Research paper
Carvedilol-loaded nanocapsules: Mucoadhesive properties and permeability across the sublingual mucosa

https://doi.org/10.1016/j.ejpb.2017.01.007Get rights and content

Highlights

  • Carvedilol was encapsulated in Eudragit® RS 100 or poly(ε)caprolactone nanocapsules.

  • Interaction of nanocapsules with mucin and porcine sublingual mucosa was evidenced.

  • Nanoencapsulated carvedilol was able to cross porcine sublingual mucosa.

  • Nanoencapsulation improved carvedilol permeation in presence of simulated salivary flux.

Abstract

Carvedilol is a drug used to treat heart failure, hypertension, and coronary artery diseases . However, it has low oral bioavailability (25–35%) due to its high first-pass hepatic metabolism. The objective of this study was to develop carvedilol-loaded mucoadhesive nanocapsules as delivery systems for the sublingual administration of the drug. Nanocapsules were prepared using poly(ε-caprolactone) (CAR-LNC) and Eudragit® RS 100 (CAR-NC) as polymeric wall. In vitro interaction of formulations with mucin was performed to predict their mucoadhesion capacity. The permeability and washability profiles of carvedilol were evaluated using porcine sublingual mucosa. The mean diameter of particles in formulations was in the nanometric range, and particles had low polydispersity and slightly acidic pH. Zeta potential values were positive for CAR-NC and negative for CAR-LNC. Encapsulation efficiency was higher than 87% and 99% for CAR-NC and CAR-LNC, respectively. Both formulations presented controlled drug release profiles and mucoadhesive properties. Carvedilol was able to permeate through the sublingual mucosa. Nanoencapsulation improved retention time on the mucosa and permeation in presence of simulated salivary flux. This study highlighted the suitability of using CAR-loaded nanocapsules in the development of innovative sublingual dosage forms.

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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