Nanostructured supramolecular hydrogels: Towards the topical treatment of Psoriasis and other skin diseases

Supramolecular hydrogels were synthesized using a bis-imidazolium based amphiphile, and incorporating chemically diverse drugs, such as the cytostatics gemcitabine hydrochloride and methotrexate sodium salt, the immunosuppressive drug tacrolimus, as well as the corticoid drugs betamethasone 17-valerate and triamcinolone acetonide, and their potential as drug delivery agents in the dermal treatment of Psoriasis was evaluated. The rheological behavior of gels was studied, showing in all cases suitable viscoelastic properties for topical drug delivery. Scanning electron microscopy (SEM) shows that the drugs included have a great influence on the gel morphology at the microscopic level, as the incorporation of gemcitabine hydrochloride leads to slightly thicker fibers, the incorporation of tacrolimus induces flocculation and spherical precipitates, and the incorporation of methotrexate forms curled fibers. 1H NMR spectroscopy experiments show that these drugs not only remain dissolved at the interstitial space, but up to 72% of either gemcitabine or methotrexate, and up to 38% of tacrolimus, is retained within the gel fibers in gels formed with a 1:1 gelator:drug molar ratio. This unique fiber incorporation not only protects the drug from degradation, but also importantly induces a Two Phase Exponential drug release, where the first phase corresponds to the drug dissolved in the interstitial space, while the second phase corresponds to the drug exiting from the gel fibers, and where the speed in each phase is in accordance with the physicochemical properties of the drugs, opening perspectives for controlled delivery. Skin permeation ex vivo tests show how these gels successfully promote the drug permeation and retention inside the skin for reaching their therapeutic target, while in vivo experiments demonstrate that they decrease the hyperplasia and reduce the macroscopic tissue damage typically observed in psoriatic skin, significantly more than the drugs in solution. All these characteristics, beside the spontaneous and easy preparation (room temperature and soft stirring), make these gels a good alternative to other routes of administration for Psoriasis treatment, increasing the drug concentration at the target tissue, and minimizing side effects

Microscale coiling in bis-imidazolium supramolecular hydrogel fibres induced by release of a cationic serine protease inhibitor

Gels formed by a gemini dicationic amphiphile incorporate a serine protease inhibitor, which could be used in a new approach to the treatment of Rosacea, within the fibres as well as in the space between them, affecting a number of gel properties but most importantly inducing remarkable fibre coiling at the microscopic level as a result of drug release from the gel. Drug release and skin permeation experiments show its potential for topical administration

Lipid Vesicles Loaded with an HIV-1 Fusion Inhibitor Peptide as a Potential Microbicide

The effective use of fusion inhibitor peptides against cervical and colorectal infections requires the development of sustained release formulations. In this work we comparatively study two different formulations based on polymeric nanoparticles and lipid vesicles to propose a suitable delivery nanosystem for releasing an HIV-1 fusion inhibitor peptide in vaginal mucosa. Polymeric nanoparticles of poly-d,l-lactic-co-glycolic acid (PLGA) and lipid large unilamellar vesicles loaded with the inhibitor peptide were prepared. Both formulations showed average sizes and polydispersity index values corresponding to monodisperse systems appropriate for vaginal permeation. High entrapment efficiency of the inhibitor peptide was achieved in lipid vesicles, which was probably due to the peptide's hydrophobic nature. In addition, both nanocarriers remained stable after two weeks stored at 4 °C. While PLGA nanoparticles (NPs) did not show any delay in peptide release, lipid vesicles demonstrated favorably prolonged release of the peptide. Lipid vesicles were shown to improve the retention of the peptide on ex vivo vaginal tissue in a concentration sufficient to exert its pharmacological effect. Thus, the small size of lipid vesicles, their lipid-based composition as well as their ability to enhance peptide penetration on vaginal tissue led us to consider this formulation as a better nanosystem than polymeric nanoparticles for the sustained delivery of the HIV-1 fusion inhibitor peptide in vaginal tissues

EIFIS: a modular extreme integral field spectrograph for the 10.4m GTC

EIFIS (Extreme Integral FIeld Spectrograph) is a modular integral field spectrograph, based on image slicers, and makes use of new, large format detectors. The concept is thought to cover the largest possible field of view while producing spectroscopy over the complete optical range (3 000 - 10 000 \r{A}) at a medium resolving power of about 2400. In the optimal concept, each module covers a field of view of 38" x 38" with 0.3" spaxels, which is fed into a double spectrograph with common collimator optics. The blue arm covers the spectral range between 3000 and 5600 \r{A} and the red arm between 5400 and 10100 \r{A}, allowing for an overlap range. The spectra are imaged onto 9.2k x 9.2k detectors using a double pseudoslit. The proposed design for the 10.4m Gran Telescopio Canarias uses a total of 6 such modules to cover a total of 2.43 square arcminutes. Here we will present the conceptual design of the instrument and a feasibility study of the optical and mechanical design of the spectrographs. We discuss the limitations and alternative designs and its potential to produce leading edge science in the era of extremely large telescopes and the James Webb Space Telescope.Comment: Submitted to the Proceedings of the SPIE, Astronomical Telescopes and Instrumentatio

Cationic supramolecular hydrogels for overcoming the skin barrier in drug delivery

A cationic bis‐imidazolium‐based amphiphile was used to form thermoreversible nanostructured supramolecular hydrogels incorporating neutral and cationic drugs for the topical treatment of rosacea. The concentration of the gelator and the type and concentration of the drug incorporated were found to be factors that strongly influenced the gelling temperature, gel‐formation period, and overall stability and morphology. The incorporation of brimonidine tartrate resulted in the formation of the most homogeneous material of the three drugs explored, whereas the incorporation of betamethasone resulted in a gel with a completely different morphology comprising linked particles. NMR spectroscopy studies proved that these gels kept the drug not only at the interstitial space but also within the fibers. Due to the design of the gelator, drug release was up to 10 times faster and retention of the drug within the skin was up to 20 times more effective than that observed for commercial products. Experiments in vivo demonstrated the rapid efficacy of these gels in reducing erythema, especially in the case of the gel with brimonidine. The lack of coulombic attraction between the gelator-host and the guest-drug seemed particularly important in highly effective release, and the intermolecular interactions operating between them were found to lie at the root of the excellent properties of the materials for topical delivery and treatment of rosacea

Caspofungin-Loaded Formulations for Treating Ocular Infections Caused by Candida spp.

Fungal keratitis causes corneal blindness worldwide. The treatment includes antibiotics, with Natamycin being the most commonly used; however, fungal keratitis is difficult to treat, so alternative therapies are needed. In situ gelling formulations are a promising alternative; this type of formulation has the advantages of eye drops combined with the advantages of ointments. This study was designed to develop and characterize three formulations containing 0.5% CSP: CSP-O1, CSP-O2, and CSP-O3. CSP is an antifungal drug that acts against a diverse variety of fungi, and Poloxamer 407 (P407) is a polymer of synthetic origin that is able to produce biocompatible, biodegradable, highly permeable gels and is known to be thermoreversible. Short-term stability showed that formulations are best stored at 4 °C, and rheological analysis showed that the only formulation able to gel in situ was CSP-O3. In vitro release studies indicated that CSP-O1 releases CSP most rapidly, while in vitro permeation studies showed that CSP-O3 permeated the most. The ocular tolerance study showed that none of the formulations caused eye irritation. However, CSP-O1 decreased the cornea's transparency. Histological results indicate that the formulations are suitable for use, with the exception of CSP-O3, which induced slight structural changes in the scleral structure. All formulations were shown to have antifungal activity. In view of the results obtained, these formulations could be promising candidates for use in the treatment of fungal keratitis

Design, Characterization, and Biopharmaceutical Behavior of Nanoparticles Loaded with an HIV‑1 Fusion Inhibitor Peptide

New therapeutic alternatives to fight against the spread of HIV-1 are based on peptides designed to inhibit the early steps of HIV-1 fusion in target cells. However, drawbacks, such as bioavailability, short half-life, rapid clearance, and poor ability to cross the physiological barriers, make such peptides unattractive for the pharmaceutical industry. Here we developed, optimized, and characterized polymeric nanoparticles (NPs) coated with glycol chitosan to incorporate and release an HIV-1 fusion inhibitor peptide (E1) inside the vaginal mucosa. The NPs were prepared by a modified double emulsion method, and optimization was carried out by a factorial design. In vitro, ex vivo, and in vivo studies were carried out to evaluate the optimized formulation. The results indicate that the physicochemical features of these NPs enable them to incorporate and release HIV fusion inhibitor peptides to the vaginal mucosa before the fusion step takes place. KEYWORDS: GB virus C, HIV-1, fusion inhibitor peptide of HIV-1, polymeric nanoparticles, factorial design, permeation studie

Permeation Protection by Waterproofing Mucosal Membranes

The permeability of the oral or nasal mucosa is higher than that of the skin. Mucosa permeabilitydepends mainly on the thickness and keratinization degree of the tissues. Their permeabilitybarrier is conditioned by the presence of certain lipids. This work has the main aim of reinforcing thebarrier effect of oral mucosa with a series of formulations to reduce permeation. Transmembranewater loss of different formulations was evaluated, and three of them were selected to be tested onthe sublingual mucosa permeation of drugs. Caffeine, ibuprofen, dexamethasone, and ivermectinwere applied on porcine skin, mucosa, and modified mucosa in order to compare the effectiveness ofthe formulations. A similar permeation profile was obtained in the different membranes: caffeine> ibuprofen~dexamethasone > ivermectin. The most efficient formulation was a liposomal formulationcomposed of lipids that are present in the skin stratum corneum. Impermeability providedby this formulation was notable mainly for the low-molecular-weight compounds, decreasing theirpermeability coefficient by between 40 and 80%. The reinforcement of the barrier function of mucosaprovides a reduction or prevention of the permeation of different actives, which could be extrapolatedto toxic compounds such as viruses, contaminants, toxins, etc.</p

Multifunctional serine protease inhibitor-coated water-soluble gold nanoparticles as a novel targeted approach for the treatment of inflammatory skin diseases

The overexpression and increased activity of the serine protease Kallikrein 5 (KLK5) is characteristic of inflammatory skin diseases such as Rosacea. The use of inhibitors of this enzyme—such as 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF·HCl) or the anti-human recombinant Kallikrein 5 (anti-KLK5) antibody—in the treatment of the disease has been limited due to their low bioavailability, for which their immobilization in drug delivery agents can contribute to making serine protease inhibitors clinically useful. In this work, we synthesized gold nanoparticles (GNP) coated with a mixture of hydroxyl- and carboxyl-terminated thiolates (GNP.OH/COOH), whose carboxyl groups were used to further functionalize the nanoparticles with the serine protease inhibitor AEBSF·HCl either electrostatically or covalently (GNP.COOH AEBSF and GNP.AEBSF, respectively), or with the anti-KLK5 antibody (GNP.antiKLK5). The synthesized and functionalized GNP were highly water-soluble, and they were extensively characterized using UV–vis absorption spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Thermogravimetric Analysis (TGA). GNP.OH/COOH and their subsequent functionalizations effectively inhibited KLK5 in vitro. Internalization of fluorophore-coated GNP.OH/COOH in human keratinocytes (HaCaT cells) was proven using confocal fluorescence microscopy. Cell viability assays revealed that the cytotoxicity of free AEBSF is importantly decreased when it is incorporated in the nanoparticles, either ionically (GNP.COOH AEBSF) or, most importantly, covalently (GNP.AEBSF). The functionalized nanoparticles GNP.AEBSF and GNP.antiKLK5 inhibited intracellular KLK5 activity in HaCaT cells and diminished secretion of IL-8 under inflammatory conditions triggered by TLR-2 ligands. This study points to the great potential of these GNP as a new intracellular delivery strategy for both small drugs and antibodies in the treatment of skin diseases such as Rosacea

Alginate Hydrogel Formulation with Ketorolac for the Treatment of Pain Related Sialolithiasis

Abstract: Sialolithiasis mainly affects the oral salivary glands due to the presence of small stones that obstruct the secretion of saliva. The treatment and control of pain and inflammation during the course of this pathology is essential to guarantee the patient's comfort. For this reason, a ketorolac calcium cross-linked alginate hydrogel was developed, and it was then applied in the area of the buccal cavity. The formulation was characterized (swelling and degradation profile, extrusion, extensibility, surface morphology, viscosity, and drug release). The drug release was studied ex vivo in static Franz cells and with a dynamic ex vivo method under artificial saliva continuous flow. The product exhibits adequate physicochemical properties considering the intended purpose, and the drug concentrations retained in the mucosa were high enough to deliver a therapeutic local concentration able to reduce the pain associated with the patient's conditions. The results confirmed the suitability of the formulation for application in the mouth