Recent Advances in Repositioning Non-Antibiotics against Tuberculosis and other Neglected Tropical Diseases
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Although drug repositioning strategies offer significant benefits, they are not devoid of drawbacks. Repositioning approaches rely on the fact that clinically approved drugs carry immense privilege as they have undergone rigorous testing in human subjects. Reliance on previously validated data could avoid high costs incurred during drug development processes and narrow the chances of attrition in advanced clinical studies. Additionally, drugs that are off-patent and inexpensive may offer even more benefits for diseases endemic in resource-poor settings. Apart from intellectual property issues, one drawback of repositioning strategies is inherent effects of repositioned drugs which may become undesirable side effects in diseases of interest. Hence, structural remodelling is seen as a viable strategy to improve pharmacokinetics and pharmacodynamics post-repositioning. Such approaches have proven successful in enhancing activities of repositioned drugs; in some cases, new chemical entities were identified with antitubercular activities more potent than parent non-antibiotics or standard antitubercular drugs. Also, inherent effects of repositioned drugs could be abrogated to improve selectivity, particularly in the example of phenothiazines. Drug formulation is another medicinal chemistry approach that goes hand in hand with drug repositioning. As with examples provided herein, drug formulation offers advantages such as targeted drug delivery and minimized dose-related toxicities or drug metabolism.
Preclinical Models for Pulmonary Drug Delivery
Anthony J. Hickey, Sandro R.P. da Rocha in Pharmaceutical Inhalation Aerosol Technology, 2019
The central value of preclinical animal models is derived from the ability to evaluate drug efficacy, safety, and dosages before investing in more comprehensive, decisive, and expensive human trials (Fernandez and Vanbever 2009). Animal models are therefore important not simply to measure drug efficacy, but also to investigate drug administration, absorption, clearance, tolerance, and toxicity (Price 2018). From these studies, important data can be generated around drug formulation characteristics, particle dispersion dynamics, and pharmacokinetic and pharmacodynamic variables. Consequently, the process of selecting an appropriate animal model requires careful consideration of both physiological specificity and suitability of animal models for proposed studies, as well as the availability of resources and expertise to maximize the utility of selected animal models (Figure 30.1).
Bayesian Methods for the Design and Analysis of Stability Studies
Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger in Bayesian Methods in Pharmaceutical Research, 2020
Once a batch of drug is produced, it starts aging, waiting in a warehouse or in pharmacies for its final destination. For the patient, it is however critical that the drug he will take is still fully potent and not toxic at the time of medication, despite degradation(s) that might occur during this aging process. Interestingly, the drug product stability or instability during the time depends upon the ways the manufacturer has designed its process, the drug formulation (excipients, preservatives…). It also depends upon how the manufacturer is able to control appropriate raw materials at reception, and finally how storage conditions are defined and controlled. Hence, for the manufacturer, in turn, the drug stability will be an ultimate control of drug consistency, from release to shelf-life. Degradation might occur naturally, but all (the quality attributes of) commercial batches are expected to degrade the same way during the time a drug is fit for consumption, i.e. during its labelled shelf-life. It should reach and remain a satisfactory level of efficacy and safety. This means a drug substance stored under the recommended conditions is expected to remain within its approved specifications. The role of stability studies is to demonstrate exactly this.
Trends in nanotechnology-based delivery systems for dermal targeting of drugs: an enticing approach to offset psoriasis
Published in Expert Opinion on Drug Delivery, 2020
Sadaf Saleem, Mohammad Kashif Iqubal, Sanjay Garg, Javed Ali, Sanjula Baboota
Psoriasis has been clearly identified as a major dermatological issue worldwide and to treat it a plethora of synthetic and herbal drugs either alone or in combination are being used. This disease is both physically and psychologically disturbing. Moreover, the treatment of psoriasis requires continuous treatment. The cost of medication and visits to doctors amounts to enormous financial losses. In spite of the presence of various conventional formulations, the current available therapies need improvement due to their poor bioavailability issues, low dermal concentrations, non-specificity, and associated systemic side-effects. The design and development of the drug delivery systems with a view to enhance the efficacy of existing formulations and analysis of drug in the pharmaceutical formulation is a continuous process in pharmaceutical industry. Nanotechnology in the twenty-first century is a key technology that offers exceptionally valuable opportunities for the Pharma industry and scientists as well.
TRYBE®: an Fc-free antibody format with three monovalent targeting arms engineered for long in vivo half-life
Published in mAbs, 2023
Emma Davé, Oliver Durrant, Neha Dhami, Joanne Compson, Janice Broadbridge, Sophie Archer, Asher Maroof, Kevin Whale, Karelle Menochet, Pierre Bonnaillie, Emily Barry, Gavin Wild, Claude Peerboom, Pallavi Bhatta, Mark Ellis, Matthew Hinchliffe, David P. Humphreys, Sam P. Heywood
TrYbes® have been successfully manufactured and purified at a clinically relevant scale (2000 L). Due to the architecture consisting of a Fab scaffold, these molecules are simple to express, resulting in crude product yields of >3 g/L from clonal stable CHO cell lines in fed-batch cultures. The disulfide linkage of scFvs is an essential feature of TrYbes®, limiting the concentration and time-dependent multimerization of the antibody as discussed previously.17,35 This is an important consideration for manufacturing and long-term stability of the drug formulation where a highly concentrated product is clinically desirable. Disulfide stabilization of scFvs in immunotoxin fusions has also been reported to impart additional properties such as reduced aggregation, thereby increasing titers when renatured from inclusion bodies expressed in Escherichia coli.20 Despite soluble titers of immunotoxins comprising ds-Fvs or ds-scFvs being significantly lower than the reported TrYbe® titers, sufficient quantities of the immunotoxins with favorable biophysical and functional profiles have been manufactured at GLP scale for clinical trials in cancer therapy.20,38,84–86
Rationale utilization of phospholipid excipients: a distinctive tool for progressing state of the art in research of emerging drug carriers
Published in Journal of Liposome Research, 2023
Koilpillai Jebastin, Damodharan Narayanasamy
The primary objective of lipid-based drug formulation is to increase the bioavailability of the medication (API). Lipids in pharmaceutical administration are not new, but they are, nevertheless, an intriguing concept. Lipid-based formulations can be customized to meet a range of product requirements, such as disease indication, administration mode, cost, product stability, toxicity, and efficacy. These formulations are also an economically viable approach to developing drugs for topical, oral, pulmonary, or parenteral administration, as shown in Table 4. Additionally, lipid-based formulations have been shown to reduce drug toxicity by directing drug bio-distribution away from sensitive organs, such as the eyes. Lipid-based nano carriers are one of the most biocompatible and adaptable ways to deliver drugs to the eyes. Topical lipid nanoparticle distribution must achieve mucoadhesion, which leads to an increase in pre-corneal retention time, as well as improved permeability due to cellular uptake by corneal epithelial cells. After intravitreal administration of lipid nanoparticles as non-viral vectors, gene transport to the retina has been demonstrated to be extremely (Battaglia et al. 2016). The variety of applications for lipid-based formulations has increased as the nature and kind of active drugs under investigation have become more diverse.
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