Research paperCarvedilol-loaded nanocapsules: Mucoadhesive properties and permeability across the sublingual mucosa
Graphical abstract
Introduction
Carvedilol (CAR) has been used for the management of important cardiovascular diseases, which are the main causes of worldwide morbidity and mortality. According to the World Health Organization (WHO), in 2012 17.5 million people died from cardiovascular diseases, and according to WHO it has also been estimated that more than 22.2 million people will die of these conditions in the year 2030 [1]. CAR is a non-selective β-adrenoceptor antagonist, α1-adrenoceptor blocker, and has antioxidant effects. It has been approved for the treatment of heart failure, hypertension, and coronary artery diseases [2]. This drug is available as tablets for oral administration; however, its systemic bioavailability is only 25–35% due to extensive hepatic first-pass metabolism [3]. In order to increase bioavailability, different strategies have been proposed for oral and nasal administration of CAR [4], [5], [6]. The sublingual route of administration is a motivating alternative when the aim is to improve the bioavailability of drugs that undergo first-pass metabolism. Since this region is highly vascularized, the drug can enter the systemic circulation directly, bypassing hepatic metabolism. However, this cavity is exposed to constant flow of saliva, and part of the drug may therefore be swallowed [7]. In order to prolong retention time in this area, studies have suggested the use of mucoadhesive systems, which are able to interact with the mucus layer covering the surface of buccal epithelia [8], [9].
Nanoparticles are promising drug carriers that have been extensively studied. These structures can control drug release, enhancing the desired effect by lowering the number of daily administrations, in addition to the possibility to reduce doses and mitigate side effects [10]. Polymeric nanocapsules are structures in which the drug is confined in an oily core surrounded by a polymeric wall [11]. The development of nanocapsules using polymers with mucoadhesive properties points to the potential of these structures as drug carriers to be administered through the sublingual route. Both poly(ε-caprolactone) (PCL) and Eudragit® RS100 (EUD), a co-polymer of poly(ethylacrylate, methyl–methacrylate methacrylic acid ester), present interesting bioadhesive properties [9], [12]. These two polymers have been used to prepare nanocapsules for different purposes, from cutaneous administration to brain delivery [11], [13], [14], [15], [16].
In view of the considerable influence of cardiovascular disease on worldwide morbidity and mortality and the multiple cardiovascular action of CAR, the design of pharmaceutical formulations to improve bioavailability of this drug becomes an important subject in research. In this scenario, this study describes a nanoencapsulation process for CAR in polymeric nanocapsules with mucoadhesive properties, to improve the drug’s sublingual retention and permeability. To the best of our knowledge, this is the first report on the development of polymeric nanocapsules intended to sublingual administration.
Section snippets
Materials
Carvedilol was obtained from Henrifarma (São Paulo, Brazil). Poly(ε-caprolactone) (MW 80,000), sorbitan monostearate and mucin from porcine stomach (type II) were acquired from Sigma-Aldrich (São Paulo, Brazil). Eudragit® RS100 was supplied by Degussa (Darmstadt, Germany), and grape seed oil was obtained from Dellaware (Porto Alegre, Brazil). Polysorbate 80, acetone, and hydrochloric acid were purchased from Vetec (Rio de Janeiro, Brazil). Basic fuchsine, sodium metabisulphite, periodic acid,
Development of nanocapsule suspensions
Nanoparticles were developed using grape seed oil as oil component. Its use has not been approved by the Food and Drug administration (FDA); however, its biological effect has been studied in humans due to its important antioxidant activity [25]. The oily phase used to produce nanoparticles may influence their size distribution, and grape seed oil has been proposed as alternative oil in nanocapsules production intended as drug delivery systems [26], [27]. Nanocapsules containing medium chain
Conclusion
Nanocapsules containing CAR produced with different polymers and core structure showed suitable nanometric and mucoadhesive properties. The nanoencapsulation of CAR improved its adherence on porcine sublingual mucosa, increasing its permeation in the presence of simulated salivary flux. Positive nanocapsules showed high interaction with sublingual mucosa when compared to negative nanocapsules. The present technological strategy opens promising perspectives for further studies to produce
Conflict of interest
The authors have no conflict of interest.
Acknowledgements
The authors thank the following Brazilian agencies for the financial support: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).
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