of growing interest as an alternative therapy for asthma across different age groups due to its bronchoprotective, anti-inflammatory and antiallergic properties. Currently, montelukast is commercialized only in oral solid dosage forms, which are the favorite of adult patients but may pose challenges in administration to children of young age or patients suffering from dysphagia. This review presents a comprehensive revision of scientific reports and patents on emerging strategies for the delivery of montelukast. A common ground to these reports is the pursue of an enhanced montelukast performance, by increasing its bioavailability and physico-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 forms for montelukast are designed for nonenteric absorption, some for absorption in the oral cavity and another two being for local action in the nasal mucosa or in the pulmonary epithelium. The review describes the emerging delivery strategies to circumvent the current limitations to the use of montelukast that are expected to ultimately lead to the development of more patient-compliant dosage forms. No :2 Abstract In the present work fast dissolving tablets of Montelukast sodium were prepared using novel coprocessed superdisintegrants consisting of crospovidone and sodium starch glycolate in the different ratios (1:1, 1:2 & 1:3) in vice versa. Montelukast sodium is a drug of choice in treatment of asthma and allergic rhinitis. Drug compatibility with excipients was checked by FTIR studies. After examining the flow properties of the powder blends the results were found to be within prescribed limits and indicated good flowing property and it was subjected to tablet compression. All the formulations were subjected to post compression parameters like hardness and friability (≤1%), indicated that tablets had a good mechanical strength and resistance. Drug content was found to be in the range of 93.51 to 98.79 %. The wetting time is an important criteria for understanding the capacity of disintegrants to swell in presence of little amount of water were found to be in the range of 20 to 55 sec. Among all the designed formulations, formulation F9 was found to be promising and showed an in-vitro disintegration time of 25 sec, which facilitates faster disintegration in the mouth. When compared to marketed product, the formulation F9 containing co-processed superdisintegrant (1:3 mixture of sodium starch glycolate and crospovidone) emerged as the overall best formulation based on drug release characteristics with 0.5% SLS in distilled water as dissolution medium. Short-term stability studies on promising formulation F9 indicated that there were no significant changes in hardness, drug content and in-vitro drug release. From this study, it can be concluded that dissolution rate of Montelukast sodium FDTs could be enhanced by tablets containing co-processed superdisintegrant. No 3: Abstract An oral press-coated tablet was prepared by using direct compression and wet granulation methods to achieve the predetermined lag time. This press-coated tablet containing montelukast sodium in the inner core was formulated with an outer barrier layer by different compositions of hydrophobic polymer ethylcellulose and hydrophilic polymer low-substituted hydroxypropylcellulose. The effect of formulation composition on the barrier layer comprising both

hydrophobic and hydrophilic excipients on the lag time of drug release was investigated. It was observed that lag time decreases with increasing concentration of low-substituted hydroxypropylcellulose. Press coated tablets coated by dry mixing and by wet granulation showed variations in lag time. As compared to dry mixed blend method wet granulation method gives less lag time.

No 4: Abstract The aim of present study is to Formulate and Evaluate Montelukast Sodium Pulsatile Drug Delivery system by Core in Cup method to mimic the circadian rhythm of the disease by releasing the drug with a distinct predetermined lag time of 7 hours. The basic design of the system consists of a rapid release core and controlled release coat. A combination of Hydroxy Propyl Methyl Cellulose and Ethyl Cellulose was used as a coating material for the tablet. Ten formulations (F1-F10) of the core were prepared by using CCS, SSG and CP as disintegrants in different proportions (5, 7.5 and 10%) to study the effect of variable concentrations of these on the characteristics of the formulation. Core blend was evaluated for Flow properties Hardness, Thickness, Friability and invitro drug release. Among the Ten formulations F9 containing CP (7.5%) as disintegrant showed a better drug release of 100% over 45minutes was selected .The core was coated with HPMC and EC with different polymer ratios (P1F9- P5F9). Among these P2F9 was optimized based on the lag time and percent of drug release (10.2% of drug release in 7 hours). No 5:Abstract Purpose: To design an orally disintegrating montelukast sodium tablet (ODT) that disintegrates in the oral cavity leaving an easy-to-swallow residue especially for pediatric and elderly patients who have difficulty swallowing tablets. Methods: Two different formulations of montelukast sodium (5 mg) orally disintegrating tablets were designed and manufactured by direct compression method, using microcrystalline (Avicel PH-102), mannitol, sodium bicarbonate, crospovidone and magnesium stearate as key excipients, and with cherry flavor and aspartame as flavor and sweetener, respectively. These formulations were then evaluated using pharmacopoeial and non-pharmacopoeial physical and chemical tests. Dissolution and assay tests were performed using USP apparatus II and ultraviolet (UV) spectrophotometry, respectively. Formulations with better results were further subjected for optimization study using central composite design method. Results: The results of prototype formulation batch (Trial-02) and the finest optimization formulation batch (FOB-01) reflected the successful development of new formulation of orally disintegrating montelukast sodium 5 mg tablet by direct compression technique. The value of similarity factor (f2 > 50), indicating that both formulations have similar drug release profiles. The formulations were further evaluated for three and six months under accelerated conditions to ascertain their stability. Conclusion: The results obtained demonstrate the suitability of the formulation as an ODT for convenient delivery of montelukast sodium for asthmatic patients. However, clinical studies are required to confirm this. No 6:Abstract The buccal route is of particular interest with regard to the systemic delivery of small molecules that are subjected to first pass metabolism or for the administration of proteins and peptides. Drug absorption through a mucosal surface is efficient because mucosal surfaces are usually rich in blood supply, providing rapid drug transport to the systemic circulation and avoiding degradation by gastrointestinal

enzymes and first pass hepatic metabolism, when placed at specific location. Mucoadhesive buccal tablets of Montelukast Sodium were prepared using Hydroxy Propyl Methyl Cellulose (HPMC), Sodium Carboxy Methyl Cellulose (NaCMC) as a mucoadhesive polymers. Nine formulations were developed with varying concentrations of polymers and excepients. Tablets were prepared by direct compression method and were subjected for evaluation of various physicochemical properties such as weight variation, tablet thickness, content uniformity, surface pH, bioadhesive strength and swelling index. In vitro bioadhesive strength showed that tablets containing intermediate concentration of HPMC & NaCMC were excellent in bioadhesive nature. The, in vitro drug release study was studied in Phosphate buffer (pH 6.8). On basis of optimization studies, formulation F 8 was found to be bearing excellent bioadhesive strength of (31.33 ±1.52 g) and exhibited sustained in vitro drug release pattern of (99.69 % for 8 h). No 7:Abstract In the present study, we have designed Montelukast sodium granules and tablets filled in HPMC capsule system, which is presented as a biphasic delivery system. Montelukast sodium is used in the treatment of chronic asthma, and to relieve symptoms of seasonal allergies. Montelukast sodium biological half-life is 2.5 to 5.5 hrs, thereby decreasing bioavailability up to 64%. So in order to improve the bioavailability and efficacy we have designed granules and mini-tablets filled in HPMC capsule system, which is presented as a biphasic delivery system. The outer layer that fills the void spaces between the minitablets was formulated to release the drug in a very short time (fast release), while the minitablets provided a sustain release. Fast releasing component comprises superdisintegrant crospovidone, while mini-tablet was formulated using different concentration of HPMC and Ethyl cellulose to obtain different drug release rates. The In-vitro performance of these systems showed the desired biphasic behavior. The drug contained in the fast releasing phase (Granular powder) dissolved within the first 10 min, whereas the drug contained in the mini-tablets was released at different rates, depending upon composition of mini tablets. The in-vitro performance of the best formulation showed the desired behavior, the drug contained in the granules for immediate release dissolved within the first 10 min, whereas the drug contained in the sustained release tablets was released over a period of 12 hrs. The formulation GMTFCS-4 shows 29.55 % of montelukast sodium release was released in 1hrs as an immediate-release phase and 99.92% of montelukast sodium was sustained for a period of 12 hrs. From this, study it can be concluded that, granules and mini-tablets filled in HPMC capsule systems containing Montelukast sodium shows both sustained release as well as immediate release may improve the bioavailability and efficacy. No 8:Abstract Background: Orally disintegrating tablets (ODTs) are a modern form of tablets that when placed in the oral cavity, disperses rapidly. These tablets have advantages, particularly good applications for children and old patients who have a complication in chewing or swallowing solid dosage forms. The aim of this study was to design, formulate, and evaluate the physicochemical properties of 5 mg montelukast ODTs for the prevention of asthma and seasonal allergies. Methods: Formulations were prepared with different amounts of super disintegrating agents and effervescent bases as disintegrant agents. Flowability and compressibility of mixed powders were evaluated. The prepared formulations were tested for hardness, thickness, friability, weight variation, drug content, wetting time, disintegration time, dissolution study, and moisture uptake studies.

Results: The compressibility index and angle of repose were in the range of 15.87%-23.43% and 32.93-34.65, respectively. Hardness, thickness, friability, wetting time, and content uniformity of formulations were in the range of 33.7-37.1 N, 3.00-3.81 mm, 0.27%-0.43%, 31-50 s and 96.28%-99.90%, respectively. Disintegration time of the tablets prepared with super disintegrating agents, effervescent bases, and combination of two were in the range of 30-50, more than 60 and 20-36 s, respectively. Conclusions: Mixture of powders and tablets passed all the specified tests. The results showed formulations prepared by super disintegrating agents and super disintegrating agents with effervescent bases had shorter disintegration time compared to formulations with effervescent bases alone. Keywords: Direct compression, montelukast, orally disintegrating tablets, prevention of asthma or seasonal allergic

No 9: Abstract Montelukast sodium fast dissolving films were prepared by solvent casting method using HPMC as film base with different concentrations of superdisintegrants like microcrystalline cellulose and crospovidone using PEG 400 as plasticizer. The physicochemical parameters of the fast dissolving films were evaluated. The compatibility of the drug in the formulation was confirmed by IR and DSC studies. Scanning electron microscopy revealed the morphology of the films. In vitro dissolution studies and mechanism of drug release was identified. The formulation F2 and F5 with 4% of crospovidone and 10% MCC respectively shows a maximum cumulative percentage drug release of 97.42% and 94.64% at the end of 30 min respectively. The release of drug from the films has followed first-order kinetics. No significant change in the physical parameters, in vitro disintegration time and drug content of F2 was observed during storage at 40±20C/75±5% RH for 3 months. The data demonstrated that 4% crospovidone and 10% MCC with 4% HPMC as a film base was suitable for developing fast dissolving films of Montelukast sodium. Keywords: Fast dissolving films, Montelukast sodium, HPMC, Crospovidone, MCC No 10:Abstract The objective of the present investigation was to develop a mucoadhesive in-situ gel with reduced nasal mucocilliary clearance in order to improve the bioavailability of the antiasthamatic drug, Montelukast Sodium. The in-situ gelation upon contact with nasal mucosa was conferred via the use of the thermo gelling Pluronic flake 127 whereas mucoadhesion and drug release enhancement were modulated via the use of Hydroxy Propyl Methyl Cellulose, Methyl Cellulose and polyethylene glycol respectively. The results revealed that the mucoadhesive polymer increased the gel viscosity but reduced its sol-gel transition temperatures and the drug release. The inclusion of polyethylene glycol polymer counteracted the effect of mucoadhesive polymer whereby it decreased the gel consistency and increased the sol-gel transition as well as in-vitro drug release. The in-vitro drug release performed through dialysis membrane and ex vivo studies performed by using sheep nasal mucosa. F10 and F2 formulations showed 88.33%±0.08 and 83.75%±0.12 of drug release at 12h respectively. So this study points to the potential of mucoadhesive in-situ nasal gel in terms of ease of administration, accuracy of dosing, prolonged nasal residence and improved nasal bioavailability. Key words: Montelukast Sodium, Mucoadhesive, Pluronics P127, Sheep Nasal Mucosa.

No 11:Abstract The main objective of the present study was to develop the matrix type transdermal films of Montelukast Sodium and to evaluate them with respect to various in-vitro and in-vivo parameters. The matrix type transdermal systems were prepared by homogeneous dispersion of drug by using different ratios of HPMC K15M & EC polymers in 8:1, 4:1 and 2:1 ratios were increased to the total weight of 540 mg. HPMC K15M and EC were dissolved in 15 ml ethanol at room temperature, HPMC K15M as the ratecontrolling membrane for all the systems. The swelling properties of the polymers were studied, and drug-polymer interaction studies were performed. The patches were subjected to various physicochemical studies, in-vitro release studies, permeation studies, and skin irritation studies. The optimized batch of HPMC K15M & EC 8:1 was selected to further study like effect of different natural permeation enhancers i.e. camphor, menthol and 1,8 cineole. This was done on the basis of invitro drug release studies. It was found that the batch F1, ratio 8:1 gave the best release rates which were found to increase with the increase in the concentration of the hydrophilic polymer HPMC K15M. All the patches with HPMC K15M: EC (8:1) showed controlled and sustained release. Formulation F5 containing 10% camphor was found to release the highest quantity of drug. Keywords: Membrane controlled, hydrophilic polymer, swelling ratio, hydrophilic drug, in-vivo study. No 12:Abstract Montelukast sodium fast dissolving films were prepared by solvent casting method using gelatin as film base with different concentrations of superdisintegrants like microcrystalline cellulose and crospovidone using PEG 400 as plasticizer. The physicochemical parameters of the fast dissolving films were evaluated. The compatibility of the drug in the formulation was confirmed by IR and DSC studies. Scanning electron microscopy revealed the morphology of the films. In vitro dissolution studies and mechanism of drug release was identified. The formulation F2 and F5 with 4% of crospovidone and 10% MCC respectively shows a maximum cumulative percentage drug release of 98.35% and 95.57% at the end of 30 min respectively. The release of drug from the films has followed first-order kinetics. No significant change in the physical parameters, in vitro disintegration time and drug content of F2 was observed during storage at 40±20 C/75±5% RH for 3 months. The data demonstrated that 4% crospovidone and 10% MCC with 4% Gelatin as a film base was suitable for developing fast dissolving films of Montelukast sodium. Keywords: Fast dissolving films, Montelukast sodium, Gelatin, Crospovidone, MCC. No 13:Abstract Montelukast, a cysteinyl leukotriene type 1 receptor antagonist, exhibits secondary anti-inflammatory properties when used at higher concentrations. Low-molecular-weight heparin (LMWH) evokes pronounced anti-inflammatory effects by interrupting leukocyte adhesion and migration. We hypothesized that inhalable particles containing montelukast plus LMWH release both drugs in a sustained fashion and protect the lungs against allergen-induced inflammation. Large porous particles of montelukast and LMWH were prepared using a double-emulsion–solvent-evaporation method. Montelukast was first encapsulated in copolymer-based particles using polyethylenimine as a porosigen; the resulting particles

were then coated with LMWH. The particles were evaluated for physicochemical properties, respirability, and release profiles. The anti-inflammatory effect of the optimized formulation was studied in ovalbuminsensitized asthmatic Sprague Dawley rats. The optimized large porous particles had a diameter of 10.3 ± 0.7 μm, exhibited numerous surface indentations and pores, showed acceptable drug entrapment efficiency (66.8% ± 0.4% for montelukast; 91.7% ± 0.8% adsorption efficiency for LMWH), demonstrated biphasic release patterns, and escaped the uptake by the rat alveolar macrophages. The number of infiltrating inflammatory cells in asthmatic rat lungs, treated with dual-drug particles, was >74% fewer than in untreated asthmatic rat lungs. Similarly, the airway walls of asthmatic animals treated with dual-drug particles were 3-fold thinner than those of untreated asthmatic animals (p < 0.001). The optimized formulation protects lungs against methacholine-induced airway hyper-reactivity. Overall, this study demonstrates the feasibility of loading 2 drugs, montelukast and LMWH, into an inhalable particulate system and establishes that this novel combination therapy produces sustained drug release and elicits a robust anti-inflammatory response in the lungs.

Keywords: asthma, combination therapy, montelukast, low-molecular-weight heparin, pulmonary delivery, microparticles

No 14: Abstract

To develop a montelukast sodium–loaded stable oral suspension bioequivalent to the commercial granules in rats, several montelukast sodium-loaded suspensions were prepared with a suspending agent, stabilizers and anti-aggregation agents, and their stabilities were investigated by visually observing the sedimentation phenomenon and determining the concentration of the degradation product. Moreover, dissolution and pharmacokinetic studies of the optimized formulation were examined in rats compared to commercial montelukast sodium-loaded granules. Avicel RC-591 (Avicel), a suspending agent, prevented the sedimentation of these suspensions at >2.496 (w/v) per cent composition. Amongst the stabilizers tested, fumaric acid provided the lowest concentration of montelukast sulphoxide (a degradation product) in these suspensions at 40 °C, demonstrating its excellent stabilizing activity. Furthermore, as an antiaggregation agent, glycerin gave lower amounts of degradation product than those with poloxamer 407 and Tween 80. In particular, montelukast-loaded oral suspension, an aqueous suspension containing montelukast sodium/Avicel/fumaric acid/glycerin at a concentration of 312/2496/15.6/62.4 (mg/100 ml), and the commercial granules exhibited similar dissolution profiles in 0.5 % (w/v) aqueous solution of sodium lauryl sulphate. Moreover, the pharmacokinetics in rats provided by this suspension was comparable to that of the commercial granules, suggesting that they were bioequivalent. In addition, it was physically and chemically stable at 40 °C for at least 6 months. Thus, this montelukast sodium-loaded oral suspension, with bioequivalence to the commercial granules and excellent stability, could be a prospective dosage form for the treatment of asthma.

Keywords

Montelukast sodium Oral suspension Stability Dissolution Bioavailability No 15:Abstract Introduction: The current research in the field of drug delivery by which fast release can be achieved has been intensified. The present study was an attempt to develop and evaluate an oral fast dissolving drug delivery system using Musa paradisiaca powder as a novel superdisintegrant. Materials and methods: The formulation contains a model drug (Montelukast sodium), a novel superdisintegrant (Musa paradisiaca powder) and film former (HPMC E15 LV) and the fast release effect was achieved with the proper combination of film former and superdisintegrant. A 32 full factorial design was employed for the optimization of developed formulation considering concentration of superdisintegrant and concentration of film former as independent variables with drug release and disintegration time as dependent variables. Results and discussion: The effect of varying concentrations of the independent variables, HPMC E15 LV and Musa paradisiaca powder on the dependent variables was studied. It was found that enhancing the polymer concentration shows negative effect on disintegration time and the drug release. But when the concentration of the Musa paradisiaca powder was increased, it had a positive impact on the disintegration time and drug release. Conclusion: It can be concluded that addition of Musa paradisiaca powder to the formulation helps to achieve a fast release of drug and hence may help in rapid onset of action that may lead to improved oral bioavailability of drug. Keywords: Fast dissolving oral film; Montelukast sodium; Musa paradisiaca powder; Solvent casting technique No 16:Abstract Solid lipid nanoparticles (SLNs) are an alternative carrier system used to load the drug for targeting, to improve the bioavailability by increasing its solubility, and protecting the drug from presystemic metabolism. The avoidance of presystemic metabolism is due to the nano-metric size range, so that the liver cannot uptake the drug from the delivery system and is not metabolized by the liver. Montelukast sodium is an anti-asthmatic drug, because of its poor oral bioavailability, presystemic metabolism, and decreased half-life; it was chosen to formulate as the solid lipid nanoparticle (SLN) system by hot homogenization followed by an ultrasonication method, to overcome the above. Compritol ATO 888, stearic acid, and glyceryl monostearate were used as a lipid matrix and polyvinyl alcohol as a surfactant.the prepared formulation have been evaluated entrapment efficiency drug content, in vitro drug release, particle size analysis, scanning electron microscopy, Fourier transform-infrared studies (FTIR), differential scanning calorimetry (DSC), and stability. Particle size and with increased carbon chain length of the facilities acids. Entrapments efficiency EE was running from 42 % to 92 %. In vitro release studies showed maximum Cumulative drug release was obtaining for F1 59.1% Containing static acid and the lowest was observed for F 18(28.1%) containing compritol ATO888after 12h and all the formulas follow the first order release kinetics. FT-IR and Dsc studies reveled no interaction between druds and lipids. Studies showed that increase in lipid concentration, increased particle size, EE, and maintained

the sustained release of drug. Among all, compritol ATO 888 was chosen as the best lipid for formulating SLN because it had high EE and sustained the drug release. Key words:Entrapment efficiency , lipid,Montelukast sodium,Solid lipid nanoparticle,surfactant. No 17:Abstract The present study was all about to deliver a drug after certain lag time. The study was to develop a multiparticulate pulsatile drug delivery system for montelukast sodium. This study was done to increase half life of drug by increasing lag time. The pulsatile drug delivery system has importance that it deliversthe drug in gastrointestinal tract after certain lag time. The mixture of Eudragit RL100 and Eudragit S100 was used for enteric coating purpose. Continuous dissolution studies were carried out in simulated gastric, intestinal, and colonic fluid with pH 1.2 (0.1 N HCl), pH 7.4 and pH 6.8 (phosphate buffer), respectively. The lag time was completely depending on ratio of acrylate polymers i.e. ERL and ES and percentage coating level used. The formulation comprising 12% coating level and 1:4 ES: ERL ratio was found to be an optimized formulation. The in vitro study showed lag time 4 to 8 hours to release the total drug in different buffers used. Key words Montelukast sodium; Lag time; Multiparticulate; Factorial design; Circadian rhythm. No 18: Abstract A method for the preparation of montelukast acid sodium salt thereof in amorphous form has been described. The method comprises of following steps: (a) generating the dilithium dianion of 1(mercaptomethyl)cyclopropane acetic acid, by reacting with alkyl lithium, (b) coupling the said dianion with wet mesylate to get montelukast acid in crude form, (c) obtaining DCHA salt in crude form by adding dicyclohexylamine (DCHA) to crude acid obtained in the above step (b), (d) purifying and converting the said DCHA salt in crude form, to montelukast acid in pure form, and (e) reacting the pure montelukast acid in a polar protic solvent with a source of sodium ion followed by evaporating the solvent and triturating of the residue with non-polar water immiscible solvent. N o 19: Abstrac Objective: This study focused on the preparation of montelukast sodium (MTK) fast release pulmonary targeted microparticles using the spray drying technique. Methods: The effect of addition of different excipients namely: mannitol, leucine and ovalbumin on the physico-chemical characteristics of MTK spray dried powders were investigated. Powder flow properties, drug association efficiency as well as microparticle size and mass median aerodynamic diameter were determined. The prepared microparticles were characterized using FT-IR and TGA. The powder crystallographic and thermal properties were studied using DSC and X-ray powder diffraction. A twin stage impinger was used to evaluate in vitro pulmonary deposition from which the inhalation indices were derived. Results: The tested excipients showed no adverse chemical interactions with the drug based on FT-IR. The best inhalation indices were obtained with powders spray dried with leucine followed by leucine/mannitol mixtures with MMAD of 1.73±0.08 and 1.36±0.16 and fine particle fraction of 60.55±1.63 and 52.31±3.52, respectively. The dried powders showed good physico-chemical stability for up to 6 mo storage.

Conclusion: The developed MTK spray dried particles may offer a good platform for the targeted pulmonary delivery of MTK overcoming the major biological barriers. Keywords: Montelukast, Spray drying, Microparticles, Pulmonary delivery, Mannitol, Albumin, Leucine.

No 20:Abstract

Reversed-phase high performance liquid chromatography (LC) method is developed for the assay of sodium montelukast in coated tables and its photodegradation kinetics. An isocratic LC separation is performed on a Zorbax XDB C18 column using a mobile phase of acetonitrile–methanol–water (pH 3.8) (75:10:15, v/v/v) at a flow rate of 0.8 mL/min and detection at 280 nm. The detector response for sodium montelukast is linear over the concentration range from 5–35 µg/mL (r = 0.9999). The specificity of the method is proved using stress conditions. The solutions are exposed to UV radiation (352 nm), alkaline and acid hydrolysis, oxidation, and temperature (80°C). The intra- and inter-day precision show suitable results (RSD < 0.49%). The accuracy of analytical method is 100.04% (RSD = 0.44%). Detection and quantification limits are 0.10 and 0.32 µg/mL respectively. The robustness of the method is assured after small changes in chromatographic conditions. The kinetic of photodegradation using a LC method is established and it can be described by zero-order kinetics. This developed method show to be viable for the determination of sodium montelukast in pharmaceutical dosage form and satisfactory in the determination of the kinetics of degradation.