Modeling the drug release from hydrogel-based matrices.

In this work the behavior of hydrogel-based matrices, the most widespread systems for oral controlled release of pharmaceuticals, has been mathematically described. In addition, the calculations of the model have been validated against a rich set of experimental data obtained working with tablets made of hydroxypropyl methylcellulose (a hydrogel) and theophylline (a model drug). The model takes into account water uptake, hydrogel swelling, drug release, and polymer erosion. The model was obtained as an improvement of a previous code, describing the diffusion in concentrated systems, and obtaining the erosion front (which is a moving boundary) from the polymer mass balance (in this way, the number of fitting parameters was also reduced by one). The proposed model was found able to describe all the observed phenomena, and then it can be considered a tool with predictive capabilities, useful in design and testing of new dosage systems based on hydrogels.

Flow induced crystallisation of polymers.

This tutorial review describes the state of current research and findings on the phenomena of polymer crystallisation under processing conditions, with particular emphasis on the effects of fluid flow. Preliminarily, it is stated why the crystallisation processes are relevant in polymer science, then the motivation of the study is briefly outlined. The remaining of the paper is divided in two parts. In the first part of the review, the basics of polymer crystallisation are summarized; the main factors acting on the process are identified; and the methods to investigate and to quantify the crystallization are described. A brief summary of the modelling approaches is also proposed. In the second part of the review, a similar path was followed in order to analyse the complex framework of phenomena collectively known as flow induced crystallisation. Therefore, the experimental techniques used are listed and the main findings are reported. A reference to the modelling approaches proposed in the literature is also summarized. Throughout the review, a selection of the literature in the field is of course cited.

In vitro dissolution of pH sensitive microparticles for colon-specific drug delivery.

OBJECTIVE: The objective of this work is to prepare oral dosage systems based on enteric materials in order to verify their possible use as Colon-Specific Drug Delivery Systems (CSDDSs). METHODOLOGY: In particular, three different copolymers of methyl-methacrylate (MMA) - acrylic acid (AA) are synthesized with increasing percentage of MMA (from 70% to 73%) and they are used to produce microparticles by the double-emulsion solvent evaporation method. The microparticles, loaded using theophylline as model drug, are then tested for drug release under varying pH to reproduce what happens in the human GI tract. RESULTS: All the investigated systems have shown an effective pH sensitiveness: they show a good gastro-resistance, releasing the model drug only at higher pH, small intestine or colon, depending on the kind of used copolymer. CONCLUSION: The results confirm the usefulness of both the materials and the methods proposed in this study for colon-specific delivery applications.

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.

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.

Microencapsulation effectiveness of small active molecules in biopolymer by ultrasonic atomization technique.

A method to produce biopolymeric (alginate) microparticles by ultrasonic assisted atomization, previously developed, has been applied to the production of microparticles loaded with a small active molecule (theophylline). Fine loaded alginate droplets have been cross-linked with divalent ions to produce microparticles. Once produced, the particles have been separated by centrifugation or filtration and then they have been dried. Drug release has been evaluated by dissolution tests, dissolving the dried particles in acidic solution at pH 1 for a given time and then at pH 7 to simulate the stomach and intestinal environment, respectively. The encapsulation efficiency and the drug loading have been investigated and the operating conditions have been changed to clarify the role of the transport phenomena on the overall process. To increase the drug loading, shorter separation time and better network's structure were identified as the key operating parameters to allow the process to gain interest from a practical point of view.

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 €.

Anti-osteoporotic drug release from ordered mesoporous bioceramics: experiments and modeling.

The release of a potent bone-resorption inhibitor such as zoledronate from a versatile drug delivery system such as SBA 15 has been modeled. The initial and boundary conditions have been defined, together with the system parameters, including the determination of equilibrium and transport parameters. Additionally, the experimental model of the same system has been observed to validate the prediction here developed. This approach represents a powerful tool for the designing of mesoporous implantable drug delivery systems because their release kinetics can be predicted in advance, and this leads to a considerable time and resources saving.

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.

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.

Enteric micro-particles for targeted oral drug delivery.

This work is focused on production of enteric-coated micro-particles for oral administration, using a water-in-oil-in-water solvent evaporation technique. The active agent theophylline was first encapsulated in cellulose acetate phthalate (CAP), a pH-sensitive well-known polymer, which is insoluble in acid media but dissolves at neutral pH (above pH 6). In this first step, CAP was chosen with the aim optimizing the preparation and characterization methods. The desired release pattern has been obtained (low release at low pH, higher release at neutral pH) but in presence of a low encapsulation efficiency. Then, the CAP was replaced by a novel-synthesized pH-sensitive poly(methyl methacrylate-acrylic acid) copolymer, poly(MMA-AA). In this second step, the role of two process parameters was investigated, i.e., the percentage of emulsion stabilizer (polyvinyl alcohol, PVA) and the stirring power for the double emulsion on the encapsulation efficiency. The encapsulation efficiency was found to increase with PVA percentage and to decrease with the stirring power. By increasing the PVA content and by decreasing the stirring power, a high stable double emulsion was obtained, and this explains the increase in encapsulation efficiency found.

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.

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 [...].

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.

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.

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.

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.