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- Optimization of two biopolymer-based oral films for the delivery of bioactive moleculesPublication . 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.
- Current state on the development of nanoparticles for use against bacterial gastrointestinal pathogens: focus on chitosan nanoparticles loaded with phenolic compoundsPublication . Madureira, Ana Raquel; Pereira, Adriana; Pintado, ManuelaGastrointestinal diseases have a huge impact especially in third world countries, making it urgent to seek new effective antimicrobial therapies. Thus, the development of nanoparticles (NPs) with bioactive compounds having antimicrobial activity has been the target of research over the past years. The development of antimicrobial drug NPs may be promising to overcome the problems associated with antibiotic resistance caused by many pathogenic bacteria. Moreover, the NPs administration of antimicrobial agents has advantages associated therewith, as use of low cost materials, contribution to the improvement of the therapeutic index and a controlled release drug by increasing the pharmacokinetics. These systems can be used to specific strains of bacteria, and to release interesting antimicrobial compounds. The phenolic compounds (PC) are a class of such bioactive compounds for which their antimicrobial activity was already tested on the production of NPs. Polymeric or lipidic NPs systems have been investigated to deliver these compounds. Chitosan is a polymer widely known for their properties, especially the antimicrobial activity and its ability to adhere to intestinal epithelium. This review article aims to evaluate and discuss recent developments in PC new delivery systems with antimicrobial activity against gastrointestinal pathogens, their production processes, activities, focusing on NPs produced using chitosan as the main structural and functional material.
- Recent insights in the use of nanocarriers for the oral delivery of bioactive proteins and peptidesPublication . Batista, Patrícia; Castro, Pedro M.; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, ManuelaBioactive proteins and peptides have been used with either prophylactic or therapeutic purposes, presenting inherent advantages as high specificity and biocompatibility. Nanocarriers play an important role in the stabilization of proteins and peptides, offering enhanced buccal permeation and protection while crossing the gastrointestinal tract. Moreover, preparation of nanoparticles as oral delivery systems for proteins/peptides may include tailored formulation along with functionalization aiming bioavailability enhancement of carried proteins or peptides. Oral delivery systems, namely buccal delivery systems, represent an interesting alternative route to parenteric delivery systems to carry proteins and peptides, resulting in higher comfort of administration and, therefore, compliance to treatment. This paper outlines an extensive overview of the existing publications on proteins/peptides oral nanocarriers delivery systems, with special focus on buccal route. Manufacturing aspects of most commonly used nanoparticles for oral delivery (e.g. polymeric nanoparticles using synthetic or natural polymers and lipid nanoparticles) advantages and limitations and potential applications of nanoparticles as proteins/peptides delivery systems will also be thoroughly addressed.
- Oral films as breakthrough tools for oral delivery of proteins/peptidesPublication . Castro, Pedro M.; Fonte, Pedro; Sousa, Flávia; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela E.Therapeutic proteins and peptides demonstrate unique, peerless, pharmacological characteristics such as high specificity to receptors and superior biological mimicking of physiological mechanisms, resulting in a better therapeutic index compared to conventional chemical-derived drugs. However, proteins also present inherent bioavailability limitations. Thus, this paper proposes several effective tools to improve protein/peptide drugs stability, permeability and pharmacokinetics with special emphasis on oral polymeric films as oral delivery platforms. Indeed, oral films present inherent characteristics that can greatly enhance biological performance of proteins and peptides and patient compliance along with other advantages that are critically discussed in this review. A rational choice of excipients addressed in and manufacture processes are also focused. In addition, possible toxicity issues to be overtaken and critical analysis regarding current market tendencies respecting oral films and protein/peptides along with future prospects are disclosed.
- Polymeric nanoparticles as oral delivery systems for a grape pomace extract towards the improvement of biological activitiesPublication . Costa, Joana R.; Xavier, Miguel; Amado, Isabel R.; Gonçalves, Catarina; Castro, Pedro M.; Tonon, Renata V.; Cabral, Lourdes M.C.; Pastrana, Lorenzo; Pintado, Manuela E.Grape pomace (GP) is a major by-product from the wine industry, known for its bioactive compounds and their impact upon gastrointestinal (GI) health. However, bioaccessibility is often poor due to their degradation during digestion. This work aimed to encapsulate bioactive GP extract (GPE) into chitosan (CS) and alginate (Alg) nanoparticles (NPs) to mitigate degradation in the GI tract. Alg and CS NPs were optimized using a rotatable central composite design and NPs were characterized for their size, polydispersity, zeta potential and total phenolics (TP) association efficiency. The best formulations showed sizes ranging 523–853 nm, polydispersity indexes of 0.11–0.36, zeta potential of −15.0–14.9 mV and TP association efficiencies of 68 and 65%. FTIR confirmed that there was no formation of new chemical groups after association of the polymers with GPE. Both formulations improved the bioaccessibility of different phenolics following in vitro GI digestion, leading to in-creased antioxidant and antimicrobial activities. Moreover, the permeability of bioactive compounds through a Caco-2/HT29-MTX co-culture was reduced, suggesting a higher residence time in the intestine. Cy5.5 was used for tracking the CS NPs, which did not affect the metabolic activity of Caco-2 and HT29-MTX cells. Confocal microscopy images confirmed the adsorption of NPs to the cellular layer and suggested a reduction of the tight junction protein occludin when cells were incubated with Cy5.5-CS in solution. This study suggests that encapsulation of GPE can offer protection against along the GI tract and improve its biological activity with significant impact for oral delivery applications, including functional foods.
- Novel and revisited approaches in nanoparticle systems for buccal drug deliveryPublication . Macedo, Ana S.; Castro, Pedro M.; Roque, Luís; Thomé, Natália G.; Reis, Catarina P.; Pintado, Maria Manuela; Fonte, PedroThe buccal route is considered patient friendly due to its non-invasive nature and ease of administration. Such delivery route has been used as an alternative for the delivery of drugs that undergo first-pass metabolism or are susceptible to pH and enzymatic degradation, such as occurs in the gastrointestinal tract. However, the drug concentration absorbed in the buccal mucosa is often low to obtain an acceptable therapeutic effect, mainly due to the saliva turnover, tongue and masticatory movements, phonation, enzymatic degradation and lack of epithelium permeation. Therefore, the encapsulation of drugs into nanoparticles is an important strategy to avoid such problems and improve their buccal delivery. Different materials from lipids to natural or synthetic polymers and others have been used to protect and deliver drugs in a sustained, controlled or targeted manner, and enhance their uptake through the buccal mucosa improving their bioavailability and therapeutic outcome. Overall, the main aim of this review is to perform an overview about the nanotechnological approaches developed so far to improve the buccal delivery of drugs. Herein, several types of nanoparticles and delivery strategies are addressed, and a special focus on pipeline products is also given.
- Production of antimicrobial chitosan nanoparticles against food pathogensPublication . Madureira, Ana Raquel; Pereira, Adriana; Castro, Pedro M.; Pintado, ManuelaChitosan nanoparticles (NPs) may be a promissory delivery system of polyphenols. The main objective of this study was to produce chitosan NPs encapsulated with polyphenols with antimicrobial and antioxidant activity against food pathogens. The NPs produced with low and high molecular weight chitosan (LMWC and HMWC) were successfully obtained showing slight variations in the particle size, in the range 300-600 nm, and zeta potential values in the range 20-30 mV, exhibiting a moderate stability. The best encapsulation performance was obtained for NPs produced with LMWC and the polyphenol rosmarinic acid. The antimicrobial studies proved that all free and encapsulated compounds have inhibitory activity upon the tested bacteria (Bacillus cereus, Escherichia coli O157, Listeria innocua, Staphylococcus aureus, Salmonella typhimurium and Yersinia enterocolitica). The images obtained by electronic microscopy showed that it was possible to obtain NPs capable of affecting the cellular structure of bacteria reinforcing their antimicrobial activity.
- Bioadhesive polymeric nanoparticles as strategy to improve the treatment of yeast infections in oral cavity: in-vitro and ex-vivo studiesPublication . Roque, Luís; Castro, Pedro; Molpeceres, Jesus; Viana, Ana S.; Roberto, Amilcar; Reis, Claúdia; Rijo, Patrícia; Tho, Ingunn; Sarmento, Bruno; Reis, CatarinaCandidiasis is by far the most common fungal infection in the oral cavity and locally antifungal drugs are generally considered the first line therapy. However, some antifungal drugs like Nystatin (Nys) have very short time in the target tissue, which generally it requires several daily applications. One of the solutions to overcome those issues could be the incorporation of Nys into small, protective and polymeric nanoparticles (NPs). In this work, unloaded NPs were prepared and fully characterized and implemented in toothpaste and an oral gel. The three-best unloaded system (smallest, stable, safe and bioadhesive) was selected for further studies. After loading, NPs presented a size range from 300 to 800 nm, high encapsulation efficiency (above 70%), prolonged release and high adhesion capacity to oral mucosa when compared with free Nys. Free Nys lost its activity when it was not encapsulated. The presented results suggested that these new bioadhesive systems could be considered as good candidates to improve the time residence of Nys in buccal mucosa, reducing the number of applications during the day, using alcohol free-formulations and easily included in the daily lives of the patients.
- Film-nanoparticle composite for enhanced oral delivery of alpha-casozepinePublication . 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.
- Hydrogels containing porphyrin-loaded nanoparticles for topical photodynamic applicationsPublication . González-Delgado, José A.; Castro, Pedro M.; Machado, Alexandra; Araújo, Francisca; Rodrigues, Francisca; Korsak, Bárbara; Ferreira, Marta; Tomé, João P.C.; Sarmento, Bruno5,10,15,20-tetrakis(1-methylpyridinium-4-yl)-porphyrin tetra-iodide (TMPyP), a potent water-soluble photosensitizer (PS) used in antimicrobial applications, was encapsulated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TMPyP-PLGA) for topical delivery purposes. Nanoparticles resulted in a mean particle size around 130nm, narrow polydispersity index (PdI), spherical morphology and association efficiency up to 93%. Free TMPyP and TMPyP-PLGA nanoparticles were incorporated into Carbopol(®) hydrogels, resulting in controlled TMPyP release of about 60% and 20% after 4.5h, respectively. Critical properties such as appearance, clarity, viscosity and pH were maintained over time, as hydrogels were stable during 6 months at 4°C, 25°C/60% RH and 40°C/75% RH. For photodynamic applications, the photoproduction of singlet oxygen from these hydrogels was quite efficient being both formulations very photostable after 20min. No TMPyP permeation through pig ear skin was observed after 24h, and histological assays did not show relevant damages in surrounding tissues. All these excellent characteristics make them promising platforms for photodynamic applications through topical clinical use.