Optimization of nano-structured lipid carriers for enhanced salbutamol delivery via buccal mucoadhesive film

Introduction

Respiratory disorders are considered as prevalent diseases all over the world with millions of cases annually diagnosed with either bacterial or viral infections. For example, we recently experienced the acute coronavirus (COVID-19) pandemic and its severe respiratory prognosis with a high number of fatalities [1].

Concerning respiratory treatments (oral, inhalations), several challenges and limitations were found to patient adherence (estimated by less than 50 %) [2] Due to frequency of administration, difficulty of using, efficacy, targeting, dose-related side effects and the pandemic COVID lightened risks of infections spread from using nebulizers and aerosols [3,4]. These concerns push towards innovative nano drug delivery systems for enhancing treatment efficacy, targeting, sustained release, fewer side effects, and enhanced patient compliance [5].

Salbutamol sulphate (SS) is a short-acting selective β2 agonist, used abundantly for bronchodilatation in controlling asthma, bronchitis, and other chronic obstructive pulmonary respiratory diseases. Salbutamol works by motivating beta 2-adrenergic receptors in the lungs causing bronchial smooth muscle relaxation. Additionally, SS prevents the production of inflammatory broncho-constricting agents from mast cells, while augmenting mucociliary clearance [6]. Despite, SS being a water-soluble drug, readily absorbed from gastrointestinal tract (GIT), it is exposed to extensive enterohepatic metabolism which leads to poor oral bioavailability where only 25 % of the administered dose reaches systemic circulation [7]. Moreover, its short plasma half-life (2–4 h) requires frequent dosing daily, causing an increase in its side effects such as tachycardia and arrhythmia which hinder patient compliance [8]. Therefore, owing to these drawbacks, the inhaled route was suggested to be more frequently used route according to previous studies [9,10]. However, metered dose inhalers (MDIs) and nebulizers displayed problems in use for some patients, especially geriatrics and pediatrics. Moreover, they lose the accuracy of dosing and safety owing to chlorofluorocarbon (CFC) emitted into the environment [11]. According to the previously mentioned issues that underscore the high possibility for poor patient adherence to SS therapeutic regimen [12], several attempts were made to enhance SS bioavailability, targeting potential, and sustained release effect represented in delivery as buccal mucoadhesive patches [13], inhaled liposomal nanocarriers [14], and SS-loaded cubosomal gel for transdermal delivery [15].

Buccal mucoadhesive films have gained popularity and diversity in drug delivery due to their simple use by patients of all ages, boosting bioavailability by increasing permeability and avoiding first-pass metabolism [16]. Besides, buccal mucoadhesive films can provide multidirectional action, fast onset, and extended duration of action [17]. The current evolution in buccal mucoadhesive delivery is the incorporation of nanocarriers that offer enriched drug permeation through mucosal layers, prolonged residence time, drug targeting, and modifying drug release kinetics such as sustained or controlled drug release [18]. According to previous studies, numerous nanocarriers could be incorporated in mucoadhesive films as liposomes, nanosuspension, noisome, and solid lipid nanocarriers [19].

There are versatile natural and synthetic polymers that can be used in film formulation which are varying in their characteristics and performance such as flexibility, acceptance, mucoadhesiveness, drug absorption, and controlling drug release [20]. Hydroxy propyl methyl cellulose (HPMC) is a non-ionic water-soluble polymer, vastly used in film formation due to its biocompatibility, flexibility with acceptable mucoadhesiveness, hydration, drug permeation and drug release controlling characteristics [21]. While chitosan is a biocompatible powerful mucoadhesive polymer with promising properties in sustaining drug release [22]. Moreover, its ability to enhance the permeation of nanoparticles through the mucosal layer as well as its antimicrobial and anti-inflammatory properties signify it for pulmonic drug delivery [1]. This study was designed to formulate SS-NLCs buccal mucoadhesive film for providing an easy route of administration, enhancing bioavailability, and targeted sustainable efficiency by combining the brilliant elements of nano-drug carriers and buccal films.

The purpose of this study was to employ full factorial design to formulate and optimize SS-NLCs using GMS and Labrasol® oil. The optimum formula was incorporated in buccal mucoadhesive film prepared from HPMC and chitosan and was subjected to in vitro and in vivo characterization.

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Materials

Salbutamol sulphate (SS) was provided by Sedico Pharmaceutical Company, (6th of October City, Egypt). Glycerol monostearate (GMS) was obtained from Central Drug House (CDH), New Delhi, India. Labrasol® (Caprylocapropyl polyoxyl-8-glycerides) was a gift from Gattefosse (Saint-Priest, France). Hydroxy propyl methyl cellulose (HPMC Cp15) and Chitosan medium molecular weight were purchased from Chemajet, Egypt. Propylene glycol and glycerol were bought from El-Nasr Pharmaceutical Chemical.

Mohamed Nasr, Mohamed Ramzy, Raghda Abdel-moneum, Rania S. Abdel-Rashid, Optimization of nano-structured lipid carriers for enhanced salbutamol delivery via buccal mucoadhesive film, Journal of Drug Delivery Science and Technology, Volume 104, 2025, 106468, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.106468.

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