Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits

• Published in: PloS one Vol. 16; no. 8; p. e0256869
• Main Authors: Kim, Junhyung, Kwak, Seongsung, Park, Mi-Sun, Rhee, Chang-Hoon, Yang, Gi-Hyeok, Lee, Jangmi, Son, Woo-Chan, Kang, Won-Ho
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27-08-2021; Public Library of Science (PLoS)
• Subjects: Albumin; Allergic reactions; Animals; Biochemistry; Biocompatibility; Biology and Life Sciences; Blood & organ donations; Body weight; Botulinum toxin type A; Botulinum Toxins - antagonists & inhibitors; Botulism - drug therapy; Cosmetics; Drug dosages; Excipients; Health aspects; Health risks; Hematology; Histopathology; Human serum albumin; Humans; Humidity; Hypersensitivity; Injection; Irritation; Laboratories; Medicine and Health Sciences; Necropsy; Neurotoxicity; Pathogens; People and places; Pharmaceuticals; Physical Sciences; Polyoxyethylene sorbitan monolaurate; Polysorbates - adverse effects; Polysorbates - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Rattus; Republic of Korea; Research and Analysis Methods; Safety; Serum albumin; Serum Albumin, Human - adverse effects; Serum Albumin, Human - therapeutic use; Skin; Surfactants; Toxicity; Toxins; Ventilation; West Nile virus; Republic of Korea; South Korea; New Zealand
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0256869

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.