Science Pool

This text underscores the significance of Orally Dispersible Tablets (ODTs) for enhancing treatment compliance, particularly for patients with swallowing difficulties. Co-processed excipients for fast-disintegrating tablets (CPE-ODT) offer a convenient solution, combining a soluble filler and superdisintegrant. These can be efficiently blended with active ingredients, lubricants, and compressed into tablets, streamlining the development process. Investigating the relationships among compaction stress, compact solid fraction, and mechanical strength is crucial for optimizing tablet composition and speeding up development. Striking a balance between inter-particle bonding strength and porosity is especially vital for ODTs, ensuring rapid disintegration with sufficient mechanical resistance for downstream processes. The study aims to establish a general pre-formulation screening method by generating compressibility, compactibility, and tablettability profiles of CPE-ODTs blended with varying drug amounts. These data offer valuable insights into the impact of drug load on compression behavior and key properties, such as friability and disintegration time, facilitating the efficient development of ODTs.

Download this poster presented at AAPS PharmSci360 2023 for comprehensive details on this formulation screening approach.

Download Now

This poster discusses the development of oral enteric dosage forms as a solution to bypass the acidic stomach environment. Coated hard-shell capsules are more time and cost-efficient in early pharmaceutical development than enteric tablets and pellets. The current study assesses acid-resistance and dissolution rate of not-banded gelatin and HPMC capsules, filled at two weights, and coated with an enteric polymer at four levels. The goal is to determine the minimum enteric polymer needed for gastro-resistance, compare gelatin and HPMC shells in the coating process, and examine the impact of filling level and curing step on dissolution profiles, with fixed coating parameters. This research is important for optimizing the coating process and advancing the understanding of factors influencing gastro-resistance in oral enteric dosage forms.

Download our poster presented at AAPS PharmSci360 2023 for in-depth insights into this critical aspect of pharmaceutical development.

Feel free to make questions to our experts!

Download the Poster Now

While simple combinations of dosage forms expedite access to First-in-human (FIH) studies, the demand for robust formulations and processes challenges quick development, particularly for tablet production. Early clinical phases face hurdles like dose uncertainty and limited active pharmaceutical ingredient availability. The study addresses these challenges by proposing a compressibility assessment method using small-scale experiments. The aim is to establish a pre-formulation screening approach based on compressibility data for active ingredients, utilizing round punches of varying diameters. By employing the smallest tooling, the study achieves a remarkable 75% reduction in the amount of active ingredient required for compressibility analysis.

Download our poster presented at AAPS PharmSci360 2023 to learn more

Download Now

Download

• The genotoxic potential is one of the major risks associated to potential pitfalls in drug development.
• True positive results in the genotoxicity screening observed during the Lead Optimization phase not always represent a showstopper, but need to be carefully characterized.
• In this scenario, the toxicologist could provide a strategy supporting the next IND enabling phase by adopting the most effective risk management to allow the highest success rate possible.
• The process proposed can be adapted to any scenario, and provides data supporting the risk assessment ensuring the lowest attrition and the ethical use of animals.

Download

Read our latest poster on Differentiated transcriptomic signatures detectable in primary human hepatocytes transduced by AAV-based vectors: A potential enabler for in vitro safety profiling.

Download

Hepatic transporter inhibition, mitochondrial dysfunction, and reactive metabolite formation are some of the most common mechanisms associated with intrinsic DILI. The cytochrome P450 (CYP450) superfamily of enzymes play an important role in phase 1 metabolism within the liver. For certain chemical entities, reactive metabolites may form with increased toxicity compared to the parent. These reactive metabolites may result in hepatotoxicity through the formation of reactive oxygen species, DNA damage, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. In our research the pan-specific CYP450 inhibitor, 1-aminobenzotriazole (1-ABT), was used in combination with high-content imaging to evaluate the effects of potential reactive metabolites on cell health parameters in hepatocytes. The endpoint assessed included nuclear features, glutathione (GSH) content, mitochondrial dysfunction, and reactive oxygen species (ROS) formation, as well as cellular ATP content. A calculated fold-shift in cell health features between the plus and minus 1-ABT dosing conditions was used to determine reactive metabolite formation. A panel of known DILI reference compounds associated with the formation of reactive metabolites were assessed through this HCI bioactivation assay within metabolically competent HepaRG cells, primary human hepatocytes (PHH) and primary mouse hepatocyte (PMH).

Download

Peripheral neuropathy can be induced by many chemotherapeutics. Symptoms include numbness, tingling or abnormal sensations which can impact on the long-term quality of a patient’s life. Animal models used to evaluate these side effects may be difficult to interpret and are labor-intensive. In this study, we further optimized a previously developed DRG assay by comparing the neurite outgrowth responses of a group of chemotherapeutics from different classes at 24 h and 72 as an in vitro cell-based model for peripheral neuropathy. Cytotoxicity was assessed alongside neurite outgrowth. Taxanes (paclitaxel, docetaxel), microtubule interfering agents (vincristine, vinblastine, colchicine, nocodazole) and epothilones (ixabepilone) were assessed.

Download

The generation of anti-drug antibodies (ADA) towards a therapeutic agent can have severe implications with respect to drug safety and efficacy. Therefore, identification of this risk during the initial phase of development is imperative to improve both patient outcomes and downstream attrition rates. As preclinical species often fail to mimic the complexity of the human immune system, the immunogenic potency of therapeutic agents and their potential to elicit a human-specific proinflammatory response can be grossly underestimated during in vivo safety assessment. In our research, a high-throughput in vitro approach to immunogenicity screening was developed using two distinct models: i) peripheral blood mononuclear cells (PBMC) and ii) monocyte-derived dendritic cells (MoDC) isolated from the blood of healthy human donors. The effect of serum-free culture conditions was also evaluated. The immunogenicity of monoclonal antibodies, small molecules associated with delayed-onset hypersensitivity reactions and oligonucleotides were assessed in each model through lymphocyte proliferation and cytokine release.

Download

The periodic activation and inactivation of various cardiac ion channels enables the regular and synchronous contraction of the heart. Therefore, any disruption of the cardiac ion channel signaling network can result in a change in membrane potential and in the shape of cardiac action potential (AP). As a result, the cardiac excitation-contraction coupling can be modified which may lead to arrhythmias and potential patient death. Local Extracellular Action Potential (LEAP) is a technique which enables non-invasive, label-free monitoring of cardiac action potential in a high-throughput real-time format. In our research, we used the Axion LEAP MEA assay to analyse the effect of various selective and non-selective ion channel inhibitors on cardiac AP by quantification of action potential morphology, repolarization irregularities, and arrhythmic risk factors such as triangulation.

Download