Andreza Ribeiro

Bioinspired imprinted PHEMA-hydrogels for ocular delivery of carbonic anhydrase inhibitor drugs.

Hydrogels with high affinity for carbonic anhydrase (CA) inhibitor drugs have been designed trying to mimic the active site of the physiological metallo-enzyme receptor. Using hydroxyethyl methacrylate (HEMA) as the backbone component, zinc methacrylate, 1- or 4-vinylimidazole (1VI or 4VI), and N-hydroxyethyl acrylamide (HEAA) were combined at different ratios to reproduce in the hydrogels the cone-shaped cavity of the CA, which contains a Zn(2+) ion coordinated to three histidine residues. 4VI resembles histidine functionality better than 1VI, and, consequently, pHEMA-ZnMA(2) hydrogels bearing 4VI moieties were those with the greatest ability to host acetazolamide or ethoxzolamide (2 to 3 times greater network/water partition coefficient) and to sustain the release of these antiglaucoma drugs (50% lower release rate estimated by fitting to the square root kinetics). The use of acetazolamide as template during polymerization did not enhance the affinity of the network for the drugs. In addition to the remarkable improvement in the performance as controlled release systems, the biomimetic hydrogels were highly cytocompatible and possessed adequate oxygen permeability to be used as medicated soft contact lenses or inserts. The results obtained highlight the benefits of mimicking the structure of the physiological receptors for the design of advanced drug delivery systems.

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

Polymeric micelles of single and mixed poloxamines (Tetronic) were evaluated regarding their ability to host the antiglaucoma agent ethoxzolamide (ETOX) for topical ocular application. Three highly hydrophilic varieties of poloxamine (T908, T1107 and T1307) and a medium hydrophilic variety (T904), possessing a similar number of propylene oxide units but different contents in ethylene oxide, were chosen for the study. The critical micellar concentration and the cloud point of mixed micelles in 0.9 per cent NaCl were slightly greater than the values predicted from the additive rule, suggesting that the co-micellization is hindered. Micellar size ranged between 17 and 120 nm and it was not altered after the loading of ETOX (2.7–11.5 mg drug g–1 poloxamine). Drug solubilization ability ranked in the order: T904 (50-fold increase in the apparent solubility) > T1107 ≅ T1307 > T908. Mixed micelles showed an intermediate capability to host ETOX but a greater physical stability, maintaining almost 100 per cent drug solubilized after 28 days. Furthermore, the different structural features of poloxamines and their combination in mixed micelles enabled the tuning of drug release profiles, sustaining the release in the 1–5 days range. These findings together with promising hens egg test-chorioallantoic membrane biocompatibility tests make poloxamine micelles promising nanocarriers for carbonic anhydrase inhibitors in the treatment of glaucoma.

Poloxamine micellar solubilization of α-tocopherol for topical ocular treatment.

Ophthalmic delivery of α-tocopherol (TOC), which is the most active and cost/effective form of vitamin E, is receiving increasing attention as a way of preventing and treating glaucoma, cataracts, and dry eye syndrome, among other ocular pathologies. The aim of this work was to elucidate the possibility of using poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO) block copolymers of poloxamine family (namely, Tetronic 1107) to develop polymeric micelles that can host TOC, enhance the apparent solubility and sustain the release of this vitamin in lachrymal fluid. The interactions of Tetronic 1107 with TOC were analyzed at the air-water interface recording the π-A isotherms at various temperatures, indicating favorable interactions as temperature increased from 10 to 29 °C. In 0.9% NaCl aqueous medium, a sharp increase in TOC solubility was observed when T1107 surpasses the critical micellar concentration (CMC); the apparent solubility in 20% T1107 being more than 600-fold and 6000-fold that observed in the absence of copolymer at 4 and 25 °C, respectively. Micelles were characterized before and after loading by means of dynamic light scattering (DLS) and transmission electronic microscopy (TEM). TOC sustained release profiles were recorded in Franz-Chien diffusion cells. After storage for 3 months at 4 °C, TOC-loaded T1107 10% micellar system retained 84% TOC solubilized, which maintained the antioxidant activity. Furthermore, the rheological properties of the micellar systems were not altered either; the viscoelastic parameters being dependent on T1107 concentration, which opens the possibility of developing from free-flowing eye-drops to in situ gelling systems.

Improvements in Topical Ocular Drug Delivery Systems: Hydrogels and Contact Lenses

PURPOSE Conventional ophthalmic systems present very low corneal systemic bioavailability due to the nasolacrimal drainage and the difficulty to deliver the drug in the posterior segment of ocular tissue. For these reasons, recent advances have focused on the development of new ophthalmic drug delivery systems. This review provides an insight into the various constraints associated with ocular drug delivery, summarizes recent findings in soft contact lenses (SCL) and the applications of novel pharmaceutical systems for ocular drug delivery. Among the new therapeutic approaches in ophthalmology, SCL are novel continuous-delivery systems, providing high and sustained levels of drugs to the cornea. The tendency of research in ophthalmic drug delivery systems development are directed towards a combination of several technologies (bio-inspired and molecular imprinting techniques) and materials (cyclodextrins, surfactants, specific monomers). There is a tendency to develop systems which not only prolong the contact time of the vehicle at the ocular surface, but also at the same time slow down the clearance of the drug. Different materials can be applied during the development of contact lenses and can be combined with natural inspired strategies of drug immobilization and release, providing successful tools for ocular drug delivery systems.

Combining strategies to optimize a gel formulation containing miconazole: the influence of modified cyclodextrin on textural properties and drug release

Background: Miconazol, an antimycotic drug, is commonly formulated into semisolid formulations designed to be applied in the oral cavity to treat oral candidiasis. However, given its limited aqueous solubility, permeation through the biological membranes is low and therefore its activity is also limited. Cyclodextrins (CDs) have been widely used to increase the solubility and stability of poorly water-soluble drugs. Aim: The aim of this study is to formulate a gel containing an inclusion complex between a modified CD, methyl-β-cyclodextrin (MβCD), and miconazole (MCZ). The influence of the CD on the textural properties of the prepared gel and the drug release from formulation were evaluated. Methods: The gels were prepared using two polymers, Carbopol 71G and Pluronic F127, which were selected taking into account their bioadhesiveness and thermal-sensitive gelling properties, respectively. Texture profile analyses were performed at two different temperatures to ascertain the influence of the temperature on the gel texture properties. The in vitro MCZ release profiles from the prepared gel and the commercial gel formulations were evaluated and compared using modified Franz diffusion cells. Results: The addition of MβCD to the gel resulted in a decrease of the gel adhesiveness and firmness, and the MCZ release profile through f1 and f2 proved to be similar to the commercial product. Conclusions: A gel comprising miconazol in the form of an inclusion complex with MβCD showed suitable textural properties to be applied to the buccal mucosa. The MβCD enhanced the solubility of the MCZ in the gel formulation resulting in adequate in vitro drug release profiles.

Cellulose-Based Hydrogels in Topical Drug Delivery: A Challenge in Medical Devices

Drug delivery is a difficult task in the field of dermal therapeutics mainly in the treatment of burns, ulcers, and wounds. Therefore, fundamental research and the development of novel advanced biomaterials as hydrogels are ongoing to overcome these issues. Currently, several approaches are starting to emerge aiming the stabilization of drug loaded in hydrogel material by increasing the mutual interactions between the polymers, the polymers, and the drug and by covalently cross-linking the polymers during hydrogel formation. Hydrogels provide mechanical support and control over architecture, topography, and biochemical characteristics that make them functionally appropriate to biomedical materials. In this regard, cellulose-based biomaterials can be considered as a gold standard for many topical pharmaceutical applications because of their versatility in fabrication, biodegradability, and biocompatibility. In open wounds, a curative ideal hydrogel is proposed for occlusion and maintenance of the moist environment. Healing through the wet medium has comparative advantages such as preventing dehydration of tissue leading to cell death, stimulating epithelization and formation of granulation tissue, facilitating the removal of necrotic tissue and fibrin, serving as a protective barrier against microorganism, and avoiding excessive fluid loss and can still take drugs. On the other hand, another recent challenge is the use of hydrogel in the manufacture of microneedles. The microneedles are able to, with little force, penetrate effectively in the tissues, maintaining the continuous contact, without causing damages in the tissue, providing a high force of adhesion. These devices may be an alternative to the infection-resistant staples used in surgeries to attach skin grafts to patients with severe wounds resulting from burns and to be used in drug release. In this chapter, we discuss recent developments in cellulose-based hydrogels with respect to drug delivery and current applications in the new devices and research settings for infections, inflammations, skin burns, and wound treatment.

Polymeric micelles as a versatile tool in oral chemotherapy

Abstract Cancer is the second cause of death in developed countries, after cardiovascular diseases. Nanocarriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles (PMs) are nanocarriers with potential for clinical success in cancer treatment due to their peculiar characteristics. In addition, the use of ligands in PMs allow drugs to be targeted to specific sites in the body (specific tumor cells), becoming a potential tool for oral chemotherapy. Oral drug delivery is an optimal route for achieving therapeutic results due to the facility of patient treatment adhesion. The use of new copolymers in PMs formulations together with vectoring of the drugs to tumor cells may help overcome this limitation, which will be beneficial for the treatment of cancer. This aspect will have a great impact on the traditional regimen of chemotherapy administration.

Biodegradable polymeric nanostructures: design and advances in oral drug delivery for neurodegenerative disorders

Several strategies have been developed to increase the oral administration of hydrophobic drugs related to neurodegenerative diseases, namely, nanocarriers like polymeric nanoparticles, polymeric micelles, dendrimers, and liposomes. Biodegradable polymeric materials, natural or synthetic, are competitive materials, used to formulate controlled release formulations and drug-targeting systems due to their peculiar physicochemical and biological properties. For this purpose they have fundamental advantages above other classes of materials: (1) they improve oral bioavailability; (2) they improve aqueous solubility of hydrophobic drugs; (3) they increase resistance time in the body; and, (4) they target drug to specific sites. This chapter highlights the main advances in polymeric nanocarriers as vehicles for oral-delivery systems used in the therapy of neurodegenerative disorders. First, a brief introduction into the field of biodegradable polymeric materials used in nanostructures formulation is presented. The next section shows a detailed description of the technologies and recent modifications to improve their specificity (functional surface building), considering their structure and characteristics. Finally, new approaches are presented with clinical applications in neurodegenerative disorders.