Freeze-dried nanocomposite gel beads for oral drug delivery. In vitro simulation of gastro-intestinal drug release

We investigated entrapment efficiency, swelling and drug release from freeze-dried gel beads prepared with Gellan gum and a synthetic clay, Laponite. Polymeric beads loaded with two model molecules having different molecular weights were prepared and subjected to in vitro release studies in simulated gastric and intestinal fluids. The experimental observations confirm that laponite may be an effective additive for fabricating sustained drug delivery systems from gellan gum by means of ionotropic gelation and freeze-drying

Chemical investigation and screening of anti-proliferative activity on human cell lines of pure and nano-formulated lavandin essential oil

Lavandin essential oil (LEO), a natural sterile hybrid obtained by crossbreeding L. angustifolia × L. latifolia, is mainly composed by active components belonging to the family of terpenes endowed with relevant anti-proliferative activity, which can be enhanced by proper application of nanotechnology. In particular, this study reports the chemical characterization and the screening of the anti-proliferative activity on different human cell lines of pure and nano-formulated lavandin essential oil (EO). LEO and its formulation (NanoLEO) were analyzed by HS/GC-MS (Headspace/Gas Chromatography-Mass Spectrometry) to describe and compare their chemical volatile composition. The most abundant compounds were linalool and 1,8-cineole (LEO: 28.6%; 27.4%) (NanoLEO: 60.4%; 12.6%) followed by α-pinene (LEO: 9.6%; NanoLEO: 4.5%), camphor (LEO: 6.5%; NanoLEO: 7.0%) and linalyl acetate (LEO: 6.5%; NanoLEO: 3.6%). The cytotoxic effects of LEO and NanoLEO were investigated on human neuroblastoma cells (SHSY5Y), human breast adenocarcinoma cells (MCF-7), human lymphoblastic leukemia cells (CCRF CEM), human colorectal adenocarcinoma cells (Caco-2) and one normal breast epithelial cell (MCF10A) by the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide)-assay. Caco-2, MCF7 and MCF10A normal cells resulted more resistant to the treatment with LEO, while CCRF-CEM and SHSY5Y cells were more sensitive. The antiproliferative effect of LEO resulted amplified when the essential oil was supplied as nanoformulation, mainly in Caco-2 cells. Scanning and transmission electron microscopy investigations were carried out on Caco-2 cells to outline at ultrastructural level possible affections induced by LEO and NanoLEO treatments

Encapsulation of Essential Oils within Lipid-Based Formulations for Enhanced Antimicrobial Activity

Aromatic plants have been used since ancient times for their medicinal properties, including potent antimicrobial activity. Strong evidence indicates that plant extracts, in general, and essential oils (EOs), in particular, can act as effective antimicrobial agents against a wide spectrum of pathogenic microorganisms. However, their poor water solubility and stability, as well as their high volatility, make the administration of EOs to achieve the desired therapeutic effects particularly challenging. Therefore, these features severely limit the application of EOs in the pharmaceutical field. In this context, nanotechnology-based strategies for developing nano-scaled carriers for the efficient delivery of EOs might offer potential solutions. In particular, considering the lipophilic nature of EOs, lipid-based nanocarriers represent the most suitable vehicles for the effective encapsulation and delivery of EOs. This chapter provides an overview of the different chemical compositions due to various endogenous and/or exogenous factors of a selection of oils and the most recent lipid-based encapsulation strategies to enhance their antimicrobial activity and promote their pharmaceutical application.&lt;br&gt;</jats:p

Enhanced Loading Efficiency and Mucoadhesion Properties of Gellan Gum Thin Films by Complexation with Hydroxypropyl-β-Cyclodextrin

Polymeric oral thin films (OTFs) were prepared by the casting method, combining gellan gum (GG), a water-soluble polysaccharide, and glycerol (Gly) as a plasticizing agent. GG-Gly films were investigated as potential systems for buccal drug delivery using fluconazole (Class I of the Biopharmaceutical Classification System) as a model drug. At a low concentration of Gly drug precipitation occurred while, for higher concentrations of Gly, a significant deterioration of mucoadhesive and mechanical properties was observed. One possible way to overcome all these problems could be the addition of hydroxypropyl-β-cyclodextrin (HP-β-CD) to the GG-Gly formulation as a drug-precipitation inhibitor. In this work the effect of cyclodextrin addition on the mechanical, mucoadhesive, swelling and release properties of GG-Gly films was investigated. In-vitro drug release studies were carried out using the paddle type dissolution apparatus (USP II) and the millifluidic flow-through device (MFTD). A moving-boundary model for swelling dynamics and release in USP II is proposed to estimate the effective diffusivity of the solvent, HP-β-CD, fluconazole and complex fluconazole/HP-β-CD in the swelling film. Experimental results, supported by theoretical modeling, confirmed that gellan gum-low glycerol thin films including HP-β-CD represent a suitable formulation for fluconazole drug delivery. A sustained release was observed when GG-Gly film is loaded with a preformed complex fluconazole/HP-β-CD

Injectable and In Situ Gelling Dextran Derivatives Containing Hydrolyzable Groups for the Delivery of Large Molecules

Recently, we reported the synthesis and characterization of a new dextran derivative obtained by grafting polyethylene glycol methacrylate to a polysaccharide backbone through a carbonate bond. This moiety was introduced because it allows for the fabrication, through a photo-induced crosslinking reaction, of biodegradable hydrogels particularly suitable for the release of high molecular weight molecules. Here, we investigate the influence of the oxyethylene chain length and the molecular weight of the starting dextran on the main properties of the polymeric solutions as well as those of the corresponding hydrogels. All synthesized polymeric derivatives were characterized by FTIR, NMR, and rheological analyses. The photo-crosslinking reaction of the polymers allowed us to obtain biodegradable networks tested for their mechanical properties, swelling, and degradation behavior. The results showed that both the oxyethylene chain length as well as the molecular weight of the starting dextran influenced swelling and degradation of the hydrogel network. As a consequence, the different behaviors in terms of swelling and degradability were able to affect the release of a large model molecule over time, making these matrices suitable candidates for the delivery of high molecular weight drug substances

The Impact of Bilayer Rigidity on the Release from Magnetoliposomes Vesicles Controlled by PEMFs

Stimuli-sensitive nanocarriers have recently been developed as a powerful tool in biomedical applications such as drug delivery, detection, and gene transfer techniques. Among the external triggers investigated, low intensity magnetic fields represent a non-invasive way to remotely control the release of compounds from a magneto-sensitive carrier. Magnetoliposomes (MLs), i.e., liposomes entrapping magnetic nanoparticles (MNPs), are studied due to their capacity to transport hydrophobic and hydrophilic agents, their easy production, and due to the ability of MNPs to respond to a magnetic actuation determining the triggered release of the encapsulated compounds. Here we investigated the design and optimization of the MLs to obtain an efficient on-demand release of the transported compounds, due to the magneto-mechanical actuation induced by applying low-intensity pulsed electromagnetic fields (PEMFs). In particular we studied the effect of the bilayer packing on the ability of MLs, with oleic acid-coated MNPs encapsulated in the bilayer, to respond to PEMFs application. Three kinds of MLs are produced with an increasing rigidity of the bilayer, defined as Liquid Disorder, Liquid Order, and Gel MLs and the delivery of a hydrophilic dye (as a model drug) is investigated. Results demonstrate the efficacy of the magnetic trigger on high-ordered bilayers, which are unable to dampen the perturbation produced by MNPs motion.</jats:p

Injectable and In Situ Gelling Dextran Derivatives Containing Hydrolyzable Groups for the Delivery of Large Molecules

Recently, we reported the synthesis and characterization of a new dextran derivative obtained by grafting polyethylene glycol methacrylate to a polysaccharide backbone through a carbonate bond. This moiety was introduced because it allows for the fabrication, through a photo-induced crosslinking reaction, of biodegradable hydrogels particularly suitable for the release of high molecular weight molecules. Here, we investigate the influence of the oxyethylene chain length and the molecular weight of the starting dextran on the main properties of the polymeric solutions as well as those of the corresponding hydrogels. All synthesized polymeric derivatives were characterized by FTIR, NMR, and rheological analyses. The photo-crosslinking reaction of the polymers allowed us to obtain biodegradable networks tested for their mechanical properties, swelling, and degradation behavior. The results showed that both the oxyethylene chain length as well as the molecular weight of the starting dextran influenced swelling and degradation of the hydrogel network. As a consequence, the different behaviors in terms of swelling and degradability were able to affect the release of a large model molecule over time, making these matrices suitable candidates for the delivery of high molecular weight drug substances

Enhanced Loading Efficiency and Mucoadhesion Properties of Gellan Gum Thin Films by Complexation with Hydroxypropyl-β-Cyclodextrin

Polymeric oral thin films (OTFs) were prepared by the casting method, combining gellan gum (GG), a water-soluble polysaccharide, and glycerol (Gly) as a plasticizing agent. GG-Gly films were investigated as potential systems for buccal drug delivery using fluconazole (Class I of the Biopharmaceutical Classification System) as a model drug. At a low concentration of Gly drug precipitation occurred while, for higher concentrations of Gly, a significant deterioration of mucoadhesive and mechanical properties was observed. One possible way to overcome all these problems could be the addition of hydroxypropyl-β-cyclodextrin (HP-β-CD) to the GG-Gly formulation as a drug-precipitation inhibitor. In this work the effect of cyclodextrin addition on the mechanical, mucoadhesive, swelling and release properties of GG-Gly films was investigated. In-vitro drug release studies were carried out using the paddle type dissolution apparatus (USP II) and the millifluidic flow-through device (MFTD). A moving-boundary model for swelling dynamics and release in USP II is proposed to estimate the effective diffusivity of the solvent, HP-β-CD, fluconazole and complex fluconazole/HP-β-CD in the swelling film. Experimental results, supported by theoretical modeling, confirmed that gellan gum-low glycerol thin films including HP-β-CD represent a suitable formulation for fluconazole drug delivery. A sustained release was observed when GG-Gly film is loaded with a preformed complex fluconazole/HP-β-CD.</jats:p

A convenient strategy to synthesize highly tunable gelatin methacryloyl with very low gelation temperature

Gelatin methacryloyl (GelMA) is a polymeric derivative of gelatin (Gel) widely used in tissue engineering, as well as in wound dressing and drug delivery field. This work offers an alternative and convenient method for the synthesis and characterization of GelMA. In particular, the methacrylation was carried out under homogeneous single-phase reaction conditions, which allows of obtaining a good reproducibility of the derivatization degree of the polymer in a simple and fast way. The experimental conditions were adequately optimized to have the methacrylation of only ε-amino groups of lysine and hydroxylysine, as confirmed by FT-IR and 1H NMR analysis. The degree of derivatization of GelMA was determined using an internal standard applied to 1H NMR analysis. Based on these measurements, it was found that the optimized reaction proceeds to complete functionalization of ε-amino groups of lysine and hydroxylysine. The effect of the reaction conditions on the rheological properties of GelMA was investigated through temperature sweep experiments and compared with those of the polymer obtained under traditional heterogeneous reaction conditions. A significant difference was found in the gelation temperature of GelMA synthesized following the two different procedures. In particular, the proposed single-phase synthetic protocol gave a polymer which behaves like a solution when used at 10% w/v concentration and even at temperatures as low as 5 °C, whereas the polymer obtained with the classic biphasic procedure behaves like a gel within the same range of temperatures and when used at the same concentration. These results are particularly interesting as they could open GelMA to new applications particularly in the biomedical field

Gellan Gum/Laponite Beads for the Modified Release of Drugs: Experimental and Modeling Study of Gastrointestinal Release

In this study, gellan gum (GG), a natural polysaccharide, was used to fabricate spherical porous beads suitable as sustained drug delivery systems for oral administration. GG was cross-linked with calcium ions to prepare polymeric beads. Rheological studies and preliminary experiments of beads preparation allowed to identify the GG and the CaCl2 concentrations suitable for obtaining stable and spherical particles. GG beads were formed, through ionotropic gelation technique, with and without the presence of the synthetic clay laponite. The resultant beads were analyzed for dimensions (before and after freeze-drying), morphological aspects and ability to swell in different media miming biological fluids, namely SGF (Simulated Gastric Fluid, HCl 0.1 M) and SIF (Simulated Intestinal Fluid, phosphate buffer, 0.044 M, pH 7.4). The swelling degree was lower in SGF than in SIF and further reduced in the presence of laponite. The GG and GG-layered silicate composite beads were loaded with two model drugs having different molecular weight, namely theophylline and cyanocobalamin (vitamin B12) and subjected to in-vitro release studies in SGF and SIF. The presence of laponite in the bead formulation increased the drug entrapment efficiency and slowed-down the release kinetics of both drugs in the gastric environment. A moving-boundary swelling model with “diffuse” glassy-rubbery interface was proposed in order to describe the swelling behavior of porous freeze-dried beads. Consistently with the swelling model adopted, two moving-boundary drug release models were developed to interpret release data from highly porous beads of different drugs: drug molecules, e.g., theophylline, that exhibit a typical Fickian behavior of release curves and drugs, such as vitamin B12, whose release curves are affected by the physical/chemical interaction of the drug with the polymer/clay complex. Theoretical results support the experimental observations, thus confirming that laponite may be an effective additive for fabricating sustained drug delivery systems