Activitat de l'aigua com a paràmetre d'estudi de l'estabilitat de medicaments: aplicació en comprimits d'àcid acetilsalicílic

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia, Universitat de Barcelona, 2015. Tutor: Josep Maria Suñé Negre.[cat] Es desenvolupa un estudi experimental per investigar si és possible i útil l’aplicació de la determinació de l’activitat de l’aigua en el disseny de formulacions medicamentoses i l’estudi de la seva estabilitat i llur control de qualitat. Així com l’activitat de l’aigua és un paràmetre que s’ha vingut utilitzant en el camp de l’alimentació, no s’aplica encara a l’estudi dels medicaments essent més important el contingut d’humitat, malgrat que a les darreres edicions de les principals farmacopees (USP i Ph Eur) ja existeix una monografia que contempla l’activitat de l’aigua, si bé tan sols relacionat amb la càrrega microbiana del medicament. Es planteja conèixer la influència de l’activitat de l’aigua en l’estabilitat fisicoquímica de medicaments en forma farmacèutica sòlida, per la qual cosa s’estableix com a fàrmac traçador l’àcid acetilsalicílic (AAS) al ser fàcilment hidrolitzable. Per fer-ho, es dissenya i desenvolupen dues formulacions d’àcid acetilsalicílic per a l’obtenció de comprimits per via directa. Una fórmula conté un diluent amb elevat contingut d’humitat i activitat de l’aigua, i l’altra un diluent amb baix contingut d’humitat i activitat de l’aigua. Posteriorment s’estudia l’estabilitat dels comprimits i la degradació del fàrmac al llarg del temps correlacionada amb l’activitat de l’aigua i el contingut en humitat.[eng] An experimental study is developed in order to investigate if it is possible and useful the application and determination of water activity in the design of drug product formulations and in its stability and quality control. Whereas water activity is used in the field of human food, it is not used in the pharmaceutical field. It is more important the moisture contain, although in the latest editions of the major Pharmacopeias (USP and Ph Eur) exist a monograph of water activity but is only related to the microbiology stability of the drug product. The aim of this study is to know the influence of water activity in the chemical stability of drug products in a solid form. To this end, it is used aspirin (acetylsalicylic acid), an hydrolisable drug. Two formulations of aspirin tablets manufactured by direct compression have been developed. The first formulation contains a diluent with high water activity and moisture contain and the other contains a diluent with low water activity and moisture contain. Next, the stability of the tablets and the degradation of the drug in relation of water activity and moisture contain is studied

Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease

Alternative splicing of pre-mRNA contributes strongly to the diversity of cell- and tissue-specific protein expression patterns. Global transcriptome analyses have suggested that >90% of human multiexon genes are alternatively spliced. Alterations in the splicing process cause missplicing events that lead to genetic diseases and pathologies, including various neurological disorders, cancers, and muscular dystrophies. In recent decades, research has helped to elucidate the mechanisms regulating alternative splicing and, in some cases, to reveal how dysregulation of these mechanisms leads to disease. The resulting knowledge has enabled the design of novel therapeutic strategies for correction of splicing-derived pathologies. In this review, we focus primarily on therapeutic approaches targeting splicing, and we highlight nanotechnology-based gene delivery applications that address the challenges and barriers facing nucleic acid-based therapeutics.Fil: Suñé Pou, Marc. Universidad de Barcelona; EspañaFil: Limeres, María José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Moreno Castro, Cristina. Institute of Parasitology and Biomedicine “López-Neyra"; EspañaFil: Hernández Munain, Cristina. Institute of Parasitology and Biomedicine “López-Neyra"; EspañaFil: Suñé Negre, Josep M.. Universidad de Barcelona; EspañaFil: Cuestas, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Suñé, Carlos. Institute of Parasitology and Biomedicine “López-Neyra"; Españ

Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease

Alternative splicing of pre-mRNA contributes strongly to the diversity of cell- and tissue-specific protein expression patterns. Global transcriptome analyses have suggested that >90% of human multiexon genes are alternatively spliced. Alterations in the splicing process cause missplicing events that lead to genetic diseases and pathologies, including various neurological disorders, cancers, and muscular dystrophies. In recent decades, research has helped to elucidate the mechanisms regulating alternative splicing and, in some cases, to reveal how dysregulation of these mechanisms leads to disease. The resulting knowledge has enabled the design of novel therapeutic strategies for correction of splicing-derived pathologies. In this review, we focus primarily on therapeutic approaches targeting splicing, and we highlight nanotechnology-based gene delivery applications that address the challenges and barriers facing nucleic acid-based therapeutics

Targeting Splicing in the Treatment of Human Disease

The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding of splicing regulation have led to the development of new tools for manipulating splicing for therapeutic purposes. Several tools, including antisense oligonucleotides and trans-splicing, have been developed to target and alter splicing to correct misregulated gene expression or to modulate transcript isoform levels. At present, deregulated AS is recognized as an important area for therapeutic intervention. Here, we summarize the major hallmarks of the splicing process, the clinical implications that arise from alterations in this process, and the current tools that can be used to deliver, target, and correct deficiencies of this key pre-mRNA processing event. Keywords: alternative splicing, precursor messenger RNA, therapy, genetic diseas

SeDeM as a Tool to Validate Drug Substance Manufacturing Processes and Assess Scalability and Suitability for Direct Compression: Supplier Screening

During the development of an oral solid form of a drug substance, a thorough understanding of the critical material attributes is necessary, as the physical properties of the active pharmaceutical ingredient (API) can profoundly influence the drug product's manufacturability, critical quality attributes, and bioavailability. The objective of this study was to validate the manufacturing process of the drug Linezolid from three different sources at both the pilot and industrial scale and to identify differences in critical material attributes between the API manufacturers. Furthermore, the scalability factor between the pilot and industrial scale and the suitability of a process for direct compression were also evaluated. In the present study, the different sources of API were characterized by SeDeM methodology, particle size distribution, and scanning electron microscopy determinations. The statistical analysis revealed that no statistically significant differences were found for any of the parameters under study for the same API source analyzed on both scales. On the other hand, for most of the parameters evaluated, statistical differences were observed between the different sources. It was concluded that SeDeM was able to successfully validate the API manufacturing process, assess scalability, and distinguish between sources. Therefore, it could be highly valuable in the formulation phase to select the best API source. Keywords: Linezolid; SeDeM expert system; critical material attribute; critical quality attribute; direct compression; drug substance manufacturers; particle size; powder characterization; preformulation; process validation

Methods for Developing a Process Design Space Using Retrospective Data

Prospectively planned designs of experiments (DoEs) offer a valuable approach to preventing collinearity issues that can result in statistical confusion, leading to misinterpretation and reducing the predictability of statistical models. However, it is also possible to develop models using historical data, provided that certain guidelines are followed to enhance and ensure proper statistical modeling. This article presents a methodology for constructing a design space using process data, while avoiding the common pitfalls associated with retrospective data analysis. For this study, data from a real wet granulation process were collected to pragmatically illustrate all the concepts and methods developed in this article

Metodologia innovadora per fomentar l'aprenentatge de competències transversals durant les pràctiques de l'especialitat farmàcia galènica i industrial (TEFIG): optimització d'una formulació farmacèutica comercialitzada

Aquest treball forma part dels projectes 2013PID-UB/009 i 2014PID-UB/050En aquest treball s'explicarà una metodologia innovadora per tal de promoure les competències d'iniciativa, creativitat, treball en equip, presa de decisió i autosuficiència dels alumnes del Títol d'Especialista en Farmàcia Industrial i Galènica(TEFIG). L'objectiu va consistir en millorar les característiques reològiques d'una premescla medicamentosa, fent ells la recerca bibliogràfica, desenvolupant les formulacions i fent la fabricació, valorant després l'assoliment de l'objectiu

Robustness Optimization of an Existing Tablet Coating Process Applying Retrospective Knowledge (rQbD) and Validation

The objective of these studies is to verify and validate the improvement in the inter-tablet coating uniformity for an industrially commercialized coated tablet, without involving changes in the approved registration dossier. Using the CPP (critical process parameters) determined from previous retrospective statistical analysis, the recommended working ranges are identified. Retrospective analysis showed that the design of experiments (DoE) provided an improved process variable configuration. Therefore, it is decided to study two critical parameters: Product temperature and drum speed, with an additional 22 experimental design. The quality results of the samples analyzed show that the aesthetic defects of the batches made with the new working ranges have been reduced. These results have also been corroborated with the 42 industrial batches manufactured with the new ranges. With the optimized parameters, tablets have been coated and the suitability of the model determined. The results demonstrated the overall reliability and effectiveness of the proposed Quality by Design approach and provides a useful tool to help optimize the industrial coating process. This study confirms that it is possible to optimize and validate the manufacturing process of an existing commercial product by means of a DoE with retrospective data. Therefore, no variation in the dossier is required

Isotretinoína para el tratamiento del acné

Se efectúa una revisión de las características fisicoquímicas, farmacológicas, toxicológicas y farmacocinéticas de la isotretinoína, retinoide utilizado en el tratamiento de algunos tipos de acné. También se abordan las ventajas e inconvenientes de su uso en terapéutica, además de posibles precauciones, controversias y contraindicaciones de la misma

Palatability and stability studies to optimize a carvedilol oral liquid formulation for pediatric use

Carvedilol (CARV) is a blocker of α- and β- adrenergic receptors, used as an “off-label” treatment for cardiovascular diseases in pediatrics. Currently, there is no marketed pediatric-appropriate CARV liquid formulation, so its development is necessary. Palatability (appreciation of smell, taste, and aftertaste) is a key aspect to be considered during the development of pediatric formulations since only formulations with good palatability also have adequate acceptability in this population. Consequently, the aim of this research was to assess the palatability and acceptability of different CARV formulations using an in vivo taste assessment (ID Number PR103/22) in order to select the highest palatability-rated CARV formulation. The preparation of CARV formulations was based on a reference 1 mg/mL CARV solution, which contains malic acid as a solubilizing agent. Subsequently, sucralose and flavoring agents were added and mixed until complete dissolution to the corresponding formulations. Adult volunteers participated in this study and evaluated the taste and odor of various CARV formulations through a questionnaire and a sensory test. The mean palatability score, measured on a 10-point scale, increased from 1.60 for the unflavored control to 7.65 for the highest-rated flavored formulation. Moreover, the bitterness of the optimized CARV formulation was reduced from 66.67% to 17.86%, and the taste pleasantness was increased from 25/100 to 73/100. This optimized CARV formulation contains a sweetening agent, sucralose, in addition to two flavoring agents at appropriate concentrations for pediatrics. Furthermore, the physicochemical and microbiological stability of the optimized CARV formulation were evaluated for 6 months at 25, 30, and 40 °C, in addition to in-use stability for 15 days at 25 °C, whose results were confirmed. Thus, we successfully developed a palatable CARV liquid solution that contains excipients appropriate for pediatrics and is stable under the studied conditions.</span