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- In vivo, ex vivo and in vitro assessment of buccal permeation of drugs from delivery systemsPublication . Pinto, Soraia; Pintado, Manuela E.; Sarmento, BrunoIntroduction: Buccal mucosa has been described as an attractive site for local and systemic drug delivery, owing its accessibility, safety, and excellent blood supply. The absorption of drugs through buccal mucosa has been assessed by in vivo, ex vivo and in vitro permeability studies, using animal and cell-based models with close resemblance to the human buccal mucosa. Areas covered: This paper focuses on the current in vivo, ex vivo and in vitro permeability studies to analyze the absorption of compounds of interest through buccal mucosa, as well as their advantages and limitations in the preclinical studies of the drugs absorption profiles. The techniques for preparation and preservation of the animal buccal tissue are also discussed to evaluate their interference in the integrity and permeability of the tissues. Expert opinion: Overall, the permeability studies have been useful to evaluate the drugs absorption and to clarify the mechanism of transport of drugs across human buccal mucosa, as well as to explain the enhancement of permeability provided by certain dosage forms. Currently, several researchers have demonstrated particular interest in ex vivo permeability studies, due to their effectiveness in the evaluation of drug absorption and low costs in the acquisition of buccal mucosa samples.
- Development and validation method for simultaneous quantification of phenolic compounds in natural extracts and nanosystemsPublication . Silva, Sara Baptista da; Oliveira, Ana; Ferreira, Domingos; Sarmento, Bruno; Pintado, ManuelaIntroductionSage and savoury (Salvia sp. and Satureja montana, respectively) are plants used in traditional medicine. The quality control of their herbal formulations is of paramount concern to guarantee the expected biological activity of their anti-oxidant compounds. Objective To establish a simple and effective high-performance liquid chromatographic (HPLC) method to evaluate simultaneously quercetin and rosmarinic acid, in a pure form, in natural extracts (sage and savoury), and encapsulated into chitosan nanoparticles. Methods Chromatography was performed on an RP C-18-column, in a gradient mode with a mobile phase comprising methanol:formic acid:water 92.5:2.5:5 (v/v) at a flow rate of 0.75mL/min and at wavelength of 280nm. Results The method was specific, linear in the range of 0.05-1mg/mL (R-2=1.00), precise at the intraday and interday levels, accurate (recovery rate 90.50.6%), and robust to changes in equipment conditions. Conclusion The method established was effective for quercetin and rosmarinic acid characterisation in natural extracts and in chitosan nanoparticles, allowing the loading capacity determination, the association efficiency as well as the in vitro release. This study shows a new HPLC method validated to simultaneous quantification of rosmarinic acid and quercetin in natural extracts and chitosan nanoparticles. This method is also able for detection and quantification of other phenolic and flavanoid compounds in natural matrix.
- The progress of essential oils as potential therapeutic agents: a reviewPublication . Baptista-Silva, Sara; Borges, Sandra; Ramos, Oscar. L.; Pintado, Manuela; Sarmento, BrunoEssential oils are products obtained from plants, by steam distillation, mechanical processes of citrus fruit epicarp, or dry distillation after separation of the aqueous phase by physical processes. They are usually composed of secondary metabolites of aromatic plants with oxygenated structures such as alcohols, ketones, aldehydes, and esters, presenting therapeutic properties such as antibacterial, antifungal and antioxidant activities. Essential oils are used in the pharmaceutical, food, and fragrance industries. The increasing use of plants by the pharmaceutical industry makes the study of essential oils crucial to design new bioactive delivery systems. This paper presents aliterature review that summarizes the best advanced data regarding the use of essential oils and their volatile constituents for biomedical applications with focuses on innovative pharmaceutical formulations. Nonetheless, it seems clear that more clinical evaluations are required until essential oils can be considered as possible applications in pharmacy or as adjuvants to current medications.
- 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.
- Technological stability of solid lipid nanoparticles loaded with phenolic compounds: drying process and stability along storagePublication . Campos, Débora A.; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Maria Manuela; Gomes, Ana MariaSolid lipid nanoparticles (SLNs) have been widely studied and tested as vehicles for natural compounds. Recently, Witepsol and Carnauba SLNs were shown to be effective systems for the entrapment of rosmarinic acid (RA) and herbal extracts. In the present work, the improvement of stability and bioactivity of these systems was studied. Thus, the freeze-drying of SLNs produced with Witepsol and Carnauba waxes loaded with RA and herbal extracts (sage and savory) were tested. The use of three different cryoprotectants (glucose, mannitol and trehalose) at two different concentrations (5 and 10%, w/v) were evaluated. Furthermore, the prepared SLNs were stored under different conditions (atmosphere, temperature, absence or presence of light) and in different packaging materials, over 365 days. The effect on the SLNs physical stability and bioactivity was assessed. The most suitable cryoprotectant was mannitol at 10% (w/v) for all formulations tested. The solid state of SLNs, with storage at room temperature, in glass flasks, protected from light and under N2 controlled atmosphere were the best storage conditions in which the SLNs bioactivity was maintained during 365 days.
- 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.
- A biofertilizer with diazotrophic bacteria and a filamentous fungus increases Pinus pinaster tolerance to the pinewood nematode (Bursaphelenchus xylophilus)Publication . Silva, M. Nunes da; Pintado, M. E.; Sarmento, B.; Stamford, N. P.; Vasconcelos, M. W.The pine wilt disease (PWD), caused by the pine wood nematode (PWN) Bursaphelenchus xylophilus, is a devastating illness that mainly affects P. pinaster trees, and that poses great environmental and economic challenges. Current disease management involves the cut down of infected trees, tree fumigation, use of nematicides, or the control of the insect vector; however, these methodologies are expensive, labour-intensive and have limited success. The aim of this work was to evaluate the effect of a biofertilizer enriched with diazotrophic bacteria and a chitosan-producing fungus, Cunninghamella elegans, in inducing P. pinaster and P. pinea resistance against the PWN. In non-inoculated (control) P. pinaster plants, PWN population significantly increased (ca. 2.3-fold) throughout the experimental period, whereas in plants treated with 7.5 and 15% of biofertilizer nematode numbers were up to 36.3-fold lower than in control plants. In P. pinea, nematode numbers decreased with time for all biofertilizer concentrations tested, and P. pinea had up to 27.3-fold lower nematode counts than P. pinaster. In addition, the biofertilizer prevented the decrease of photosynthetic pigments and the reduction of water content in infected P. pinaster plants. In P. pinea the biosynthesis of phenolics increased in PWN-inoculated plants, especially in the presence of the biofertilizer. The addition of this biofertilizer to soils forested by P. pinaster may improve plant defence and could be a potentially simple and inexpensive strategy for the control of the PWD.
- Therapeutic and nutraceutical potential of rosmarinic acid-Cytoprotective properties and pharmacokinetic profilePublication . Nunes, Sara; Madureira, Ana Raquel; Campos, Débora; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Manuela; Reis, FlávioRosmarinic acid (RA) is a natural polyphenolic antioxidant derived from many common herbal plants. This compound displays several important biological properties, including anti-inflammatory, antiviral, antibacterial, antidepressant, anticarcionogenic, and chemopreventive properties. The importance of its activities and its possible application in processed foods as a natural antioxidant has reached a new interest levels in recent years. The health effects of this polyphenol depend greatly on both its intakes and bioavailability. This review focuses on the importance of RA as a dietary supplement, and summarizes its pharmacokinetics and metabolism, including the factors that limit its oral bioavailability which leads to a lower therapeutic action. Further experimental investigations are needed to optimize and enhance the oral bioavailability of this natural compound which consequently will help increasing therapeutic efficacy of RA in vivo.
- Chitosan nanoparticles for daptomycin delivery in ocular treatment of bacterial endophthalmitisPublication . Silva, Nádia C.; Silva, Sara; Sarmento, Bruno; Pintado, ManuelaContext: Chitosan nanoparticles were prepared to encapsulate daptomycin and proposed as a delivery system of this antibiotic to the eye for the treatment of bacterial endophthalmitis. Objective: The aim of this study was to develop daptomycin-loaded nanoparticles to apply directly to the eye, as a possible non-invasive and less painful alternative for the treatment of endophthalmitis, increasing the effectiveness of treatment and reducing toxicity associated with systemic administration.Materials and methods: Nanoparticles were obtained by ionotropic gelation between chitosan and sodium tripolyphosphate (TPP). Physicochemical and morphological characteristics of nanoparticles were evaluated, as well as determination of antimicrobial efficiency of encapsulated daptomycin and stability of the nanoparticles in the presence of lysozyme and mucin.Results: Loaded nanoparticles presented mean particle sizes around 200 nm, low polydispersity index, and positive zeta potential. Morphological examination by scanning electron microscopy (SEM) confirmed their small size and round-shaped structure. Encapsulation efficiency ranged from 80 to 97%. Total in vitro release of daptomycin was obtained within 4 h. Determination of minimum inhibitory concentrations (MICs) showed that bacteria were still susceptible to daptomycin encapsulated into the nanoparticles. Incubation with lysozyme did not significantly affect the integrity of the nanoparticles, although mucin positively affected their mucoadhesive properties. Discussion and conclusion: The obtained nanoparticles have suitable characteristics for ocular applications, arising as a promising solution for the topical administration of daptomycin to the eye.