An integrated buccal delivery system combining chitosan films impregnated with peptide loaded PEG-b-PLA nanoparticles

https://doi.org/10.1016/j.colsurfb.2013.07.019Get rights and content

Highlights

  • Insulin loaded nanoparticles have been embedded into buccal chitosan films.

  • 3 mg of NPs per film showed excellent mucoadhesion and swelling properties.

  • A 1.8-fold enhancement of insulin permeation via EpiOral™ buccal tissue construct.

Abstract

Peptide (insulin) loaded nanoparticles (NPs) have been embedded into buccal chitosan films (Ch-films-NPs). These films were produced by solvent casting and involved incorporating in chitosan gel (1.25% w/v), NPs-Insulin suspensions at three different concentrations (1, 3, and 5 mg of NPs per film) using glycerol as plasticiser. Film swelling and mucoadhesion were investigated using 0.01 M PBS at 37 °C and texture analyzer, respectively. Formulations containing 3 mg of NPs per film produced optimised films with excellent mucoadhesion and swelling properties. Dynamic laser scattering measurements showed that the erosion of the chitosan backbone controlled the release of NPs from the films, preceding in vitro drug (insulin) release from Ch-films-NPs after 6 h. Modulated release was observed with 70% of encapsulated insulin released after 360 h. The use of chitosan films yielded a 1.8-fold enhancement of ex vivo insulin permeation via EpiOral™ buccal tissue construct relative to the pure drug. Flux and apparent permeation coefficient of 0.1 μg/cm2/h and 4 × 10−2 cm2/h were respectively obtained for insulin released from Ch-films-NPs-3. Circular dichroism and FTIR spectroscopy demonstrated that the conformational structure of the model peptide drug (insulin) released from Ch-films-NPs was preserved during the formulation process.

Introduction

There has been significant interest in mucoadhesive buccal formulations including films in recent years. The interest in film based formulations is driven not only by the promise of improved patient compliance [1], [2], but also by the possibility to deliver various therapeutic drug classes such as peptides and vaccines as an alternative to currently used parenteral administration. Buccal films avoid first pass effect by exploiting absorption through the venous system that drains from the cheek area [3]. For example, Donnelly et al. [18] and Singh et al. [6] formulated buccal films to release drug locally in order to treat oral candidiasis. Similarly, films containing drugs, meant for systemic activity, such as insulin, octreotide and leuprolide [4], [5], have been reported in the literature. However, drug bioavailability through the buccal mucosa, especially for peptides, is quite low (i.e. 0.1–5.0%) due to the relatively large molecular size, presence of both physical (mucous layer that lines a multi-layered epithelium) and chemical (presence of peptidases and proteolytic enzymes) barriers [4], [5].

In the light of these challenges, numerous approaches have been investigated for improving drug permeability [6]. One of such approaches is the formulation of nanoparticles (NPs) incorporated into carrier vehicles such as mucoadhesive buccal films [7]. NPs can improve the stability of active substances [8] and be compatible with tissue and cells when synthesised from biocompatible and biodegradable materials [9]. Moreover, NPs show promise as active vectors due to their capacity to encapsulate and release drugs [10]. In addition, their sub-cellular size allows relatively higher uptake compared to other particulate systems [11], [12]. Cui and co-workers demonstrated that films containing NPs exhibited higher mucoadhesion than blank films [13]. This higher mucoadhesion effect was attributed to the high number of carboxyl groups of NPs which increased the chances of hydrogen bonding with the buccal mucosa.

In this paper, we investigated chitosan based films as drug delivery systems. The films were loaded with NPs containing insulin. NPs were manufactured using PEG-b-PLA copolymer, which were loaded with different amounts of insulin. The films were characterised for mucoadhesiveness, swelling and physico-chemical properties. The dissolution studies were conducted to understand the release of peptide drug (insulin) from chitosan films loaded with NPs. Furthermore, EpiOral™ buccal tissue construct was used as an ex vivo model to study the permeability of insulin. The rationale behind this therapeutic approach was to combine in one delivery system, two innovative approaches, i.e. mucoadhesive chitosan films and NP carriers, for the sustained buccal delivery of macromolecular drugs.

Section snippets

Materials

Poly(ethylene glycol)methyl ether-block-polylactide (PEG average Mn  5000, polylactide average Mn  5000) (PLA-b-PEG), insulin (from porcine pancreas, Mw 5777.54 Da), chitosan (medium molecular weight, 75–85% deacetylated), polyvinylalcohol (PVA, Mowiol® 40–88), polyvinylpyrrolidone (PVP), trehalose (TH), sodium phosphate dibasic anhydrous, sodium hydroxide, dichloromethane, trifluoroacetic acid (TFA), isopropanol and acetic acid were supplied by Sigma–Aldrich (UK). EpiOral™ kit was purchased from

Preparation of chitosan films containing insulin loaded PEG-b-PLA NPs

Due to its poor water solubility, chitosan powder was solubilised in aqueous acetic acid (1% w/v) to produce 1.25% (w/v) gels. The Ch-films in which NPs (1, 3 and 5 mg of NPs per film) had been dispersed, were neutralised with 1 w/v NaOH which removed excess acetic acid and carefully washed with ultrapure water [20] to obtain highly uniform and optically transparent films with no physical defects.

Swelling capacity

Swelling-time profiles for the Blank Ch-films, Ch-films-NP-1, Ch-films-NP-3 and Ch-films-NPs-5 are

Conclusion

Optimised Ch-films-NPs-3 demonstrated excellent swelling and mucoadhesion properties. The rate of NPs release from the Ch-films was controlled by erosion of the chitosan backbone as determined by DLS measurements after 6 h of incubation. A controlled release of insulin (70%) was observed after incubation (15 days) of Ch-films-NPs-3 during the in vitro study. The novel platform for the delivery of macromolecules via the buccal mucosa further showed permeation of the peptide via EpiOral™ buccal

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