Marco Cespi

Colloidal soft matter as drug delivery system

Growing interest is being dedicated to soft matter because of its potential in delivering any type of drugs. Since hydrophilic, lipophilic, small and big molecules can be loaded into these colloidal systems and administered through the parenteral or nonparenteral route, soft matter systems have been used to solve many biomedical and pharmaceutical problems. In fact, they make possible to overcome difficulties in the formulation and delivery of poorly water-soluble drug molecules, settle some stability issues typical of biological drug molecules, design parenteral sustained release forms and provide functionalized soft particles that are very effective in drug targeting. This review deals with the important role that colloids play in the drug delivery and targeting, with particular attention to the more currently used systems such as microemulsions, organogels, liposomes, micelles, and dendrimers. Though significant progress has been made in drug targeting, some challenges still remain. Further efforts will be required to better understand the characteristics of targets and to discover new ones. In-depth knowledge of the physico-chemical structure and properties of the systems used for targeting is fundamental for understanding the mechanism of interaction with the biological substrate and the consequent drug release.

Characterization and Stability of Emulsion Gels Based on Acrylamide/Sodium Acryloyldimethyl Taurate Copolymer

Sepineo P 600, a concentrated dispersion of acrylamide/sodium acryloyldimethyl taurate copolymer in isohexadecane, has self-gelling and thickening properties and the ability to emulsify oily phases, which make it easy to use in the formulation of gels and o/w emulsion gels. In this paper, gels were prepared using a Sepineo P 600 concentration between the 0.5% and 5% (w/w), and then emulsion gel was also prepared from the 3% Sepineo gel by adding a specific amount of almond oil. All the prepared systems were analyzed and characterized by oscillation rheology and acoustic spectroscopy. The particle size of the oil droplets and the microrheological extensional moduli (G′ and G″) of the systems were determined from acoustic parameters and used together with the classical oscillatory rheological tests to assess the stability of the systems. Classical oscillatory analysis revealed that the dynamic moduli were very dependent on polymer concentration; as this parameter increased, there was progressive improvement in the sample elasticity. In fact, the mechanical spectra of the 0.5% and 1% (w/w) Sepineo samples were characterized by strong frequency dependence and multiple crossover points, typical of dilute polymer solution with no organized structure. On the other hand, the 3–5% (w/w) concentration systems showed typical gel-like spectra, marked by the absence of crossover points between the dynamic moduli and by weak dependence on frequency. Nevertheless, the elastic properties of the gel-like structure even at elevated polymer concentrations were not strongly long-lasting, as demonstrated by the increase of the viscous contribution in the low frequency range during acoustic spectroscopy analysis. This fact could indicate that the gel structure is characterized by weak polymer–polymer interactions, an advantageous characteristic for topical administration, as the sample is thus easier to rub into the skin. Finally, both rheology and acoustic spectroscopy indicated that addition of the oily phase caused minimal changes to the elastic character of the gel. Thus, Sepineo P 600 gel and emulsion gel are very effective systems for use in topical and other types of applications.

Effect of temperature increase during the tableting of pharmaceutical materials

Scale-up of tableting process is particularly difficult due to specific concerns related exclusively to the process itself and that cannot be determined on a smaller scale, which are the effect of compression speed and the build-up of heat due to the length of the compaction operations. In this work, it has been simulated the rise of temperature observed during the tablets manufacturing in a full production scale by means of an appropriate modification of a R&D rotary tablet machine. Four common pharmaceutical excipients, characterized by different chemical nature, consolidation behaviour and temperature sensitiveness have been analysed in terms of compaction mechanism (Heckel and energy analysis) and tabletability, in order to verify any effect of the increase of temperature. The results showed a relevance of the temperature on mechanical tablets properties only on materials characterized by low temperature thermal transitions (melting or glass transition), while, for compounds which do not exhibit thermal events at low temperature, it becomes less important for ductile materials and irrelevant for brittle materials. Heckel analysis highlighted a noticeable increase of ductility only in those materials whose tablets mechanical properties depended on the temperature. On the other hand, energy analysis showed low sensitivity failing to identify any temperature effect on compaction materials properties. This work showed how to simulate the process of temperature rise on a small scale and the influence of temperature on materials compaction properties. The use of a modified tableting machine, able to control the temperature and moisture levels and also capable of monitoring the punch movements, resulted in identifying the effect of temperature both on mechanical and compaction properties on materials. Thus, it represents a valuable tool in order to provide useful information at an early stage during the development of tablets formulations.

Characterization of the interaction between chitosan and inorganic sodium phosphates by means of rheological and optical microscopy studies

The physicochemical and rheological properties of chitosan and two different inorganic sodium phosphate dispersions (NaH(2)PO(4) and Na(3)PO(4)) were investigated in order to elucidate the role of different factors, such as ratios between polymer and sodium inorganic phosphates, different pHs and storage stability, on the gelling properties of chitosan. This was deemed opportune since physico-chemical characterizations of chitosan in the literature often appear incomplete and questionable. We also compared the elastic modulus values of the different chitosan/inorganic phosphate systems and examined their behaviour through optical microscopy analyses. The most efficient formulations that showed a thermogelling capacity with a significant gel transition behaviour after 24h were the NaH(2)PO(4)/chitosan and Na(3)PO(4)/chitosan systems at ratio 2 and pH 7.0. These results confirmed the importance of the pH value and ratio selection for the final systems.

Activity of essential oil-based microemulsions against Staphylococcus aureus biofilms developed on stainless steel surface in different culture media and growth conditions

Food safety is a fundamental concern for both consumers and the food industry, especially as the numbers of reported cases of food-associated infections continue to increase. Industrial surfaces can provide a suitable substrate for the development and persistence of bacterial organized in biofilms that represent a potential source of food contamination. The negative consumer perception of chemical disinfectants has shifted the attention to natural substances, such as plant extracts. The aim of this study was to investigate the possibility of using the essential oils (EOs) in the fight against S. aureus biofilms. First, the Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Minimum Biofilm Inhibitory Concentration (MBIC), Minimum Biofilm Eradication Concentration (MBEC) of eleven EOs against S. aureus were determined. Cinnamomum cassia and Salvia officinalis EOs showed the greatest antibacterial properties with 1.25% MIC and MBC, 1.25% MBIC and 2.5% MBEC respectively. Gas Chromatography/Mass Spectrometry analysis revealed cinnamaldehyde (82.66%) and methoxy cinnamaldehyde (10.12%) as the most abundant substances of C. cassia, while cis-thujone (23.90%), camphor (19.22%) and 1.8-cineole (10.62%) of S. officinalis. Three different microemulsions, formulated with C. cassia, S. officinalis or both, were finally tested against S. aureus biofilms in different culture media and growth conditions, causing a >3 logarithmic reductions in S. aureus 24h-old biofilms and desiccated biofilms, and up to 68% of biofilm removal after 90min of exposure. The obtained data suggest the potential use of EOs, alone or in combination, for the formulation of sanitizers as alternative or in support in the disinfection of contaminated surfaces.

Oleanolic Acid Loaded PEGylated PLA and PLGA Nanoparticles with Enhanced Cytotoxic Activity against Cancer Cells.

Oleanolic acid (OA) is a natural triterpenoid with anticancer properties, but its hydrophobic nature and poor aqueous solubility pose challenges in pharmaceutical formulation development. The present study aimed at developing OA-loaded mPEG-PLGA or mPEG-PLA nanoparticles (NPs) to improve the delivery of OA. The NPs were prepared by nanoprecipitation, and their physicochemical properties were characterized. The OA encapsulation efficiency of the NPs was between 40 and 75%. The size of the OA-loaded NPs was around 200-250 nm, which fell within the range required for tumor targeting by means of the enhanced permeability and retention (EPR) effect, and the negatively charged NPs remained physically stable for over 20 weeks with no aggregation observed. The OA-loaded NPs produced significant cytotoxic effects through apoptosis in cancer cell lines. Overall, the OA-loaded mPEG-PLGA NPs and mPEG-PLA NPs shared similar physicochemical properties. The former, especially the OA-loaded mPEG-P(D,L)LGA NPs, were more cytotoxic to cancer cells and therefore were more efficient for OA delivery.

Rheological Evaluation of Silicon/Carbopol Hydrophilic Gel Systems as a Vehicle for Delivery of Water Insoluble Drugs

The present study analyzed the thickening properties of Carbopol 974 and 971 in a 50:50 mixture of water/Silsense™ A-21, a new cationic silicon miscible in any proportion with water. Samples were prepared by simply dispersing different Carbopol amounts (0.5–4%) at room temperature or at 70°C without neutralizing. Temperature sweep and time sweep analysis did not reveal significant structural changes at increasing temperature in the samples prepared following the first procedure. On the other hand systems obtained at 70°C possessed higher elastic character particularly at polymer concentration higher than 2% (w/v). Analysis of the G′ and G″ vs frequency curves by using different fitting equations (linear fitting, power law) gave information about the viscoelastic properties of the systems. The fitting of the frequency spectra and the calculation of the relaxation times from the master curves outlined the structural differences within the samples prepared with the two different procedures, confirming stronger gel-like behaviour for the samples prepared by the heating procedure. High preparation temperature promoted the polymer–solvent interactions, aiding the solvation of Carbopol. Heating facilitated polymer–solvent and polymer–polymer interaction, giving rise to a better organised structure typical of gel-like systems. Furthermore this preparation method provided good stability properties as shown by the stress sweeps tests performed during the three months of storage. The interpretation of the rheological results was supported by statistical analysis. A design methodology (screening and optimisation) was also applied in order evaluate the influence on dynamic rheological moduli of several parameters (polymer type and concentration, preparation method, temperature of the tests). This last method showed the relevance of the interaction of two main factors: polymer concentration and preparation procedure. Thus, statistical analysis confirmed that temperature increased the polymer–solvent interaction and improved the viscoelastic properties of the systems, particularly when Carbopols were present in considerable amounts.

Poloxamer Thermogel Systems as Medium for Crystallization

ABSTRACTPurposeTo prepare a thermoreversible gel system able to work as a medium for crystallization at around 20°C, allowing easy retrieval of crystals by simply decreasing the gel temperature. Lactose was selected has model substance for crystallization.MethodsWater solutions with different% of poloxamer 407, α-Lactose monohydrate, and ethanol were prepared and analysed by rheology to understand how the different components alter the gelling temperature. The systems with the required characteristics for lactose crystallization were prepared and the crystals recovered by cooling and then filtering the dispersion.ResultsRheological analysis showed interaction between the poloxamer and lactose. Increasing the quantity of poloxamer or lactose lowered the gelation temperature while the addition of small amounts of ethanol had a modest effect on the same property. These data were used to identify the ideal concentration of the components in order to prepare a system matching the features of our purpose. Such system yielded high quality crystals, with well-defined geometry and narrow particle size distribution.ConclusionPoloxamer is a very interesting polymer in that it is able to generate a reversible gelling medium from which crystals can be harvested by filtering, without the addition of any chemicals to promote the sol–gel transition.

Monitoring the aggregation behaviour of self-assembling polymers through high-resolution ultrasonic spectroscopy

Poloxamer 407 is a well-known self-assembling polymer with a wide range of temperature- and concentration-dependent phase behaviour, such as micellization and gelation. This work was carried out to demonstrate the potential of high-resolution ultrasonic spectroscopy in evaluating aggregation-deaggregation behaviour of self-assembling polymers. In order to achieve this objective, six different concentrations of Poloxamer 407 water dispersion were prepared and analysed between 5 and 35 degrees C using ultrasonic spectroscopy. For comparison, the same samples were also analysed by the DSC technique. The results showed that polymer aggregation process can be successfully monitored using both ultrasonic parameters of sound speed and attenuation. Furthermore, good agreement with DSC data was observed in terms of characteristic transition temperatures and also in terms of micellization kinetics and related parameters.

Determination of factors controlling the particle size and entrapment efficiency of noscapine in PEG/PLA nanoparticles using artificial neural networks.

In this study, di- and triblock copolymers based on polyethylene glycol and polylactide were synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance and gel permeation chromatography. Nanoparticles containing noscapine were prepared from these biodegradable and biocompatible copolymers using the nanoprecipitation method. The prepared nanoparticles were characterized for size and drug entrapment efficiency, and their morphology and size were checked by transmission electron microscopy imaging. Artificial neural networks were constructed and tested for their ability to predict particle size and entrapment efficiency of noscapine within the formed nanoparticles using different factors utilized in the preparation step, namely polymer molecular weight, ratio of polymer to drug, and number of blocks that make up the polymer. Using these networks, it was found that the polymer molecular weight has the greatest effect on particle size. On the other hand, polymer to drug ratio was found to be the most influential factor on drug entrapment efficiency. This study demonstrated the ability of artificial neural networks to predict not only the particle size of the formed nanoparticles but also the drug entrapment efficiency. This may have a great impact on the design of polyethylene glycol and polylactide-based copolymers, and can be used to customize the required target formulations.