Paulo Lobão

In situ gelling systems: a strategy to improve the bioavailability of ophthalmic pharmaceutical formulations.

The low therapeutic efficacy exhibited by conventional ophthalmic solutions owing to precorneal elimination of the drug, drainage by gravity, nasolacrimal drainage, conjunctival absorption, and the absence of controlled release and of bioadhesive properties, can be overcome by the use of in situ gelling systems. The combination in the same formulation of different in situ gelling polymers with different stimuli-responsiveness mechanisms exploiting the unique physicochemical characteristics of the ocular tissues is one such strategy that has produced improved results compared with conventional systems. As we discuss here, the recent use of biodegradable and biocompatible polymers in colloidal carrier systems has proved to be the most effective strategy, resulting in the exponential increase of the bioavailability of the ophthalmic drugs.

Photodegradation of avobenzone: Stabilization effect of antioxidants

Avobenzone is one of the most common UVA-filters in sunscreens, and is known to be photounstable. Some of the strategies used to stabilize this filter present some drawbacks like photosensitization reactions. Antioxidants are widely used as cosmetic ingredients that prevent photoageing and complement the photoprotection offered by the UV-filters preventing or reducing photogenerated reactive species. The purpose of this work was to study the effect of antioxidants in the photostabilization of avobenzone. The filter dissolved in dimethyl sulfoxide or incorporated in a sunscreen formulation was irradiated with simulated solar radiation (750 W/m(2)). The tested antioxidants were vitamin C, vitamin E, and ubiquinone. The area under the curve of the absorption spectrum for UVA range and the sun protection factor (SPF) were calculated. Vitamin E (1:2), vitamin C (1:0.5) and ubiquinone (1:0.5) were the more effective concentrations increasing the photostability of avobenzone. In sunscreen formulations, the most effective photostabilizer was ubiquinone which also promoted an increase in SPF. This knowledge is important to improve effectiveness of sunscreen formulation. Antioxidants can be valuable ingredients for sunscreens with a triple activity of filter stabilization, SPF boosting and photoageing prevention.

Applications of poloxamers in ophthalmic pharmaceutical formulations: an overview

Introduction: An ideal ophthalmic formulation is one that not only prolongs the contact time of the vehicle on the ocular surface but also slows down the drug elimination. The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems. In situ gelling systems increase the viscosity by changing the pH or temperature in the pre-corneal region and lead to an increase of drug bioavailability by slowing drainage. Poloxamers are polyols with thermal gelling properties which are frequently included in ophthalmic formulations to improve the ocular bioavailability of drugs by increasing vehicle viscosity. Areas covered: An overview on the unique physiological characteristics of ocular globe and the limitations and disadvantages of the conventional ophthalmic pharmaceutical formulations. Readers will appreciate the different strategies to improve the absorption of drugs in the ocular globe, especially the incorporation of poloxamers in ophthalmic formulations, understanding the main advantages of the poloxamers and also learning about the different examples of applications of these polymers in ophthalmic pharmaceutical formulations. Expert opinion: Poloxamers offers a new strategy to improve bioavailability and decrease the side effects induced by the systemic absorption of topically applied ophthalmic drugs.

Degradation of UV filters 2-ethylhexyl-4-methoxycinnamate and 4-tert-butyl-4′-methoxydibenzoylmethane in chlorinated water

Environmental context The increasing use of sun-creams containing UV-filtering chemicals has led to increased inputs of these compounds to the aquatic environment. Chlorinated waters can convert these chemicals into chlorinated products whose toxic effects are of primary concern. To better understand the environmental fate of sun-cream chemicals, we studied the stability of two UV-filtering compounds under varying conditions of pH, chlorine concentration, temperature, dissolved organic matter and solar irradiation. Abstract The stability of the UV filters 2-ethylhexyl-4-methoxycinnamate (EHMC) and 4-tert-butyl-4′-methoxydibenzoylmethane (BDM) in chlorinated water was studied. High-performance liquid chromatography (HPLC)-UV-diode array detection (DAD) was used to follow the reaction kinetics of both UV filters and HPLC-tandem mass spectrometry (MS/MS) was used to tentatively identify the major transformation by-products. Under the experimental conditions used in this work both UV filters reacted with chlorine following pseudo-first order kinetics: rate constant k=0.0095±0.0007min–1 and half-life t1/2=73±4min for EHMC and rate constant k=0.006±0.001min–1 and half-life t1/2=119±14min for BDM (mean±standard deviation). The chemical transformation of the UV filters in chlorinated water led to the formation of chlorinated by-products that were tentatively identified as mono- and dichloro-substituted compounds that resulted from substitution of the hydrogen atoms in the benzene rings by one or two chlorine atoms. Experimental Box–Behnken designs were used to assess the effect of experimental factors: pH, temperature, chlorine concentration, dissolved organic matter and artificial sunlight irradiation on the transformation of the UV filters.

Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations: present and future considerations.

The unique properties and characteristics of ocular tissues and the whole set of defence mechanisms of the ocular globe make the instillation of ocular drugs into a difficult task with a low rate of therapeutic response. One of the challenges for the new generation of ophthalmic pharmaceutical formulations is to increase the bioavailability of drugs administered by the ocular route and, therefore, their therapeutic efficacy. This can be achieved with the use of some strategies that provide an increase in the formulation pre-corneal residence time, mucoadhesion and penetration across the eye tissues. Colloidal carrier systems have been very successfully used for the selective and targeted delivery of drugs for several routes of administration. In this context, nanoparticles prepared with specific polymers or lipids and coated, dispersed or suspended in polymer solutions with mucoadhesion properties or in situ gelling properties will be an excellent strategy that deserves attention and further research. In this review, the characteristics and main properties of polymeric and lipid nanoparticles are discussed and examples and advantages of the application of these colloidal carrier systems for the ophthalmic administration of drugs are presented. The future directions of the research required in this specific field are also presented.

Liposomes as a model for the biological membrane: studies on daunorubicin bilayer interaction.

In this study the interaction of the antitumoral drug daunorubicin with egg phosphatidylcholine (EPC) liposomes, used as a cell membrane model, was quantified by determination of the partition coefficient (Kp). The liposome/aqueous-phase Kp of daunorubicin was determined by derivative spectrophotometry and measurement of the zeta-potential. Mathematical models were used to fit the experimental data, enabling determination of Kp. In the partition of daunorubicin within the membrane both superficial electrostatic and inner hydrophobic interactions seem to be involved. The results are affected by the two types of interaction since spectrophotometry measures mainly hydrophobic interactions, while zeta-potential is affected by both interpenetration of amphiphilic charged molecules in the bilayer and superficial electrostatic interaction. Moreover, the degree of the partition of daunorubicin with the membrane changes with the drug concentration, due mainly to saturation factors. Derivative spectrophotometry and zeta-potential variation results, together with the broad range of concentrations studied, revealed the different types of interactions involved. The mathematical formalism applied also allowed quantification of the number of lipid molecules associated with one drug molecule.

Preparation, characterization and biocompatibility studies of thermoresponsive eyedrops based on the combination of nanostructured lipid carriers (NLC) and the polymer Pluronic F-127 for controlled delivery of ibuprofen

Abstract Context: Nanostructured lipid carrier (NLC) dispersions present low viscosity and poor mucoadhesive properties, which reduce the pre-corneal residence time and consequently, the bioavailability of ocular drugs. Objective: The aim of this study was to prepare thermoresponsive eyedrops based on the combination of lipid nanoparticles and a thermoresponsive polymer with mucomimetic properties (Pluronic® F-127). Materials and methods: NLCi dispersions were prepared based on the melt-emulsification and ultrasonication technique. Physicochemical and morphological characteristics of the colloidal dispersions were evaluated. The formulation was also investigated for potential cytotoxicity in Y-79 human retinoblastoma cells and the in vitro drug release profile of the ibuprofen was determined. Results: NLCi showed a Z-average below 200 nm, a highly positive zeta potential and an efficiency of encapsulation (EE) of ∼90%. The gelification of the NLCi dispersion with 15% (w/w) Pluronic® F-127 did not cause significant changes to the physicochemical properties. The potential NLC-induced cytotoxicity was evaluated by the Alamar Blue reduction assay in Y-79 cells, and no relevant cytotoxicity was observed after exposure to 0–100 µg/mL NLC for up to 72 hours. The optimized formulations showed a sustained release of ibuprofen over several hours. Discussion and conclusion: The strategy proposed in this work can be successfully used to increase the bioavailability and the therapeutic efficacy of conventional eyedrops.

Comparative study of sustained-release lipid microparticles and solid dispersions containing ibuprofen

Ibuprofen is one of the most important non-steroidal anti-inflammatory drugs used in the treatment of inflammatory diseases. In its pure state, ibuprofen presents poor physical and mechanical characteristics and its use in solid dosage forms needs the addition of excipients that improve these properties. The selection of the best excipients and the most suitable pharmaceutical dosage form to carry ibuprofen is very important for the industrial success of this drug. Given these factors, lipid microparticles and solid dispersions of ibuprofen with cetyl alcohol, stearic acid, and hydrogenated castor oil were prepared. These formulations were intended to improve the physical and mechanical characteristics and to sustain the release of this drug. Physical mixtures were also prepared with the same ingredients in similar proportions. The solid dispersions of ibuprofen/stearic acid and ibuprofen/hydrogenated castor oil showed the best flow characteristics compared with pure ibuprofen. Further, gelatin capsules filled with lipid microparticles and solid dispersions were submitted to dissolution tests in order to study the influence of the prepared systems in the release profiles of ibuprofen. Prolonged release of ibuprofen was achieved with the lipid microparticles and solid dispersions prepared with the different types of excipients.

New Thermoresponsive Eyedrop Formulation Containing Ibuprofen Loaded-Nanostructured Lipid Carriers (NLC): Development, Characterization and Biocompatibility Studies

The low bioavailability and consequently the poor therapeutic response of traditional ophthalmic formulations is caused by reduced pre-corneal residence time of the formulation in contact with the ocular surface. The use of colloidal carrier systems, namely lipid nanoparticles in combination with in situ gelling polymers, is an excellent strategy which results in the exponential increase of the bioavailability of ophthalmic drugs. In the present study, we have developed thermoresponsive eyedrops prepared with nanostructured lipid carriers (NLC) dispersions for the controlled delivery of ibuprofen. Lipid solubility studies and DSC measurements have proved that the lipids solubilise ibuprofen and present a good compatibility. NLC were prepared based on the melt-emulsification and ultrasonication technique and lipid nanoparticles with a Z-average of 120-150 nm, polydispersity index below 0.3, highly positive zeta potential and an efficacy of encapsulation of ~87% were obtained. The cytotoxicity of NLC was evaluated by the Alamar Blue reduction assay using the Y-79 human retinoblastoma cell line, and no relevant toxicity was observed after exposure to 0-100 μg/mL NLC for up to 72 hours. The HET-CAM assay was used to assess the product eye compatibility, confirming that the developed product does not exhibit irritant potential. The in vitro release studies showed ibuprofen release over several hours.

Drugs obtained by biotechnology processing

In recent years, the number of drugs of biotechnological origin available for many different diseases has increased exponentially, including different types of cancer, diabetes mellitus, infectious diseases (e.g. AIDS Virus / HIV) as well as cardiovascular, neurological, respiratory, and autoimmune diseases, among others. The pharmaceutical industry has used different technologies to obtain new and promising active ingredients, as exemplified by the fermentation technique, recombinant DNA technique and the hybridoma technique. The expiry of the patents of the first drugs of biotechnological origin and the consequent emergence of biosimilar products, have posed various questions to health authorities worldwide regarding the definition, framework, and requirements for authorization to market such products.