Vulvovaginal Candidiasis is the second most common infection in women of childbearing age, in about 70 to 90% of cases; the associated etiologic agent is C. albicans. The increase in the incidence of non-albicans species has led to the emergence of cases of resistance to antifungals, which is why the importance of new approaches in treatment. The objective of the present work was to develop and test in vivo a nanostructured system containing fluconazole and Green Propolis for the treatment of Vulvovaginal Candidiasis. The nanoparticles containing Fluconazole and Green Propolis were prepared following the technique of ionic gelation and presented satisfactory physical characteristics for the intended purpose. The association efficiency for the complexed compounds was performed using the technique of High Performance Liquid Chromatography (HPLC) and UV spectrophotometry. The Minimum Inhibitory Concentrations (MIC) for Fluconazole, Green Propolis and nanoparticles were determined, showing efficacy for use and fungistatic action on C. albicans ATCC 10231. Release analyzes of up to 72 hours with stabilization up to 96 hours were verified in the nanoparticles. The toxicity tests by hemolysis and Galleria mellonella, demonstrated positive results for propolis and negative for nanoparticles, suggesting safety in their use in a method with a murine model. In vivo tests were performed with an indication of efficacy for the proposed formulation.

This work focuses on the development of a computational platform able to provide a comprehensive analysis of dissolution profiles, exploring mathematical models, similarity analysis, and lag time using R programming. Also, a pharmaceutical approach conducting the study of the in vitro behavior of oral films, based on hydrogels and lipid nanoparticles co-encapsulating drugs with distinct physicochemical characteristics was performed. Subsequently, the computational approach developed was used to analyse the dissolution profiles experimentally obtained.Two general approaches for comparing dissolution profiles were examined: model independent and model dependent approaches. In the former approach, an integrated program following regulatory specifications was developed. Values of fit factors, mean dissolution times, Mahalanobis Distance and the graphical data visualization are presented, providing an easy interpretation for the user. For model dependent approaches, several tools were developed taking into account different situations. Akaike information criterion and adjusted coefficient of determination, are used to define the model that better fits the dissolution points. An approach to identify the presence and quantify the lag time was also explored.Nanotechnology was explored using loaded lipid nanoparticles (LLN) co-encapsulating drugs for the production of oral films. The drugs possess a low aqueous solubility, and the purpose is increasing the bioavailability, and overcoming other limitations associated to conventional dosage forms. Oral films promote patient compliance, and provide a very appealing system for the administration of drugs in the geriatric and paediatric populations. Specifically, LLN for co-delivery of olanzapine (OL) and simvastatin (SV) were developed and characterized, showing appropriate values of particle size, zeta potential, encapsulation efficiency and drug loading. Hydrogels containing different hydroxypropyl methylcellulose (HPMC) grades were tested after mixing with LLN, to provide a promising method to obtain a homogeneous formulation for oral films. In general, all films presented attractive adhesive properties. The addition of plasticizer, PEG 400, on the hydrogels showed an improvement on the final appearance of the oral films, such as an enhanced flexibility and an easier detachment from the support.In the in vitro tests with simulated saliva, no substantial differences were detected between the oral films, in which no more than 10% of each drug was released during the test. Conversely, the behavior of each drug in situations mimicking the human gastrointestinal tract conditions was distinct. For OL, the whole amount was released within 2 hours, thus no significant control was detected. For SV, the impact of the polymer grade on the release was apparent, with a larger amount of drug being released when the lower molecular weight HPMC was employed. Also, the inclusion of PEG 400 increased the extent of drug release.The computational approach developed demonstrates to be an important tool to characterize the dissolution profiles obtained with the oral films. It is also concluded that model independent and several model dependent approaches yielded numerical results that can serve as objective and quantitative metrics for comparing the dissolution profiles.

O principal desafio na administração transdérmica de fármacos consiste em transpor a camada córnea, a mais externa da pele. Têm sido desenvolvidas diferentes estratégias para promover a penetração de fármacos através desta barreira, as quais incluem métodos passivos, activos ou uma combinação de ambos. O presente trabalho teve como objectivo o desenvolvimento de um sistema transdérmico para a administração simultânea de olanzapina e sinvastatina. De forma a atingir este objectivo, foi abordada como estratégia passiva a combinação de nanopartículas lipídicas com promotores químicos de penetração. Por seu lado, a administração de nanopartículas recorrendo a microagulhas enquanto método activo foi avaliada como estratégia alternativa para potenciar o transporte de fármacos através da pele. As nanopartículas lipídicas, compreendendo as nanopartículas lipídicas sólidas (SLN) e os transportadores lipídicos nanoestruturados (NLC), foram preparadas pelos métodos de emulsificação-evaporação do solvente (SE/E) e homogeneização a alta pressão (HPH). Recorreu-se a planeamentos factoriais, do tipo 2k, para racionalizar e optimizar a composição das formulações, condições de produção e respectiva aplicação. O efeito combinado das nanopartículas lipídicas e promotores químicos foi investigado recorrendo a metodologias in vitro, in silico e estudos de viabilidade celular. As formulações foram adicionalmente avaliadas numa abordagem combinada in vitro/in vivo. Como resultado da reduzida solubilidade da olanzapina no lípido sólido, tripalmitina, foram utilizadas NLC para a co-encapsulação. A técnica HPH a quente foi seleccionada para a produção das NLC, uma vez que permitiu uma maior capacidade de carga de fármaco, uma libertação mais sustentada, uma melhor permeação, evitar o recurso a solventes orgânicos e tempos de produção mais curtos, apresentando também a possibilidade de transposição de escala. Os ensaios in vitro demonstraram que o meio externo da dispersão NLC influenciou marcadamente a permeação. Verificou-se também um efeito sinérgico entre as NLC e os promotores químicos seleccionados, etanol e limoneno, evidenciado pelas acentuadas razões xii de permeação, em comparação com soluções de referência. A olanzapina apresentou uma permeação superior à sinvastatina, resultados que foram confirmados nos ensaios in vivo referidos mais adiante. A posterior gelificação do sistema levou a uma redução para cerca de metade nos fluxos de permeação. As simulações de dinâmica molecular e os resultados experimentais permitiram estabelecer uma correlação entre o posicionamento dos promotores químicos (terpenos) numa bicamada lipídica e o seu efeito de intensificação na permeação. O estudo da interacção entre o limoneno, o etanol e o Carbopol Ultrez ® 10NF, como gelificante, com a dispersão de NLC, abrangendo as propriedades reológicas, mecânicas e físico-químicas, sugeriu que a formulação desenvolvida era adequada para administração transdérmica. Verificou-se, também, não ser irritante. Para a avaliação da eficácia do conceito acima desenvolvido, foram conduzidos ensaios in vivo em ratos, cuja administração transdérmica permitiu atingir o estado estacionário após 10 horas, mantendo-o durante 48 h. As dispersões de NLC caracterizaram-se por um melhor desempenho, in vivo, comparativamente aos hidrogéis, em concordância com os resultados in vitro. Estas diferenças foram, no entanto, mitigadas nos valores de fluxo, justificando a utilização de hidrogel como formulação final. A perfuração da pele promovida pelo dispositivo de microagulhas apenas aumentou ligeiramente a velocidade de permeação. Estes resultados corroboraram que a formulação, por si só, constitui a principal força motriz para a permeação de fármacos através da pele. Em geral, estes resultados indicam as formulações baseadas em NLC como promissoras para o desenvolvimento de um sistema transdérmico clínico, abrangendo uma abordagem terapêutica inovadora.

Nisin, a bacteriocin widely used in the food industry, and curcumin, the yellow pigment extracted from turmeric (Curcuma longa L.) stand out among the numerous natural preservatives that have antimicrobial activity. The conversion of these compounds into nanoparticles could be interesting as an alternative to improve technological aspects (such as the low water solubility of curcumin) and to evaluate how synergism could take place in the case of co-encapsulation. The main objective of the present work was to evaluate the combination of nisin (Nis) with nanoencapsulated curcumin (NCur, nanoencapsulated to promote water solubility), as well as the co-encapsulated curcumin and nisin (NCurNis), against the foodborne bacteria Staphylococcus aureus, Escherichia coli and Salmonella Typhimurium. Minimum inhibitory concentration and the minimum bactericidal concentration were evaluated for NCur and Nis, as well as their combination with the fractional inhibitory concentration assay. High effectiveness was found against S. aureus and the combination of both compounds resulted in Nis- nisin; synergism against the same microorganism. The co-encapsulation of curcumin and nisin was carried out based on the synergism tests and the characterization analyses demonstrated that a solid dispersion of the components in the PVP matrix was formed. The inhibitory effect of the curcumin and nisin co-encapsulate was improved when compared to the curcumin nanoparticles or nisin alone.

Chronic wounds represent a significant and growing public health problem, being characterized by delayed healing and exacerbated and prolonged inflammation, with a profound impact on patients’ quality of life and healthcare systems. Thymol and berberine are two natural compounds known for their antioxidant, antimicrobial, and anti-inflammatory properties, which make them promising phytochemicals for promoting chronic wound healing. However, the potential cytotoxicity and differences in water solubility of both compounds (which result in distinct skin permeation profiles) limit their effective topical administration. In this context, the encapsulation of these compounds in liposomes, nanosystems widely studied for topical delivery, emerges as an advanced and promising technological strategy to overcome these limitations. Furthermore, liposomes differ from most other available nanosystems due to their ability to simultaneously encapsulate hydrophobic (such as thymol) and hydrophilic (such as berberine) compounds. The main objective of this dissertation was to develop and optimize a novel topical liposomal formulation co-encapsulating thymol and berberine to enhance chronic wound healing. The developed liposomes, containing either thymol alone or both phytochemicals simultaneously, were characterized regarding particle size, polydispersity index, zeta potential, encapsulation efficiency, and storage stability at 4 ˚C and room temperature (25 ˚C). Moreover, the in vitro release profile and antioxidant activity were evaluated, as well as their biocompatibility with a human immortalized keratinocyte cell line (HaCaT).For this purpose, liposomes composed of phosphatidylcholine and cholesterol were prepared using the thin-film hydration method. The small particle size (below 200 nm) and high homogeneity (polydispersity index below 0.2) exhibited by optimized liposomes demonstrated their suitability for skin administration. Both phytochemicals were successfully encapsulated, with encapsulation efficiency values of 91.43 ± 1.50% for thymol and 44.56 ± 6.18% for berberine. The dual-loaded liposomes remained stable for at least 6 weeks when stored at 4 ˚C and showed a controlled release profile, as well as significant antioxidant activity. The berberine-loaded liposomes stimulated keratinocyte proliferation at a concentration of 4.96 µg/mL, which is an essential process in the context of wound healing, while dual-loaded liposomes showed biocompatibility up to 73.63 µg/mL (thymol) and 7.69 µg/mL (berberine). The findings obtained suggest that the developed liposomes constitute promising nanosystems for the co-encapsulation of thymol and berberine, with strong potential to improve chronic wound healing through topical administration.

Abstract This study evaluated the effect of microencapsulation and addition of mango peel powder on the survival of Lactobacillus acidophilus and Bifidobacterium lactis, overrun, apparent viscosity, and overall acceptability of symbiotic ice cream during storage at -20 °C for 180 days. Six formulations of vanilla-flavored ice cream were prepared: three with addition of probiotic cultures at a concentration of 108 CFU/g and 0, 2%, and 3% mango peel powder microencapsulated in a sodium alginate matrix, and three with free addition. Analytical evaluations were performed after 1, 30, 60, 90, 120 and 180 days of storage. The results showed that microencapsulation of probiotics and prebiotics statistically influenced (p < 0.05) the characteristics evaluated. The formulation with microencapsulated probiotics and 2% mango peel powder was considered as the best product. This formulation is promising for future commercial application as a functional food because, at the end 180 days of storage, it showed probiotics population >106 CFU/g, 72.97% overrun, 292 mPA apparent viscosity, and good overall acceptance (7.6 points) equivalent to “I like it very much”.

Nanostructured polymeric and lipid systems are capable of improving therapeutic index of encapsulated drugs, especially when it comes to antitumor drugs. In this work, co-encapsulation of paclitaxel (PTX) and genistein (GEN) was obtained by developing a multilayered nanocarrier for controlled release of drugs. Nanocapsules (NC) encapsulating PTX were obtained by interfacial deposition of preformed polymer method. They were further coated with a phospholipid bilayer entrapping GEN and their physical-chemical properties were characterized. Coated nanoparticles presented an entrapment efficiency of about 98% for both drugs. Particles were in the range of 150 nm and showed a monomodal distribution. Multiple light scattering analyses presented an increase of only 2% of the backscattering profile both in the top and in the bottom of the sample, indicating a slight sedimentation and creaming behaviors, both reversible phenomena. In vitro drug release showed that GEN was completely released within 48 hours, whereas in that same period, less than 10% of PTX was released and reached almost 70% after 60 days of analysis. The results suggest that we have developed a biodegradable device for a sustained release of GEN and PTX in different stages. In vivo antitumor activity assays with Ehrlich ascites tumor (EAT) bearing mice evaluated intra-tumoral administration of the developed formulation in three different concentrations of PTX in the presence or absence of GEN. Results presented more than 90% tumor inhibition in EAT-bearing mice compared to the control group when a dose of nanostructured PTX about 5 times lower than the equivalent dose used in conventional chemotherapy was used. When a low dose of PTX (0.2 mg/kg/day) was used in the treatment, 11% tumor inhibition was achieved, but when associated with a dose of 12 mg/kg/day of GEN, there was 44% tumor inhibition and a decrease of about 58% in VEGF levels compared to animals treated with blank nanoparticles. The antiangiogenic effect of GEN was evident when associated with PTX, inhibiting formation of new vascular network formed by tortuous and congested vessels in peritoneal region of mice when compared with groups treated only with PTX. Co-encapsulation of GEN and PTX in a controlled-release multicompartimental nanosystem promoted additive effect of antiangiogenic activity associated with antitumor effect, intending to be a formulation with high potential for anticancer treatment.

The co-delivery of bioactive compounds with contrasting polarities remains a major challenge in the design of lipid-based systems for functional foods. Here, we report a cold homogenization strategy enabling the simultaneous encapsulation of hydrophilic caffeine and lipophilic curcumin within solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) formulated with food-grade excipients. The developed systems exhibited mean particle sizes in the range of 650–800 nm with narrow size distributions (PDI ≤ 0.3), indicating good colloidal uniformity. Notably, encapsulation efficiencies exceeded 90% for both compounds, demonstrating the effectiveness of this approach in overcoming thermodynamic partitioning limitations typically associated with hydrophilic molecules in lipid matrices. Fourier-transform infrared spectroscopy confirmed the molecular incorporation of both bioactives, suggesting intermolecular interactions within the lipid structure. The nanoparticles showed high retention (>98% over 72 h) and sustained co-release profiles without burst effects, with distinct release behaviors depending on carrier structure (e.g., curcumin release of 43.6% from SLN vs. 17.7% from NLC). These results highlight the role of matrix architecture in modulating the release of dual-polarity compounds. Overall, this work demonstrates, for the first time to the best of our knowledge, that cold homogenization enables efficient and stable co-encapsulation of hydrophilic and lipophilic nutraceuticals in a single lipid system using GRAS-compliant materials. This approach provides a scalable and versatile platform for the development of multifunctional delivery systems, with direct relevance for the formulation of next-generation functional foods and beverages.

The co-delivery of bioactive compounds with contrasting polarities remains a major challenge in the design of lipid-based systems for functional foods. Here, we report a cold homogenization strategy enabling the simultaneous encapsulation of hydrophilic caffeine and lipophilic curcumin within solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) formulated with food-grade excipients. The developed systems exhibited mean particle sizes in the range of 650–800 nm with narrow size distributions (PDI ≤ 0.3), indicating good colloidal uniformity. Notably, encapsulation efficiencies exceeded 90% for both compounds, demonstrating the effectiveness of this approach in overcoming thermodynamic partitioning limitations typically associated with hydrophilic molecules in lipid matrices. Fourier-transform infrared spectroscopy confirmed the molecular incorporation of both bioactives, suggesting intermolecular interactions within the lipid structure. The nanoparticles showed high retention (>98% over 72 h) and sustained co-release profiles without burst effects, with distinct release behaviors depending on carrier structure (e.g., curcumin release of 43.6% from SLN vs. 17.7% from NLC). These results highlight the role of matrix architecture in modulating the release of dual-polarity compounds. Overall, this work demonstrates, for the first time to the best of our knowledge, that cold homogenization enables efficient and stable co-encapsulation of hydrophilic and lipophilic nutraceuticals in a single lipid system using GRAS-compliant materials. This approach provides a scalable and versatile platform for the development of multifunctional delivery systems, with direct relevance for the formulation of next-generation functional foods and beverages.