Cell penetrating peptides in ocular drug delivery: State of the art.

Despite the increasing number of effective therapeutics for eye diseases, their treatment is still challenging due to the presence of effective barriers protecting eye tissues. Cell Penetrating Peptides (CPPs), synthetic and natural short amino acid sequences able to cross cellular membrane thanks to a transduction domain, have been proposed as possible enhancing strategies for ophthalmic delivery. In this review, a general description of CPPs classes, design approaches and proposed cellular uptake mechanisms will be provided to the reader as an introduction to ocular CPPs application, together with an overview of the main problems related to ocular administration. The results obtained with CPPs for the treatment of anterior and posterior segment eye diseases will be then introduced, with a focus on non-invasive or minimally invasive administration, shifting from CPPs capability to obtain intracellular delivery to their ability to cross biological barriers. The problems related to in vitro, ex vivo and in vivo models used to investigate CPPs mediated ocular delivery will be also addressed together with potential ocular toxicity issues.

Synthesis of stabilized hydroxyapatite nanosuspensions for enamel caries remineralization.

BACKGROUND: The aim of this study was to develop and evaluate a method for synthesizing a stable suspension of hydroxyapatite nanoparticles and to test its efficacy for remineralizing carious enamel lesions. METHODS: Hydroxyapatite (HA) particles were synthesized using wet chemistry. Synthesized particles were introduced into a high-pressure homogenizer (5-10 homogenization passes at 15 000 psi) in the presence of different stabilizers. Size and distribution of the resultant particles were determined using dynamic light scattering (DLS). The morphology and composition of the nanoparticles were determined using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). Subsequently, artificial lesions were treated with HA nanosuspension plus artificial saliva or a fluoride-containing artificial saliva only. Visual analysis and quantification of the lesion mineral density before and after remineralization were performed using microcomputed tomography. RESULTS: DLS and SEM results confirmed the formation of nonagglomerated HA nanoparticles (20-40 nm) following high-pressure homogenization treatment. Quantitative evaluation of the lesions showed that remineralization of the lesion with hydroxyapatite nanosuspension led to a significantly higher level of mineral gain compared to the control group (P < 0.05). CONCLUSION: High-pressure homogenization is an effective method for facile preparation of a stable suspension of hydroxyapatite nanoparticles. Treatment of artificial lesions with nonagglomerated spherical HA nanoparticles improves the remineralization of enamel lesion.

Nasal powders of thalidomide for local treatment of nose bleeding in persons affected by hereditary hemorrhagic telangiectasia.

In this work nasal powder formulations of thalidomide were designed and studied to be used by persons affected by hereditary hemorrhagic telangiectasia as a complementary anti-epistaxis therapy, with the goal of sustaining the effect obtained with thalidomide oral treatment after its discontinuation for adverse effects. Three nasal powders were prepared using as carriers ß-CD or its more hydrophilic derivatives such as hydropropyl-ß-CD and sulphobutylether-ß-CD and tested with respect to technological and biopharmaceutical features after emission with active and passive nasal powder devices. For all formulated powders, improved dissolution rate was found compared to that of the raw material, making thalidomide promptly available in the nasal environment at a concentration favouring an accumulation in the mucosa. The very limited transmucosal transport measured in vitro suggests a low likelihood of significant systemic absorption. The topical action on bleeding could benefit from the poor absorption and from the fact that about 2-3% of the thalidomide applied on the nasal mucosa was accumulated within the tissue, particularly with the ß-CD nasal powder.

Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.

Tamoxifen citrate is an anticancer drug slightly soluble in water. Administered orally, it shows great intra- and inter-patient variations in bioavailability. We developed a nanoformulation based on phospholipid and chitosan able to efficiently load tamoxifen and showing an enzyme triggered release. In this work the permeation of tamoxifen released from lecithin/chitosan nanoparticles across excised rat intestinal wall mounted in an Ussing chamber was investigated. Compared to tamoxifen citrate suspension, the amount of the drug permeated using the nanoformulation was increased from 1.5 to 90 times, in absence or in presence of pancreatin or lipase, respectively. It was also evidenced the formation of an active metabolite of tamoxifen, 4-hydroxy tamoxifen, however, the amount of metabolite permeated remained roughly constant in all experiments. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded nanoparticles were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/chitosan nanoparticles improved the non-metabolized drug passing through the rat intestinal tissue via paracellular transport.

Single layer transdermal film containing lidocaine: water and lidocaine mobility determined using neutron scattering.

The diffusivity of lidocaine through a polymer film developed for transdermal drug administration has been characterized by macroscopic permeation experiments and by neutron quasielastic spectroscopy that provides information on microscopic diffusivity parameters. It turns out that film hydration plays a key role on the performance and efficiency of the investigated system. Diffusion of lidocaine, at the microscopic level, is triggered by the presence of "mobile water." At hydration levels below 15% (weight water/weight hydrated film) neither lidocaine nor water show any appreciable long-range diffusion. At higher hydration levels, the onset of water long-range diffusion triggers diffusion of lidocaine through the film. The use of neutron quasielastic scattering makes it possible to measure lidocaine mobility within the film without the need of any additional physical barrier.

Novel platforms for oral drug delivery.

The aim of this review is to provide the reader general and inspiring prospects on recent and promising fields of innovation in oral drug delivery. Nowadays, inventive drug delivery systems vary from geometrically modified and modular matrices, more close to "classic" pharmaceutical manufacturing processes, to futuristic bio micro-electro-mechanical systems (bioMEMS), based on manufacturing techniques borrowed from electronics and other fields. In these technologies new materials and creative solutions are essential designing intelligent drug delivery systems able to release the required drug at the proper body location with the correct release rate. In particular, oral drug delivery systems of the future are expected to have a significant impact on the treatment of diseases, such as AIDS, cancer, malaria, diabetes requiring complex and multi-drug therapies, as well as on the life of patients, whose age and/or health status make necessary a multiple pharmacological approach.

Structure of self-organized multilayer nanoparticles for drug delivery.

The combined use of cryo-TEM, dynamic light scattering, and small-angle X-ray and neutron scattering techniques allows a detailed structural model of complex pharmaceutical preparations of soybean lecithin/chitosan nanoparticles used as drug vectors to be worked out. Charge-driven self-organization of the lipid(-)/polysaccharide(+) vesicles occurs during rapid injection, under mechanical stirring, of an ethanol solution of soybean lecithin into a chitosan aqueous solution. We conclude that beyond the charge inversion region of the phase diagram, i.e., entering the redissolution region, the initial stages of particle formation are likely to be affected by a re-entrant condensation effect at the nanoscale. This behavior resembles that at the mesoscale which is well-known for polyion/amphiphile systems. Close to the boundary of the charge inversion region, nanoparticle formation occurs under a maximum condensation condition at the nanoscale and the complexation-aggregation process is driven toward a maximum multilamellarity. Interestingly, the formulation that maximizes vesicle multilamellarity corresponds to that displaying the highest drug loading efficiency.

Formation of self-organized nanoparticles by lecithin/chitosan ionic interaction.

In this work the production of auto-assembled nanoparticles obtained by the mixing of chitosan and lecithin is presented. The size and surface charge of the nanoparticles were studied as function of the weight ratio between components, the viscosity of the polysaccharide and the pH of the colloidal suspension. In order to elucidate the structure of nanoparticles, micro-FT-IR and elastic neutron scattering experiments have been performed. Results evidenced a strong electrostatic interaction between components and a structure that is neither that of homogeneous spheres nor of coated unilamellar vesicles. Preliminary encapsulation experiments with progesterone, as model lipophilic drug, showed good encapsulation efficiencies.