Synthesis and Properties of Sucrose- and Lactose-Based Aromatic Ester Surfactants as Potential Drugs Permeability Enhancers

The delivery of therapeutics across biological membranes (e.g., mucosal barriers) by avoiding invasive routes (e.g., injection) remains a challenge in the pharmaceutical field. As such, there is the need to discover new compounds that act as drug permeability enhancers with a favorable toxicological profile. A valid alternative is represented by the class of sugar-based ester surfactants. In this study, sucrose and lactose alkyl aromatic and aromatic ester derivatives have been synthesized with the aim to characterize them in terms of their physicochemical properties, structure–property relationship, and cytotoxicity, and to test their ability as permeability enhancer agents across Calu-3 cells. All of the tested surfactants showed no remarkable cytotoxic effect on Calu-3 cells when applied both below and above their critical micelle concentration. Among the explored molecules, lactose p-biphenyl benzoate (URB1420) and sucrose p-phenyl benzoate (URB1481) cause a reversible ~30% decrease in transepithelial electrical resistance (TEER) with the respect to the basal value. The obtained result matches with the increased in vitro permeability coefficients (Papp) calculated for FTIC-dextran across Calu-3 cells in the presence of 4 mM solutions of these surfactants. Overall, this study proposes sucrose- and lactose-based alkyl aromatic and aromatic ester surfactants as novel potential and safe permeation enhancers for pharmaceutical applications

Toxicological profiles and surface properties at physiological pH of N-decanoyl amino acids

Meeting title: From Food to Pharma: the polyhedral nature of polymersPURPOSE: N-acyl amino acids based surfactants are an attractive class of anionic amphiphiles alternative to sulphate-based surfactants potentially employed as excipients in all pharmaceutical applications at which an anionic surfactant (eg. sodium dodecyl sulphate SDS) is needed (1, 2). The aim of this work is to correlate surface properties of N-decanoyl amino acids at physiological pH and their toxicological profile in order to explore the potential use of these surfactants for …postprin

Chitosan nanoparticles embedded hydrogels as a novel nanomedicine based strategy for the treatment of vaginal infections

The use of chitosan as a mucoadhesive and antimicrobial biopolymer in topical formulations has been widely explored [1]. Particularly, chitosan-based hydrogels have been formulated for vaginal administration in order to prolong the residential time of the formulation in the vaginal cavity and to enhance the antibacterial or antifungal activity of the delivered drug [2]. In this field, a nanomedicine-based approach employing chitosan as a nanocarrier has been developing in recent year for the treatment of vaginal infections [3,4]. We propose here the formulation of a mixed hydrogel based on chitosan nanoparticles embedded inside a hydroxypropyl methylcellulose (HPMC) matrix for the vaginal delivery of metronidazole as an antimicrobial drug. HPMC hydrogels containing chitosan as a free polymer were also prepared as comparison. Firstly, chitosans with different molecular weights (Mw) and degree of acetylation (DD) were screened in acetate buffer at pH 4.5 in term of size and stability of the prepared nanoparticles. Then, chitosan with a low Mw (90%) was chosen and the hydrogels containing 0.1%, 0.5% and 1% w/w of nanoparticles were prepared. The hydrogels were characterized in terms of their rheological behaviour and mucoadhesiveness. The presence of chitosan as free polymer or as nanoparticles did not markedly affect the strength of the hydrogel, but it slightly increased its mucoadhesive properties. The antimicrobial activity of the hydrogels was assessed in agar well diffusion method (AWDM) by testing the formulation containing 1% of chitosan (as free polymer or nanoparticles) loaded or unloaded with 0.75% w/w of metronidazole against three human clinical isolates of Candida spp. The growth inhibition area clearly indicated the crucial role exerted by chitosan in the formulation against Candida spp. Our results demonstrate the possibility of incorporating chitosan nanoparticles inside a polymeric hydrogel and its effectiveness as a promising formulation for the treatment of vaginal infection

Antioxidant Properties of Ester Derivatives of Cinnamic and Hydroxycinnamic Acids in Nigella sativa and Extra-Virgin Olive Oils-Based Emulsions

New hydrophobic derivatives of cinnamic and hydroxycinnamic (ferulic and cumaric) acids obtained by chemical esterification of the carboxylic group with C10 linear alcohol were studied to evaluate their antioxidant capacity toward the superoxide anion and hydrogen peroxide in physiological buffer and in extra-virgin olive oil (EVO) or Nigella sativa oils. Results showed that cumaric and ferulic acids have higher antioxidants activity against superoxide anion and hydrogen peroxide than the other compounds. Cumaric acid and its C10-ester derivative were selected to be incorporated into EVO or Nigella sativa oil-based emulsions. The prepared emulsions had a comparable particle size distribution (in the range of 3-4 µm) and physical stability at least up to three months. Nigella sativa oil-based emulsions loaded with cumaric acid or its C10-ester showed a higher capacity to scavenger superoxide anion and hydrogen peroxide than EVO oil-based emulsions. In conclusion, cumaric acid or its C10-ester could promote the antioxidant properties of Nigella sativa oil when formulated as emulsions

Liquid crystalline nanoparticles for drug delivery: The role of gradient and block copolymers on the morphology, internal organisation and release profile

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

Environmentally Friendly Method of Assembly of Cardanol and Cholesterol into Nanostructures Using a Continuous Flow Microfluidic Device

This study shows a viable and straightforward microfluidic method of assembly of cardanol (CA) and cholesterol (CH) into amphiphile nanostructures obtained through a hydrodynamic focusing approach according to which an alcoholic solution of CA and CH is constrained within a two-dimensional lamina shape by two lateral streams of borate buffer solution. The process is performed within glass-made cross-shaped micro-sized fluidic chips specially designed to achieve a laminar regime. CA, distilled from the cashew nut shell liquid, is demonstrated as a surface-active molecule in borate buffer basic medium and when mixed with CH it produces versatile nanovesicles through an in-batch solvent-free process. Compared to this conventional method, the microfluidic route allows operating under continuous flows, with a reduced amount of reagents and at lower experimental temperatures, ensuring no waste formation and the achievement of size-monodisperse amphiphile nanostructures that do not need further steps of purification. Electron microscopy analyses demonstrate that upon increasing CH in the lipid mixture, a switchover from spherical CA micelles to CA/CH mixed closed vesicles occurs. Differential scanning microcalorimetry confirms the formation of vesicular structures and evidences the primary role of CH, which increasingly lowers the temperature of transition depending on its concentration

Unveiling the Performance of Co-Assembled Hybrid Nanocarriers: Moving towards the Formation of a Multifunctional Lipid/Random Copolymer Nanoplatform

Despite the appealing properties of random copolymers, the use of these biomaterials in association with phospholipids is still limited, as several aspects of their performance have not been investigated. The aim of this work is the formulation of lipid/random copolymer platforms and the comprehensive study of their features by multiple advanced characterization techniques. Both biomaterials are amphiphilic, including two phospholipids (1,2-dioctadecanoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)) and a statistical copolymer of oligo (ethylene glycol) methyl ether methacrylate (OEGMA) and 2-(diisopropylamino) ethyl methacrylate (DIPAEMA). We examined the design parameters, including the lipid composition, the % comonomer ratio, and the lipid-to-polymer ratio that could be critical for their behavior. The structures were also probed in different conditions. To the best of the authors' knowledge, this is the first time that P(OEGMA-co-DIPAEMA)/lipid hybrid colloidal dispersions have been investigated from a membrane mechanics, biophysical, and morphological perspective. Among other parameters, the copolymer architecture and the hydrophilic to hydrophobic balance are deemed fundamental parameters for the biomaterial co-assembly, having an impact on the membrane's fluidity, morphology, and thermodynamics. Exploiting their unique characteristics, the most promising candidates were utilized for methotrexate (MTX) loading to explore their encapsulation capability and potential antitumor efficacy in vitro in various cell lines