Supporting Information

Smart delivery of flexible azithromycin cationic niosomes for improved bioavailability and targeting efficiency

The Supplementary Information includes:

Supplementary Figures 1.

Supplementary Tables 1-2.

Supplementary Figure 1.Formulation optimization of AMCNS, i.e., effect of mass ratio of cholesterol to polysorbate 80, octadecylamineconcentration, amount of AM on incorporation efficiency and drug loading capacity (n=3).

Supplementary Table 1. The changes of size, zeta potential, and encapsulation efficacy when the AMCNS vesicles were placed at 4℃for 15 days.

Supplementary Table 2. Mathematical models of mean cumulative release rate versus time of AMCNS and AM.

Supplementary Table 3. The similarity between the dissolution profiles AMCNSand AM in different dissolution media.

Supplementary Figure 1. Formulation optimization of AMCNS, i.e., effect of mass ratio of cholesterol to polysorbate 80, octadecylamineconcentration, amount of AM onincorporation efficiency and drug loading capacity (n=3).The incorporation efficiencies were determined by reverse dialysis methods.

Supplementary Table 1. The changes of size, zeta potential, and encapsulation efficacy when the AMCNS vesicles were placed at 4℃for 15 days. (n=3)

Parameters / AMCNS-S stored in 4℃ / AMCNS-L stored in 4℃
0 day / In 15 days / 0 day / in 15 days
Size (μm) / (0.95 ± 0.10) / (1.01 ± 0.07) / (5.87 ± 1.80) / (5.90 ± 0.04)
Zeta (mV) / (14.63 ± 0.02) / (13.83 ± 0.05) / (12.51 ± 0.02) / (12.43 ± 0.06)
Encapsulation efficacy (%) / (80.46 ± 0.54) / (79.55 ± 0.88) / (92.87 ± 0.77) / (91.70 ± 0.21)

Supplementary Table2. Mathematical models of mean cumulative release rate versus time of AMCNS and AM.

Formulation / Release medium / 0.1 mol/L HCl / pH 6.8 PBS / pH 7.4 PBS
AM / Zero-order kinetic model / Q=1.3448t+63.023, r=0.704 / Q=1.5993t+56.024, r=0.770 / Q=2.1617 t+58.669, r=0.736
First-order kinetic model / ln(1-Q)=-0.0531t-0.3897, r=0.971 / ln(1-Q)=-0.0563t-0.2905, r=0.980 / ln(1-Q)=-0.1449t+0.7773, r=0.960
Higuchi model / Q=10.718t1/2+47.505, r=0.828 / Q=12.557t1/2+38.091, r=0.891 / Q=14.106t1/2+41.124, r=0.853
Hixcon-Crowell
model / (100-Q)1/3=-0.0797t+3.3203, r=0.900 / (100-Q)1/3=-0.0875t+3.552, r=0.923 / (100-Q)1/3=-0.0814t+3.4258, r=0.899
Ritger-peppas
model / lnQ=0.1081lnt+1.6862, r=0.863 / lnQ=0.1241lnt+1.6305 r=0.942 / lnQ=0.2823lnt+3.8593, r=0.873
Weibull model / lnln[1/1-Q]=0.248lnt-0.5404, r=0.965 / lnln[1/1-Q]=0.2722lnt-0.0.635, r=0.972 / lnln[1/1-Q]=0.5773lnt+0.4147, r=0.955
AMCNS-S / Zero-order kinetic model / Q=1.3035t+70.247, r=0.646 / Q=1.0914t+ 58.658, r=0.643 / Q=1.2519t+51.72, r=0.695
First-order kinetic model / ln(1-Q)=-0.0758t-1.2623 r=0.861 / ln(1-Q)=-0.0684t-0.909, r=0.927 / ln(1-Q)=-0.0695t-0.702, r=0.945
Higuchi model / LnQ=8.7845t1/2+59.014, r=0.773 / Q=10.415t1/2+41.723, r=0.797 / Q=11.584t1/2+33.328, r=0.835
Hixcon-Crowell
model / (100-Q)1/3=-0.0625t+3.0512, r=0.859 / (100-Q)1/3=-0.052t+3.3944, r=0.836 / (100-Q)1/3=-0.0557t+3.6183, r=0.874
Ritger-peppas
model / lnQ=0.1586lnt+4.1387, r=0.789 / lnQ=0.312lnt+3.6622, r=0.886 / lnQ=0.3759lnt+3.4482, r=0.893
Weibull model / lnln[1/1-Q]=0.3451lnt +0.035, r=0.925 / lnln[1/1-Q]=0.578lnt-0.6845, r=0.965 / lnln[1/1-Q]=0.641lnt -0.9699, r=0.964
AMCNS-L / Zero-order kinetic model / Q=0.1435t+77.799, r=0.521 / Q=0.2654t+51.927, r=0.795 / Q=0.2678t+45.69, r=0.833
First-order kinetic model / ln(1-Q)=-0.0155t-0.4943, r=0.948 / ln(1-Q)=-0.0141t-0.7315, r=0.958 / ln(1-Q)=-0.0112t-0.5727, r=0.975
Higuchi model / Q=0.29399t1/2+68.369, r=0.678 / Q=4.8152t1/2+38.276, r=0.915 / Q=4.7454t1/2+32.607, r=0.937
Hixcon-Crowell
model / (100-Q)1/3=-0.0118t+3.7916, r=0.950 / (100-Q)1/3=-0.0115t+3.608, r=0.950 / (100-Q)1/3=-0.0102t+3.7954, r=0.939
Ritger-peppas
model / lnQ=0.2239lnt+3.421, r=0.978 / lnQ=0.2219lnt+3.4934, r=0.908 / lnQ=0.241lnt+3.3351, r=0.980
Weibull model / lnln[1/1-Q]=0.4066lnt-1.1317, r=0.968 / lnln[1/1-Q]=0.4174lnt-1.0318, r=0.989 / lnln[1/1-Q]=0.401lnt-1.2009, r=0.991

Q means cumulative AM release at time t.

Supplementary Table3. The similarity between the dissolution profiles AMCNSand AM in different dissolution media.

Release profile 1 / Release profile 2 / f2 / Difference
Formulation / Release medium / Formulation / Release medium
AMCNS-S / pH 1.2 HCl solution / AM / pH 1.2 HCl solution / 45.11 / +
AMCNS-L / pH 1.2 HCl solution / AM / pH 1.2 HCl solution / 24.13 / +
AMCNS-S / pH 1.2 HCl solution / AMCNS-L / pH 1.2 HCl solution / 42.50 / +
AMCNS-S / pH 6.8 PBS / AM / pH 6.8 PBS / 47.70 / +
AMCNS-L / pH 6.8 PBS / AM / pH 6.8 PBS / 31.80 / +
AMCNS-S / pH 6.8 PBS / AMCNS-L / pH 6.8 PBS / 29.59 / +
AMCNS-S / pH 7.4 PBS / AM / pH 7.4 PBS / 45.37 / +
AMCNS-L / pH 7.4 PBS / AM / pH 7.4 PBS / 26.90 / +
AMCNS-S / pH 7.4 PBS / AMCNS-L / pH 7.4 PBS / 30.90 / +
AMCNS-S / pH 1.2 HCl solution / AMCNS-S / pH 6.8 PBS / 28.39 / +
AMCNS-S / pH 1.2 HCl solution / AMCNS-S / pH 7.4 PBS / 29.46 / +
AMCNS-S / pH 6.8 PBS / AMCNS-S / pH 7.4 PBS / 48.66 / +
AMCNS-L / pH 1.2 HCl solution / AMCNS-L / pH 6.8 PBS / 58.86 / -
AMCNS-L / pH 1.2 HCl solution / AMCNS-L / pH 7.4 PBS / 67.11 / -
AMCNS-L / pH 6.8 PBS / AMCNS-L / pH 7.4 PBS / 56.30 / -
AM / pH 1.2 HCl solution / AM / pH 6.8 PBS / 53.20 / -
AM / pH 1.2 HCl solution / AM / pH 7.4 PBS / 62.38 / -
AM / pH 6.8 PBS / AM / pH 7.4 PBS / 68.23 / -