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Alginate is a biopolymer widely used on delivery systems when bioactive protection at acidic pH is required, while chitosan can enhance mucoadhesion and controlled release at alkaline pHs. In this work, alginate ionotropic gelation and electrostatic complexation to chitosan were evaluated concomitantly or in a two-step approach to improve the delivery properties of systems in different pHs. The effect of pH on alginate gelation and chitosan interactions were also evaluated. Alginate microspheres were prepared by ionotropic gelation in CaCl2 at different pH values (2.5 and 6.0) by extrusion. Complexation with chitosan was carried out during alginate ionotropic gelation (one-step approach) or after alginate gel formation (two-step approach). Alginate microparticles without chitosan showed larger pores and lower mechanical strength. Extruded microspheres at pH 6.0 were more stable to pH and showed smaller pores than the formed at pH 2.5. One-step production retained a large amount of bioactive at pH 7.0 and resulted in lower release at the pH of intestinal digestion. The two-step approach retained less amount of bioactive but confer more protection to the pH of the stomach phase and higher release in pH of the intestinal phase than one-step samples. These results indicate that the formation of alginate gels by ionotropic gelation followed by the complexation with chitosan (in two-step) is promising for the transport and delivery of bioactives into intestinal conditions, whereas the ionotropic gelation concomitantly to electrostatic complexation (one-step approach) is indicated to the delivery of bioactives into lower pH environments.

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The stability and release properties of all bioactive capsules are strongly related to the composition of the wall material. This study aimed to evaluate the effect of the wall materials during the encapsulation process by ionotropic gelation on the viability of Lactobacillus fermentum K73, a lactic acid bacterium that has hypocholesterolemia probiotic potential. A response surface methodology experimental design was performed to improve bacterial survival during the synthesis process and under simulated gastrointestinal conditions by tuning the wall material composition (gelatin 25% w/v, sweet whey 8% v/v, and sodium alginate 1.5% w/v). An optimal mixture formulation determined that the optimal mixture must contain a volume ratio of 0.39/0.61 v/v sweet whey and sodium alginate, respectively, without gelatin, with a final bacterial concentration of 9.20 log10 CFU/mL. The mean particle diameter was 1.6 ± 0.2 mm, and the experimental encapsulation yield was 95 ± 3%. The INFOGEST model was used to evaluate the survival of probiotic beads in gastrointestinal tract conditions. Upon exposure to in the vitro conditions of oral, gastric, and intestinal phases, the encapsulated cells of L. fermentum decreased only by 0.32, 0.48, and 1.53 log10 CFU/mL, respectively, by employing the optimized formulation, thereby improving the survival of probiotic bacteria during both the encapsulation process and under gastrointestinal conditions compared to free cells. Beads were characterized using SEM and ATR-FTIR techniques.

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Phenolic compounds that are present in pineapple by-products offer many health benefits to the consumer; however, they are unstable to many environmental factors. For this reason, encapsulation is ideal for preserving their beneficial effects. In this work, extracts were obtained by the combined method of solid-state fermentation with Rhizopus oryzae and ultrasound. After this process, the encapsulation process was performed by ionotropic gelation using corn starch, sodium alginate, and Weissella confusa exopolysaccharide as wall material. The encapsulates produced presented a moisture content between 7.10 and 10.45% (w.b), a solubility of 53.06 ± 0.54%, and a wettability of 31.46 ± 2.02 s. The total phenolic content (TPC), antioxidant capacity of DPPH, and ABTS of the encapsulates were also determined, finding 232.55 ± 2.07 mg GAE/g d.m for TPC, 45.64 ± 0.9 µm Trolox/mg GAE for DPPH, and 51.69 ± 1.08 µm Trolox/mg GAE for ABTS. Additionally, ultrahigh performance liquid chromatography (UHPLC) analysis allowed us to identify and quantify six bioactive compounds: rosmarinic acid, caffeic acid, p-coumaric acid, ferulic acid, gallic acid, and quercetin. According to the above, using ionotropic gelation, it was possible to obtain microencapsulates containing bioactive compounds from pineapple peel extracts, which may have applications in the development of functional foods.

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The accumulation of chitin waste from the seafood industry is a serious environmental problem. However, this residue can be degraded by chitinases and its subproducts, such as chitosan, economically exploited. In this study, a chitinase producer bacteria, identified as Paenibacillus illinoisensis, was isolated from the Brazilian coastal city of Terra de Areia - Rio Grande Do Sul (RS) and was immobilized within alginate beads to evaluate its chitinase production. The alginate beads containing cells presented an average size of 4 mm, 99% of immobilization efficiency and increased the enzymatic activity in 40.71% compared to the free cells. The biomass during enzymatic production increased 62.01% and the total cells leaked from the alginate beads corresponded to 6.46% after 96 h. Immobilized cells were reused in a sequential batch system and remained stable for production for up to four 96-h cycles, decreasing only 21.04% of the initial activity at the end of the fourth cycle. Therefore, the methodology used for cell immobilization resulted in adequate beads to maintain cell viability during the enzymatic production, increasing enzymatic activity, showing low cell leakage from the support and appropriate recyclable capacity.

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Biopolymer beads can be used as carrier and encapsulation system for a wide variety of materials in food, medical, pharmaceutical, cosmetics, agricultural, and environmental applications. Beads of low acyl gellan gum (0.4-1.2% w/w) were produced using extrusion technique (dripping) followed by an ionotropic gelation step with calcium or potassium chloride. In this methodology, gel formation is accomplished by cations diffusion at room temperature and, as a consequence, different structure and gel properties could be obtained. Gellan beads were subjected to uniaxial compression measurements. The force-displacement curves showed that the occurrence of structural failure under tested conditions depended on beads formulation and was only observed at polysaccharide concentration above 0.8% (w/w). Maximum force or force at failure was mainly dependent on the type (monovalent or divalent cation) and salt concentration. Moreover, at fixed salt amounts, higher values of maximum force were reached using a concentration of 1% (w/w) gellan. Young modulus, determined using Hertz approach, showed values between 445 and 840 kPa depending on polysaccharide concentration and salt type added. Mechanical properties are critical features of gel beads and can define their suitability for a specific application. Therefore, the results obtained, mainly intrinsic properties such as Young modulus, could be a tool for comparing and choosing polysaccharides for specific uses.

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Polymeric nanoparticulate systems allow the encapsulation of bio-active substances, giving them protection against external agents and increasing the drug's bioavailability. The use of biocompatible and biodegradable polymers usually guarantees the harmless character of the formulation, and a controlled drug release is also assured. A relatively easy procedure to obtain polymeric formulations of bioactive agents is ionotropic gelation, which allows the synthesis of chitosan (CS) - sodium tri-polyphosphate nanoparticles (NPs) loading encapsulated proteins. In this work, Bovine serum albumin (BSA) model protein and a recombinant porcine alpha interferon variant were used to obtain nanoparticulate formulations. The internalization of the encapsulated material by cells was studied using a BSA-fluorescein system; the fluorescent conjugate was observable inside the cells after 20 h of incubation. The therapeutic CS-alpha interferon formulation showed a maximum of protein released in vitro at around 90 h. This system was found to be safe in a cytotoxicity assay, while biological activity experiments in vitro showed antiviral protection of cells in the presence of encapsulated porcine alpha interferon. In vivo experiments in pigs revealed a significant and sustained antiviral response through overexpression of the antiviral markers OAS2 and PKR. This proves the preservation of porcine alpha interferon biological activity, and also that a lasting response was obtained. This procedure is an effective and safe method to formulate drugs in nanoparticulate systems, representing a significant contribution to the search for more effective drug delivery strategies.

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Natural polysaccharides have been investigated as vehicles for oral insulin administration. Because of their non-toxic, renewable, low cost and readily available properties, gums find multiple applications in the pharmaceutical industry. This work aimed to develop a Sterculia striata gum-based formulation associated with additional biopolymers (dextran sulfate, chitosan, and albumin), a crosslinking agent (calcium chloride) and stabilizing agents (polyethylene glycol and poloxamer 188), to increase the oral bioavailability of proteins. Insulin was used as a model drug and the methods used to prepare the formulation were based on ionotropic pregelation followed by electrolytic complexation of oppositely charged biopolymers under controlled pH conditions. The developed formulation was characterized to validate its efficacy, by the determination of its average particle size (622 nm), the insulin encapsulation efficiency (70%), stability in storage for 30 days, and the in vitro mucoadhesion strength (92.46 mN). Additionally, the developed formulation preserved about 64% of initial insulin dose in a simulated gastric medium. This study proposed, for the first time, a Sterculia striata gum-based insulin delivery system with potential for the oral administration of protein drugs, being considered a valid alternative for efficient delivery of those drugs.

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Microencapsulation of lipase from Yarrowia lipolytica IMUFRJ 50682 was performed by ionotropic gelation with sodium alginate. Sodium alginate, calcium chloride and chitosan concentrations as well as complexation time were evaluated through experimental designs to increase immobilization yield (IY) and immobilized lipase activity (ImLipA) using p-nitrophenyl laurate as substrate. To adjust both parameters (IY and ImLipA), the desirability function showed that microcapsule formation with 3.1%(w/v) sodium alginate, 0.19%(w/v) chitosan, 0.14 M calcium chloride, and 1 min complexation time are ideal for maximal immobilization yield and immobilized lipase activity. A nearly twofold enhancement in Immobilization yield and an increase up to 280 U/g of the lipase activity of the microcapsules were achieved using the experimental design optimization tool. Chitosan was vital for the high activity of this new biocatalyst, which could be reused a second time with about 50% of initial activity and for four more times with about 20% of activity.

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ABSTRACT Flurbiprofen (FLB), a NSAID, widely used for preventing pain generally for arthritis or dental problems. In this study, FLB loaded chitosan microspheres were prepared by ionotropic gelation method. In this method, microspheres were formed by dropping chitosan solutions containing FLB into sodium alginate solutions including sodium tripolyphosphate (TPP). A variety of formulation parameters like drug:polymer ratio, drug concentration, polymer's molecular weight, polymer concentration, pH and the concentration of TPP solutions, drying method and stirring time were analyzed. The dissolution studies were performed in a shaking water bath in pH 7.4 phosphate buffer saline (PBS) at 37 °C. Laser diffractometer was used for particle size analysis, and scanning electron microscope (SEM) was used for morphological properties. Drug loading and loading efficiency were calculated by using UV spectrophotometer. The particles obtained were spherical with 0.7-1.3 mm size range, and the loading efficiency was approximately 21-79%. The dissolution studies conducted revealed that drug:polimer ratio and the polymer type and concentration affected the drug release from microspheres. It was observed that increasing the polymer concentration, polymer's molecular weight and TPP concentration decreased the FLB release from microspheres, which was according to Higuchi kinetics.

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Active nanoparticles based on chitosan could be applied as a support for the modulation of gallic acid delivery. In this sense, these nanostructures could be employed in different fields such as food, packaging, and pharmaceutical areas. The design parameters of chitosan-based nanoparticles functionalized with gallic acid (GA) were optimized through RSM by means of the analysis of zeta potential (ZP) and percentage encapsulation efficiency (PEE). The nanoparticles were prepared by ionotropic gelation using tripolyphosphate (TPP), at different combinations of chitosan (CH) concentration, CH:TPP ratio and GA. Global desirability methodology allowed finding the optimum formulation that included CH 0.76% (w/w), CH:TPP ratio of 5 and 37mgGA/gCH leading to ZP of +50mV and 82% of PEE. Analysis through QuickScan and turbidity demonstrated that the most stable nanoparticle suspensions were achieved combining concentrations of chitosan ranging between 0.5 and 0.75% with CH:TPP ratios higher than 3. These suspensions had high stability confirmed by means ZP and transmittance values which were higher than +25mV and 0.21 on average, respectively, as well as nanoparticle diameters of about 140nm. FTIR revealed the occurrence of both hydrogen bond and ionic interactions of CH-TPP which allowed the encapsulation and the improvement of the stability of the active agent.

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Gellan gum microspheres were obtained by ionotropic gelation technique, using the trivalent ion Al(3+). The percentage of entrapment efficiency ranged from 48.76 to 87.52% and 2(2) randomized full factorial design demonstrated that both the increase of polymer concentration and the decrease of crosslinker concentration presented a positive effect in the amount of encapsulated drug. Microspheres size and circularity ranged from 700.17 to 938.32 µm and from 0.641 to 0.796 µm, respectively. The increase of polymer concentration (1-2%) and crosslinker concentration (3-5%) led to the enlargement of particle size and circularity. However, the association of increased crosslinker concentration and reduced polymer content made the particles more irregular. In vitro and ex vivo tests evidenced the high mucoadhesiveness of microspheres. The high liquid uptake ability of the microspheres was demonstrated and the pH variation did not affect this parameter. Drug release was pH dependent, with low release rates in acid pH (42.40% and 44.93%) and a burst effect in phosphate buffer pH (7.4). The Weibull model had the best correlation with the drug release data, demonstrating that the release process was driven by a complex mechanism involving the erosion and swelling of the matrix or by non-Fickian diffusion.

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This study aimed to formulate, characterize and evaluate the Gliclazide (GLZ) microcapsules prepared with sodium alginate, guar gum and pectin in different ratios by ionotropic-gelation method. The microcapsules were evaluated against different parameters such as particle size and shape, Carr's index, Hausner's ratio, rheological studies and drug release kinetics. Fourier Transform Infra Red (FTIR) and Differential Scanning Calorimetric (DSC) studies demonstrated the absence of any drug - polymers interaction. Promising characteristics were observed in rheological behavior and release kinetics. The size of microcapsules and percentage yield was in the range of 676 to 727 µm and 69 to 77%, respectively. Scanning electron micrographs revealed that microcapsules were discrete, spherical and free flowing. Entrapment efficiency and uniform drug release kinetics were some of the probable characteristics depicting the novel formulation design of Gliclazide microcapsules.

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The objective of this study was to formulate an oral sustained release delivery system of sodium diclofenac(DS) based on sodium alginate (SA) as a hydrophilic carrier in combination with chitosan (CH) and sodium carboxymethyl cellulose (SCMC) as drug release modifiers to overcome the drug-related adverse effects and to improve bioavailability. Microspheres of DS were prepared using an easy method of ionotropic gelation. The prepared beads were evaluated for mean particle size, entrapment efficiency, swelling capacity, erosion and in-vitro drug release. They were also subjected to various studies such as Fourier Transform Infra-Red Spectroscopy (FTIR) for drug polymer compatibility, Scanning Electron Microscopy for surface morphology, X-ray Powder Diffraction Analysis (XRD) and Differential Scanning Calorimetric Analysis (DSC) to determine the physical state of the drug in the beads. The addition of SCMC during the preparation of polymeric beads resulted in lower drug loading and prolonged release of the DS. The release profile of batches F5 and F6 showed a maximum drug release of 96.97 ± 0.356% after 8 h, in which drug polymer ratio was decreased. The microspheres of sodium diclofenac with the polymers were formulated successfully. Analysis of the release profiles showed that the data corresponds to the diffusion-controlled mechanism as suggested by Higuchi.

O objetivo deste estudo foi elaborar um sistema de entrega de oral de liberação sustentada de diclofenaco sódico (DS) com base em alginato de sódio (SA), como um transportador hidrofílico em combinação com quitosana (CH) e carboximetilcelulose de sódio (SCMC) como modificadores de liberação de fármaco para diminuir os efeitos adversos e melhorar a biodisponibilidade. Prepararam-se microesferas de DS usando um método fácil de geleificação ionotrópica. Avaliaram-se os grânulos preparados quanto ao tamanho médio de partícula, eficiência de compressão, inchaço in vitro, erosão e capacidade de liberação de fármacos. Estes tammbém foram submetidos a vários estudos, como espectrometria no infravermelho com transformada de Fourier (FTIR) para compatibilidade de fármaco e polímero, microscopia eletrônica de varredura para morfologia de superfície, análise de difração de raios-X (XRD) do pós e análise calorimétrica diferencial de varredura (DSC) para determinar o estado físico do fármaco nos grânulos. A adição de SCMC durante a preparação de grânulos do polímero resultou em fármacos com menor carga de fármaco e liberação prolongada do DS. O perfil de liberação dos lotes F5 e F6 apresentou máximo de fármaco liberado de 96,97±0,356% após 8 h após o que a proporção do fármaco no polímero foi diminuída. As microesferas de diclofenaco de sódio com os polímeros foram formuladas com sucesso. A análise dos perfis de liberação mostrou que os dados correspondem ao mecanismo de difusão controlada, como sugerido por Higuchi.

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The objective of this study was to develop a sustained release dosage form of Trimetazidine dihydrochloride (TMZ) using a natural polymeric carrier prepared in a completely aqueous environment. TMZ was entrapped in calcium alginate beads prepared with sodium alginate by the ionotropic gelation method using calcium chloride as a crosslinking agent. The drug was incorporated either into preformed calcium alginate gel beads (sequential method) or incorporated simultaneously during the gelation stage (simultaneous method). The beads were evaluated for particle size and surface morphology using optical microscopy and SEM, respectively. Beads produced by the sequential method had higher drug entrapment. Drug entrapment in the sequential method was higher with increased CaCl2 and polymer concentration but lower with increased drug concentration. In the simultaneous method, drug entrapment was higher when polymer and drug concentration were increased and also rose to a certain extent with increase in CaCl2 concentration, where further increase resulted in lower drug loading. FTIR studies revealed that there is no interaction between drug and CaCl2. XRD studies showed that the crystalline drug changed to an amorphous state after formulation. Release characteristics of the TMZ loaded calcium alginate beads were studied in enzyme-free simulated gastric and intestinal fluid.

O objetivo deste estudo foi desenvolver forma de liberação controlada de dicloridrato de trimetazidina (TMZ) utilizando transportador plomérico natural em ambiente completamente aquoso. A TMZ foi presa em pérolas de alginato de cálcio preparadas com alginato de sódio pelo método de gelatinização ionotrópica, usando cloreto de cálcio como agente de formação de ligações cruzadas. O fármaco foi incorporado nas pérolas de gel de alginato de cálcio (método sequencial) ou incorporado, simultaneamente, durante o estágio de gelificação (método simultâneo). As pérolas foram avaliadas quanto ao tamanho das partículas e morfologia da superfície utilizando microscopia óptica de SEM, respectivamente. As pérolas produzidas pelo método sequencial apresentaram maior capacidade de inclusão. No método sequencial, a inclusão de fármaco foi maior com o aumento de CaCl2 e da concentração do plímero, mas menor com o aumento da concentração de fármaco. No método simultâneo, a inclusão de fármaco foi mais alta quando as concentrações de fármaco e plímero foram aumentadas e, também, atingiram certa extensão com aumento na concentração de CaCl2, cujo aumento posterior resultou em carga menor de fármaco. Estudos de FTIR revelaram que não há interação entre fármaco e CaCl2. Estudos de XRD mostraram que o fármaco mudou do estado cristalino para o amorfo após a formulação. As características de liberação de TMZ das pérolas carregadas com alginato de cálcio foram estudadas em fluidos simulados, gástrico e intestinal, livres de enzima.

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