Agarose Cryogels: Production Process Modeling and Structural Characterization.

A cryogel is a cross-linked polymer network with different properties that are determined by its manufacturing technique. The formation of a cryogel occurs at low temperatures and results in a porous structure whose pore size is affected by thermal conditions. The adjustable pore sizes of cryogels make them attractive for diverse applications. In this study, the influence of the external operational temperature, which affects the cooling and freezing rates, on the production of cryogels with 2% w/w agarose is investigated. Moreover, a mathematical model is developed to simulate the cryogel production process and provide an initial estimate of the pore size within the structure. The predictions of the model, supported by qualitative light microscopy images, demonstrate that cryogels produced at higher process temperatures exhibit larger pore sizes. Moreover, the existence of pore size distribution within the gel structure is confirmed. Finally, stress relaxation tests, coupled with an image analysis, validates that cryogels produced at lower temperatures possess a higher stiffness and slower water release rates.

A New Productive Approach and Formulative Optimization for Curcumin Nanoliposomal Delivery Systems.

The use of natural resources and the enhancing of technologies are outlining the strategies of modern scientific-technological research for sustainable health products manufacturing. In this context, the novel simil-microfluidic technology, a mild production methodology, is exploited to produce liposomal curcumin as potential powerful dosage system for cancer therapies and for nutraceutical purposes. Through simil-microfluidic technology, based on interdiffusion phenomena of a lipid-ethanol phase in an aqueous flow, massive productions of liposomes at nanometric scale can be obtained. In this work, studies on liposomal production with useful curcumin loads were performed. In particular, process issues (curcumin aggregations) were elucidated and formulation optimization for curcumin load was performed. The main achieved result has been the definition of operative conditions for nanoliposomal curcumin production with interesting loads and encapsulation efficiencies.

A low-cost push-pull syringe pump for continuous flow applications.

Syringe pumps are very useful tools to ensure a constant and pulsation-free flow rate, however usability is limited to batch processes. This article shows an open-source method for manufacturing a push pull syringe pump, valid for continuous processes, easy to build, low-cost and programmable. The push-pull syringe pump (PPSP) is driven by an Arduino nano ATmega328P which controls a NEMA 17 in microstepping via the A4988 stepper driver. The Push-Pull Syringe Pump setup is configurable by means of a digital encoder and an oled screen programmed using C ++. A PCB was designed and built to facilitate the assembly of the device. The continuous flow is guaranteed by four non-return valves and a dampener, which has been sized and optimized for use on this device. Finally, tests were carried out to evaluate the flow rates and the linearity of the flow. The device is achievable with a cost of less than 100 €.

Gelation process of carboxymethyl chitosan-zinc supramolecular hydrogel studied with fluorescence imaging and mathematical modelling.

Herein we report on a detailed study about the gelation kinetics of carboxymethyl chitosan-zinc (CMCh-Zn) supramolecular hydrogel by taking advantage of its intrinsic fluorescence property. A specific gelation device is designed and the gel front can be directly visualized under 365 nm UV light. The results show that when increasing Zn2+ concentration from 0.1 M to 1.0 M, the apparent diffusion coefficient increases gradually from 2.72 × 10-6 cm2/s to 4.50 × 10-6 cm2/s. The gelation kinetics then is described with a "zero order" mathematical model, proving that the gel thickness is related to the square root of the gelation time and the diffusion step is the controlling step of the gelation process. Later a more advanced model, developed in 1D geometry and solved numerically, is used to describe and predict experimental results, proving its reliability and the correct description of all the phenomena involved in the gelation process of CMCh-Zn hydrogel.

Polymer-Lipid Pharmaceutical Nanocarriers: Innovations by New Formulations and Production Technologies.

Some issues in pharmaceutical therapies such as instability, poor membrane permeability, and bioavailability of drugs can be solved by the design of suitable delivery systems based on the combination of two pillar classes of ingredients: polymers and lipids. At the same time, modern technologies are required to overcome production limitations (low productivity, high energy consumption, expensive setup, long process times) to pass at the industrial level. In this paper, a summary of applications of polymeric and lipid materials combined as nanostructures (hybrid nanocarriers) is reported. Then, recent techniques adopted in the production of hybrid nanoparticles are discussed, highlighting limitations still present that hold back the industrial implementation.

Microwave Treatments of Cereals: Effects on Thermophysical and Parenchymal-Related Properties.

Dielectric heating is one of the most interesting techniques for pest disinfestation. However, most of the literature works give information about the ability of microwave treatments at different power-time conditions to kill insects; less is given about the analysis of matrices structural properties and heat transport. Accordingly, the aim of this work is to investigate the effect of microwave treatments, applied for pest disinfestation, on heat transport behavior and physical/structural properties, such as water uptake capability, mineral losses, texture change, and germination capability, of most consumed cereals in human diet, such as weak wheat, durum wheat, and corn. Two different radiative treatments were performed: one in time-temperature conditions capable of inactivating the weed fauna, and the other at high temperatures of ~150 °C, simulating uncontrolled treatments. Heat transport properties were measured and showed to keep unvaried during both effective and uncontrolled microwave treatments. Instead, grain physical properties were worsened when exposed to high temperatures (reduction of germination ability and texture degradation). The achieved results, on the one hand, provide new structural and heat transport data of cereals after microwave treatments, actually not present in the literature, and on the other, they confirm the importance of correctly performing microwave treatments for an effective disinfestation without affecting matrices physical properties and nutritional features.

Mechanics and drug release from poroviscoelastic hydrogels: Experiments and modeling.

Hydrogels are peculiar soft materials formed by a 3D polymeric network surrounded by water molecules. In these systems the mechanical and the chemical energy are well balanced and an applied external stimulus (mechanical or chemical) can cause a distinctive response, where the contributions of the mechanics and the mass transport are combined to form a "poroviscoelastic" behavior. In this work the poroviscoelastic behavior of the agarose gels has been investigated, from the experimental and modeling points of view, by applications of external mechanical stimuli. The pure gel, brought in the non-equilibrium condition, showed that the combined effect of mechanical viscoelasticity and water transport were essential to reach the new equilibrium condition. Furthermore, the agarose gel loaded with a model drug, theophylline, showed that the mechanical stimulus can enhance the drug release from the system by stretching the polymeric chains, modifying the mesh size and therefore the drug diffusion coefficient.

Advances in Nanoliposomes Production for Ferrous Sulfate Delivery.

In this study, a continuous bench scale apparatus based on microfluidic fluid dynamic principles was used in the production of ferrous sulfate-nanoliposomes for pharmaceutical/nutraceutical applications, optimizing their formulation with respect to the products already present on the market. After an evaluation of its fluid dynamic nature, the simil-microfluidic (SMF) apparatus was first used to study the effects of the adopted process parameters on vesicles dimensional features by using ultrasonic energy to enhance liposomes homogenization. Subsequently, iron-nanoliposomes were produced at different weight ratios of ferrous sulfate to the total formulation components (0.06, 0.035, 0.02, and 0.01 w/w) achieving, by using the 0.01 w/w, vesicles of about 80 nm, with an encapsulation efficiency higher than 97%, an optimal short- and long-term stability, and an excellent bioavailability in Caco-2 cell line. Moreover, a comparison realized between the SMF method and two more conventional production techniques showed that by using the SMF setup the process time was drastically reduced, and the process yield increased, achieving a massive nanoliposomes production. Finally, duty-cycle sonication was detected to be a scalable technique for vesicles homogenization.

Drug Delivery of siRNA Therapeutics.

Small interfering RNA (siRNA) is a class of nucleic acid-based drugs (NABDs) able to block gene expression by interaction with mRNA before its translation [...].

Hydrogel-based commercial products for biomedical applications: A review.

Hydrogels are hydrophilic polymer networks, able to absorb large amount of water, increasing their volume and showing a plethora of different material behaviors. Since their first practical application, dating from sixties of last century, they have been employed in several fields of biomedical sciences. After more than half a century of industrial uses, nowadays a lot of hydrogels are currently on the market for different purposes, and offering a wide spectra of features. In this review, even if it is virtually impossible to list all the commercial products based on hydrogels for biomedical applications, an extensive analysis of those materials that have reached the market has been carried out. The hydrogel-based materials used for drug delivery, wound dressing, tissue engineering, the building of contact lens, and hygiene products are enlisted and briefly described. A detailed snapshot of the set of these products that have reached the commercial maturity has been then obtained and presented. For each class of application, the basics of requirements are described, and then the materials are listed and classified on the basis of their chemical nature. For each product the commercial name, the producer, the chemical nature and the main characteristics are reported.

Lipid Delivery Systems for Nucleic-Acid-Based-Drugs: From Production to Clinical Applications.

In the last years the rapid development of Nucleic Acid Based Drugs (NABDs) to be used in gene therapy has had a great impact in the medical field, holding enormous promise, becoming "the latest generation medicine" with the first ever siRNA-lipid based formulation approved by the United States Food and Drug Administration (FDA) for human use, and currently on the market under the trade name Onpattro™. The growth of such powerful biologic therapeutics has gone hand in hand with the progress in delivery systems technology, which is absolutely required to improve their safety and effectiveness. Lipid carrier systems, particularly liposomes, have been proven to be the most suitable vehicles meeting NABDs requirements in the medical healthcare framework, limiting their toxicity, and ensuring their delivery and expression into the target tissues. In this review, after a description of the several kinds of liposomes structures and formulations used for in vitro or in vivo NABDs delivery, the broad range of siRNA-liposomes production techniques are discussed in the light of the latest technological progresses. Then, the current status of siRNA-lipid delivery systems in clinical trials is addressed, offering an updated overview on the clinical goals and the next challenges of this new class of therapeutics which will soon replace traditional drugs.

Micronutrients encapsulation in enhanced nanoliposomal carriers by a novel preparative technology.

Micronutrients administration by fortification of staple and complementary foods is a followed strategy to fight malnutrition and micronutrient deficiencies and related pathologies. There is a great industrial interest in preparation of formulations for joint administration of vitamin D3 and vitamin K2 for providing bone support, promoting heart health and helping boost immunity. To respond to this topic, in this work, uncoated nanoliposomes loaded with vitamin D3 and K2 were successfully prepared, by using a novel, high-yield and semi continuous technique based on simil-microfluidic principles. By the same technique, to promote and to enhance mucoadhesiveness and stability of the produced liposomal structures, chitosan was tested as covering material. By this way polymer-lipid hybrid nanoparticles, encapsulating vitamin D3 and vitamin K2, with improved features in terms of stability, loading and mucoadhesiveness were produced for potential nutraceutical and pharmaceutical applications.

Polymer-lipid hybrid nanoparticles as enhanced indomethacin delivery systems.

Non-steroidal anti-inflammatory drugs (NSAIDs), i.e. indomethacin used for rheumatoid arthritis and non-rheumatoid inflammatory diseases, are known for their injurious actions on the gastrointestinal (GI) tract. Mucosal damage can be avoided by using nanoscale systems composed by a combination of liposomes and biodegradable natural polymer, i.e. chitosan, for enhancing drug activity. Aim of this study was to prepare chitosan-lipid hybrid delivery systems for indomethacin dosage through a novel continuous method based on microfluidic principles. The drop-wise conventional method was also applied in order to investigate the effect of the two polymeric coverage processes on the nanostructures features and their interactions with indomethacin. Thermal-physical properties, mucoadhesiveness, drug entrapment efficiency, in vitro release behavior in simulated GI fluids and stability in stocking conditions were assayed and compared, respectively, for the uncoated and chitosan-coated nanoliposomes prepared by the two introduced methods. The prepared chitosan-lipid hybrid structures, with nanometric size, have shown high indomethacin loading (about 10%) and drug encapsulation efficiency up to 99%. TEM investigation has highlighted that the developed novel simil-microfluidic method is able to put a polymeric layer, surrounding indomethacin loaded nanoliposomes, thicker and smoother than that achievable by the drop-wise method, improving their storage stability. Finally, double pH tests have confirmed that the chitosan-lipid hybrid nanostructures have a gastro retentive behavior in simulated gastric and intestinal fluids thus can be used as delivery systems for the oral-controlled release of indomethacin. Based on the present results, the simil-microfluidic method, working with large volumes, in a rapid manner, without the use of drastic conditions and with a precise control over the covering process, seems to be the most promising method for the production of suitable indomethacin delivery system, with a great potential in industrial manufacturing.

On the relevance of thermophysical characterization in the microwave treatment of legumes.

This study is focused on the characterization of the thermal behavior and physical properties of the most consumed legumes in the daily diet such as beans, lentils and chickpeas. Because of a lack of information in the literature about the effect of microwave treatments on legumes, characterization protocols have been applied before and after subjecting them to microwave irradiation suitable for pest disinfestation. The effects of two different radiative treatments, one suitable for inactivating the infesting fauna and the other simulating uncontrolled treatments, characterized by very high temperatures, were tested. The impacts of microwave treatments on legumes, in terms of thermal behavior, germination capability, tannin and total polyphenol composition and other physical properties (water uptake capability, texture change, mineral losses), after typical soaking cooking processes, are also studied. The thermal properties of the examined legumes were found to be comparable for all samples. Similarly, no significant differences in antinutritional factors, polyphenol and tannin content among all samples were detected. From the structural point of view, samples exposed to high temperatures showed texture degradation and in turn, loss of mineral nutrients during soaking processes. Moreover, their germination capability was drastically reduced. These latter results highlighted why it is important to correctly perform the radiative microwave process in order to both ensure effective and safe disinfestation and avoid nutritional value loss and the worsening of physical properties.

Design and production of hybrid nanoparticles with polymeric-lipid shell-core structures: conventional and next-generation approaches.

Liposomes constitute a class of prominent drug delivery systems due their cell-mimetic behaviour. Despite their high biocompatibility, biodegradability and low intrinsic toxicity, their poor stability in biological fluids as well as in stock conditions (high tendency to degrade or aggregate) have led to new approaches for liposome stabilization (e.g., surface covering with polymers). Here, liposomes were enwrapped by the natural biocompatible polymer chitosan to achieve stable shell-core nanostructures. Covered nanoliposomes were produced using an innovative continuous method based on microfluidic principles. The produced hybrid polymeric-lipid nanoparticles were characterized in terms of structural properties, size and stability. Moreover, phenomenological aspects in formation of nanoliposomal vesicles and chitosan layering, product quality (structure, size) and manufacturing yield related to this novel method were compared with those of the conventional dropwise method and the obtained products. The proposed simil-microfluidic method led to the production of stable and completely chitosan-covered liposomes with a shell-core nanostructure that avoided the disadvantages inherent in the conventional method (which are time-consuming and/or require bulky and more expensive equipment).

A physiologically-based model to predict individual pharmacokinetics and pharmacodynamics of remifentanil.

Remifentanil based anesthesia is nowadays spread worldwide. This drug is characterized by a rapid onset of the analgesic effects, but also by a rapid onset of the side effects. For this reason, the knowledge of the remifentanil concentration in the human body is a key topic in anesthesiology. The aims of this work are to propose and validate a physiologically based pharmacokinetic model capable to predict both the pharmacokinetics and pharmacodynamics of remifentanil, and to take into account the inter-individual differences among the patients (such as height and body mass). The blood concentration of remifentanil has been successfully simulated and compared with experimental literature data. The pharmacodynamics, in terms of effect of remifentanil on minute ventilation and electroencephalogram, has been implemented in this model. Moreover, the remifentanil concentration in various organs and tissues is predicted, which is a significant improvement with respect to the traditional compartmental models. The availability of the model makes possible the prediction of the effects of remifentanil administration, also accounting for individual parameters.

HPMC granules by wet granulation process: Effect of vitamin load on physicochemical, mechanical and release properties.

Due to its versatile properties, hydroxypropyl methylcellulose (HPMC) is largely used in many applications and deeply studied in the various fields such as pharmaceuticals, biomaterials, agriculture, food, water purification. In this work, vitamin B12 loaded HPMC granules were produced to investigate their potential application as nutraceutical products. To this aim the impact of vitamin load on physico-chemical, mechanical and release properties of granules, achieved by wet granulation process, was investigated. In particular, three different loads of B12 (1%, 2.3% and 5% w/w) were assayed. Unloaded granules (used as control) and loaded granules were dried, sieved, and then the suitable fraction for practical uses, 0.45-2mm in size, was fully characterized. Results showed that the vitamin incorporation of 5% reduced the granulation performance in the range size of 0.45-2mm and led granules with higher porosity, more rigid and less elastic structures compared to unloaded granules and those loaded at 1% and 2.3% of B12. Vitamin release kinetics of fresh and aged granules were roughly found the same trends for all the prepared lots; however, the vitamin B12 was released more slowly when added with a load at 1% w/w, suggesting a better incorporation.

Effects of HPMC substituent pattern on water up-take, polymer and drug release: An experimental and modelling study.

The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Ficks law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices.

Determination of the release mechanism of Theophylline from pellets coated with Surelease®-A water dispersion of ethyl cellulose.

The aim of this study was to investigate the water transport over free standing films based on the aqueous ethyl cellulose (EC) coating Surelease® and the drug (Theophylline) release mechanism from coated pellets. It was found that the main drug release rate from pellets was controlled by a diffusion mechanism. However, the drug release rate was altered by addition of sodium chloride to the external release medium. A decrease in the drug release rate when sodium chloride is added to the release medium has traditionally been used to indicate an osmotic drug release mechanism. However, our findings that the release rate decreased by sodium chloride addition could be explained by sodium chloride diffusing through the coating layer into the inner parts of the pellets, decreasing the solubility of Theophylline. This gave a reduced drug concentration gradient over the coating layer and thus a slower release rate. Furthermore, this study shows, as expected, that the transport of water through Surelease® films into the pellets was faster than the transport out of Theophylline (approx. seven times), which was the reason why the pellets were swelling during the release. It was also shown that the drug release rate, determined for both whole dose release and for single pellets, decreased with increasing thickness (from 16 to 51µm) of the coating layer controlling the drug release rate.