Biopharmaceutics And Pharmacokinetics By Venkateswarlu Pdf
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Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Especially, various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the analysis of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.
Changes in pharmacokinetic characteristics of nanomedicines are due to changes in pharmacokinetic properties of their active pharmaceutical ingredients (API), which include longer stay in the body and greater distribution to target tissues, possibly increasing their efficacy and alleviating adverse reactions (Onoue et al. 2014). Regulation of efficacy and/or adverse reactions of nanomedicines is affected by alteration of pharmacokinetics such as in vivo absorption, distribution, metabolism and excretion in the body.
Based on the above concepts connecting and efficacy/toxicity, Table 1 shows targeted delivery methods that can lead to changes in the pharmacokinetics of nanomedicines in the body. Delivery mechanisms of nanomedicines can be divided into intracellular transport, epileptic transport and other types (Table 1). Intercellular transport is regulated and facilitated by intracellularization, transporter-mediated endocytosis, and permeation enhancement through interactions involving particle size and/or cell surface (Francis et al. 2005; Jain and Jain 2008; Petros and DeSimone 2010; Roger et al. 2010). In general, a smaller particle size of nanomedicines increases intercellular transport, which facilitates cell permeation and affects absorption, distribution, and excretion of nanomedicines. In particular, cell internalization by transporter-mediated endocytosis depends on particle size of nanomedicines. When nanomedicine particles are large, opsonization occurs rapidly and their removal from the blood by endothelial macrophages is accelerated. It has been reported that affinity of cell surface transporters to nanomedicines varies depending on the particle size of nanomedicines, and this could also influence rapid removal of large particles from the blood by macrophages. In addition, nanomedicines containing non-charged polymers, surfactants, or polymer coatings which degrade in in vivo due to their hydrophilicity, interact with cell surface receptors or ligands to increase permeability or promote internalization of nanomedicines (Francis et al. 2005; Jain and Jain 2008; Petros and DeSimone 2010; Roger et al. 2010).
Using the enhanced permeability and retention (EPR) effect, it is possible to increase anti-cancer efficacy through increasing tumor permeation and retention time. The EPR effect also makes it possible to selectively deliver nanomedicines to target tissue via conjugation to an antibody, protein, peptide, or polysaccharide, which can be used to modify delivery of nanomedicines to target tissues using receptor/ligand interactions or other physiologically specific target cell interactions, modulating drug efficacy or adverse reactions. Nanomedicines coated with hydrophilic material have improved stability, and their opsonization or accumulation in mucus is prevented. By inhibiting macrophage-induced or mucosal instability, nanomedicines can be retained in vivo, e.g., in lung tissue for prolonged periods of time through particle size, control and avoiding removal by mucus ciliates, which could lead to degradation or macroscopic effects in lung mucosa (Bur et al. 2009). Therefore, a variety of formulations have been developed to use delivery mechanisms which can control pharmacokinetics and pharmacodynamics of nanomedicines.
Based on guidelines and reports from the FDA, considerations for evaluation of nanomedicines are as follows. Evaluation of nano-formulation properties of nanomedicines comprises evaluating physicochemical properties of the nanomaterials, constituents and proportions of the nanomaterials, and quality and manufacturing of the nanomaterials (Eifler and Thaxton 2011; FDA 2010). First, pharmacokinetics of nanomedicines are assessed in the context of their systemic exposure considering (1) rate and amount of absorption and retention in circulation based on blood concentration over time, (2) relationship between prolongation of half-life and whole body exposure duration, and (3) bioavailability changes (Eifler and Thaxton 2011; FDA 2010, 2015). Second, assessment of nanomedicine distribution to blood and tissue is recommended to be done based on apparent volume of distribution, and distribution or accumulation to positive targeting sites based on time-dependent changes. Third, in the context of metabolism, it is important to evaluate whether decomposition or metabolism of nano-formulations or their active pharmaceutical ingredients occur. Fourth, elimination of raw materials used in nano-formulations, and products from decomposition and/or metabolism of nano-formulations and their active pharmaceutical ingredients are recommended for evaluation. The accumulation of nano-formulations in target tissues and elimination through MPS are also investigated. Finally, toxicity assessment of nanomedicines needs to be conducted.
The article ?Nanomedicines: current status and future perspectives in aspect of drug delivery and pharmacokinetics?, written by Young Hee Choi and Hyo?Kyung Han, was originally published electronically on the publisher?s internet portal (currently SpringerLink) on 28 November 2017 without open access. 2b1af7f3a8