Biopharmaceutical Study of Triamcinolone Acetonide Semisolid Formulations for Sublingual and Buccal Administration.

The mouth can be affected by important inflammatory processes resulting from localized or systemic diseases such as diabetes, AIDS and leukemia, among others, and are manifested in various types of buccal sores typically presenting pain. This work focuses on the design, formulation, and characterization of four semisolid formulations for oral mucosa in order to symptomatically treat these painful processes. The formulations have two active pharmaceutical ingredients, triamcinolone acetonide (TA) and lidocaine hydrochloride (LIDO). The formula also contains, as an excipient, Orabase®, which is a protective, hydrophobic, and anhydrous adhesive vehicle, used to retain or facilitate the application of active pharmaceutical ingredients to the oral mucosa. After designing the formulations, an analytical method for TA was validated using HPLC so as to achieve reliable analytical results. Franz-type diffusion cells were used to perform drug release studies using synthetic membrane, and permeation studies using buccal mucosa, estimating the amount and rate of TA permeated across the tissue. Additionally, sublingual permeation studies were carried out to evaluate a scenario of a continuous contact of the tongue with the applied formulation. Permeation fluxes and the amount of TA retained within sublingual mucosa were similar to those in buccal mucosa, also implying anti-inflammatory activity in the part of the tongue that is in direct contact with the formulation. In addition, the dynamic conditions of the mouth were recreated in terms of the presence of phosphate buffered saline, constant movement of the tongue, pH, and temperature, using dissolution equipment. The amount of TA released into the phosphate buffered saline in dynamic conditions (subject to being ingested) is well below the normal oral doses of TA, for which the formulation can be considered safe. The formulations applied to buccal or sublingual mucosas under dynamic conditions permit the successful retention of TA within either tissue, where it exerts anti-inflammatory activity. The four formulations studied show a pseudoplastic and thixotropic behavior, ideal for topical application. These results evidence the potential of these topical formulations in the treatment of inflammatory processes in the buccal mucosa.

Improved synthesis and characterization of cholesteryl oleate-loaded cationic solid lipid nanoparticles with high transfection efficiency for gene therapy applications.

The development of new nanoparticle formulations that are capable of high transfection efficiency without toxicity is essential to provide new tools for gene therapy. However, the issues of complex, poorly reproducible manufacturing methods, and low efficiencies during in vivo testing have prevented translation to the clinic. We have previously reported the use of cholesteryl oleate as a novel excipient for solid lipid nanoparticles (SLNs) for the development of highly efficient and nontoxic nucleic acid delivery carriers. Here, we performed an extensive characterization of this novel formulation to make the scale up under Good Manufacturing Practice (GMP) possible. We also describe the complete physicochemical and biological characterization of cholesteryl oleate-loaded SLNs to ensure the reproducibility of this formula and the preservation of its characteristics before and after the lyophilization process. We defined the best manufacturing method and studied the influence of some parameters on the obtained nanoparticles using the Quality by Design (ICH Q8) guideline to obtain cholesteryl oleate-loaded SLNs that remain stable during storage and guarantee in vitro nucleic acid delivery efficacy. Our results indicate that this improved formulation is suitable for gene therapy with the possibility of scale-up the manufacturing of nanoparticles under GMP conditions.

Optimization of the Cohesion Index in the SeDeM Diagram Expert System and application of SeDeM Diagram: An improved methodology to determine the Cohesion Index.

In this study, we suggest optimizing the methodology to determine the Cohesion Index (Icd) in order to avoid mistaken characterizations due to powder bulk density. For this purpose, five different excipients, with different bulk densities and of different chemical nature, were compressed at different heights. Their compression and their tablet characterization enable establishing a powder weight for compression in accordance with its bulk density. Therefore, the resulting tablet will have a height within a defined range of heights where it has no critical effects on its hardness. Then, the impact of this optimization is shown in a formula development, one of the main SeDeM's applications. A mathematical equation was used to calculate the theoretical amount of excipient to formulate the API according to both methodologies. The compression results demonstrate that the characterization with the NM-Icd is more accurate than the previous one while preserving its simplicity.

Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy.

BACKGROUND: Cationic solid lipid nanoparticles (SLNs) have been given considerable attention for therapeutic nucleic acid delivery owing to their advantages over viral and other nanoparticle delivery systems. However, poor delivery efficiency and complex formulations hinder the clinical translation of SLNs. AIM: The aim of this study was to formulate and characterize SLNs incorporating the cholesterol derivative cholesteryl oleate to produce SLN-nucleic acid complexes with reduced cytotoxicity and more efficient cellular uptake. METHODS: Five cholesteryl oleate-containing formulations were prepared. Laser diffraction and laser Doppler microelectrophoresis were used to evaluate particle size and zeta potential, respectively. Nanoparticle morphology was analyzed using electron microscopy. Cytotoxicity and cellular uptake of lipoplexes were evaluated using flow cytometry and fluorescence microscopy. The gene inhibition capacity of the lipoplexes was assessed using siRNAs to block constitutive luciferase expression. RESULTS: We obtained nanoparticles with a mean diameter of approximately 150-200 nm in size and zeta potential values of 25-40 mV. SLN formulations with intermediate concentrations of cholesteryl oleate exhibited good stability and spherical structures with no aggregation. No cell toxicity of any reference SLN was observed. Finally, cellular uptake experiments with DNA-and RNA-SLNs were performed to select one reference with superior transient transfection efficiency that significantly decreased gene activity upon siRNA complexation. CONCLUSION: The results indicate that cholesteryl oleate-loaded SLNs are a safe and effective platform for nonviral nucleic acid delivery.

Osmolality predictive models of different polymers as tools in parenteral and ophthalmic formulation development.

During the development of parenteral dosage forms, different physicochemical studies are required to ensure stable, effective and safe formulations. The osmolality of this kind of dosage forms should bear a close similarity to the body fluids to prevent local irritation, pain or even more significant side effects like endothelial damage. The osmotic studies performed in Polyethylene glycol 400 (PEG 400), Polyethylene glycol 4000 (PEG 4000), Poloxamer 407 (P407), Sodium Hyaluronate (SH), Chondroitin Sulphate Sodium (CS), Cremophor RH 40 (CRE40) and Polyvinyl alcohol (PVA) aqueous solutions, showed that the theoretical determination of the osmolality based on their molecular weight as the only determinant factor did not agree with the values obtained by the measurement of colligative properties such as the freezing point depression. The data obtained from this study and its analysis, provided predictive equations that can be used as tools in the primary development to estimate formulation's osmolality at different concentrations; and its evolution over a period at the hypothetical worst-case scenario of storage temperature.

Preformulation and characterization of a lidocaine hydrochloride and dexamethasone sodium phosphate thermo-reversible and bioadhesive long-acting gel for intraperitoneal administration.

The search for new formulations of anaesthetic agents that allow a localized administration and provide a prolonged effect is of great interest in the multimodal management of postoperative pain. The pre-formulation and characterization of a lidocaine and dexamethasone thermosensitive and bioadhesive long-acting gel for intraperitoneal administration was done as a tool in the management of pain in abdominal surgeries. The pre-formulation process was conducted by a systematic variation of the concentration of the different polymers, until setting it, in a suitable concentration that allowed an adequate gelation temperature. The poloxamer 407 (P407) was used as the main polymer; hydroxypropyl methylcellulose (HPMC) as the bioadhesive agent and polyvinyl pyrrolidone (PVP) to adjust the gelation temperature and physicochemical properties. The formulations were characterized by gelation temperature, pH, viscosity at 25°C and 37°C, gelation time, density and osmolality. Gelation temperature was decreased when increasing the concentration of hydroxypropyl methylcellulose and poloxamer 407, this effect was also observed when adding lidocaine hydrochloride and dexamethasone sodium phosphate to the formulations. The gelation temperature did not have statistically significant relation with the PVP concentration (P-value of 0.6797), even though, there is a tendency in the gelation temperature by varying it. Between the developed formulations, the 12.5/3.3/0.4% (P407/HPMC/PVP) formulation presents an appropriate gelation temperature, a suitable viscosity for administration by syringe, an adequate and stable pH and osmolality to prevent tissue damage and a correct gelation time that allowed the formation of a prolonged release implant.

Establishment of criteria for the selection and adaptation of objectives and indicators in ISO9001: 2008 quality system in a university pharmaceutical pilot plant / Establecimiento de criterios para la selección y adaptación de objetivos e indicadores en un sistema de calidad ISO9001:2008 en una planta piloto farmacéutica universitaria

Aims: The aim of this work is the correct establishment and follow-up of quality objectives and indicators as the cornerstones of a quality assurance system, in this case focused on ISO9001. Materials and methods: In this work, the authors present the criteria that, in their view, an organization must follow for a better selection and adaptation of the ISO9001:2008 quality system objectives and indicators applied to a university pharmaceutical pilot plant. The evolution of errors in setting objectives and indicators is assessed. Results: Based on the experience of several years at the SDM (Service of Development of Medicines) at the Faculty of Pharmacy of the University of Barcelona, the results show that the establishing of appropriate objectives and indicators is not an easy task. A careful selection of both objectives and indicators must be a compulsory step prior to the establishment of a robust, reliable quality assurance system through years. Conclusions: Experience over time proves to be a powerful tool to end up selecting the right quality objectives and indicators for such quality system. Since this task is not always easy to carry out, is necessary to set a selection of criteria in order to obtain useful information that contributes to the continuous improvement of the quality system

Objetivos: El objetivo de este trabajo es el correcto establecimiento y seguimiento de los objetivos de calidad y sus indicadores, como pilar fundamental de un sistema de garantía de calidad, en este caso centrado en ISO9001. Material y métodos: En este trabajo, los autores presentan los criterios que, a su juicio, una organización debe seguir para una mejor selección y adaptación de objetivos e indicadores en el marco de la norma de calidad ISO9001:2008, aplicada a una planta piloto farmacéutica universitaria. Se realiza una evaluación de los errores en el establecimiento de objetivos e indicadores. Resultados: En base a la experiencia de varios años en SDM (Servicio de Desarrollo del Medicamento) en la Facultad de Farmacia de la Universidad de Barcelona, los resultados muestran que el establecimiento de objetivos e indicadores apropiados no resulta una tarea sencilla. Una cuidadosa selección tanto de objetivos como de indicadores debe ser un paso obligado para el establecimiento de un sistema de aseguramiento de calidad robusto y fiable a lo largo del tiempo. Conclusiones: El aprendizaje basado en la experiencia de años demuestra ser una herramienta poderosa para acabar seleccionando los objetivos e indicadores correctos que se adapten al sistema de calidad en cuestión. Dado que este hecho no siempre resulta fácil, es necesario establecer unos criterios con el objetivo de obtener información útil que contribuya a la mejora continua del sistema de calidad (AU)