Giulia Auriemma

Dry powder inhalers of gentamicin and leucine: formulation parameters, aerosol performance and in vitro toxicity on CuFi1 cells

The high hygroscopicity of gentamicin (G) as raw material hampers the production of respirable particles during aerosol generation and prevents its direct use as powder for inhalation in patients suffering from cystic fibrosis (CF). Therefore, this research aimed to design a new dry powder formulation of G studying dispersibility properties of an aminoacid, L-leucine (leu), and appropriate process conditions. Spray-dried powders were characterized as to water uptake, particle size distribution, morphology and stability, in correlation with process parameters. Aerodynamic properties were analyzed both by Single Stage Glass Impinger and Andersen Cascade Impactor. Moreover, the potential cytotoxicity on bronchial epithelial cells bearing a CFTR F508/F508 mutant genotype (CuFi1) were tested. Results indicated that leu may improve the aerosol performance of G-dried powders. The maximum fine particle fraction (FPF) of about 58.3% was obtained when water/isopropyl alcohol 7:3 system and 15-20% (w/w) of leu were used, compared to a FPF value of 13.4% for neat G-dried powders. The enhancement of aerosol efficiency was credited both to the improvement of the powder flowability, caused by the dispersibility enhancer (aminoacid), and to the modification of the particle surface due to the influence of the organic co-solvent on drying process. No significant degradation of the dry powder was observed up to 6 months of storage. Moreover, particle engineering did not affect either the cell viability or cell proliferation of CuFi1 over a 24 h period.

Design and production of gentamicin/dextrans microparticles by supercritical assisted atomisation for the treatment of wound bacterial infections

In this work, the supercritical assisted atomisation (SAA) is proposed, for the first time, for the production of topical carrier microsystems based on alginate-pectin blend. Gentamicin sulphate (GS) was loaded as high soluble and hygroscopic antibiotic model with poor flowability. Particularly, different water solutions of GS/alginate/pectin were processed by SAA to produce spherical microparticles (GAP) of narrow size (about 2 μm). GS loading was varied between 20% and 33% (w/w) with an encapsulation efficiency reaching about 100%. The micronised powders also showed high flow properties, good stability and constant water content after 90 days in accelerated storage conditions. The release profiles of the encapsulated drug were monitored using vertical diffusion Franz cells to evaluate the application of GAP microsystems as self-consistent powder formulation or in specific fibres or gels for wound dressing. All formulations showed an initial burst effect in the first 6h of application (40-65% of GS loaded), and in particular GAP4 produced with a GS/alginate/pectin ratio of 1:3:1, exhibited the ability to release GS continuously over 6 days. Antimicrobial tests against Staphylococcus aureus indicated that GS antibiotic activity was preserved at 6 days and higher than pure GS at 12 and 24 days for all SAA formulations, especially for GAP1.

Design of Alginate-Based Aerogel for Nonsteroidal Anti-Inflammatory Drugs Controlled Delivery Systems Using Prilling and Supercritical-Assisted Drying

In this study, a novel preparation method for alginate-based aerogels charged with nonsteroidal anti-inflammatory drugs (NSAIDs) was developed using prilling in combination with supercritical fluid technique. Nanoporous carriers were prepared by laminar jet breakup of drug/alginate solutions or suspensions followed by cross-linking in ethanol or aqueous CaCl(2) solutions, water replacement, and supercritical-CO(2) -assisted drying. A substantial drug loss was observed for highly soluble ketoprofen lysinate, whereas encapsulation efficiency was satisfying for slightly soluble ketoprofen. The tandem technique successfully produced almost spherical aerogels (sphericity coefficient 0.97-0.99) in narrow size distribution with reduced particle shrinkage and smooth surface (surface roughness 1.10-1.13); the internal porous texture of the parent hydrogels was preserved and appeared as a network of nanopores with diameters around 200 nm. Drug release profiles were monitored using a pH change method to evaluate the possible application of the aerogels as fast dissolving NSAIDs formulation. Aqueous cross-linking led to aerogels encapsulating ketoprofen in the amorphous form and with an enhanced burst effect in simulated gastric fluid (75% in 30 min), whereas ethanol cross-linking produced aerogels embedding drug in crystal clusters with slower dissolution rate. The system appears an interesting potential carrier for the fast delivery of slightly soluble drugs in the upper gastrointestinal tract.

Prilling for the development of multi-particulate colon drug delivery systems: Pectin vs. pectin–alginate beads

This paper proposes a multi-particulate drug delivery system produced by prilling technique in combination with an enteric coating. Optimization of process parameters, such as feed viscosity at nozzle, selection of cross-linker, pH of the gelling solution and cross-linking time, allows to obtain beads with strong gelled matrix. Results showed that dextran/piroxicam beads demonstrated high encapsulation efficiency, very narrow dimensional distribution and high sphericity. Coated beads retained shape and narrow size distribution of the uncoated particles. Moreover, the strength of the produced Zn(2+)-pectinate beads allows to reduce Eudragit coating thickness. Piroxicam loaded multi-particulate systems show an interesting prolonged drug release in intestinal fluids. Hence, such platforms could be proposed for the treatment of inflammatory bowel diseases.

Piroxicam loaded alginate beads obtained by prilling/microwave tandem technique: Morphology and drug release

This paper presents a tandem technique, based on the combination of prilling and microwave (MW) assisted treatments, to produce biodegradable alginate carriers of piroxicam with different drug controlled release behaviours. Results showed that alginate/piroxicam beads demonstrated high encapsulation efficiency and very narrow dimensional distribution. Beads dried by MW retained shape and size distribution of the hydrated particles while drying rate was strongly increased compared to convective drying processes. Moreover, different MW irradiation regimes promoted interactions between the drug and alginate matrix, affected drug polymorphism as well as inner and surface matrix structure leading to different piroxicam release profiles. High level MW irradiation led to beads with highly porous and swellable matrix able to release piroxicam in few minutes in the intestine while convective drying produced gastro-resistant beads that exhibit sustained piroxicam release (total release in 5.5h) in intestinal environment. On these results the tandem technique prilling/MW irradiation appears to be promising to obtain alginate carrier with tailored NSAIDs release depending on drug characteristics and MW irradiation.

In situ forming antibacterial dextran blend hydrogel for wound dressing: SAA technology vs. spray drying

This study focuses on designing microparticulate carriers based on high-mannuronic alginate and amidated pectin blend loaded with gentamicin sulphate able to move rapidly from dry to soft hydrogel. Supercritical assisted atomization was used to produce microparticles in form of dry powder and characteristics were compared with those obtained by spray-drying. Particles with very high encapsulation efficiency (approximately 100%) and small diameter (less than 2 μm) showed good flowability and high fluid uptake enabling wound site filling and limiting bacterial proliferation. Moisture transmission of the in situ formed hydrogel was about 95 g/m(2)h, ideal to avoid wound dehydration or occlusion phenomena. All formulations presented a burst effect, suitable to prevent infection spreading at the beginning of the therapy, followed by prolonged release (4-10 days) related to drug/polymers ratio. Antimicrobial tests showed stronger effect than pure GS over time (up-to 24 days) and the ability to degrade preformed biofilms, essential to properly treat infected wounds.

A combined technique based on prilling and microwave assisted treatments for the production of ketoprofen controlled release dosage forms

In this study the feasibility of joining prilling and microwave (MW) assisted treatments as combined technique to produce controlled release alginate beads was tested. Beads were produced by prilling (laminar jet break-up) using different polymer concentrations and loaded with ketoprofen, a slightly soluble non-steroidal anti-inflammatory BCS class II drug characterized by low melting point. MW assisted treatments applied using different irradiating conditions were performed as drying/curing step. The effect of formulation conditions and process variables on drying kinetics, particle micromeritics, shape, surface and inner characteristics of the matrix as well as drug loading and drug release behaviour was studied (USP pH change method). The properties of MW dried particles were compared to those dehydrated by convective methods (room conditions and tray oven 105°C). Results showed that MW dried ketoprofen loaded beads were obtained in a very narrow dimensional range retaining shape and size distribution of the hydrates particles. Compared to the traditional drying methods, MW treatments were able to strongly increase drying rate of the hydrated beads achieving faster and controllable dehydration kinetics. Moreover, different regimes of irradiation affected structural properties of the particles such as matrix porosity as well as the solid state of the loaded drug. DSC, X-ray and FTIR analyses indicated complex chemical interactions between the drug and polymer matrix induced by MW, related with the regime of irradiation, that contributes to the differences in release profiles. In fact, MW treatments under different time and irradiating regimes are able to modulate drug release from alginate beads; high levels of irradiation led to beads suitable for immediate release oral dosage forms whereas the lowest regime of irradiation led to beads that achieved a prolonged/sustained release of the drug till 8h in simulated intestinal medium. This study showed that prilling in combination with microwave treatments is a useful and simple tandem technique to prepare dextran-based dried beads.

Novel co-axial prilling technique for the development of core–shell particles as delayed drug delivery systems

In this study, biocompatible double layered beads consisting of pectin core and alginate shell were prepared through a single step manufacturing process based on prilling apparatus equipped with co-axial nozzles. The core was loaded with piroxicam (PRX) as model non-steroidal anti-inflammatory drug (NSAID). Morphology, size distribution and shape of the double layered beads varied depending on the operative conditions and polymer concentrations. Co-axial nozzles size, applied vibration frequency, gelling conditions and, mainly, polymers mass ratio were identified as critical variables. Particularly, the relative viscosity of polymeric feed solutions inside the nozzle was the key parameter to obtain homogeneous and well-formed coated particles. The produced beads were investigated for the release kinetic in different media. Once PRX was encapsulated within the pectin core, a controlled release pattern was observed. Particularly, beads produced with 4:1 core/shell ratio (F4) released less than 30% of PRX in simulated gastric fluid (SGF) while total liberation of the drug was achieved during the next 3h in simulated intestinal fluid (SIF). More interesting, F4 tested in SIF was able to release drug in a delayed and sustained manner at established time points (2h_8.2%, 3h_32.2%, 4h_70.1% and 5h_about 100%). Based on the above results, co-axial prilling approach is expected to provide success in manufacturing systems with delayed drug release profiles. Such systems may be potentially useful in targeting diseases which are affected by the circadian rhythm, such as chronic inflammation.

Gentamicin and leucine inhalable powder: What about antipseudomonal activity and permeation through cystic fibrosis mucus?

The aim of this study was to evaluate the permeation properties of gentamicin (G) in a novel dry powder form for inhalation through an artificial mucus model. Moreover, since respiratory infections sustained by Pseudomonas are a major cause of sickness and death in CF patients, the susceptibility of P. aeruginosa to engineered G powders was investigated. Micronized G and G/leucine (85:15) formulations were produced by co-spray-drying, using process parameters and conditions previously set. Powders were characterized in terms of yield, drug content and aerodynamic profiles, analyzed by Andersen Cascade Impactor. Different mucus models were prepared, showing composition and viscosity similar to those of the native CF mucus. To investigate the impact on drug permeation, Franz-type vertical diffusion cells were used; the powders were applied directly on a synthetic membrane with or without the interposition of the artificial mucus layer. In buffer, gentamicin showed a diffusion controlled release; the presence of leucine reduced powder wettability and, consequently, the permeation rate. Otherwise, mucus delayed drug permeation from both G and G/leucine formulations, with a faint influence of the aminoacid. Antimicrobial tests revealed that G/leu engineered particles are able to preserve the antipseudomonal activity, even in presence of the mucus.

Natural polysaccharides platforms for oral controlled release of ketoprofen lysine salt

Abstract Context: Ketoprofen lysinate (KL) is one of the most widely used non-steroidal anti-inflammatory drugs in the symptomatic treatment of some chronic inflammatory diseases. Compared to ketoprofen, KL shows better pharmacokinetics and tolerability. However, due to its short half-life of 1–2 h, a multiple dose regimen is required for oral administration. Thus, the present work deals with its encapsulation in a hydrogel-based system by prilling in order to prolong its activity. Objective: In this paper, we propose alginate and pectin as carriers and release tailoring agent for the development of hydrogel-based beads for KL retarded and sustained release. Materials and methods: Beads were produced by a Nisco Encapsulator® using alginate or pectin. Operative variables were optimized to produce beads with desired morphology and size. Solid state properties were analyzed by SEM and DSC. Drug release performance was studied by Pharmacopeia pH-change assay to simulate gastrointestinal environment. Results and discussion: Prilling technique was successfully used to encapsulate high soluble drugs as KL in polysaccharides-based hydrogels. Pectin proved to be a proper polymer able to encapsulate ketoprofen lysine salt. Formulation (F8) showed good morphological properties and size, high drug content (15.6%) and encapsulation efficiency (93.5%) and promising drug release profiles. Hosting F8 in an acid-resistant capsule (DR®caps) a delivery platform has been developed to control KL release in a delayed (90 min lag time) and prolonged way (270 min complete release). Conclusion: The platform may be proposed as potentially useful in the oral administration of NSAIDs in chronic inflammatory diseases affected by circadian rhythm.