Subcutaneously injected ivermectin-loaded mixed micelles: formulation, pharmacokinetics and local irritation study

Figures & data

Figure 1. Chemical structure of ivermectin.

Figure 2. Influence of the mass concentration ratio of SPC and SDC on IVM solubilizing efficiency at 25°C (N = 3).

Figure 3. Influence of the total concentration of SPC and SDC on IVM solubilizing efficiency at 25°C (N = 3).

Table 1. Influence of IVM concentration on the stability of IVM-SPC-SDC-MMs.

IVM	SPC + SDC	Time (h)
(mg/mL)	(mg/mL)	0	1	2	24
2	72	Y	Y	Y	Y
4	72	Y	Y	Y	Y
5	72	Y	Y	Y	Y
6	72	C	C	C	C
8	72	C	C	C	C

Y = settled solution; C = IVM crystallization; N = 3

Figure 4. Plot of the fluorescence of pyrene I₁/I₃ intensity ratio versus concentration of SPC/SDC mixed micelles (mass ratio 1:1.4) in distilled water at 25 °C (N = 3).

Table 2. Solubilizing efficiency and drug loading of IVM-SPC-SDC-MMs.

Sample	Solubility (mg/mL)^a	Solubilizing effeciency (%)^a	Drug loading(%)^a
IVM-SPC-SDC-MMs	4.79 ± 0.02	94 ± 2.8	6.22 ± 0.26

^aReported as means ± standard deviation; N = 3.

Figure 5. Size distribution of IVM-SPC-SDC-MMs. (A) Size distribution of IVM-SPC-SDC-MMs detected by DLS. (B) TEM of IVM-SPC-SDC-MMs.

Figure 6. Mean plasma concentration–time curve of IVM after subcutaneous administration of commercially available IVM injection and IVM-SPC-SDC-MMs in rabbits. Data represent mean ± standard deviation (N = 5).

Table 3. The main pharmacokinetic parameters of IVM obtained after subcutaneous administration of the commercially available IVM injection and the IVM-SPC-SDC-MMs formulation at a dose of 5.0 mg/mL in rabbits.

Parameter	IVM-SPC-DOC-MMs	IVM injection
AUC(0–t)^a (µg. mL–1 min)	8864.14 ± 24.90	6626.91 ± 10.40
AUC(0–∞)^a (µg. mL–1 min)	10321.44 ± 28.20	7912.54 ± 24.30
MRT(0–t)^a (min)	47.77 ± 8.70	52.20 ± 6.12
MRT(0–∞)^a (min)	60.79 ± 37.80	82.75 ± 47.03
Cmax^a (µg/mL)	15.09 ± 9.87	109.46 ± 17.10
t1/2z^a (min)	33.67 ± 18.64	45.66 ± 28.76
CLz^a (mL/min g)	0.54	0.66

^aReports as mean ± standard deviation; (N = 5).

Figure 7. Pathological paraffin sections from local injection site of rabbits after injection on the Days 4 and 14 (magnification, ×100). (A), (B) and (C) Skin samples from rabbits given the commercially available IVM injection. (A) Small amount of inflammatory cell infiltration was shown at the injection site on the fourth day. (B), (C) Until 14th day, severer inflammation and hemorrhage appeared and crystals were also observed. (D), (E) Skin samples from rabbits administered IVM-SPC-SDC-MMs on fourth and 14th days, respectively. (F) Skin sample from rabbits given sodium chloride injection. The phenomenon shown in (A), (B) and (C) were not observed in (D), (E) or (F).