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

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.

Magnetic-Responsive Photosensitizer Nanoplatform for Optimized Inactivation of Dental Caries-Related Biofilms: Technology Development and Proof of Principle

“…Polysorbate 20 is well-known for being safe and biocompatible . Besides, a recent investigation demonstrates its high safety when it was injected intramuscularly in animals . The polysorbate 20 viscosity, rather than its cytotoxicity, interfered with the cell attachment during the incubation, resulting in less viable cells.…”

Botulinum Toxins for Esthetic Facial Injections: A Scientific Review to Support Evidence-Based Best Practice

“…Especially the role of human serum albumin as a stabilizing agent has been discussed (13). Some new BoNTA formulations use polysorbate 20 instead, which has the advantage of no need for any human driven proteins but goes along with other potential health and allergy issues (14).…”

“…14 Some new BoNTA formulations use polysorbate 20 instead which has the advantage of no need for any human-driven proteins but goes along with other potential health and allergy issues. 15 The pooled analysis of a systemic review in terms of a meta-analysis revealed that the overall incidence of neutralizing antibodies for OnaBoNTA, AboBoNTA, and IncoBoNTA was relatively low. Especially for indications with average dosages of AboBoNTA were associated with a higher incidence compared with OnaBoNTA and IncoBoNTA.…”

“…14 Some new BoNTA formulations use polysorbate 20 instead which has the advantage of no need for any human-driven proteins but goes along with other potential health and allergy issues. 15…”

Not the Usual Suspects: Alternative Surfactants for Biopharmaceuticals

“…Polysorbates have a common structure based on a sorbitan ring including poly­(ethylene oxide) at the hydroxyl positions and are distinct only in the fatty acid side chains. PS20 and PS80 possess good protein stabilization effect, − and their safety has been proven in several studies. − However, they are prone to chemical (auto-oxidation or hydrolysis) and enzymatic degradation, ,− leading to severe consequences such as loss of functions and particle formation, which may ultimately lead to product rejection or costly and lengthy root-cause investigations coupled to complicated control strategies. In addition, polysorbates are chemically heterogeneous mixtures, implying that the level of purity, process intermediates, and contaminants vary between manufactures and even lots. , While their degradation mechanisms have been extensively characterized in the last decade and their respective analytical methods have been improved and harmonized, , these procedures represent only control strategies and do not tackle the underlying issue.…”