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Highlights • β-caseins from human milk and from donkey, goat, and sheep milk have been purified. • Similar self-assembling behaviour between β-casein from different species was found. • Lower hypoallergenic potential of donkey and human β-caseins was determined. • Possible use of β-casein from other milk sources as nanocarriers has been suggested. Graphical abstract Abstract Caseins are a family of proteins constituted by α-caseins (αs-1 and αs-2 caseins), β-caseins and κ-caseins. β-caseins, in particular, show a temperature and concentration-dependent self-assembling behaviour. Recently, β-casein micelles have been proposed as natural nanocarriers for the delivery of hydrophobic compounds, promoting their bioavailability. Until now, all studies regarding both chemical-physical characterization and applications of β-caseins have employed the protein of bovine origin. However, it could be interesting to exploit the use of β-caseins from other milk sources for their potential encapsulation ability and immunogenicity but, at present, no information on the self-assembling behaviour is available for β-caseins from the milk of species different from bovine. In this work, for the first time, β-caseins from human milk and from donkey, goat, and sheep milk were purified and their self-assembling behaviour was compared to that of a commercial bovine β-casein, the only one for which the concentration and temperature aggregation behaviour is known. Furthermore, a preliminary evaluation of the immunogenicity potential of β-casein from other milk sources has been performed by cross-reaction experiments using anti-β-casein antibodies from bovine origin. The results indicated a similar self-assembling profile among all β-caseins examined compared to the bovine β-casein, suggesting the possible use of β-casein from other milk sources as nanocarriers. Since donkey and human β-casein do not cross-react with bovine anti-β-casein antibodies, they could be particularly interesting for the development of self-assembling systems with lower hypoallergenic potential. [ABSTRACT FROM AUTHOR]

Acoustics is one of the emerging technologies developed to minimize processing, maximize quality and ensure the safety of pharmaceutical, food and chemical products. The operating principle of acoustic spectroscopy is the measurement of the ultrasound pulse intensity and phase after its propagation through a sample. The main goal of this technique is to characterise concentrated colloidal dispersions without dilution, in such a way as to be able to analyse non-transparent and even highly structured systems. This review presents the state of the art of ultrasound-based techniques in pharmaceutical pre-formulation and formulation steps, showing their potential, applicability and limits. It reports in a simplified version the theory behind acoustic spectroscopy, describes the most common equipment on the market, and finally overviews different studies performed on systems and materials used in the pharmaceutical or related fields. [ABSTRACT FROM AUTHOR]

Dextrans are a class of carbohydrate polymers extensively applied in pharmaceutical applications, particularly as drug conjugate macromolecular carriers or drug delivery systems. These polysaccharides improve the stability of the therapeutics enabling also the control of their release, via either the parenteral and or oral routes. In the latter case, due to their gel forming ability they may have potential as hydrophilic matrix tablets for sustained drug release. In this paper, we investigated the behaviour of different molecular weight (1, 40, 500 and 2300 kDa) dextrans as tabletting excipients. Powder particle size and hygroscopic studies have been reported, together with tabletability, tablet stability and tablet swelling. Moreover we use tramadol as model compound to evaluate the ability of dextrans to control drug dissolution. The results suggest that dextrans with lower molecular weights may be a promising excipient to be used as filler for immediate release tablets, due to their good tabletability and fast dissolution rate, while dextrans with higher molecular weights could be an efficient disintegrant due to their swelling ability. [ABSTRACT FROM AUTHOR]

Purpose: This work investigated the influence of a model protein, bovine serum albumin (BSA), on the properties of a thermogelling formulation intended for administration inside body compartments where there is high albumin content, as in the case of inflamed joints; it also explored the relation between the variation of these properties and release performance of methotrexate (MTX), a drug used to treat forms of arthritis and rheumatic conditions. Methods: The influence of BSA on the micellisation and gelation behaviour of Poloxamer 407, chosen as a model copolymer, was studied by differential scanning calorimetry (microDSC), dynamic light scattering (DLS), fluorescence spectroscopy and rheology studies. A release study of MTX loaded inside the hydrogel in presence and in absence of BSA was performed. Results: DLS and microDSC data revealed that the micellisation process was not affected by the protein, as demonstrated by unaltered micellar size and thermodynamic parameters. While the presence of BSA in the copolymer system reduced gel consistency, the hydrogel release performance was only slightly affected. Conclusion: Our results suggested that the kinetics of MTX release mainly depended on the presence of the thermogelling copolymer, although other mechanisms related to BSA could be involved. Finally, the study assessed the feasibility of using a thermogelling hydrogel for in situ drug administration in areas with the presence of high protein concentrations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop and evaluate a delivery system comprising a thermosensitive gel for the sustained release of steroidal hormones in fish, over an extended period of time after a single intramuscular ( i.m. ) injection and for the improved reproductive performance in fish. Controlled delivery systems based on thermosensitive gels are easy to prepare, low cost and high versatility dosage forms, which have been shown to be effective in several animal species for sustained release of hormones. In this work, a thermosensitive gel system based on poloxamer 407 in water:ethanol medium, able to work as a prolonged release carrier for 17β-estradiol (E2), has been developed. Such a system was able to solubilize the lipophilic E2 and to gel at the required water temperature for fish rearing (20 °C). Moreover, the system exhibited the best injection condition at temperatures below 15 °C when the system behaved as a low viscosity Newtonian liquid. The thermosensitive gel system was tested in vivo in the fish model, Carassius auratus , and the results compared with a single i.m. injection of E2 dissolved in corn-oil and other relevant control systems not containing E2. The results were particularly interesting, since fish injected with the E2 thermosensitive gel formulation, showed significantly higher levels of the circulating hormone than corn oil-E2 treated animals at 72 and 96 h after injection. In addition, the thermogel system was able to sustain the plasma level of E2 for about 11 days. The increased plasma levels of E2 were also accompanied by maintained higher values of plasma vitellogenin (VTG), thus suggesting that the thermosensitive polymer based delivery system could prevent rapid hepatic clearance of E2, resulting in prolonged stimulation of estrogen receptor-mediated pathways in goldfish. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: “Ready to use” products for the coating of solid dosage forms are constituted by film forming polymers and suitable additives in a fixed ratio. Despite the wide literature available for the single polymers and the impact of additives on their properties, the uncertainty on the composition of the “ready to use” products (for patent reasons) make their behaviour still not well known, at least outside the suggested conditions of use. Among the “ready to use” products, some of them, especially those for coloured films, are formed by two different formulated blends to mix together. The aim of this work is the characterization of one of these coating systems, the Sepifilm–Sepisperse platform, in terms of rheological properties of water dispersions and of thermo-mechanical properties of the free films, highlighting the effect of the ratio of the two products that have to be added together. Polymeric water dispersions were prepared with different concentrations of Sepifilm and several ratios of Sepifilm–Sepisperse. The prepared systems were then analysed in terms of viscosity and viscoelasticity. The results highlighted in both cases that it is the film former polymer concentration to mainly influence the system features. Polymeric free films were prepared by casting the water dispersion and drying the films at ambient conditions. The films were analysed by DMA applying tests able to characterize rheological and thermal properties. The results showed that the ratio of the two products influences the final free film properties, both in terms of glassy phase stiffness and transition from glassy to rubbery phase (glass transition, activation energy and fragility). [Copyright &y& Elsevier]

Abstract: This study shows novel and interesting applications of acoustic spectroscopy for characterisation of ternary systems such as isopropylmiristate (IPM)/polysorbate 80 (T)/water (W). Particle size and microrheological extensional moduli (i.e. G′ and G″) of different systems were determined by means of acoustic parameters such as sound attenuation and speed. Electric conductivity was also measured using the same instrument. The ultrasonic profile in terms of attenuation and sound speed in the megahertz frequency range, allowed the characterisation of the different zones of the ternary diagram such as microemulsion, emulsion and gel zones, as well as the evaluation of water state and particle size. This last parameter is a very effective tool in quantifying the phase transitions of systems and understanding which system is formed in any phase diagram zone. In fact, it is possible to analyse samples without dilution and despite their degree of turbidity, allowing complete characterisation of both properties and structure. [Copyright &y& Elsevier]

Purpose: To 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. Methods: Water 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. Results: Rheological 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. Conclusion: Poloxamer 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. [ABSTRACT FROM AUTHOR]

Abstract: It is common practice to coat oral solid dosage forms with polymeric materials for controlled release purposes or for practical and aesthetic reasons. Good knowledge of thermo-mechanical film properties or their variation as a function of polymer grade, type and amount of additives or preparation method is of prime importance in developing solid dosage forms. This work focused on the dynamic mechanical thermal characteristics of free films of hypromellose 2910 (also known as HPMC), prepared using three grades of this polymer from two different manufacturers, in order to assess whether polymer chain length or origin affects the mechanical or thermo-mechanical properties of the final films. Hypromellose free films were obtained by casting their aqueous solutions prepared at a specific concentrations in order to obtain the same viscosity for each. The films were stored at room temperature until dried and then examined using a dynamic mechanical analyser. The results of the frequency scans showed no significant differences in the mechanical moduli E′ and E″ of the different samples when analysed at room temperature; however, the grade of the polymer affected material transitions during the heating process. Glass transition temperature, apparent activation energy and fragility parameters depended on polymer chain length, while the material brand showed little impact on film performance. [Copyright &y& Elsevier]

Abstract: 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°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. [Copyright &y& Elsevier]

Abstract: This paper seeks to demonstrate the feasibility of using a novel analytical technique, acoustic spectroscopy, to characterize the dissolution kinetics of hydrophilic polymers, in particular, three different model polysaccharides: lambda carrageenan, gellan gum, and xanthan gum. The influence of particle size and of analysis temperature (25 or 45°C) was evaluated through the evolution over time of the microrheological acoustic parameters G′ and G″. This new method was then compared with classical rheological analysis. To better compare acoustic spectroscopy and rheological analysis, the initial dissolution rate from the slope of the first part of the G′ or viscosity versus time curves was calculated. Both analytical techniques gave the same rank order of kinetics for the powder types and fractions examined; differences in absolute values were due to the fact that the two methods measured different parameters and had different stirring efficiencies. The rheological data obtained with both methods of analysis and their modelling confirmed that acoustic spectroscopy is an effective tool for monitoring and quantifying dissolution kinetics and hence affords a powerful technique for following over time a great number of physical changes occurring in a specific system. [Copyright &y& Elsevier]

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. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1–42, 2009 [ABSTRACT FROM AUTHOR]

Acoustic spectroscopy affords a new and unique way to characterize concentrated suspension and emulsion while avoiding the limitations imposed by dilution, an undesirable step, particularly with highly structured samples. This study sought to illustrate the potentialities of this technique by using it to characterize the self-assembling behaviour of Poloxamer 407 systems (3–25%, w/v), both alone or after the addition of various amounts of hydroxypropyl β-cyclodextrin (5–20%, w/v). Particle size and the microrheological extensional moduli (G′ and G″) of the systems were determined from acoustic parameters such as sound attenuation and speed. By monitoring the variation of the particle size and the rheological extensional moduli at increasing temperatures, it was possible to define and outline the Poloxamer 407 transitions and the effect of the HP β-CD on them. Poloxamer 407 micelle formation due to progressive dehydration occurred within a temperature interval of 15°C (including gelation) and was dependent on poloxamer concentration. Particularly, particle size of the aggregates changed within this interval. Mean diameters were 600 nm at the onset of micelle formation and decreased after the thermogel formation to more or less 75 nm. The presence of HP β-CD changed the basic self-assembling mechanism of Poloxamer 407 by increasing micelle formation and particularly thermogelation temperatures. The results confirm that acoustic spectroscopy offers a powerful method for characterizing heterogeneous systems, thus indicating its potential for applications in the pharmaceutical field. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2217–2227, 2008 [ABSTRACT FROM AUTHOR]

Abstract: This paper deals with the rheological and thermal characterisation of the self-assembling behaviour of different Poloxamer 407 systems (15–30%, w/v), both alone or after the addition of various amounts of hydroxypropyl β-cyclodextrin (5–20%, w/v). The knowledge of the interactions existing between the two kinds of molecules could allow the development of systems for parenteral administration containing also proteins or peptides drugs. A rheology (temperature sweep and frequency sweep test) study has been performed to characterise the thermogelation process while thermal analysis (nanoDSC) allowed the determination of both micellization and sol/gelation transition processes. These two techniques were also utilised to outline the variation in the critical micelle temperature (cmT) or in the sol/gel temperature (sgT,) of the systems containing also hydroxypropyl β-cyclodextrin (HP β-CD). Both the rheology and thermal analysis showed the presence of interesting interactions between the HP β-CD and the Poloxamer 407, which cause a shift of both cmT and sgT. The presence of HP β-CD modified also Poloxamer samples elastic characters and microrheological structure as demonstrated by the G′–G″ mechanical spectra. Rheological and thermal results outlined how these new systems could open the possibility to join the thermogelling behaviour offered by Poloxamer 407 with the well-known stabilization and protection ability of HP β-CD, which could make possible the formulation of systems for the parenteral delivery of peptides and proteins. [Copyright &y& Elsevier]

Abstract: The characterization of the mechanical properties of single uncoated pellets was performed in order to verify if these parameters could be used to predict the pellets aptitude to be compressed or utilized differently. Different ratios of microcrystalline cellulose and lactose monohydrate were used for the preparation of four batches of pellets by an extrusion/spheronization process. The 0.6–0.71mm pellet fraction was used for the tests. Crushing strength and stress relaxation tests were carried out on the single pellets. The first test provided information of both the mechanical strength and the fragmentation aptitude. The second test provided information about their deformation ability (viscous flow) and residual elasticity (stress relaxation modulus). The results obtained from these tests were then compared with those obtained from the Heckel analysis. An excellent consistency was discovered between the parameters obtained from both the stress relaxation and crushing strength tests on one side and the Heckel parameters on the other side. Tests performed on single pellets are very useful tools to predict their deformation and fragmentation aptitude under compression and can be used for early insight of the pellet aptitude to be compressed. [Copyright &y& Elsevier]

Abstract: The aim of this work was to verify how and to what extent rheological tests, carried out under dynamic (Heckel) and static (creep, stress/strain) porosity conditions, may serve as a valuable complement to the classic Heckel tests in the characterization of viscoelastic and densification properties of solid materials for pharmaceutical use. Six different modified (pregelatinized) starches were compressed in a rotary tablet machine equipped to measure force and punch displacement. Tablets were obtained using flat-faced 6mm diameter punches at different compression pressures. Compression cycles performed at the maximal pressure of 200MPa were used to build the Heckel plots. Ejected tablets at the 10%, 20%, 30%, and 40% porosity levels were used for the stress/strain and creep tests. Parameters obtained with both types of tests were consistent with each other. In particular, among the six starches, lower viscosity values corresponded to lower P Y values, and lower elastic modulus values corresponded to lower elastic recovery of the tablet. Mechanical properties of materials can be better characterized if viscoelastic tests performed under dynamic porosity conditions (Heckel analysis) are supported by classical viscoelastic tests carried out under conditions of static porosity. [Copyright &y& Elsevier]

Abstract: Film coating is a technique widely used in the pharmaceutical field to improve and modify technological and release characteristics of capsules, tablets and granules. In this paper physical and mechanical properties of free films of Amprac 01, obtained by the solvent cast method, were studied in order to investigate the film forming ability of this modified starch and the effects of the addition of different plasticizers. A morphological microscopical analysis (SEM) was performed to study surface properties of the films, while thermal analysis (DSC) was carried out to investigate the influence of different types of plasticizers on the glass transition temperature of the polymer. Then a mechanical characterization permitted to evaluate important parameters such as film crack resistance and deformation at break. Extensional creep/relaxation tests were also performed to investigate the viscoelastic characteristics. As clearly demonstrated by the T g values, the residual water present in the films acted as plasticizers, making possible the formation of free films characterised by good macroscopical and mechanical properties. Except glycerol, the kind and amount of the other tested plasticizers did not markedly improve the mechanical and crack resistance of the films. [Copyright &y& Elsevier]

This article evaluated the thickening properties of two different Eudragits, L and RS, in tetraglycol cosolvent in order to obtain high viscosity systems characterized by controlled release properties. Tetraglycol was chosen for its ability to dissolve a wide range of water insoluble drugs, while Eudragit RS and L for their specific dissolution and permeability properties under physiological conditions. Study of the rheological properties was performed to characterize elastic and viscous properties of Eudragit/tetraglycol samples in function of frequency and temperature. For all systems, the results outlined a liquid like behavior, as observed for dilute polymer solutions. In fact the fitting of the log G′-log G′′ versus frequency curves showed a good agreement with the Rouse or Zimm models. So despite the increase in viscosity, samples still behaved like liquid systems. After the addition of paracetamol the release characteristics were defined pointing out the great release control properties of both Eudragit L and RS, which showed different release kinetics depending on the pH of the environment. Semisolid Eudragits/tetraglycol systems can be considered as a new alterative for the sustained release of insoluble or poorly water-soluble drugs. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:726–736, 2006 [ABSTRACT FROM AUTHOR]

Abstract: Gels dosage forms are successfully used as drug delivery systems considering their ability to control drug release and to protect medicaments from an hostile environment. This study deals with the gelation properties of Carbopol 971 e 974 polymeric systems in tetraglycol, a water-miscible cosolvent. In this paper, the attention was noted of the thickening properties of the different Carbopol in tetraglycol solvent at increasing temperatures, in order to obtain gels avoiding neutralisation and, at the same time, to make possible the dissolution in these gels of insoluble or poorly soluble water drugs. Samples were prepared by simply dispersing different Carbopols amount (0.5–4%) were added to tetraglycol and different systems were prepared at room temperature and by heating at 70°C. All these systems were then characterised rheologically. Frequency sweep, creep-recovery, temperature sweep and time sweep analyses outlined that Carbopol 971 and 974 in tetraglycol gave rise after heating to gels with satisfactory rheological behaviour: the elastic modulus was greater than the viscous one and a remarkable elastic character was found to be present. Systems obtained by heating procedure were examined also from a mechanical point of view using a texture profile analysis. Besides, being Carbopols well known mucoadhesive polymers, gels adhesive properties were also studied using the ex vivo method. Texture and adhesion characterisation confirmed rheological results pointing out a certain greater elasticity and adhesiveness of Carbopol 974 systems. Then, the possible cutaneous irritation was also tested using the in vivo method (Draize test). No signs of cutaneous irritation were obtained for all the samples that were analysed. After rheological and mucoadhesive properties were set, paracetamol as a model drug was inserted in the composition of the gels and the release characteristics were defined. Dissolution tests pointed out the greater release control properties of tetraglycol/Carbopol 971 samples. These studies showed tetraglycol/Carbopol systems as a first-rate alternative to traditional water gels when low water-soluble drugs have to be added. [Copyright &y& Elsevier]

A series of glyceryl monoolein/water gel systems containing 10%, 22%, and 30% w/w water has been investigated using two complementary techniques, oscillatory rheology and dielectric analysis, in order to establish the utility of these two techniques in conjunction and to investigate the influence of the inclusion of a model peptide, cyclosporin A, on the properties of the gels. Oscillatory rheology was performed in two modes; frequency sweeps at 20, 37, and 70°C and temperature sweeps from 20 to 70°C. Dielectric spectroscopy was performed in the kHz to mHz frequency range over a temperature range of 20–70°C. Both rheology and dielectric spectroscopy were able to identify structural changes in the systems analyzed, with the 10% and 30% (w/w) water sample showing typical features of the lamellar and cubic phase respectively at 20°C, while the 22% (w/w) system showed intermediate behavior. The thermotropic phase transitions could be monitored using rheological temperature sweeps. Drug loading resulted in marked changes in rheological and dielectric response of the 10% w/w water system, causing a decrease in both elasticity and permittivity values, while a less marked effect was observed for the 22% and, in particular, the 30% w/w systems. The investigation has demonstrated that rheological and dielectric measurements yield distinct yet complementary information and that the inclusion of a model peptide may alter the properties of the gel, the extent of the effect being dependent on the phase composition of the system. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2452-2462, 2005 [ABSTRACT FROM AUTHOR]

Carbopol is one of the most common thickening agent for water phases. It is used after neutralisation and its rheological properties in the aqueous medium are well known. The aim of this work was to investigate the gelation properties of Carbopol 971 e 974 polymeric systems in water-miscible cosolvents such as glycerine and PEG 400. Since in these cosolvents, carboxypolymethylene precipitates after neutralisation with a base, then the attention was pointed out of the gelation properties of the different systems at increasing temperature, in order to obtain Carbopols gels avoiding neutralisation and, at the same time, making possible the dissolution in these gels of insoluble or poorly soluble water drugs. Rheological properties of PEG 400 and glycerine samples were compared with similar systems in water by performing oscillatory analyses and measuring the main rheological parameters, G′, G″ and δ. The results obtained showed that Carbopol 971 and 974 in PEG 400 gave rise after heating to gels that show a satisfactory rheological behaviour. The elastic modulus is greater than the viscous one showing a remarkable elastic character of these samples and the performed frequency sweeps show a typical spectrum of a “gel-like” structure. Being Carbopols well-known mucoadhesive polymers, gels adhesive properties were studied using the ex vivo method. Then, the possible cutaneous irritation were also tested using the in vivo method (Draize test). No signs of cutaneous irritation and good mucoadhesive properties were obtained for the PEG 400 and water gels of Carbopol 974 prepared by heating.After rheological and mucoadhesive properties were set, paracetamol as a model drug was then inserted in the composition of the gels and the release characteristics were defined. Dissolution tests pointed out the greater release control properties of PEG 400-Carbopol 971 samples. These studies showed PEG 400-Carbopol systems as a first-rate alternative to traditional water gels. [Copyright &y& Elsevier]

Ketoprofen controlled release microspheres were prepared, by emulsion/solvent evaporation, at 15 °C, in order to avoid the formation of semisolid particles. An identical procedure was carried out at 60 °C to speed up the solvent evaporation and the formed semisolid microspheres were directly microencapsulated by complex coacervation and spray-dried in order to recover them as free flowing powder. Microspheres and microcapsules were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray diffractometry, in vitro dissolution studies, and then used for the preparation of tablets. During this step, the compressibility of the prepared powders was measured. Microspheres and microcapsules showed compaction abilities by far better than those of the corresponding physical mixtures. In fact, it was impossible to obtain tablets by direct compressing drug and polymer physical mixtures, but microspheres and microcapsules were easily transformed into tablets. Finally, in vitro dissolution studies were performed and the release control of the tablets was pointed out. Microspheres were able to control ketoprofen release only after their transformation into tablets. Tablets containing eudragit RS were the most effective in slowing down drug release. [Copyright &y& Elsevier]

PLGA-PEG-PLGA are copolymers, able to form temperature-dependent hydrogels or sol dispersions at selective conditions. A general overview about the rheological characterization of their aqueous dispersions, focusing how the structural characteristics (e.g. molecular weight, PEG/PLGA ratio) affect their temperature-dependent behaviour, is presented. Different PLGA-PEG-PLGA were synthesized by varying the amount of lactide and glycolide and the amount and molecular weight of PEG. All polymers were characterized by gel-permeation chromatography and differential scanning calorimetry. Then, polymeric dispersions in water (15%–25% w/w) were analysed by oscillatory rheological measurements. At solid state, all copolymers are amorphous and the calculated glass transition temperatures were dependent on PEG/PLGA ratio. As regard aqueous dispersions, the temperature-dependent rheological behaviour named "partially thermogelling" has been described, in addition to the commonly reported thermogelling one. In these samples, the consistency increases over temperature without forming a three-dimensional network as for real hydrogels. All rheological characteristics can be explained according to the proposed categorization (thermogel, partial thermogel and sol dispersion). Image 1 • All PLGA-PEG-PLGA copolymers are amorphous; T g values were dependent on the PEG/PLGA. • Aqueous dispersions were categorised in terms of temperature-dependent behaviour. • Partial thermogelling, thermogelling and sol rheological behaviours were described. • In partially thermogels, consistency increases over temperature without a 3D network. • Thermogels were observed for copolymers having a PEG/PLGA ratio around 0.45–0.5. [ABSTRACT FROM AUTHOR]

The coating process for solid dosage forms is widely used in the pharmaceutical industry but presents challenges for small-scale production, needed in personalized medicine and clinical or galenic settings. This study aimed to evaluate immersion coating, a cost-effective small-scale method, for enteric-coated gelatin capsules using standard equipment. Two enteric coating polymers and different polymer concentrations were tested, along with API solubility. Results were compared with commercially available enteric capsule shells. Successful preparation of enteric coating capsules via immersion necessitates a comprehensive grasp of API and enteric polymer behavior. However, utilizing commercially available enteric capsule shells does not guarantee ease or robustness, as their efficacy hinges on the attributes of the active ingredient and excipients. Notably, coating with Eudragit S100 stands out for its superior process robustness, requiring minimal or no development time, thus representing the best option for small-scale enteric capsule production. [ABSTRACT FROM AUTHOR]

Carlina acaulis root essential oil (EO) is one of the most potent mosquito larvicides (LC50 < 2 ppm). This EO is mainly composed of carlina oxide (> 90%). Poor water solubility and rapid degradation from UV light and oxygen in the environment limit the real-world use of this EO. Herein, we developed nanocarrier-based formulations, namely micro- and nanoemulsions (ME and NE, respectively) containing C. acaulis EO or carlina oxide (both at 0.5%) as active ingredients (a.i.). The larvicidal activity of ME and NE was evaluated against Culex quinquefasciatus. The highest larvicidal activity was achieved by the ME containing 0.5% of the EO (M1); its LC50(90) was 579.1 (791.3) µL L−1. Sublethal effects of this ME and its a.i. were assessed testing both at the LC16, LC30, LC50 and LC90 on mosquito larvae exposed to each product for 1–7 h, and then monitoring mortality for 18 days. At variance with the EO, ME application, even at LC16, led to 100% mortality at 18 days. The EO and its encapsulated form were scarcely toxic to human keratinocytes (HaCaT) and human fibroblast (NHF A12) cell lines. The acute toxicity of C. acaulis EO and its ME (M1) was also evaluated in Wistar rats through oral administration; EO LD50 was 1098 mg kg−1 bw, whereas its ME, even at 5000 mg kg−1 bw (considered the upper testing limit to establish safety to mammals), was not toxic. This study highlights the outstanding efficacy of C. acaulis EO ME for developing long-lasting and safe larvicides against Cx. quinquefasciatus. [ABSTRACT FROM AUTHOR]

Ropinirole is a non-ergolinic dopamine agonist used to manage Parkinson's disease and it is characterized by poor oral bioavailability. This study aimed to design and develop advanced drug delivery systems composed of poloxamer 407, a non-ionic surfactant (Tween 80), and cyclodextrins (methyl-β-CD or hydroxy-propyl-β-CD) for possible brain targeting of ropinirole after nasal administration for the treatment of Parkinson's disease. The hybrid systems were formed by the thin-film hydration method, followed by an extensive physicochemical and morphological characterization. The in vitro cytotoxicity of the systems on HEK293 cell lines was also tested. In vitro release and ex vivo mucosal permeation of ropinirole were assessed using Franz cells at 34 °C and with phosphate buffer solution at pH 5.6 in the donor compartment, simulating the conditions of the nasal cavity. The results indicated that the diffusion-controlled drug release exhibited a progressive increase throughout the experiment, while a proof-of-concept experiment on ex vivo permeation through rabbit nasal mucosa revealed a better performance of the prepared hybrid systems in comparison to ropinirole solution. The encouraging results in drug release and mucosal permeation indicate that these hybrid systems can serve as attractive platforms for effective and targeted nose-to-brain delivery of ropinirole with a possible application in Parkinson's disease. Further ex vivo and in vivo studies to support the results of the present work are ongoing. [ABSTRACT FROM AUTHOR]

Industrial hemp (Cannabis sativa L.), due to its bioactive compounds (terpenes and cannabinoids), has gained increasing interest in different fields, including for medical purposes. The evaluation of the safety profile of hemp essential oil (EO) and its encapsulated form (nanoemulsion, NE) is a relevant aspect for potential therapeutic applications. This study aimed to evaluate the toxicological effect of hemp EOs and NEs from cultivars Carmagnola CS and Uso 31 on three cell lines selected as models for topical and inhalant administration, by evaluating the cytotoxicity and the cytokine expression profiles. Results show that EOs and their NEs have comparable cytotoxicity, if considering the quantity of EO present in the NE. Moreover, cells treated with EOs and NEs showed, in most of the cases, lower levels of proinflammatory cytokines compared to Etoposide used as a positive control, and the basal level of inflammatory cytokines was not altered, suggesting a safety profile of hemp EOs and their NEs to support their use for medical applications. [ABSTRACT FROM AUTHOR]

Isofuranodiene is a bioactive furanosesquiterpene occurring as the major volatile compound in the essential oil from Smyrnium olusatrum (Apiaceae). It has a notable potentiality to be used as a botanical insecticide. However, its low solubility together with susceptibility to oxidation and thermal degradation limits its application on a wide scale. To face these challenges, isofuranodiene was encapsulated in stable microemulsions (MEs) at two concentrations (ME 750: 0.75%, ME 375: 0.375%). We assessed the larvicidal activity in the short term and after several days of exposure of pure isofuranodiene and its MEs against the filariasis vector Culex quinquefasciatus. The impact of ME-based larvicide at sublethal concentrations on adult emergence was evaluated. Finally, to shed light on potential ecotoxicology risks for nontarget invertebrates, MEs were tested on the aquatic microcrustacean Daphnia magna and on the earthworm Eisenia fetida. Pure isofuranodiene and S. olusatrum leaf essential oil, used as controls, showed their potential as mosquito larvicidal agents (LC50 of 29.2 and 18.6 μL L−1, respectively). Isofuranodiene formulated in ME 750 was effective against C. quinquefasciatus larvae, leading to significant larval mortality over time and a marked decrease in adult emergence. Both isofuranodiene MEs showed little impact on the nontarget aquatic microcrustacean Daphnia magna (ME 750 and ME 375: mortality < 19% after 48 h of exposure at 32 mL L−1 and 20 mL L−1, respectively) as well as on earthworms (ME 750 and ME 375: no mortality and mortality < 7% after 14 days of exposure to 1000 mg kg−1, respectively), outlining their potential employ in vector control operations. [ABSTRACT FROM AUTHOR]

Doxil ® is a stealth marketed PEGylated liposomal formulation, containing the anticancer drug doxorubicin. After loading via a pH gradient, fibrillar supramolecular structures of doxorubicin sulfate originates inside the core of the liposomes. Recently, the crystallinity of doxorubicin sulfate has been confirmed by high-resolution calorimetry. However, no detailed information are available on the nature of doxorubicin sulfate nanocrystals and on the effect of different thermal treatments. Thus, the aim of this work was to characterize the thermal behaviour of Doxil ® in comparison to the unloaded liposomes using microcalorimetry, dynamic light scattering and high-resolution ultrasound spectroscopy (HR-US). Different thermal programmes were applied with the aim to highlight the effect of the treatments on the formulation. The used techniques confirmed the ordered state of doxorubicin nanocrystals inside PEGylated liposomes. Particularly, microcalorimetry and HR-US highlighted the changes in the thermal behaviour of the drug under different heating programmes. Doxorubicin nanocrystals were found to be stable after heating up to 80 °C, but an irreversible thermal behaviour was observed after a prolonged heating at elevated temperature (2 h at 80 °C). The non-reversibility could be related to the formation of a different ordered structure and enhanced by the slight leakage of the drug occurring after a prolonged heating. [ABSTRACT FROM AUTHOR]

The use of surfactants as drug permeability enhancers across epithelial barriers remains a challenge. Although many studies have been performed in this field using synthetic surfactants, the possibility of employing surfactants produced by bacteria (the so called biosurfactants”) has not been completely explored. Among them, one of the most well characterized class of biosurfactants are rhamnolipids. The aim of the study was to investigate the effect of rhamnolipids on the epithelial permeability of fluorescein isothiocyanate-labelled dextrans 4 kDa and 10 kDa (named FD4 and FD10, respectively) as model for macromolecular drugs, across Caco-2 and Calu-3 monolayers. These cell lines were selected as an in vitro model for the oral and respiratory administration of drugs. Before performing permeability studies, rhamnolipids mixture was analysed in terms of chemical composition and quantification through mass analysis and HPLC. Cytotoxicity and transepithelial electrical resistance (TEER) studies were also conducted using Caco-2 and Calu-3 cell lines. A dose-dependent effect of rhamnolipids on TEER and FD4 or FD10 permeability across both cell lines was observed at relatively safe concentrations. Overall, results suggest the possibility of using rhamnolipids as absorption enhancers for macromolecular drugs through a reversible tight junction opening (paracellular route), despite more investigations are required to confirm their mechanism of action in term of permeability. [ABSTRACT FROM AUTHOR]

This study has investigated the potential use of zein protein from corn as a pharmaceutical excipient for formulation of oral controlled-release matrices. SMCC (silicified microcrystalline cellulose)-Prosolv® 90, SMCC HD-Prosolv® 90 HD, Avicel® PH 102 and Mannitol 60 were evaluated as co-excipients to improve the processability of zein powder. Zein/SMCC-Prosolv® 90 blend had the best flowability and tabletability. Tablets with tramadol hydrochloride, zein and SMCCProsolv® 90 were prepared by direct compression. Drug release from the tablets was measured by dissolution testing. The dissolution profiles obtained were compared using the dissolution efficiency (DE) and were fitted to the Korsmeyer–Peppas equation. Controlled drug release, governed by anomalous (non-Fickian) drug transport, was obtained over the test duration. Drug release rate and mechanism were dependent on formulation parameters, such as tablet hardness, zein/SMCC ratio and drug loading, as well as medium pH. Dynamics of tablets swelling correlated well with drug release rate and mechanism, with faster drug release and greater contribution of polymer relaxation being obtained at increased swelling. In conclusion, the present work has shown that zein/SMCC based matrix formulation can be used as a new platform for oral-controlled drug delivery which can be easily customized by adjusting formulation parameters. The use of this formulation could be attractive for customers and manufacturers who prefer to avoid synthetic or chemically modified excipients. [ABSTRACT FROM AUTHOR]

Purpose: Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections. Methods: Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations. Results: Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution. Conclusions: Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

A dietary supplement potentially employed for the treatment and/or prevention of hyperlipidemia was developed. The proposed product is composed of a combination of natural macromolecules as chitosan (CH), α-cyclodextrin (α-CD), and lupin proteins (LP). First, the anti-hyperlipidemic effect of the α-CD and LP binary mixture was assessed and compared to that of the extensively utilized anti-hyperlipidemic CH, using a hyperlipidemic rat model. The anti-hyperlipidemic effect of their combination was also demonstrated. Additionally, ligand–target and protein–protein docking studies were performed. The in vivo results displayed that on intergroup comparison, blending CH, α-CD, and LP promised a superior therapeutic effect over α-CD and LP mixture, CH, and the marketed atorvastatin, potentiating a considerable reduction of serum lipid profile and the calculated atherogenic risk predictor indices. Molecular docking study revealed a weak hydrophobic cholesterol–CH and cholesterol–α-CD interactions, while protein–protein docking study showed a good lipase–LP interaction, involving eight hydrogen bonds. Then, on the base of the in vivo and docking study results, a tablet formulation was produced aimed to overcome the negative technological effects of the anti-hyperlipidemic macromolecules: long disintegration time and tablets mechanical resistance. The optimized tablet formulation has a disintegration time shorter than 15 min and a weight loss from friability test lower than 1%, which are in line with the regulatory specifications for uncoated tablets. Overall, this anti-hyperlipidemic formulation is attractive for the dietary and nutraceutical market, despite further clinical studies are required to assess the efficacy, possible side effects, and product compliance. [ABSTRACT FROM AUTHOR]

The aim of this research was to prepare novel block copolymer-surfactant hybrid nanosystems using the triblock copolymer Pluronic 188, along with surfactants of different hydrophilic to lipophilic balance (HLB ratio—which indicates the degree to which a surfactant is hydrophilic or hydrophobic) and thermotropic behavior. The surfactants used were of non-ionic nature, of which Tween 80® and Brij 58® were more hydrophilic, while Span 40® and Span 60® were more hydrophobic. Each surfactant has unique innate thermal properties and an affinity towards Pluronic 188. The nanosystems were formulated through mixing the pluronic with the surfactants at three different ratios, namely 90:10, 80:20, and 50:50, using the thin-film hydration technique and keeping the pluronic concentration constant. The physicochemical characteristics of the prepared nanosystems were evaluated using various light scattering techniques, while their thermotropic behavior was characterized via microDSC and high-resolution ultrasound spectroscopy. Microenvironmental parameters were attained through the use of fluorescence spectroscopy, while the cytotoxicity of the nanocarriers was studied in vitro. The results indicate that the combination of Pluronic 188 with the above surfactants was able to produce hybrid homogeneous nanoparticle populations of adequately small diameters. The different surfactants had a clear effect on physicochemical parameters such as the size, hydrodynamic diameter, and polydispersity index of the final formulation. The mixing of surfactants with the pluronic clearly changed its thermotropic behavior and thermal transition temperature (Tm) and highlighted the specific interactions that occurred between the different materials, as well as the effect of increasing the surfactant concentration on inherent polymer characteristics and behavior. The formulated nanosystems were found to be mostly of minimal toxicity. The obtained results demonstrate that the thin-film hydration method can be used for the formulation of pluronic-surfactant hybrid nanoparticles, which in turn exhibit favorable characteristics in terms of their possible use in drug delivery applications. This investigation can be used as a road map for the selection of an appropriate nanosystem as a novel vehicle for drug delivery. [ABSTRACT FROM AUTHOR]

BACKGROUND: Solvent‐free microwave‐assisted extraction (MAE) is a green extraction method capable of boosting the yield and quality profile of hemp essential oil when compared with other conventional extraction techniques. During this process, two by‐products are produced, namely the aqueous residue containing bioactive phenolics and the residual deterpenated biomass, which can be used for further extraction and purification of phytocannabinoids. To date, the hemp industry has not utilized these products, although they can be valuable for the food, cosmetic, nutraceutical and pharmaceutical market. RESULTS: This study assessed and optimized the variables affecting MAE efficiency, namely microwave irradiation power, extraction time and added water, which were studied using a central composite design approach, and results were used to optimize the extraction process for recovering three valuable fractions: essential oil, polyphenols and phytocannabinoids. The products obtained using the optimized conditions were characterized in terms of yield, chemical profile and antioxidant potential. Moreover, the by‐products obtained during the optimized run were further analyzed in terms of their biological activity using both enzymatic and non‐enzymatic assays. The aqueous residue demonstrated a powerful α‐glucosidase inhibition, a good activity in terms of superoxide radical scavenging activity, a modest efficacy in terms of inhibition of advanced glycation end products formation and no activity in terms of lipase inhibition. The residual deterpenated biomass did not possess significant biological activity. CONCLUSION: This work demonstrated valorization of industrial hemp essential oil and its by‐products, obtained by a sustainable and eco‐friendly extraction method, through an almost waste‐free approach. Cannabinoids as well as other valuable bioactive compounds such as glycosidic flavones may be recovered from the residues of the essential oil extraction, representing interesting substances in the pharmaceutical, cosmetic and nutraceutical fields. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Essential oils (EOs) represent innovative and safe botanical pesticides to be exploited in different fields, including agriculture, being often obtained by cheap and easily available plant crops. However, their use is threatened by some limits, which are mainly linked to their physico-chemical properties. In this regard, the use of nanoemulsions (NEs) usually enables to overcome these limits but often also to improve the biological activities of these products. Bunium persicum (Boiss.) B Fedtsch. and Ziziphora clinopodioides Lam. are two aromatic plants of economic interest well known for their traditional food and medical uses. Their EOs exhibited several biological properties, including a remarkable insecticidal activity against different targets. Here, the chemical analysis of the two EOs revealed the predominance of γ -terpinene (35.8%), cumin aldehyde (16.6%), γ -terpinen-7-al (14.0%), and α -terpinen-7-al (11.7%) for B. persicum , and pulegone (55.6%), piperitenone (12.8%), and iso -menthone (8.0%) for Z. clinopodioides. NEs were successfully obtained by high-pressure homogenization or ultrasonication method, using polysorbate 80 as emulsifier. The EOs and their 10% NEs were evaluated against larvae and pupae of Culex quinquefasciatus Say mosquitoes. In detail, both EOs exhibited a good larvicidal efficacy (LC 50 of 35.8 and 68.9 µL L−1 for B. persicum and Z. clinopodioides , respectively). Bunium persicum EO NE showed higher efficacy than the EO alone (LC 50 = 290.4 µL L−1), considering that only the 10% of the EO was encapsulated. Conversely, Z. clinopodioides NE showed the same efficacy than the EO alone (LC 50 of 759.8 µL L−1). In addition, both NEs displayed significantly better sublethal toxicity compared with the EOs. Moreover, even if no significant mortality was detected in the pupal stage, only 12% of the larvae pupated and emerged as adults in the case of the NE from B. persicum. In conclusion, both EOs and their NEs could be promising candidates for the development of botanical pesticides, also considering the commercial availability and affordability of these EOs. • Bunium persicum and Ziziphora clinopodioides are valuable sources of essential oils. • Their nanoemulsions were obtained by obtained by high-pressure homogenization. • Nanoemulsions evaluated for toxicity and sublethal effects on Culex quinquefasciatus. • Nanoemulsions showed same contact toxicity than essential oils alone. • Nanoemulsions showed better sublethal toxicity than essential oils. [ABSTRACT FROM AUTHOR]

High-resolution ultrasound spectroscopy (HR-US) is a spectroscopic technique using ultrasound waves at high frequencies to investigate the structural properties of dispersed materials. This technique is able to monitor the variation of ultrasound parameters (sound speed and attenuation) due to the interaction of ultrasound waves with samples as a function of temperature and concentration. Despite being employed for the characterization of several colloidal systems, there is a lack in the literature regarding the comparison between the potential of HR-US for the determination of phospholipid thermal transitions and that of other common techniques both for loaded or unloaded liposomes. Thermal transitions of liposomes composed of pure phospholipids (dimyristoylphosphatidylcholine, DMPC; dipalmitoylphosphatidylcholine, DPPC and distearoylphosphatidylcholine, DSPC), cholesterol and their mixtures were investigated by HR-US in comparison to the most commonly employed microcalorimetry (mDSC) and dynamic light scattering (DLS). Moreover, tramadol hydrochloride, caffeine or miconazole nitrate as model drugs were loaded in DPPC liposomes to study the effect of their incorporation on thermal properties of a phospholipid bilayer. HR-US provided the determination of phospholipid sol-gel transition temperatures from both attenuation and sound speed that are comparable to those calculated by mDSC and DLS techniques for all analysed liposomal dispersions, both loaded and unloaded. Therefore, HR-US is proposed here as an alternative technique to determine the transition temperature of phospholipid membrane in liposomes. [ABSTRACT FROM AUTHOR]

[Display omitted] • Microwave extraction enhanced spilanthol content in Acmella oleracea essential oil. • Spilanthol was isolated and used for comparative purposes. • The essential oil was encapsulated into a nanoemulsion. • Its acute toxicity and impact on fertility were evaluated on Culex quinquefasciatus. • Cytotoxicity and anti-inflammatory effects were determined in human cells. Acmella oleracea (L.) R.K. Jansen, also named jambù, is an edible and medicinal plant native to Brazil but extensively cultivated all over the world due to its diverse utilizations in food, cosmetics, pharmaceutics, and pest management science. Most of applications are related to the presence of active ingredients, namely alkylamides, among which spilanthol is the most important one. On the other hand, the plant biomass resulting from the large-scale cultivation of A. oleracea may yield an essential oil (EO), which can be used for some industrial purposes, for instance as larvicide against vector mosquitoes. This EO is mainly characterized by mono- and sesquiterpenes, however also spilanthol can be detected in the mixture. To maximize the content of spilanthol in the A. oleracea EO, A. oleracea aerial parts obtained from a cultivation in central Italy were subjected to microwave-assisted extraction (MAE). This procedure allowed to obtain a higher yield and spilanthol content when compared with traditional hydrodistillation (0.47 v 0.22 %, and 13.31 vs 2.24 %, respectively). The EO terpene fraction was mainly represented by β- pinene (10.8 %), myrcene (12.3 %), (E)-caryophyllene (19.4 %) and α- humulene (1.1 %). The A. oleracea EO was encapsulated into a nanoemulsion (NE) containing 6 % EO using a high-energy method. The formulation physical stability was assessed by optical microscope and DLS analyses at different timepoints showing stability up to one year of storage. The A. oleracea EO and its NE, along with the isolated spilanthol, were evaluated for acute toxicity against the 3rd instar larvae of Culex quinquefasciatus , a filariasis and arbovirus vector of public health importance, achieving LC 50 values of 16.1, 407.5, and 3.1 μL/L, respectively. The larvicidal activity seemed to be not dependent on the interaction with the cholinergic system, as shown by the high IC 50 values of A. oleracea EO and spilanthol exhibited in the anti-acetylcholinesterase (AChE) assay. Testing LC 30 values, the A. oleracea -borne products showed a significant impact on larval development, fecundity, fertility and natality of C. quinquefasciatus. Testing LC 30 values, the A. oleracea EO-NE provided a higher efficacy than spilanthol, reducing the adult fertility, in terms of egg hatchability (%) and the overall abundance of F 1 larvae. These results can be considered as promising for the development of new mosquito larvicides. The safety use of A. oleracea EO, NE and spilanthol was demonstrated in assays on mammalian fibroblasts and microglia cells, showing low level of cytotoxicity coupled with protective effects against inflammation. [ABSTRACT FROM AUTHOR]

[Display omitted] • The development of green insecticides for real-world use is a major challenge. • This review focuses on Apiaceae-borne botanicals effectiveness against mosquitoes. • Essential oils and main constituents as mosquitocidal/repellent agents are reviewed. • Modes of action of Apiaceae essential oils and their major compounds are discussed. • Toxicity on non-target species and micro/nano-formulation development is analysed. Apiaceae is a family encompassing medicinal and aromatic plants. They produce essential oils (EOs) inside oil canals, known as ducts and vittae, which occur in their vegetative and reproductive organs. Given the high EO yields and the availability of raw material from cultivations widespread all over the world, Apiaceae are exploitable for different industrial applications. An interesting perspective is their utilization in the fabrication of botanical insecticides effective against insect vectors of public importance such as mosquitoes, aiming to be eco-friendly alternatives to synthetic insecticides. On this basis, in the current review, we collected scientific evidence supporting the use of Apiaceae EOs and their major constituents as active ingredients in insecticidal formulations against larvae and adults of several mosquitoes that are important pathogen vectors (e.g., Anopheles , Aedes and Culex species). For this purpose, we analysed the published data on their larvicidal, ovicidal, oviposition deterrent, pupicidal, adulticidal, and repellent effects, using efficacy thresholds as in the case of larvicidal activity (LC 50 (lethal concentration killing 50 % of the exposed population) < 50 ppm). Toxicity to non-target organisms, including vertebrates, has also been reviewed. The major EO constituents have been highlighted, each with its spectrum of mosquitocidal activity, providing insights on their multiple modes of action. The urgent need to develop highly stable micro/nano-formulations for real-world use has been outlined. Current weaknesses and strengths in the steps toward the development of botanical insecticides have been analysed to increase awareness of the future challenges necessary to open the doors to the industrial utilization of Apiaceae EOs by agrochemical companies. [ABSTRACT FROM AUTHOR]

The effect of punch tilting on the mechanism of punch penetration in the die of a rotary tablet machine during the compression cycle was evaluated by installing four displacement transducers on one station of a rotary machine. Two transducers were symmetrically positioned beside the upper punch in the upper turret, and the other two transducers were similarly placed beside the lower punch in the lower turret. Microcrystalline cellulose and dicalcium phosphate dihydrate were compressed at 5, 10, 15 and 20 kN using two different machine speeds, in order to quantify the effect of punch tilting in the evaluation of punch penetration. These compression data served to construct the powder bed reduction curves, from which it was possible to establish that punch tilting is directly proportional to the compression force used. Tilting is maximal at the beginning of the dwell time, disappears at half dwell time, and reaches a new maximum at the end of the dwell time. In latter case, tilting occurred in the direction opposite that of the first maximum. The impact of tilting in powder densification behaviour, evaluated through the construction of Heckel plots, depends on the compression force used in the analysis. Heckel plots are as distorted as the compression force is elevated. Consequently, the calculated Heckel parameters differ from the real values. Unless a very low compression force is used, a proper Heckel analysis can be performed in a rotary machine only if it is fitted with a device that includes the effect of punch tilting in the evaluation of punch penetration. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1277–1284, 2008 [ABSTRACT FROM AUTHOR]

Abstract: Differences in the dynamics of powder densification between eccentric and rotary machine were pointed out by compressing at different compression pressures microcrystalline cellulose, lactose monohydrate and dicalcium phosphate dihydrate and recovering the corresponding stress/strain data in both machines equipped to monitor punches displacement and compression forces. Heckel plots were then obtained from these stress/strain data. Curves obtained in the rotary machine possess a narrower zone of linearity for the calculation of P Y and D A. The effect of the different compression mechanism of the rotary machine on the shape of the Heckel plot is more noticeable in a non-deforming material such as dicalcium phosphate. The effect of the longer dwell time of the rotary machine on the porosity reduction occurring after the maximum pressure has been reached, is more noticeable in a ductile material such as microcrystalline cellulose. Heckel parameters obtained in the rotary press are in some cases different from those recovered in the eccentric machine because of the longer dwell time, machine deflection and punch tilting occurring in the rotary machine, although theoretically they could better describe the material densification in a high speed production rotary machine. [Copyright &y& Elsevier]

Well known mucoadhesive polymers such as Carbopol 974P and Pharmacoat 606 and three different mucosas (sublingual, oesophageal and duodenal bovine) were used to verify how the mucoadhesive properties of materials may depend on the mucosa characteristics and if a polymer may reveal more mucoadhesive than another and vice versa by changing the type of interacting mucosa. So, tablets of Carbopol 974P and Pharmacoat 606 were prepared and their mucoadhesion on the three mucosas was set in terms of maximum load and work of detachment, using a texture analyzer. At the same time, mucosas were characterized by immunohistochemical techniques and lectin histochemistry. Results obtained from the Tensile test analyses show that the adhesive power of the two polymers is different in the three mucosas. Particularly, in the sublingual mucosa, Carbopol was more mucoadhesive than Pharmacoat. On the contrary, Pharmacoat was more mucoadhesive than Carbopol in duodenal mucosa. The significantly different behavior of polymers was correlated with the desquamation layer thickness and the differential sialic acid and fucose exposition in the targeted mucosas. [Copyright &y& Elsevier]

• mPEG-PLGA NPs, loaded with saquinavir mesylate (SQV), were incorporated inside carbopol (C974)-based hydrogel as a vaginally administered prevention or therapeutic treatment for HIV infection. • Hydrogel consistency was reduced by increasing NPs amount at a fixed C974 concentration. • mPEG-PLGA NPs had a relevant effect in promoting the incorporation of the drug inside hydrogel despite its moderate loading. • As a consequence, the incorporation NPs in the formulation led to a higher amount of the drug released from the hydrogel, using an immersion cell release apparatus. • The in vitro findings of the study could have an impact also on the in vivo bioavailability of the drug. Saquinavir mesylate (SQV) is a protease inhibitor commonly employed for the treatment of human immunodeficiency virus-1 infection. It is generally administered orally as tablets in combination with other antiviral drugs. Another promising route of administration can be represented by the vaginal one through topically applied formulations. This delivery can reduce the first-pass effect in the case of systemic drug adsorption or prevent HIV infection. We propose the formulation of a Carbopol® 974 (C974) hydrogel containing biodegradable mPEG-PL(L)GA nanoparticles (NPs) for the vaginal delivery of SQV, intended both as a prevention and a therapeutic strategy. mPEG-PL(L)GA NPs were incorporated into the C974 polymeric matrix, leading to a reduction of the hydrogel consistency dependent on NPs and C974 concentrations. Despite the moderate drug loading into NPs, the presence of the NPs had an impact on the in vitro release of the drug from the hydrogel at pH 5.5 using immersion cells. A higher amount of the drug was released, probably due to the effect of NPs in promoting the incorporation of the drug into the hydrogel at a high SQV dose. These findings can be useful for the development of topically applied hydrogels for SQV delivery, possibly having improved in vivo therapeutic outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Formulation development and non-target effect studies are two crucial steps for the registration of new botanical insecticides. Previous reports put in evidence the potential of hemp (Cannabis sativa L.) essential oil (EO) as a new candidate ingredient for developing green insecticides. However, the validation of its target and non-target effects after proper encapsulation is missing so far. In the current work, we investigated the insecticidal efficacy of the EO obtained from the hemp variety 'Kompolti', and we optimized its formulation development into a nanoemulsion (NE). The latter was assayed against larvae of Culex quinquefasciatus Say, a well-known vector of Wuchereria bancrofti Cobbold, avian malaria, and several arboviruses, such as Western equine encephalitis virus, St. Louis encephalitis virus, West Nile virus, and Zika virus. Considering the percentage of encapsulated EO (7.5% w/w), the developed NE showed mortality on Cx. quinquefasciatus larvae, in terms of LC 50(90) values [72.2 (207.2) ppm], like those of pure EO [50.8(142.3) ppm]. Non-target toxicity experiments showed limited toxicity on the aquatic microcrustacean Daphnia magna Straus (i.e., mortality <16% after 48 h of exposure to the EO-based NE at the LC 90 estimated on mosquito larvae). Considering that the LC 50 values detected in this study are lower than those belonging to many EOs, and that the application at sublethal doses caused mortality between 39.1% and 40.8% as well as a reduction in mosquito fertility resulting in a reduction in natality of 40.4% and 45.1% for the EO and EO-based NE, respectively, both products may be considered as potential environmentally friendly and sustainable insecticides. [Display omitted] • Kompolti hemp essential oil was encapsulated in nanoemulsions. • The insecticidal efficacy of hemp essential oil and its nanoemulsion was assessed. • Both formulations had high acute toxicity on Culex quinquefasciatus larvae. • Both products had limited impact on the aquatic microcrustacean Daphnia magna. [ABSTRACT FROM AUTHOR]

Amphiphilic polymers represent one of the main class of stabilizers for non-lamellar lyotropic liquid crystalline nanoparticles, being essential for their formation and stability. In the present study, poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO- b -PCL) block copolymers and poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (MPOx) gradient copolymers were incorporated as stabilizers in liquid crystalline nanoparticles prepared from glyceryl monooleate. The polymers were chosen according to their high biocompatibility and promising stealth properties, in order to develop safe and efficient drug delivery nanosystems. The physicochemical characteristics and fractal dimension of the resultant nanosystems were obtained from light scattering techniques, while their micropolarity and microfluidity from fluorescence spectroscopy. The effect of temperature, serum proteins and ionic strength on the physicochemical behavior was monitored. Their morphology was assessed by cryo-TEM, while their thermal behavior by microcalorimetry and high-resolution ultrasound spectroscopy. Their properties were dependent on the stabilizer chemistry and topology (block/gradient copolymer) and its concentration. Subsequently, resveratrol, as model hydrophobic drug, was loaded into the nanosystems, the entrapment efficiency was calculated and in vitro release studies were carried out, highlighting how the different stabilizer can differentiate the drug release profile. In conclusion, the proposed copolymers broaden the toolbox of polymeric stabilizers for the development of liquid crystalline nanoparticles intended for drug delivery applications. [ABSTRACT FROM AUTHOR]

• Hemp essential oil was obtained by microwave-assisted extraction. • The operative conditions were optimized using a central composite design. • CBD-enriched essential oil can be obtained by MAE optimization. • Hydrodistillation was carried out for comparative purposes. • The enantiomeric ratio of chiral terpenes was determined. The increase of cultivation of industrial hemp (Cannabis sativa L.) all over the world offers new opportunities for the industry to manufacture innovative products from this multipurpose crop. In this regard, the hemp essential oil represents a niche product with potential interest for the pharmaceutical, nutraceutical, cosmeceutical and agrochemical companies. On this basis, in the present work we used the microwave-assisted extraction (MAE) to get an essential oil enriched in bioactive compounds, especially cannabidiol (CBD), from the dry inflorescences of the Italian variety CS (Carmagnola Selezionata). For this purpose, the operative conditions to increase the essential oil yield and CBD concentration in terms of microwave irradiation power (W/g), extraction time (min) and water added to the plant matrix after moistening (%), were optimized using a central composite design (CCD) approach using a Milestone ETHOS X device. The conventional hydrodistillation (HD) performed for 240 min was used for comparative purposes. The qualitative compositions of essential oils obtained by MAE and HD were analysed by GC-MS, whereas the quantitative detection of CBD and main terpenoids (α-pinene, β-pinene, myrcene, limonene, terpinolene, (E)-caryophyllene, α-humulene and caryophyllene oxide) was achieved by GC-FID. Furthermore, the enantiomeric distribution of the chiral constituents (α-pinene, β-pinene, limonene, (E)-caryophyllene and caryophyllene oxide) was determined using chiral chromatography. Results showed that the MAE treatment, using high irradiation power and relatively long extraction times, increased significantly the content of CBD in the essential oil while maintaining high oil yield values when compared with conventional HD. The enantiomeric excess of three chiral monoterpenes (α-pinene, β-pinene and limonene) was determined, with the (+)-enantiomers being predominant, whereas (E)-caryophyllene and caryophyllene oxide were enantiomerically pure. In conclusion, the MAE was successfully applied to hemp dry inflorescences in order to obtain a CBD-rich essential oil which may be exploited in several industrial applications. [ABSTRACT FROM AUTHOR]

The interest around essential oils is constantly increasing thanks to their biological properties exploitable in several fields, from pharmaceuticals to food and agriculture. However, their widespread use and marketing are still restricted due to their poor physico-chemical properties; i.e., high volatility, thermal decomposition, low water solubility, and stability issues. At the moment, the most suitable approach to overcome such limitations is based on the development of proper formulation strategies. One of the approaches suggested to achieve this goal is the so-called encapsulation process through the preparation of aqueous nano-dispersions. Among them, micro- and nanoemulsions are the most studied thanks to the ease of formulation, handling and to their manufacturing costs. In this direction, this review intends to offer an overview of the formulation, preparation and stability parameters of micro- and nanoemulsions. Specifically, recent literature has been examined in order to define the most common practices adopted (materials and fabrication methods), highlighting their suitability and effectiveness. Finally, relevant points related to formulations, such as optimization, characterization, stability and safety, not deeply studied or clarified yet, were discussed. [ABSTRACT FROM AUTHOR]

Nowadays the use of sustainable polymers as poly-lactic acid (PLA) and poly-δ-decalactone (PDL) in drug delivery is advantageous compared to polymers derived from fossil fuels. The present work aimed to produce microparticles (MPs) derived from novel sustainable polymers, loaded with triamcinolone acetonide (TA) for treatment of rheumatoid arthritis via intra-articular (IA) delivery. PDL was synthesized from green δ-decalactone monomers and co -polymerized with methoxy-polyethylene glycol (mPEG) forming PEG-PDL with different molecular weights. The Hansen's solubility parameters were applied to select the most compatible polymer with the drug. An o/w emulsion/solvent evaporation technique was used for MPs fabrication, using 3 [ 3 ] full factorial design. Selection of the optimized MPs was performed using Expert Design® software's desirability function. The optimized formulations were characterized using scanning electron microscope, powder X-ray diffraction, differential scanning calorimetry, infrared spectroscopy and in vitro release studies. The inhibition percents of inflammation and histopathological studies were assessed in complete Freund's adjuvant-induced rats' knee joints evaluating the effect of IA injections of selected MPs compared to the free drug suspension. Solubility studies revealed high compatibility and miscibility between TA and PEG-PDL 1700 , which was blended with PLA for convenient MPs formation. The in vitro characterization studies confirmed the formation of drug-copolymer co-crystals. The in vivo studies ensured the superiority of the newly designed composite MPs in inflammation suppression, compared to the free drug suspension and PLA MPs as well. The present study proved the advantage of using sustainable polymers in a novel combination for effective drug delivery and suggesting its usefulness in designing versatile platforms for therapeutic applications. Unlabelled Image • Six different PEG-PDL copolymers were synthesized using ring opening polymerization. • Hansen's solubility parameters confirmed high drug–copolymer compatibility. • TA-loaded PLA/PEG-PDL MPs were developed and optimized via a statistical design. • In vitro characterization studies endorsed the formation of TA-copolymer co-crystal. • The composite MPs showed a sustained anti-inflammatory action in rats' arthritic joints. [ABSTRACT FROM AUTHOR]

[Display omitted] Lubricants are excipients used in tablet formulations to reduce friction and adhesion forces within the die or on the punches surface during the manufacturing process. Despite these excipients are always required for the tablets production, their amount must be carefully evaluated since lubricants can negatively impact on mechanical strength, disintegration and dissolution behavior of solid dosage forms. Alternative compounds have been suggested to overcome the issues of conventional lubricants and sodium lauryl sulfate (SDS) is one of the most promising one. Despite SDS has been object of several investigations, a definitive conclusion on its effectiveness cannot still be drawn. Particularly, its efficacy on tablets disaggregation and API dissolution is still unclear. Here, the effect of SDS on all the relevant features of tablets and tableting process has been evaluated on immediate release hydrophobic tablets formulations in comparison with conventional lubricants. The results of this investigation are quite outspoken: SDS has a low lubricant power while it determines only a limited improvement on tablets hardness. It greatly improves the tablets wettability but only on model formulations, the presence of superdisintegrants resets its effectiveness and any possible effect on tablets disaggregation. None of the tested formulations showed improvement on the API dissolution rate. [ABSTRACT FROM AUTHOR]