Ultra-small micelles based on polyoxyl 15 hydroxystearate for ocular delivery of myricetin: optimization, in vitro, and in vivo evaluation

Abstract

2019) Ultra-small micelles based on polyoxyl 15 hydroxystearate for ocular delivery of myricetin: optimization, invitro, and invivo evaluation, Drug Delivery, 26:1, 158-167, ABSTRACT The aim was to develop a nanocarrier based on polyoxyl 15 hydroxystearate (KolliphorV R HS15, HS15) micelles for the solubility, stability, and ocular delivery of myricetin (Myr). An optimized ratio of HS15 and Myr was prepared to fabricate HS15-Myr micelle ophthalmic solution. Myr-encapsulating HS15 micelles (HS15-Myr micelles) were subjected to physicochemical characterizations. The chemical stability of Myr in HS15 micelles and storage stability of HS15-Myr micelle ophthalmic solutions were evaluated. In vitro parallel artificial membrane permeability assay and antioxidant activity of Myr in HS15 micelles were also measured. In vivo ocular tolerance, corneal permeation, and anti-inflammatory efficacy studies were conducted following ocular topical administration. HS15-Myr micelles were successfully prepared and presented transparent appearance with high encapsulation (96.12 ± 0.31%), ultra-small micelle size (a mean diameter of 12.17 ± 0.73 nm), uniform size distribution (polydispersity index [PDI] ¼ 0.137 ± 0.013), and negative surface charge (À [4.28 ± 0.42] mV). Myr in HS15 micelle solution demonstrated higher aqueous stability than the free Myr solution among the accepted pH range for eyedrops. HS15-Myr micelle ophthalmic solution demonstrated high storage stability at 4 C and 25 C. HS15 micelles could significantly improve in vitro antioxidant activity and faster membrane permeation of Myr. No irritations or corneal damage were revealed in rabbit eyes after ocular administration of HS15-Myr micelle solution.In vivo corneal permeation study demonstrated that HS15-Myr micelles could penetrate the cornea efficiently in mouse eyes. Further, HS15-Myr micelles also demonstrated significant in vivo anti-inflammatory activity. It can be concluded that HS15 micelles are a potential ophthalmic delivery nanocarrier for poorly soluble drugs such as Myr. ARTICLE HISTORY

Myricetin bioactive effects: moving from preclinical evidence to potential clinical applications

“…Hou et al [ 61 ] studied the antioxidant effect of HS15-Myr micelles and independent myricetin by using FRAP (ferric reducing antioxidant power) and ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) assays. The ABTS assay displayed an improved value from 22.20 to 41.77% in HS15-Myr micelles and 0 to 6.12% in independent myricetin at two different concentrations and incubation periods.…”

New micelle myricetin formulation for ocular delivery: improved stability, solubility, and ocular anti-inflammatory treatment

“…Though many researchers explored ocular delivery with micelle formulation, most of their explored nanomaterials were not authorized pharmaceutical excipients, and the ocular biocompatibility of these materials has been the subject of debate (Song et al., 2018). An ultra-small nanocarrier based on polyoxyl 15 hydroxystearate (Kolliphor ® HS15, HS15) micelles was explored to evaluate the formulation potential of Myr to ocular topical administration in previous report (Hou et al., 2019). Though the in vivo ocular tolerance tests revealed that the micelle formulations based on HS15 showed excellent ocular tolerance (Zhou et al., 2017; Hou et al., 2019), the ocular safety concerns of HS15 and its formulation should be kept in mind, and a recent publication also hinted the safety concern of this nonionic surfactant HS15 used in drug delivery formulations (Cavanagh et al., 2019).…”

“…(The t 1/2 of Myr in the PVCL-PVA-PEG micelle solution was 2.61-, 3.93-, 7.48-, 19.20-, 34.28-, and 36.43-fold higher than that of Myr in the HS15 micelle solution with pH values of 6.0, 6.2, 6.5, 6.8, 7.0, and 7.4, respectively. Data were calculated from this article and our previous report (Hou et al., 2019). ) The ultra-low CMC of PVCL-PVA-PEG might contribute this high potential of improvement of Myr’s chemical stability (the CMC of PVCL-PVA-PEG was 3.68 × 10 −8 M, and HS15 was 1.16 × 10 −3 M in artificial tears; Guo, Zhang et al., 2015; Hou et al., 2019).…”

“…Data were calculated from this article and our previous report (Hou et al., 2019). ) The ultra-low CMC of PVCL-PVA-PEG might contribute this high potential of improvement of Myr’s chemical stability (the CMC of PVCL-PVA-PEG was 3.68 × 10 −8 M, and HS15 was 1.16 × 10 −3 M in artificial tears; Guo, Zhang et al., 2015; Hou et al., 2019). Low CMC of the formulation is desired to prevent the disruption of micelles by factors of environment including pH value.…”

“…(The in vivo corneal permeation of Cou6-labeled Myr PVCL-PVA-PEG micelle ophthalmic solution was 2.56-, 0.78-, and 1.11-fold higher than that of Cou6-labeled Myr HS15 micelle ophthalmic solution at the 30, 60, and 120 min time points, respectively. Data were calculated from this manuscript and our previous report (Hou et al., 2019). ) And these results seemed some contradictory to the existing knowledge, as generally speaking, smaller particles are able to more efficiently enter a cell or tissue (the micelle size was about 60 nm to Myr PVCL-PVA-PEG micelles and about 12 nm to Myr HS15 micelles; Hou et al., 2019).…”