A promising eco-sustainable wound dressing based on cellulose extracted from Spartium junceum L. and impregnated with Glycyrrhiza glabra L extract: Design, production and biological properties.

Glycyrrhiza glabra extract is widely known for its antioxidant and anti-inflammatory properties and can improve the wound healing process. The aim of this work was to shorten the time of the healing process by using an eco-sustainable wound dressing based on Spanish broom flexible cellulosic fabric by impregnation with G. glabra extract-loaded ethosomes. Chemical analysis of G. glabra extract was performed by LC-DAD-MS/MS and its encapsulation into ethosomes was obtained using the ethanol injection method. Lipid vesicles were characterized in terms of size, polydispersity index, entrapment efficiency, zeta potential, and stability. In vitro release studies, biocompatibility, and scratch test on 3 T3 fibroblasts were performed. Moreover, the structure of Spanish broom dressing and its ability to absorb wound exudate was characterized by Synchrotron X-ray phase contrast microtomography (SR-PCmicroCT). Ethosomes showed a good entrapment efficiency, nanometric size, good stability over time and a slow release of polyphenols compared to the free extract, and were not cytotoxic. Lastly, the results revealed that Spanish broom wound dressing loaded with G. glabra ethosomes is able to accelerate wound closure by reducing wound healing time. To sum up, Spanish broom wound dressing could be a potential new green tool for biomedical applications.

Azithromycin-loaded liposomes and niosomes for the treatment of skin infections: Influence of excipients and preparative methods on the functional properties.

The aim of this study was to develop azithromycin (AZT)-loaded liposomes (LP) and niosomes (NS) useful for the treatment of bacterial skin infections and acne. LP based on phosphatidylcholine from egg yolk (EPC) or from soybean lecithin (SPC), and NS composed of sorbitan monopalmitate (Span 40) or sorbitan monostearate (Span 60) were prepared through the thin film hydration (TFH) and the ethanol injection (EI) methods. The formulations were subsequently characterized for their physico-chemical and functional properties. Vesicles prepared through TFH showed higher average sizes than the corresponding formulations obtained by EI. All the vesicles presented adequate encapsulation efficiency and a negative ζ potential, which assured good stability during the storage period (except for LP-SPC). Formulations prepared with TFH showed a more prolonged AZT release than those prepared through EI, due to their lower surface area and multilamellar structure, as confirmed by atomic force microscopy nanomechanical characterization. Finally, among all the formulations, NS-Span 40-TFH and LP-EPC-TFH allowed the highest drug accumulation in the skin, retained the antimicrobial activity and did not alter fibroblast metabolism and viability. Overall, they could ensure to minimize the dosing and the administration frequency, thus representing promising candidates for the treatment of bacterial skin infections and acne.

Mucoadhesive and mucopenetrating chitosan nanoparticles for glycopeptide antibiotic administration.

The use of nanoparticles (NPs) represents a useful strategy for peptide antibiotic delivery to mucosal membranes by either prolonging drug residence time at the target site (mucoadhesive NPs) or by enhancing diffusion across mucus layer to reach the underlying epithelium (mucopenetrating NPs). The purpose of this study was to design chitosan (CH) NPs and to evaluate their employment as mucoadhesive and/or mucopenetrating systems for vancomycin (VM) delivery. NPs were prepared by ionic gelation of CH with sodium carboxymethylcellulose (CMC), sodium alginate (ALG), sodium tripolyphosphate (TPP) or phytic acid (PA) and characterized in terms of size, zeta-potential, morphology, drug encapsulation efficiency, mucoadhesion and mucopenetrating ability. Moreover, in vitro tests were conducted to evaluate VM release and the antibacterial activity against Staphylococcus aureus and Bacillus subtilis. NPs showed sizes ranged from 150 nm to 350 nm with good polydispersity index and positive zeta-potential. The selection of the suitable crosslinker allowed to modulate the mucoadhesive/mucopenetrating properties: CH/TPP NPs showed the best mucoadhesive ability, while CH/PA and CH/CMC NPs were characterized by an improved diffusion across the mucus layer. Further, NPs allowed a fast and complete release of VM, maintaining the antibacterial activity against the tested bacteria species.

Microparticles based on chitosan/carboxymethylcellulose polyelectrolyte complexes for colon delivery of vancomycin.

The aim of this work was to prepare polyelectrolyte complexes based on chitosan (CH) and carboxymethylcellulose (CMC) for colon delivery of vancomycin (VM). Various batches of polyelectrolyte complexes, using three different CH/CMC weight ratios (3:1, 1:1 and 1:3), were prepared and collected as microparticles by spray-drying process. Microparticles were characterized in terms of yield, encapsulation efficiency, drug loading, morphology and mucoadhesion properties. Microparticles water-uptake and VM release as well as its protection against gastric pepsin degradation were also investigated. Finally, the antibacterial activity against Staphylococcus aureus, a Gram-positive model strain, was evaluated. The best formulation CH/CMC 1:3 was selected based on the encapsulation efficiency, water-uptake and drug release rate. Moreover, microparticles were able to prevent VM degradation and showed a good antibacterial activity against S. aureus. Finally, to improve the release of VM in the colon the selected formulation was coated with lauric acid.

Chitosan based micro- and nanoparticles for colon-targeted delivery of vancomycin prepared by alternative processing methods.

The aim of this work was to prepare chitosan (CH) based particulate formulations for colon delivery of vancomycin (VM). Chitosan microparticles (MPs) and nanoparticles (NPs) loaded with VM were prepared using different CH/tripolyphosphate (TPP) molar ratios and different technological processes. In particular, nanoparticles were prepared by ionic gelation and freeze-drying to recover these particles, or, alternatively, by spray-drying method. Microparticles were prepared using a different spray-dryer. Micro- and nanoparticles were characterized in terms of size distributions by photon correlation spectroscopy (PCS), while encapsulation and drug loading efficiencies were studied using a dialysis method. Fourier Transform Infrared Spectroscopy (FT-IR) was employed to determine the surface composition of the micro- and nanoparticles respectively, and the morphologies of the developed systems were studied by scanning electron microscopy (SEM). Water uptake as well as drug release profiles were also measured. Antibacterial activity against Staphylococcus aureus, a Gram-positive model strain, was evaluated. FT-IR results suggested an electrostatic interaction between VM and CH/TPP particles. Moreover, the particles were found to hold a positive zeta-potential, indicating the presence of CH on the particle surfaces. Particle size and encapsulation efficiency were mainly influenced by the different manufacturing processes employed. Nanoparticles obtained by spray-drying showed the best results in terms of water uptake and drug release rate. Moreover, they showed a good bactericidal activity against S. aureus.

Chitosan/alginate complexes for vaginal delivery of chlorhexidine digluconate.

Chitosan/alginate complexes were prepared at different polycation/polyanion molar ratios and freeze-dried vaginal inserts were obtained for chlorhexidine digluconate local delivery in genital infections. Complex yield, FT-IR spectra, and TGA thermograms were studied to confirm the interaction between the two polyions. The influence of different complexes on physical handling, morphology, and drug distribution in the samples were evaluated by friability test, scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS), respectively. In vitro water-uptake, mucoadhesion and release tests were performed as well as microbiological tests toward pathogenic vaginal microorganisms. The results showed that the selection of suitable chitosan/alginate molar ratio and drug loading allowed modulate insert ability to hydrate, adhere to the mucosa, and release chlorhexidine digluconate. The insert containing an excess of alginate was found to be the best performing formulation and showed good antimicrobial activity toward the pathogens Candida albicans and Escherichia coli.

Chitosan/pectin polyelectrolyte complexes: selection of suitable preparative conditions for colon-specific delivery of vancomycin.

The influence of polyelectrolyte complexes composed of chitosan and pectin on the release behaviour of vancomycin has been investigated. Polyelectrolyte complexes between chitosan and pectin were prepared in various pH regions and at different molar ratios by mixing solutions of pectin and chitosan with the same ionic strength. The precipitates were collected by spray-drying and tablets were obtained with the different complexes and vancomycin. FT-IR spectra and TGA thermograms were analysed to study the degree of interactive strength between polyions. In vitro swelling, mucoadhesion and release tests were performed in order to investigate the chitosan/pectin complex ability in the delivery of vancomycin in the gastro-intestinal tract. The results confirmed the formation of polyelectrolyte complexes between pectin and chitosan at pH values in the vicinity of the pKa interval of the two polymers. Chitosan/pectin complexes showed a pH-sensitive swelling ability and drug release behaviour suggesting their possible use for colon-specific localization of vancomycin. Among the different complexes, chitosan/pectin complex prepared in molar ratio of 1:9 showed the highest mucoadhesive properties and a pH-dependent swelling sensitivity suitable for colon-delivery. Moreover, the particular composition of these complexes improved vancomycin availability at alkaline pH on the bases of an enzyme-dependent degradation as confirmed from release studies performed in presence of beta-glucosidase.

Capillary electrophoretic analysis of the antibiotic vancomycin in innovative microparticles and in commercial formulations.

A new fast capillary electrophoretic method has been developed for the analysis of the glycopeptide antibiotic vancomycin in formulations. An electrophoretic run is completed within 3.0 min; fused silica capillaries (100 microm i.d., 8.5 cm effective length and 48.5 cm total length) and a background electrolyte consisting of 12.5 mM, pH 2.5 phosphate buffer are used. The applied voltage is -20.0 kV; samples are injected by pressure (30 mbar x 3 s) at the anodic end of the capillary. The method was successfully applied to innovative controlled release microparticles consisting of a coated albumin core containing vancomycin. A simple procedure has been developed to obtain complete vancomycin extraction from microparticles using a 5% (w/v) sodium dodecyl sulphate aqueous solution. The method has been validated in terms of linearity, precision and accuracy. Good linearity was found in the 0.25-5.00 microg/mL range. Satisfactory precision was obtained, with relative standard deviation values always lower than 3.9%; accuracy was satisfactory, with recovery values between 97.8 and 102.2%. The method is also suitable for vancomycin determination in commercial capsules.

Bovine serum albumin nanospheres carrying progesterone inclusion complexes.

Bovine serum albumin nanospheres carrying cyclodextrin complexes for the delivery of progesterone were produced. Inclusion complexes composed of progesterone and hydroxypropyl-beta-cyclodextrin or dimethyl-beta-cyclodextrin were prepared by spray-drying or freeze-drying methods. Prog alone and its inclusion complexes were incorporated into bovine serum albumin nanospheres using a coacervation method and cross-linking with heating. The nanosphere suspensions were essicated by spray-drying or freeze-drying. The inclusion complexes and the nanospheres were characterized by Fourier Transform-Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC). Phase-solubility diagrams and stability constants were determined in distilled water at different temperatures (10, 25, and 37 degrees C). Size of nanospheres, their drug loading capacity and swelling ability were evaluated, as well as the in vitro controlled release profiles at pH 5.5 and 7.4.

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems.

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a beta-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.

Micelles based on polyvinyl alcohol substituted with oleic acid for targeting of lipophilic drugs.

Polymeric micelles based on polyvinyl alcohol substituted with oleic acid were used as vehicles for progesterone and folic acid. The ability of this amphiphilic polymer to entrap lipophilic drugs and to generate stable micelles in aqueous neutral medium makes it a good candidate for drug delivery. The release of the loaded drugs in acidic environments represents another important property of these systems. Size of micelles, their stability, and their drug-loading capacity were evaluated, as well as the in vitro controlled-release profiles at pH 7.4 and 5.5.

Polymeric nanoparticles composed of fatty acids and polyvinylalcohol for topical application of sunscreens.

Benzophenone-3 (BZP) or oxybenzone is widely used in many cosmetic formulations, such as sunscreen lotions or emulsions, shampoos and hair sprays. The nature of the vehicle used can enhance or block the percutaneous absorption of UV filter. In this work, we hydrophobically modified polyvinylalcohol 10 000 (PVA) with fatty acids (FAs) to obtain PVA-FA derivatives for the preparation of lipophilic polymeric nanoparticles able to prevent BZP movement towards the skin. Synthesized PVA-FA derivatives were confirmed by H1 NMR. Nanoparticles loaded with BZP were prepared using a solvent extraction method. The particle size was monitored by means of dynamic light scattering measurements. In-vitro skin permeation studies were performed.

Crosslinked poly(methyl vinyl ether-co-maleic anhydride) as topical vehicles for hydrophilic and lipophilic drugs.

Poly(methyl vinyl ether-co-maleic anhydride) crosslinked with ethylene glycol (GZ-ET), 1,4-butanediol (GZ-BUT), 1,6-exandiol (GZ-EX), 1,8-octanediol (GZ-OCT), 1,10-decanediol (GZ-DEC) or 1,12-dodecanediol (GZ-DOD) was prepared and employed as a supporting material for aqueous topical gels containing pyridoxine hydrochloride (PYCL) chosen as a hydrophilic model molecule or for O/A emulsion containing beta-carotene chosen as a hydrophobic model molecule. We analyzed the effect of the nature of the crosslinker on the permeation of hydrophilic and lipophilic vitamins through porcine skin by in vitro permeation studies. The vehicles formed by crosslinked poly(methyl vinyl ether-co-maleic anhydride) showed enhanced vitamins permeation with respect to the same vehicles formed by noncrosslinked poly(methyl vinyl ether-co-maleic anhydride) (GZ). The decrease in the crosslinker acyl chain length provides vehicles accelerating the drug permeability through the skin.

Analytical methods for the determination of folic acid in a polymeric micellar carrier.

Amphiphilic copolymers have been the object of growing scientific interest due to their ability to form polymeric micelles in aqueous environments entrapping lipophilic drugs in their inner core. In this study, polyvinylalcohol substituted with oleic acid was employed as an amphiphilic micellar carrier for folic acid (FA), a model drug similar for its chemical-physical characteristics to methotrexate. In order to investigate the stability of the polymeric micelles, the drug incorporation and the kinetic aspects of drug release from these systems, selective analytical methods are required. The development of three analytical methods suitable for selectively identifying and reliably determining FA contained in the micelles and in the delivery systems is reported. UV derivative (first and second order) spectrophotometry was first applied to the aqueous solution of the FA containing micelles obtained at pH 9.0 and provided a characteristic spectral profiling with sharp peaks, related to the analyte, whose amplitude was used for quantitative application. A second approach involved a solid phase extraction (strong anion exchanger), which provided an effective clean up of the FA micelles solution, allowing accurate analysis to be performed also by a conventional spectrophotometric method. A RP-HPLC method, selectively supplying the FA separation from the micelles' components, was then used as a reference method to determine the accuracy of the spectrophotometric methods. These methods were applied to various micelle composition and to the delivery system study.

Controlled release of vancomycin from freeze-dried chitosan salts coated with different fatty acids by spray-drying.

The aim of this study was to describe a controlled drug release system based on chitosan salts for vancomycin hydrochloride delivery. Chitosan aspartate (CH-Asp), chitosan glutamate (CH-Glu) and chitosan hydrochloride (CH-HCl) were prepared by freeze-drying and coated with stearic, palmitic, myristic and lauric acids by spray-drying technique. Vancomycin hydrochloride was used as a peptidic model drug whose sustained release should minimize its inactivation in the upper part of the gastrointestinal tract. This study evaluated, in vitro, the influence of chitosan salts on the release behaviour of vancomycin hydrochloride from the freeze-dried and spray-dried systems at pH 2.0 and 7.4.

Effect of chitosan on progesterone release from hydroxypropyl-beta-cyclodextrin complexes.

An inclusion complex composed of progesterone (Prog) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) was prepared by the spray-drying and freeze-drying methods. Prog alone and its inclusion complex with HPbetaCD were incorporated into chitosan by spray-drying and freeze-drying. The inclusion complex was characterized by IR and DSC. The inclusion complex was investigated in solution by phase solubility diagrams and stability constant was determined at pH 7.4 and at different temperatures (10, 25 and 37 degrees C) to obtain the thermodynamic parameters of inclusion. The results indicate that the Prog-HPbetaCD inclusion complex is more water soluble than Prog alone. Release data from all samples showed significant improvement of the dissolution rate of Prog and a controlled release is obtained in the presence of chitosan.

Chitosan salts as nasal sustained delivery systems for peptidic drugs.

The aim of this study was to describe a sustained drug release system based on chitosan salts for vancomycin hydrochloride delivery. Chitosan lactate, chitosan aspartate, chitosan glutamate and chitosan hydrochloride were prepared by spray-drying technique. Vancomycin hydrochloride was used as a model peptidic drug, the nasal sustained release of which should avoid first-pass metabolism in the liver. This in-vitro study evaluated the influence of chitosan salts on the release behaviour of vancomycin hydrochloride from the physical mixtures at pH 5.5 and 7.4. In-vitro release of vancomycin was retarded by chitosan salts and, in particular, chitosan hydrochloride provided the lowest release of vancomycin.

Physically cross-linked chitosan hydrogels as topical vehicles for hydrophilic drugs.

Physically cross-linked chitosan hydrogels with lauric, myristic, palmitic or stearic acid were prepared by freeze-drying and have been studied for topical use. This study selected propranolol hydrochloride as a hydrophilic model drug to design a transdermal delivery system. We evaluated the effect of the nature of the cross-linker on drug permeation through porcine skin and the main permeation parameters (diffusion coefficient, flux and lag time) were calculated. All the chitosan hydrogels analysed provided more transcutaneous permeation of propranolol hydrochloride than the corresponding solution of the commercial drug. Among the different chitosan vehicles, chitosan-laurate and chitosan-myristate hydrogels enhanced lyophilised drug diffusion through the skin with respect to chitosan-palmitate and chitosan-stearate hydrogels. This can been explained by the interaction of the hydrogels with the stratum corneum, increasing the solubility of the drug in the skin.

Poly(vinylalcohol-co-vinyloleate) for the preparation of micelles enhancing retinyl palmitate transcutaneous permeation.

The amphiphilic properties of poly(vinylalcohol) substituted with oleic acid was evaluated to assess the possibility to prepare polymeric micelles in an aqueous phase containing a hydrophobic core able to host lipophilic drugs such as retinyl palmitate and thereby enhance its transcutaneous absorption in the stratum corneum. The effect of the increased drug absorption suggests the possibility of interaction between the substituted polymer and the components present in the intercorneocyte spaces. Correlations between the drug concentration in the preparative mixture, micelle size, and drug permeation were evaluated to establish the best functional properties of the micellar systems enhancing retinyl palmitate absorption. Transcutaneous absorption increased with decreasing micelle size, and micelle size decreased on decreasing the drug concentration in the preparative mixture.

Hydrogels formed by crosslinked poly(vinyl alcohol) as sustained drug delivery systems.

Poly(vinyl alcohol) was crosslinked with ethylene glycol diglycidyl ether to obtain hydrogel-forming polymers. The polymers were also substituted with oleoyl chloride, providing hydrogels with weak solubility. These new polymeric materials were evaluated for the formulation of sustained drug delivery systems. Vancomycin hydrochloride was used as a peptidic model drug whose sustained release should minimize its inactivation in the upper part of the gastrointestinal tract. Spray-dried mixtures of the drug and the polymer [at 1:4 and 1:8 (w:w) ratios] were prepared and the release of the drugs from the mixtures was evaluated in vitro at pH 2.0, 5.5, 7.4, and 8.0. The results indicated that the crosslinked polymers slowed down the release of the drugs with respect to the pure drug at each pH. The degree of crosslinking of ethylene glycol diglycidyl ether and the extent of substitution with oleoyl chloride were found to influence drug release.