Development of oral strips containing nanoencapsulated bioactive compounds

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Organic nanocomposites for the delivery of bioactive molecules

Publication . Castro, Pedro M.; Sarmento, Bruno; Madureira, Ana Raquel; Pintado, Maria Manuela

Controlling the size of organic nanoparticles has been proven to be important concerning the overall behavior when administered in living organisms. Indeed, reducing the particle size maximizes the functional properties (e.g., pharmacokinetics, biodistribution) and a superior performance is achieved when used as delivery systems. Nanoparticle systems serve a wide array of purposes in biomedical engineering, especially as drug delivery systems, in theragnostics, food functionalization, and phytopharmacy. Characteristics of nanoparticles can be tailored to different purposes by the development of functionalized composites. Nanocomposites can be developed as nanoparticles with special features such as targeted delivery of molecules, binding to site-specific targets, development of theragnostic agents for specific diseases, contamination of food and medical devices, or even for the controlled release of phytopharmaceuticals only on required events, with relevant decrease of pollutant effect. This chapter focuses on the main methods of composite nanoparticle production, prominent uses in key areas, potential toxicity, and future perspectives with special emphasis to a critical review of available information regarding their use in biomedical engineering.

2019Book part

Restricted access

Development and characterization of chitosan microparticles-in-films for buccal delivery of bioactive peptides

Publication . Batista, Patrícia; Castro, Pedro; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela

Nowadays, bioactive peptides are used for therapeutic applications and the selection of a carrier to deliver them is very important to increase the efficiency, absorption, release, bioavailability and consumer acceptance. The aim of this study was to develop and characterize chitosan-based films loaded with chitosan microparticles containing a bioactive peptide (sequence: KGYGGVSLPEW) with antihypertensive properties. Films were prepared by the solvent casting method, while the microparticles were prepared by ionic gelation. The final optimized chitosan microparticles exhibited a mean diameter of 2.5 m, a polydispersity index of 0.46, a zeta potential of +61 mV and a peptide association efficiency of 76%. Chitosan films were optimized achieving the final formulation of 0.79% (w/v) of chitosan, 6.74% (w/v) of sorbitol and 0.82% (w/v) of citric acid. These thin ( 0.100 mm) and transparent films demonstrated good performance in terms of mechanical and biological properties. The oral films developed were flexible, elastic, easy to handle and exhibited rapid disintegration (30 s) and an erosion behavior of 20% when they came into contact with saliva solution. The cell viability (75–99%) was proved by methylthiazolydiphenyl-tetrazolium bromide (MTT) assay with TR146 cells. The chitosan mucoadhesive films loaded with peptide–chitosan microparticles resulted in an innovative approach to perform administration across the buccal mucosa, because these films present a larger surface area, leading to the rapid disintegration and release of the antihypertensive peptide under controlled conditions in the buccal cavity, thus promoting bioavailability.

2019Journal article

Open access

Combination of PLGA nanoparticles with mucoadhesive guar-gum films for buccal delivery of antihypertensive peptide

Publication . Castro, Pedro M.; Baptista, Patrícia; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela E.

Oral administration of proteins and peptides still is a challenging task to overcome due to low permeability through absorptive epithelia, degradation and metabolism that lead to poor bioavailability. Attempting to overcome such limitations, an antihypertensive peptide derived from whey protein, with KGYGGVSLPEW sequence, was incorporated for the first time into polymeric nanoparticles. An experimental design was followed in order to optimize drug-loading, association efficiency, mean particle size, zeta-potential and polydispersity index of a formulation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles as carriers for bioactive peptides. In sequence, peptide-loaded PLGA nanoparticles were incorporated in a guar-gum film matrix, resulting in a combined delivery system aiming to promote slow release and permeation across buccal epithelium. Neither PLGA nanoparticles, guar-gum films nor the conjugation of PLGA nanoparticles and guar-gum films (GfNp) significantly compromised in vitro TR146 human buccal carcinoma cell line viability after 12 h contact, as assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide reduction assay (MTT). In vitro release assay for developed formulations allowed to conclude that the combination of orodispersible film and nanoparticles granted a slower release of AhP when compared with PLGA or guar-gum films alone or with control. GfNp offered more effective, synergistic, in vitro permeation of TR146 cell multilayer in comparison with guar-gum films or PLGA nanoparticles alone. The combination of PLGA nanoparticles with guar-gum films represent a suitable alternative to conventional per os delivery systems, leading to an increased buccal permeability of carried antihypertensive peptide.

2018Journal article

Restricted access

Optimization of two biopolymer-based oral films for the delivery of bioactive molecules

Publication . Castro, Pedro M.; Fonte, Pedro; Oliveira, Ana; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela E.

An experimental design was established in order to optimize the mechanical properties of two oral film formulations intended for oral delivery of bioactive compounds. Carboxymethylcellulose (CMC) and gelatin type A (GelTA) were selected as polymeric matrix. Scanning electron microscopy revealed that caffeine crystals were homogeneously dispersed onto oral film matrix. Fourier-transform infrared analysis did not indicate formation of new chemical entities. USP modified dissolution assay revealed that GelTA was more effective in controlling caffeine release since maximum caffeine release (97.4%±0.95) after 20min. On the other hand, CMC is better indicated for immediate release since maximum caffeine release (81.1%±2.14) occurred after 4min. Simulation of gastrointestinal tract with ex vivo permeability assay was in accordance with USP dissolution assay (42.0%±7.79 and 15.3%±4.0 of caffeine released from CMC and GelTA oral films (OF), respectively, permeated porcine intestinal mucosa after 120min). CMCOF and GelTAOF optimized formulations represent two suitable oral delivery systems for immediate and controlled release, respectively.

2017Journal article

Restricted access

Film-nanoparticle composite for enhanced oral delivery of alpha-casozepine

Publication . Castro, Pedro M.; Baptista, Patricia; Zuccheri, Giampaolo; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela E.

Whey-derived alpha-casozepine bioactive peptide (YLGYLEQLLR) was associated with previously optimized guar-gum film-PLGA nanoparticles, aiming to increase both stability across gastrointestinal tract and permeability across absorptive epithelia. Oral films associated with nanoparticles (FNp) enhance buccal absorption along with protection of carried bioactive molecules that are swallowed, with inherent increase of bioavailability. None of developed formulations induced significant loss of cell viability. Permeability across both buccal and intestinal cell barriers was enhanced when alpha-casozepine was carried by FNp system, when compared with film and nanoparticles alone, in a simulated gastrointestinal tract environment. Moreover, differences in permeability profile across buccal and intestinal epithelia were in accordance with the slower erosion of PLGA nanoparticles in a media of neutral pH, resembling oral cavity conditions, and a faster erosion in acidic conditions, as occurs in stomach, as observed by a continuous analysis of nanoparticle morphology over 980 min by atomic force microscopy. Additionally, apparent permeability of alpha-casozepine across TR146 human buccal carcinoma cells and Caco-2/HT29-MTX co-culture, carried by FNp was indeed superior when compared with peptide loaded in PLGA nanoparticles and in films alone or with free peptide control solution. Both FNp and PLGA nanoparticles alone enhanced the permeability of relaxing peptide compared with guar-gum films alone. An increased tongue adhesion when PLGA nanoparticles were added to the guar-gum films was also observed. Developed formulations improved both buccal an intestinal absorption of carried bioactive molecules without compromising cell viability.

2019Journal article

Open access