3D Printing of Temporary Prostheses for Controlled-Release of Drugs: Design, Physical Characterization and Preliminary Studies.

In recent years, the use of 3D printing technologies in orthopedic surgery has markedly increased, as they offer the possibility of printing personalized prostheses. The work presented in this article is a preliminary study of a research project which aims to manufacture customized spacers containing antibiotics for use in joint replacement surgery. The objective of this work was to design and print different 3D constructs to evaluate the use of different materials, their properties after the process of 3D printing, such as resistance, and the release kinetics of drugs from the constructs. Different designs and different materials were analyzed to obtain a 3D construct with suitable properties. Our design takes advantage of the micropores created between the layers of the 3D printed filaments to release the contained drug. Using polylactic acid (PLA) we were able to print cylindrical structures with interconnected micropores and a hollow chamber capable of releasing methylene blue, which was selected as a model drug. The final PLA 3D construct was printed with a 10% infill. The physical and technological characteristics, morphological changes at body temperature and interaction with water were considered to be acceptable. The PLA 3D printed constructs were found to have sufficient strength to withstand a force of 500 kg. The results obtained allow to continue research in this project, with the aim of manufacturing prostheses containing a reservoir of antibiotics or other drugs in their interior for their subsequent controlled release.

HPLC-UV analytical validation of a method for quantification of progesterone in ex vivo trans-corneal and trans-scleral diffusion studies.

Progesterone (PG) diminishes free radical damage and thus can afford protection against oxidative stress affecting the retina. The therapeutic use of PG is limited because it is a highly hydrophobic steroid hormone with very low solubility in water. This is the main drawback for the therapeutic application of PG at ocular level. The aims of this study were: (i) to analyze if PG causes ocular irritation (ii) to validate a HPLC method to determine PG in ex vivo studies and (iii) to evaluate PG permeation through cornea and sclera. A high performance liquid chromatographic method was developed and validated to detect PG incorporated to ß-cyclodextrin using a Waters Sunfire C18 (150 × 4.6 mm) reverse-phase column packed with 5 µm silica particles using a mobile phase consisted of a mixture of acetonitrile (ACN) and pure water 80:20 (v/v), pH 7.4. The limit of detection and the limit of quantification for 50 µL injection of PG were found to be 0.42 and 1.26 µg/mL, respectively. The calibration curve showed excellent linearity over the concentration range (0.5 µg/mL to 100 µg/mL). As proof of concept, ex-vivo experiments to investigate PG permeation through cornea and sclera with vertical diffusion cells were carried out to quantify PG diffusion. Ex vivo experiments demonstrate its applicability to investigate permeation levels of PG from 6.57 ±â€¯0.37 µg/cm2 at cornea and 8.13 ±â€¯0.85 µg/cm2 sclera. In addition, at the end of diffusion studies the amount of PG retained in each tissue was also quantified, and it was 40.87 ±â€¯9.84 µg/cm2 (mean ±â€¯SD; n = 6) in cornea and 56.11 ±â€¯16.67 µg/cm2 (mean ±â€¯SD; n = 6) in sclera.

Ex-Vivo Trans-Corneal and Trans-Scleral Diffusion Studies with Ocular Formulations of Glutathione as an Antioxidant Treatment for Ocular Diseases.

Exposure to sunlight and contact with atmospheric oxygen makes the eye particularly susceptible to oxidative stress, which can potentially produce cellular damage. In physiological conditions, there are several antioxidant defense mechanisms within the eye. Glutathione (GSH) is the most important antioxidant in the eye; GSH deficit has been linked to several ocular pathologies. The aim of this study was to explore the potential for newly developed formulations allowing controlled delivery of antioxidants such as GSH and vitamin C (Vit C) directly to the eye. We have investigated the stability of antioxidants in aqueous solution and assessed ex-vivo the diffusion of GSH through two ocular membranes, namely cornea and sclera, either in solution or included in a semisolid insert. We have also carried out the hen's egg-chlorioallantoic membrane test (HET-CAM) to evaluate the ocular irritancy of the different antioxidant solutions. Our results showed that GSH is stable for up to 30 days at 4 °C in darkness and it is not an irritant to the eye. The diffusion studies revealed that the manufactured formulation, a semisolid insert containing GSH, could deliver this tripeptide directly to the eye in a sustained manner.

Evaluación de los conocimientos y habilidades de los alumnos del grado de Farmacia: Prueba ECOE (Evaluación Clínica Objetiva Estructurada) / Assessment of the knowledge and skills of Pharmacy graduates: Objective Structured Clinical Examination (OSCE)

La enseñanza universitaria evoluciona hacia la formación basada en problemas. La prueba ECOE (Evaluación Clínica Objetiva Estructurada) permite evaluar la capacidad del alumno en tres de los cuatro escalones de la pirámide de Miller; saber, saber cómo y demostrar cómo (conocimientos, habilidades y actitudes). Esta es la prueba de evaluación de las practicas tuteladas y en la Universidad Cardenal Herrera CEU se ha impartido en los dos últimos cursos a un total de 79 alumnos con resultados satisfactorios. El alumno debe pasar por 5 estaciones donde en 5 minutos en cada una debe resolver el problema práctico que se le plantea. Un profesor entrenado hace de paciente y otro profesor evalúa las habilidades del alumno. Luego se pasó una encuesta de satisfacción anónima a los alumnos siendo el resultado de 4,12/6.Es necesario ir modificando los problemas planteados a los alumnos para que cada vez más se adapten a la realidad que se encontraran al obtener el grado como profesionales farmacéuticos

Higher education evolves towards Problem Based Learning. The Objective Structured Clinical Examination (OSCE) assesses students’ competencies in three of the four levels of Miller’s pyramid; Knows, Knows How, and Shows How (knowledge, competence, and performance). In the last two years, a total of 79 students at Cardenal Herrera University CEU were assessed with this examination, with good results. Student are asked to go through 5 stations, in which they have 5 minutes to resolve a practical problem. A trained teacher acts as the patient, while another evaluates the student’s abilities. Next, an anonymous satisfaction survey is given to the students, with the result 4,12/6.The problems presented to the students must be changed constantly so that each time they increasingly adapt to the situations they will find in their real-life practice once the graduate as professional pharmacists

Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics.

The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm² were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm² were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle and skin and diffusivity through skin place them as practical and potentially insightful approach to quantify and, ultimately, optimize topical bioavailability.

Ex vivo rabbit cornea diffusion studies with a soluble insert of moxifloxacin.

The objective of this research was to develop and evaluate an ocular insert for the controlled drug delivery of moxifloxacin which could perhaps be used in the treatment of corneal keratitis or even bacterial endophthalmitis. We have evaluated the ex vivo ocular diffusion of moxifloxacin through rabbit cornea, both fresh and preserved under different conditions. Histological studies were also carried out. Subsequently, drug matrix inserts were prepared using bioadhesive polymers. The inserts were evaluated for their physicochemical parameters. Ophthalmic ex vivo permeation of moxifloxacin was carried out with the most promising insert. The formulate insert was thin and provided higher ocular diffusion than commercial formulations. Ocular diffusion studies revealed significant differences between fresh and frozen corneas. Histological examinations also showed differences in the thickness of stroma between fresh and frozen corneas. The ophthalmic insert we have developed allows a larger quantity of moxifloxacin to permeate through the cornea than existing commercial formulations of the drug. Ocular delivery of moxifloxacin with this insert could be a new approach for the treatment of eye diseases.

Evaluation of percutaneous absorption of esculetin: effect of chemical enhancers.

Percutaneous transdermal absorption of esculetin (6,7-dihydroxycoumarin), an oxidative damage inhibitor, was evaluated by means of in vitro permeation studies in which vertical Franz-type diffusion cells and pig ear skin were employed. To determine the absorption of esculetin, we validated a simple, accurate, precise, and rapid HPLC-UV method. Additionally, the effects of several percutaneous enhancers were studied. Pretreatment of porcine skin was performed with ethanol (control vehicle), decenoic acid, oleic acid, R-(+)-limonene, and laurocapram (Azone®) (5% in ethanol, w/w, respectively). Pretreatment of skin with oleic acid or laurocapram led to statistically significant differences in the transdermal flux of esculetin with respect to controls. Of the two enhancers, laurocapram showed the greatest capacity to enhance the flux of esculetin across pig skin.

Elastic vesicles of sumatriptan succinate for transdermal administration: characterization and in vitro permeation studies.

Elastic liposomes, including sumatriptan succinate, were prepared for their transdermal administration. Lipid vesicles containing 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or l-α-phosphatidylcholine dilauroyl (DLPC) phospholipids were characterized for various parameters, including size, particle-size distribution (i.e., polydispersity index), and elasticity. In vitro transdermal experiments for the study of the skin penetration of sumatriptan succinate contained in liposomes were performed by using flow-through diffusion cells. The diameter of sumatriptan liposomes with different lipid compositions varied between 279 and 282 nm, and the polydispersity index value for the size distribution of liposomal formulations was <0.5. DLPC vesicles proved to be more elastic and provided a higher sumatriptan transdermal flux than vesicles formulated with DOPC phospolipid.

Combined strategies for enhancing the transdermal absorption of midazolam through human skin.

OBJECTIVES: Midazolam administration by intravenous or intramuscular injection produces pain and stress. For this reason, alternative methods of administration have been proposed. The transdermal administration of midazolam could improve patient comfort, which is especially important for children in the pre-operative period. We aimed to assess the effect of iontophoresis and chemical percutaneous enhancers applied individually and together, to determine if a synergistic effect is achieved when both enhancement techniques are simultaneously employed. METHODS: This work reports the characterization of the passive diffusion of midazolam hydrochloride through human skin in vitro and evaluates the effect of iontophoresis application and chemical percutaneous enhancers on said diffusion when employed both individually and in combination. KEY FINDINGS: Percutaneous absorption assays demonstrated that the physical technique of iontophoresis, when applied alone, moderately increased midazolam hydrochloride permeation flux through human skin, producing a similar effect to that obtained with R-(+)-limonene chemical enhancer. Among the strategies assayed, it was observed that Azone produced the most pronounced enhancement effect when applied separately. The combination of pre-treatment with Azone and iontophoresis exhibited a higher capacity for enhancing the transdermal flux of midazolam through human skin than Azone alone. CONCLUSIONS: In conclusion, when applied individually, Azone exhibited the greatest enhancement effect on the transdermal diffusion of midazolam of the various strategies assayed. The combination of Azone and iontophoresis produce the highest transdermal steady-state flux of midazolam but no synergic effect was achieved when the two enhancement strategies were applied in combination, showing that although selecting the best conditions for iontophoresis application, it is less effective for augmenting the transdermal delivery of midazolam than the chemical enhancer Azone.

Comparing metoclopramide electrotransport kinetics in vitro and in vivo.

The purpose of this work was to investigate the transdermal iontophoretic delivery of metoclopramide and to determine (i) the dependence of electrotransport on current density and drug concentration, (ii) the relative contributions of electromigration and electroosmosis and (iii) the feasibility of administering therapeutic amounts of drug, using a drug-sparing iontophoretic configuration. Iontophoretic delivery of metoclopramide (MCL) across dermatomed porcine ear skin was investigated in vitro as a function of concentration (10, 20, 40, 80 and 100mM) and current density (0.1, 0.2 and 0.3mAcm(-2)) using vertical flow-through diffusion cells. In vivo studies were performed in Wistar rats (40mM MCL, 0.3mAcm(-2), 5h); the anodal and drug formulation compartments were separated by a salt bridge. Cumulative delivery in vitro after 7h of current application (40mM MCL; 0.3mAcm(-2)) in the absence of electrolyte was 624.45+/-99.45microgcm(-2) (flux - 2.55+/-0.35microgcm(-2)min(-1)). There was a linear relationship between flux and both current density and drug concentration. Co-iontophoresis of acetaminophen confirmed that electromigration was the major transport mechanism (accounting for approximately 80% of MCL delivery). Electroosmotic inhibition, albeit modest, was only observed at the highest MCL concentration (100mM). Although the delivery rate observed in vivo in male Wistar rats (1.21+/-0.55microgcm(-2)min(-1)) was lower than that observed in vitro, the results suggest that drug input rates would be sufficient to achieve therapeutic levels in humans using non-invasive transdermal iontophoresis.