Inulin-Based Polymeric Micelles Functionalized with Ocular Permeation Enhancers: Improvement of Dexamethasone Permeation/Penetration through Bovine Corneas

Ophthalmic drug delivery is still a challenge due to the protective barriers of the eye. A common strategy to promote drug absorption is the use of ocular permeation enhancers, while an innovative approach is the use of polymeric micelles. In the present work, the two mentioned approaches were coupled by conjugating ocular permeation enhancers (PEG2000, carnitine, creatine, taurine) to an inulin-based co-polymer (INU-EDA-RA) in order to obtain self-assembling biopolymers with permeation enhancer properties for the hydrophobic drug dexamethasone (DEX). Inulin derivatives were properly synthetized, were found to expose about 2% mol/mol of enhancer molecules in the side chain, and resulted able to self-assemble at various concentrations by varying the pH and the ionic strength of the medium. Moreover, the ability of polymeric micelles to load dexamethasone was demonstrated, and size, mucoadhesiveness, and cytocompatibility against HCE cells were evaluated. Furthermore, the efficacy of the permeation enhancer was evaluated by ex vivo permeation studies to determine the performance of the used enhancers, which resulted in PEG2000 > CAR > TAU > CRE, while entrapment ability studies resulted in CAR > TAU > PEG2000 > CRE, both for fluorescent-labelled and DEX-loaded micelles. Finally, an increase in terms of calculated Kp and Ac parameters was demonstrated, compared with the values calculated for DEX suspension

HYALURONIC ACID DERIVATIVE MICELLES AS OCULAR PLATFORMS TO DRUG RELEASE AND CORNEAL PERMEATION

In traditional ocular formulations, only small amount of the administered drug penetrates the cornea to reach the intraocular tissue. One approach to improve the drug ocular bioavailability was to develop colloidal drug delivery systems. Polymeric micelles seem to be very promising for their capacity to dissolve a variety of hydrophobic drugs by enhancing their water solubility and so their bioavailability. They are able to increase ocular drug permeability due to interact with the complex corneal structure. Considering the advantages to use mucoadhesive polymer to increase drug residence time on the ocular surface, the aim of this work was to prepare hyaluronic acid-based micelles as a platform to release corticosteroids on the ocular surface. Three amphiphilic derivatives of hyaluronic acid (HA), bearing different amount of hexadecylamine chains (C16), were synthesised and characterized. These are able to form micelles by using the co-solvent evaporation method. All HAC16 derivatives have shown the ability of durable mucoadhesive interactions and resulted potentially useful for corticosteroids encapsulation. Drug-loaded micelles were prepared and characterized in term of drug loading amount and particle size. Moreover, the in vitro drug release studies from micellar systems were carried out in comparison with the dissolution profile of the free drug suspension. Cytocompatibility studies also were performed with HCEpiC cells. HAC16b (DDC16mol%=12%) micelles are selected as the best nanosystems, and their capacity to improve the drugs permeability across corneal barrier are evaluated. Thus, the ex vivo permeation studies were conducted using bovine corneas and Franz type diffusion cells

Modulation of physical and biological properties of a composite PLLA and polyaspartamide derivative obtained via thermally induced phase separation (TIPS) technique

In the present study, blend of poly l-lactic acid (PLLA) with a graft copolymer based on α,β-poly(N-hydroxyethyl)-dl-aspartamide and PLA named PHEA-PLA, has been used to design porous scaffold by using Thermally Induced Phase Separation (TIPS) technique. Starting from a homogeneous ternary solution of polymers, dioxane and deionised water, PLLA/PHEA-PLA porous foams have been produced by varying the polymers concentration and de-mixing temperature in metastable region. Results have shown that scaffolds prepared with a polymer concentration of 4% and de-mixing temperature of 22.5 °C are the best among those assessed, due to their optimal pore size and interconnection. SEM and DSC analysis have been carried out respectively to study scaffold morphology and the influence of PHEA-PLA on PLLA crystallization, while DMF extraction has been carried out in order to quantify PHEA-PLA into the final scaffolds. To evaluate scaffold biodegradability, a hydrolysis study has been performed until 56 days by incubating systems in a media mimicking physiological environment (pH 7.4). Results obtained have highlighted a progressive increase in weight loss with time in PLLA/PHEA-PLA scaffolds, conceivably due to the presence of PHEA-PLA and polymers interpenetration. Viability and adhesion of bovine chondrocytes seeded on the scaffolds have been studied by MTS test and SEM analysis. From results achieved it appears that the presence of PHEA-PLA increases cells affinity, allowing a faster adhesion and proliferation inside the scaffold

OCULAR DRUG CARRIERS NANOSTRUTTURATI PER IL TRATTAMENTO DELLE PATOLOGIE DEGENERATIVE DELLA RETINA

Il lavoro di ricerca svolto è stato incentrato sulla preparazione e caratterizzazione di diversi ocular drug carriers nanostrutturati in grado di veicolare molecole bioattive per il trattamento delle retinopatie. Tali sistemi sono stati preparati utilizzando differenti derivati polimerici, ottenuti a partire dall’acido ialuronico (HA) a differente peso molecolare (10-240 kDa). Allo scopo di ottenere micelle polimeriche per la veicolazione di corticosteroidi, sono stati sintetizzati diversi derivati polimerici partendo dall’HA con MW di 10 kDa. Il derivato siglato HAC16b ha mostrato delle caratteristiche vantaggiose, in termini di dimensione, proprietà mucoadesive, valori di drug loading e profilo di rilascio dei corticosteroidi incorporati, azione da permeation e penetration enhancers, tali da presupporre una potenziale somministrazione oculare topica. Per la veicolazione dell’imatinib sono state attuate due strategie tecnologiche differenti. La prima strategia ha previsto il caricamento del farmaco all’interno di micelle polimeriche, costituite da polimeri anfifilici ottenuti a partire dall’HA con MW di 10 kDa. I derivati polimerici in questione sono siglati HA-EDA-C16, HA-EDA-C16-PEG e HA-EDA-C16-CRN. Questi sistemi sono risultati essere efficaci per la veicolazione dell’imatinib attraverso la barriera corneale; inoltre garantiscono un rilascio opportuno del farmaco e una rilevante inibizione dello sprouting vascolare su un modello in vitro di neoangiogenesi. La seconda strategia tecnologica ha previsto invece la realizzazione di nanoparticelle polimeriche utilizzando i derivati HAxs-EDA-C18 e HAxs-EDA-C18-RGDC, sintetizzati a partire dall’HAxs con MW di 100 kDa. I carriers, realizzati mediante tecnica microfluidica, presentano un opportuno profilo dimensionale e sono in grado di incorporare efficacemente l’imatinib. Il farmaco è in grado di inibire lo sprouting vascolare in un modello in vitro di neoangiogenesi, quando incorporato all’interno dei sistemi carriers progettati

HYALURONIC ACID BASED-MICELLES FOR OFF-LABEL USE OF IMATINIB IN RETINOPATHIES TREATMENT

The aim of this work was to obtain polymeric micelles able to cross corneal barrier and to improve the permeation of imatinib free base. Micelles were prepared by using hyaluronic acid (HA) derivatives containing ethylenediamine (EDA), chains of hexadecyl (C16), polyethylene glycol (PEG) and/or L-carnitine (CRN). The resulting samples, named as HA-EDA-C16, HA-EDA-C16-PEG and HA-EDA-C16-CRN micelles, were designed to allow a non-invasive way of administration, i.e. topical ocular instillation. These nanocarriers showed an optimal particle size in aqueous media and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. An interesting in vitro study was conducted to investigate imatinib inhibitory effect on a choroideal neovascularization process (1). Imatinib was able to inhibit endothelial cell sprouting and to reduce the formation of functional vessels. In addition, imatinib released from polymeric micelles was able to inhibit cell tube formation and to promote cell tube disruption. Obtained results suggested that prepared micelles could represent optimal candidates for off-label use of imatinib in the treatment of retinopathies

Imatinib-Loaded Micelles of Hyaluronic Acid Derivatives for Potential Treatment of Neovascular Ocular Diseases

In this work, new micellar systems able to cross corneal barrier and to improve the permeation of imatinib free base were prepared and characterized. HA-EDA-C16, HA-EDA-C16−PEG, and HA-EDA-C16−CRN micelles were synthesized starting from hyaluronic acid (HA), ethylenediamine (EDA), hexadecyl chains (C16), polyethylene glycol (PEG), or L-carnitine (CRN). These nanocarriers showed optimal particle size and mucoadhesive properties. Imatinibloaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. In addition, a study was conducted to understand the in vitro imatinib inhibitory effect on a choroidal neovascularization process. Imatinib released from polymeric micelles was able to inhibit endothelial cell sprouting and to promote cell tube disruption

Mucoadhesive PEGylated inulin-based self-assembling nanoparticles: In vitro and ex vivo transcorneal permeation enhancement of corticosteroids

As transcorneal drug delivery is still a challenge, the scope of the present study was to prepare useful nanosystems able to enhance transcorneal permeation/penetration of drugs. Moreover, this work aims to evaluate the effectiveness of inulin-based nanosystems in the specific field of ocular drug delivery and the effect of PEG chains to promote mucoadhesion, stability and transcorneal penetration/permeation enhancer effect of self-assembling nanoparticles in vitro (transwell systems and HCE) and ex vivo (Franz cells and bovine cornea). In particular, inulin was chosen as the starting natural polysaccharide polymer to design a novel amphiphilic derivative named INU-EDA-RA-PEG capable of self-assembling to form self-assembling nanoparticles and corticosteroids-loaded self-assembling nanoparticles. As observed, self-assembling nanoparticles show appropriate particle size values, mucoadhesivity and cytocompatibility. Moreover, self-assembling nanoparticles are able to act efficiently as permeation/penetration enhancer. Additionally, the presence of PEG has positive influence. Thus, the developed inulin-based nanosystems represent a promising tool to improve transcorneal delivery of corticosteroids