HA-based dermal filler: downstream process comparison, impurity quantitation by validated HPLC-MS analysis, and in vivo residence time study

Abstract

The success of hyaluronic acid (HA)-based dermal fillers, with more than 2 million minimally invasive procedures conducted in 2016 in the US alone, is due to their hygroscopic properties of biocompatibility and reversibility. The type and density of HA cross-linkage, as well as the manufacturing technology, may influence not only the in vivo persistence but also the safety profile of dermal fillers. 1,4-Butanediol diglycidyl ether (BDDE) is the cross-linker used in most market-leading HA fillers; 1,4-butanediol di-(propan-2,3-diolyl) ether (BDPE) is the major impurity obtained from the HA–BDDE cross-linking (HBC) process. In this work, a new process to obtain high purity HBC fillers was developed. A new HPLC-MS method was validated for the quantification of BDPE content in HBC dermal fillers. In vitro cytotoxicity of BDPE was evaluated in fibroblasts (IC50 = 0.48 mg/mL). The viscoelasticity was monitored during the shelf-life of the HBC-10% hydrogel and was correlated with in vitro hyaluronidase resistance and in vivo residence time in a rabbit model. This analysis showed that elasticity is the best parameter to predict the in vivo residence time. Finally, a series of parameters were investigated in certain marketed dermal fillers and were compared with the results of the HBC-10% hydrogel.

Evaluation of the Rheologic and Physicochemical Properties of a Novel Hyaluronic Acid Filler Range with eXcellent Three-Dimensional Reticulation (XTR™) Technology

“…Ultimately, the goal is to achieve minute amounts, i.e., <2 ppm, of remaining unreacted BDDE, a limit of detection recommended by the US Food and Drug Administration (FDA) [17]. BDDE levels are used as a parameter for testing and releasing each manufactured batch of fillers with XTR™ technology [3,18]. The size, crosslinking and purity of HA polymers used for filler materials is critical as these properties determine the biological effects of HA on skin tissue [13].…”

Ultrasound assessment of tissue integration of the crosslinked hyaluronic acid filler VYC‐25L in facial lower‐third aesthetic treatment: A prospective multicenter study

“…5,6 Among the different aforementioned factors, crosslinking is essential to slow down the enzymatic degradation rate of the HA by endogenous hyaluronidase and therefore to prolong the product's half-life. 6,7 However, the degree of crosslinking appeared to potentially affect filler biocompatibility, which might have clinical implications. 3 The extent and amount of crosslinking critically impact, not only on the biophysical, but also on the biological properties of a particular filler, including tissue integration, water uptake (swelling), and resistance to degradation.…”

“…3 The extent and amount of crosslinking critically impact, not only on the biophysical, but also on the biological properties of a particular filler, including tissue integration, water uptake (swelling), and resistance to degradation. 6,7 Additionally, the type and density of HA crosslinkage, as well as the manufacturing technology, may influence not only the in vivo persistence but also the safety profile of dermal fillers. 6,7 When HA filer is injected, the effect of soft tissue volume and shape enhancement is in theory limited to 6-18 months depending on the type of filler used, the anatomical site, and the individual patient's genetics.…”

“…6,7 Additionally, the type and density of HA crosslinkage, as well as the manufacturing technology, may influence not only the in vivo persistence but also the safety profile of dermal fillers. 6,7 When HA filer is injected, the effect of soft tissue volume and shape enhancement is in theory limited to 6-18 months depending on the type of filler used, the anatomical site, and the individual patient's genetics. 3 Nevertheless, there is evidence suggesting that the effects of VYC-20L (Juvéderm Voluma ® ; Allergan plc, Dublin, Ireland) may last for a longer time.…”

“…Among the different aforementioned factors, crosslinking is essential to slow down the enzymatic degradation rate of the HA by endogenous hyaluronidase and therefore to prolong the product's half‐life 6,7 . However, the degree of crosslinking appeared to potentially affect filler biocompatibility, which might have clinical implications 3 .…”