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The goal of this study was the methodological development of Raman microscopy application for advanced and reliable monitoring of pharmaceutical tablets disintegration in aqueous media. First step of the development involved new design and testing of static, flow cell and tablet holders. On-line Raman mapping method enables observation of the tested tablet interphase changes, particularly the changes of tablet composition during interaction of the solid-state drug form with disintegration medium. Furthermore, the quantitative information of tablet components (% w/w) from Raman maps was calculated. Second part of this study performs off-line Raman mapping, which was focused on the mapping of disintegrated tablet residua. Time-dependent Raman chemical maps provide an understanding of the role of several synergic processes, e.g. solvation, solvent penetration, both active pharmaceutical ingredient and excipient dissolution etc., which occur simultaneously on the surface of dissolving tablet. Raman data of disintegration process were evaluated by a chemometric method - Principal Component Analysis (PCA).
- MeSH
- analýza hlavních komponent MeSH
- časové faktory MeSH
- chemie farmaceutická metody MeSH
- farmaceutická technologie metody MeSH
- léčivé přípravky chemie MeSH
- pomocné látky chemie MeSH
- Ramanova spektroskopie metody MeSH
- rozpouštědla chemie MeSH
- tablety MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
Rapid tablet disintegration is a requirement for the efficient dissolution of the active pharmaceutical ingredient (API) from immediate release tablets. From the mechanistic viewpoint, tablet disintegration begins by the wetting of the tablet surface and the ingress of dissolution medium into the tablet pore structure, followed by the loosening of inter-particle bonds. The present work introduces a new methodology for probing and quantifying the early stages of tablet disintegration by stress relaxation measurements using texture analysis (TA). The method is based on applying a pre-defined load on the tablet by means of a needle-shaped probe and measuring the tablet resistance in time after the addition of the dissolution medium. This measurement provides information about the extent and rate of stress relaxation within the tablet upon hydration. Using a tablet formulation containing ibuprofen as the API and lactose as excipient, the effect of the API content, compaction pressure, and pH of the dissolution medium on the stress relaxation rate was systematically investigated. It is shown that using a dissolution medium pre-saturated by the formulation components has only a minor effect on the tablet disintegration rate compared to a pure phosphate buffer, meaning that the surface dissolution of particles within the tablet is not the main pre-requisite of disintegration in this case. On the other hand, pH of the dissolution medium was found to have a very strong effect on the stress relaxation rate in the tablet after wetting, suggesting that van der Waals interactions rather than solid bridges are the predominant particle bonding mechanism in the investigated formulations.
Efficient tablet disintegration is a pre-requisite for fast and complete drug dissolution from immediate release formulations. While the overall tablet disintegration time is a routinely measured quality attribute of pharmaceutical products, little attention is usually paid to the analysis of disintegration fragments and the cascade of elementary steps that lead to their formation. In this work, we investigate the disintegration pathways of directly compressed tablets by a unique combination of three methods: (i) magnetic resonance imaging (MRI), to gain insight into structural changes of tablets during disintegration; (ii) texture analysis, to measure the disintegration kinetics; and (iii) static light scattering, to characterise the size distribution of disintegration fragments. By systematically varying the tablet composition (50-90% of ibuprofen as a model active ingredient, 0-4% of croscarmellose sodium disintegrant, 6-50% of lactose monohydrate filler), a relationship between the tablet formulation, the size distribution of the disintegration fragments and the dissolution rate of the active ingredient has been established. To interpret the experimental observations, we analyse the disintegration fragments by Raman mapping and relate their composition and structure to the micro-scale arrangement of individual formulation components inside the tablet.
OBJECTIVES: Clinically very serious condition of ischaemia and brain injury which are often associated with brain oedema is frequently accompanied by the impairment of the structural integrity of axons. We wondered whether the brain oedema (without ischemia brain injury) can induce structural axonal impairment. METHODS: Brain oedema was induced by osmotic blood-brain barrier opening with 20% mannitol applied selectively into the internal carotid. Axonal changes were recognized as signs of myelin disintegration (oedematous vesicles, varicosity, myelin fragmentation) at histological sections stained with Black Gold in hippocampal areas CA1 and CA3 and in the dentate gyrus and cerebral cortex at time intervals of one hour, one day, three days and one week after the oedema induction. RESULTS: Impairment of the structural integrity was identified in myelin sheets in all areas studied in all experimental groups. Whereas in the control group axon were of the uniform diameter, in the experimental groups various forms of myelin disintegration were observed. The progression of myelin damage depended on the time elapsed after the oedema induction. CONCLUSION: Opening the blood-brain barrier with an osmotic insult induces brain oedema which represents a factor triggering axonal impairment accompanied with myelin changes. The development of axonal changes initiated by brain oedema only (without ischemia brain injury) is a novel observation.
- MeSH
- analýza rozptylu MeSH
- axony patologie MeSH
- časové faktory MeSH
- edém mozku chemicky indukované patologie patofyziologie MeSH
- gyrus dentatus patologie patofyziologie MeSH
- hematoencefalická bariéra patologie patofyziologie MeSH
- krysa rodu rattus MeSH
- mannitol MeSH
- myelinová pochva patologie MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A stepwise sequential assimilation algorithm is proposed based on an optimisation approach for recursive parameter estimation and tracking of radioactive plume propagation in the early stage of a radiation accident. Predictions of the radiological situation in each time step of the plume propagation are driven by an existing short-term meteorological forecast and the assimilation procedure manipulates the model parameters to match the observations incoming concurrently from the terrain. Mathematically, the task is a typical ill-posed inverse problem of estimating the parameters of the release. The proposed method is designated as a stepwise re-estimation of the source term release dynamics and an improvement of several input model parameters. It results in a more precise determination of the adversely affected areas in the terrain. The nonlinear least-squares regression methodology is applied for estimation of the unknowns. The fast and adequately accurate segmented Gaussian plume model (SGPM) is used in the first stage of direct (forward) modelling. The subsequent inverse procedure infers (re-estimates) the values of important model parameters from the actual observations. Accuracy and sensitivity of the proposed method for real-time forecasting of the accident propagation is studied. First, a twin experiment generating noiseless simulated "artificial" observations is studied to verify the minimisation algorithm. Second, the impact of the measurement noise on the re-estimated source release rate is examined. In addition, the presented method can be used as a proposal for more advanced statistical techniques using, e.g., importance sampling.
Transferring an existing marketed pharmaceutical product from batch to continuous manufacturing (CM) without changes in regulatory registration is a challenging task in the pharmaceutical industry. Continuous manufacturing can provide an increased production rate and better equipment utilisation while retaining key quality attributes of the final product. Continuous manufacturing necessitates the monitoring of critical quality attributes in real time by appropriate process analytical tools such as near infra-red (NIR) probes. The present work reports a successful transfer of an existing drug product from batch to continuous manufacturing process without changing the formulation. A key step was continuous powder blending, whose design and operating parameters including weir type, agitation rate, dynamic hold-up and residence time were systematically investigated with respect to process repeatability. A NIR-based multivariate data model for in-line composition monitoring has been developed and validated against an existing quality control method for measuring tablet content uniformity. A continuous manufacturing long-run with a throughput of 30 kg/h (approx. 128,000 tablets per hour), uninterrupted for 320 min, has been performed to test and validate the multivariate data model as well as the batch to continuous process transfer. The final disintegration and dissolution properties of tablets manufactured by the continuous process were found to be equivalent to those manufactured by the original batch process.
- MeSH
- blízká infračervená spektroskopie metody MeSH
- chemie farmaceutická metody MeSH
- farmaceutická technologie * metody MeSH
- pomocné látky chemie MeSH
- prášky, zásypy, pudry chemie MeSH
- příprava léků metody MeSH
- řízení kvality MeSH
- rozpustnost MeSH
- tablety * MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
The growing incidence of multidrug-resistant bacterial strains presents a major challenge in modern medicine. Antibiotic resistance is often exhibited by Staphylococcus aureus, which causes severe infections in human and animal hosts and leads to significant economic losses. Antimicrobial agents with enzymatic activity (enzybiotics) and phage therapy represent promising and effective alternatives to classic antibiotics. However, new tools are needed to study phage-bacteria interactions and bacterial lysis with high resolution and in real-time. Here, we introduce a method for studying the lysis of S. aureus at the single-cell level in real-time using atomic force microscopy (AFM) in liquid. We demonstrate the ability of the method to monitor the effect of the enzyme lysostaphin on S. aureus and the lytic action of the Podoviridae phage P68. AFM allowed the topographic and biomechanical properties of individual bacterial cells to be monitored at high resolution over the course of their lysis, under near-physiological conditions. Changes in the stiffness of S. aureus cells during lysis were studied by analyzing force-distance curves to determine Young's modulus. This allowed observing a progressive decline in cellular stiffness corresponding to the disintegration of the cell envelope. The AFM experiments were complemented by surface plasmon resonance (SPR) experiments that provided information on the kinetics of phage-bacterium binding and the subsequent lytic processes. This approach forms the foundation of an innovative framework for studying the lysis of individual bacteria that may facilitate the further development of phage therapy.
- MeSH
- bakteriofágy * MeSH
- lidé MeSH
- mikroskopie atomárních sil MeSH
- povrchová plasmonová rezonance MeSH
- stafylokokové infekce * MeSH
- Staphylococcus aureus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Arytmická búrka je vážna komplikácia u pacientov s ICD. Definuje sa najmenej 3 samostatnými epizódami komorovej tachykardie alebo fibrilácie komôr/24 h. Prejavuje sa mnohopočetnými zákrokmi ICD. Spúšťacie faktory – akútna ischémia, akútny infarkt myokardu, zhoršenie srdcového zlyhania, teplotné stavy, minerálny rozvrat a tyreotoxikóza – sa nájdu iba u 1/3 postihnutých. Ohrození sú starší pacienti s dysfunkciou ľavej komory a štrukturálnym ochorením srdca. Manažment je komplexný. Je to liečba betablokátorom, amiodarónom, odstránenie spúšťačov a reprogramovanie ICD. Zriedkavejšie sú potrebné antiarytmiká triedy I. Rádiofrekvenčná katétrová ablácia substrátu v komorách slúži na redukciu počtu zákrokov ICD. Zriedka sú potrebné iné nefarmakologické intervencie.
Arrhythmic storm is a severe complication in patients with ICD. It is defined with at least 3 single episodes of ventricular tachycardia or fibrillation/24 hrs. It is manifested by multiple interventions of ICD. Trigger factors – acute ischemia, acute myocardial infarction, heart failure deterioration, hyperpyrexia, mineral disintegration and thyreotoxicosis – are found in 1/3 of afflicted patients. Older patients with left ventricle dysfunction and structural heart disease are at risk. Management is complex – it is therapy with beta blockers, amiodaron, rejecting of triggers and re-programming of ICD. Class I antiarrhythmics are rarely needed. Radiofrequent catheter ablation of substrate in ventricles can reduce the number of intervention of ICD. Non-pharmacological interventions are rarely needed.
