Compendium of the most significant studies with reference to properties, intake, effects.

Kim J, Kwak S, Park MS, Rhee CH, Yang GH, Lee J, Son WC, Kang WH. Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits. PLoS One. 2021 Aug 27;16(8):e0256869. doi: 10.1371/journal.pone.0256869.

Abstract. Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.

McCartan A, Mackay J, Curran D, Mrsny RJ. Modelling intramuscular drug fate in vitro with tissue-relevant biomimetic hydrogels. Int J Pharm X. 2022 Aug 13;4:100125. doi: 10.1016/j.ijpx.2022.100125.

Abstract. Parenteral administrations are a mainstay of clinical drug delivery. Intramuscular (IM) injections deposit drug directly into skeletal muscle bellies, providing rapid systemic uptake due to the highly vascularized nature of this site. The potential to inject particulate or non-aqueous materials have also made IM injections useful for long-acting formulations. These attributes have supported a plethora of medicines being approved for IM administration. Despite these many approvals across multiple pharmaceutical categories, mechanisms that control drug release from the injection site, and thus its pharmacokinetic properties, remain poorly understood....© 2022 The Authors.

Kishore RS, Kiese S, Fischer S, Pappenberger A, Grauschopf U, Mahler HC. The degradation of polysorbates 20 and 80 and its potential impact on the stability of biotherapeutics. Pharm Res. 2011 May;28(5):1194-210. doi: 10.1007/s11095-011-0385-x. 

Abstract. Purpose: To study the potential impact of the degradation of Polysorbates (PS) 20 and 80 on the stability of therapeutic proteins in parenteral formulations....Conclusions: Although some degradants can potentially influence the stability of the protein (as discerned from spiking studies), degradation of polysorbates did not impact the stability of the different proteins tested in pharmaceutically relevant temperature and storage conditions.

Singh SM, Bandi S, Jones DNM, Mallela KMG. Effect of Polysorbate 20 and Polysorbate 80 on the Higher-Order Structure of a Monoclonal Antibody and Its Fab and Fc Fragments Probed Using 2D Nuclear Magnetic Resonance Spectroscopy. J Pharm Sci. 2017 Dec;106(12):3486-3498. doi: 10.1016/j.xphs.2017.08.011. 

Abstract. We examined how polysorbate 20 (PS20; Tween 20) and polysorbate 80 (PS80; Tween 80) affect the higher-order structure of a monoclonal antibody (mAb) and its antigen-binding (Fab) and crystallizable (Fc) fragments, using near-UV circular dichroism and 2D nuclear magnetic resonance (NMR). ...Copyright © 2017 American Pharmacists Association®

Huille S, Brun TWVL. Industry perspective on the use and characterization of polysorbates for biopharmaceutical products Part 2: Survey report on control strategy preparing for the future. J Pharm Sci. 2022 Aug 21:S0022-3549(22)00358-6. doi: 10.1016/j.xphs.2022.08.021. 

Abstract. ... The current part 2 of the survey focusses on understanding, monitoring, prediction, and mitigation of PS degradation pathways in order to propose an effective control strategy. The results of the survey and extensive cross-company discussions are put into relation with currently available scientific literature. Copyright © 2022. Published by Elsevier Inc.

Paschen CA, Klemm D, Graf T, Kopf R, Pinto C, Müller C, Bell CH, Pfaff J. Simultaneous quantification of polysorbate 20 and poloxamer 188 in biopharmaceutical formulations using evaporative light scattering detection. J Pharm Biomed Anal. 2021 Jan 5;192:113640. doi: 10.1016/j.jpba.2020.113640.

Abstract. Polysorbates and Poloxamer 188 constitute the most common surfactants used in biopharmaceutical formulations owing to their excellent protein-stabilizing properties and good safety profiles. In recent years, however, a vast number of reports concerning potential risk factors closely related with their applications, such as the accumulation of degradation products, their inherent heterogeneity and adsorption effects of proteins at silicon/oil interfaces have drawn the focus to potential alternatives....Copyright © 2020 The Author(s).

Capra P, Musitelli G, Perugini P. Wetting and adhesion evaluation of cosmetic ingredients and products: correlation of in vitro-in vivo contact angle measurements. Int J Cosmet Sci. 2017 Aug;39(4):393-401. doi: 10.1111/ics.12388.

Abstract. Objective: The aim of this work was to use the contact angle measurement in order to predict the behaviour of ingredients and finished cosmetic products on skin to improve skin feel and product texture....© 2017 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

Verbrugghe M, Cocquyt E, Saveyn P, Sabatino P, Sinnaeve D, Martins JC, Van der Meeren P. Quantification of hydrophilic ethoxylates in polysorbate surfactants using diffusion H1 NMR spectroscopy. J Pharm Biomed Anal. 2010 Feb 5;51(3):583-9. doi: 10.1016/j.jpba.2009.09.025.

Abstract. ...Diffusion H1 NMR spectroscopy on a solution of polysorbate 20 in D2O revealed that only one diffusion coefficient was found for the fatty acyl part. Using the Stokes-Einstein equation, it became obvious that this diffusion behavior was caused by micelles. On the other hand, two significantly different diffusion coefficients were found for the methylene groups of ethylene oxide (EO). This indicates the presence of two distinct EO containing species in solution. ...

Moesgaard L, Reinholdt P, Nielsen CU, Kongsted J. Mechanism behind Polysorbates' Inhibitory Effect on P-Glycoprotein. Mol Pharm. 2022 Jul 4;19(7):2248-2253. doi: 10.1021/acs.molpharmaceut.2c00074. 

Abstract. Much effort has been invested in the search for modulators of membrane transport proteins such as P-glycoprotein (P-gp) to improve drug bioavailability and reverse multidrug resistance in cancer. Nonionic surfactants, a class of pharmaceutical excipients, are known to inhibit such proteins, but knowledge about the exact mechanism of this inhibition is scarce. Here, we perform multiscale molecular dynamics simulations of one of these surfactants, polysorbate 20 (PS20), to reveal the behavior of such compounds on the molecular level and thereby discover the molecular mechanism of the P-gp inhibition. We show that the amphiphilic headgroup of PS20 is too hydrophobic to partition in the water phase, which drives the binding of PS20 to the amphiphilic drug-binding domain of P-gp and thereby causes the inhibition of the protein. Based on our findings, we conclude that PS20 primarily inhibits P-gp through direct binding to the drug-binding domain (DBD) from the extracellular leaflet.