Oral gel loaded with penciclovir–lavender oil nanoemulsion to enhance bioavailability and alleviate pain associated with herpes labialis

Figures & data

Table 1. The independent factors and responses for the design of experiments.

Run	Coded values			Actual values
	Factor A	Factor B	Factor C	Factor A	Factor B	Factor C
	Lavender oil	Surfactant mixture	Lauroglycol-FCC	Lavender oil (%)	Surfactant mixture (%)	Lauroglycol-FCC (%)
1	0.157322	0.436232	0.406446	15.7	43.6	40.7
2	0.11	0.42556	0.46444	11.0	42.6	46.4
3	0.25	0.39	0.36	25.0	39.0	36.0
4	0.179863	0.460137	0.36	18.0	46.0	36.0
5	0.145034	0.39	0.464966	14.5	39.0	46.5
6	0.179478	0.39	0.430522	17.9	39.0	43.1
7	0.11	0.460572	0.429428	11.0	46.1	42.9
8	0.11	0.39	0.5	11.0	39.0	50.0
9	0.11	0.53	0.36	11.0	53.0	36.0
10	0.133466	0.483083	0.38345	13.3	48.3	38.4
11	0.11	0.39	0.5	11.0	39.0	50.0
12	0.25	0.39	0.36	25.0	39.0	36.0
13	0.11	0.53	0.36	11.0	53.0	36.0
14	0.204559	0.412952	0.382489	20.5	41.3	38.2
15	0.179863	0.460137	0.36	18.0	46.0	36.0

Table 2. Compositions of the different chitosan oral gel samples/formulations.

Formulation	Composition
O1	Chitosan hydrogel (plain)
O2	Chitosan hydrogel loaded with PV powder
O3	Chitosan hydrogel loaded with optimized PV-LO-SNEDDs

Table 3. Solubility data of penciclovir (PV) in SNEDDS formulation components.

Component	Solubility of penciclovir (mg/mL)
Basil oil	210 ± 15
Thyme oil	320 ± 19
Peppermint oil	250 ± 11
Rosemary oil	95 ± 10
Lavender oil	445 ± 17
Citronella oil	170 ± 11
Verbena oil	200 ± 15
Camphor oil	154 ± 18
Tween80:Span80 (5.33:4.67)	67 ± 3
Steareth-2: Steareth-21 (4.9:5.1)	85 ± 8
Labrasol:Labrafil 1944 (6:4)	105 ± 9
Brij 30	52 ± 4
Lauroglycol-FCC	79 ± 4
Lutrol-E400	50 ± 5
Propylene glycol	65 ± 3
Transcutol	55 ± 7

Figure 1. Pseudoternary-phase diagram in formulation components of penciclovir-loaded lavender oil-containing self-nanoemulsifying drug delivery systems (PV-LO-SNEDDS), using lavender oil (LO) as the oil phase, Labrasol:Labrafil 1944 in the ratio of 6:4 (HLB value = 10) as the surfactant mixture, and Lauroglycol-FCC as the co-surfactant.

Table 4. The independent factors and responses for the design of experiments.

Run	Factor A	Factor B	Factor C	Response 1	Response 2
	Lavender oil (%)	Surfactant mixture (%)	Lauroglycol-FCC (%)	Globule size (nm)	Stability index (%)
1	15.7	43.6	40.7	155	86
2	11.0	42.6	46.4	320	90
3	25.0	39.0	36.0	312	71
4	18.0	46.0	36.0	219	75
5	14.5	39.0	46.5	239	91
6	17.9	39.0	43.1	223	88
7	11.0	46.1	42.9	319	87
8	11.0	39.0	50.0	295	93
9	11.0	53.0	36.0	250	76
10	13.3	48.3	38.4	200	83
11	11.0	39.0	50.0	294	93
12	25.0	39.0	36.0	313	72
13	11.0	53.0	36.0	252	77
14	20.5	41.3	38.2	287	82
15	18.0	46.0	36.0	219	75

Table 5. ANOVA data for globule size of PV-LO-SNEDDS prepared in various runs.

Source	Sum of squares	Degrees of freedom	Mean square	F-value	p Value	–
Model	35660.23	8	4457.53	6409.04	<.0001	Significant
Linear Mixture	4226.42	2	2113.21	3038.37	<.0001	–
AB	5242.72	1	5242.72	7537.99	<.0001	–
AC	6779.88	1	6779.88	9748.12	<.0001	–
BC	2334.13	1	2334.13	3356.02	<.0001	–
A²BC	3514.40	1	3514.40	5053.01	<.0001	–
AB²C	716.35	1	716.35	1029.96	<.0001	–
ABC²	2943.63	1	2943.63	4232.36	<.0001	–
Residual	4.17	6	0.6955	–	–	–
Lack of fit	1.17	2	0.5865	0.7820	.5168	Not significant
Pure error	3.00	4	0.7500	–	–	–
Cor total	35,664.40	14	–	–	–	–

Figure 2. Various design plots for the globule size and stability index of PV-LO-SNEDDS: (a) trace plot for globule size, (b) simplex contour plot for globule size, (c) 3D plot for globule size, (d) trace plot for stability index, (e) simplex contour plot for stability index, and (f) 3D plot for stability index.

Table 6. ANOVA data for stability index of PV-LO-SNEDDS prepared in various runs.

Source	Sum of squares	Degrees of freedom	Mean square	F-value	p Value	–
Model	837.96	8	104.75	383.97	<.0001	Significant
Linear Mixture	760.22	2	380.11	1393.37	<.0001	–
AB	1.25	1	1.25	4.60	.0758	–
AC	29.95	1	29.95	109.78	<.0001	–
BC	4.85	1	4.85	17.78	.0056	–
A²BC	6.25	1	6.25	22.93	.0030	–
AB²C	3.59	1	3.59	13.14	.0110	–
ABC²	3.23	1	3.23	11.83	.0138	–
Residual	1.64	6	0.2728	–	–	–
Lack of Fit	0.6368	2	0.3184	1.27	.3733	Not significant
Pure Error	1.0000	4	0.2500	–	–	–
Cor Total	839.60	14	–	–	–	–

Table 7. Optimum formula suggested for the PV-LO-SNEDDS formulation and the predicted and observed responses for the optimized formula.

Independent factors
Factor	Variable	Level
A	Lavender oil (%)	0.1398
B	Surfactant mixture (%)	0.4048
C	Lauroglycol-FCC (%)	0.4554
Total =		1.0000
Responses
	Predicted value	Observed value
Globule size (nm)	155	157 ± 9
Stability index (%)	87.8218	88 ± 4

Figure 3. Plots of the shear rate (G) versus the viscosity (η) for: (a) plain chitosan oral hydrogel (O1) and (b) chitosan oral hydrogel loaded with the optimized PV-LO SNEDDs (O3). Values are expressed as mean ± SD (n= 3).

Table 8. Rheological parameters of plain chitosan hydrogel and chitosan hydrogel loaded with optimized PV-LO-SNEDDS.

Formulations	Viscosity* (maximum) (cP)	Viscosity* (minimum) (cP)	Farrow’s constant (N)	Flow behavior
Plain chitosan hydrogel (O1)	119,663 ± 9123	6123 ± 1075	3.718	Pseudoplastic
Chitosan hydrogel loaded with optimized PV-LO-SNEDDs (O3)	135,436 ± 12654	8112 ± 1548	4.117	Pseudoplastic

*Data are expressed as mean ± SD (n = 3).

Figure 4. Rheograms of (a) plain chitosan oral hydrogel (O1) and (b) chitosan oral hydrogel loaded with the optimized PV-LO-SNEDDs (O3).

Figure 5. Plots of the logarithm of the shear rate (G) versus the logarithm of the shear stress (F) for (a) plain chitosan oral hydrogel (O1) and (b) chitosan oral hydrogel loaded with the optimized PV-LO-SNEDDs (O3). Values are expressed as mean ± SD (n= 3).

Figure 6. In vitro release profile of PV from chitosan hydrogel loaded with PV powder (O2), chitosan hydrogel loaded with optimized PV-LO SNEDDs (O3), marketed PV cream (1%), and 1% PV aqueous suspension. *Data are expressed as mean ± SD (n = 3).

Table 9. Evaluation parameters of PV permeation across the buccal mucosa from different formulations.

Parameters of PV permeation*	Chitosan hydrogel loaded with optimized PV-LO-SNEDDs (O3)	Chitosan hydrogel loaded with PV powder (O2)	1% PV aqueous suspension	Marketed PV (1%) cream
Cumulative amount permeated (μg/cm^2)	4911 ± 405	1402 ± 142	1028 ± 109	2373 ± 221
Steady state flux, Jss, (μg/cm^2.min)	13.222	5.911	4.115	8.512
Permeability coefficient, PC, (cm/min)	11.5 × 10^−4	4.7 × 10^−4	3.6 × 10^−4	8.6 × 10^−4
Diffusion coefficient, D, (cm^2/min)	39 × 10^−4	15 × 10^−4	11 × 10^−4	26 × 10^−4
Relative permeation rate (RPR)	2.069	0.59	0.433	–
Enhancement factor (EF)	4.777	1.363	–	2.308

*Data are expressed as mean ± SD (n= 3).

Table 10. Comparative pharmacokinetic parameters of different PV formulations and marketed cream (mean ± SD, n= 6).

PK parameters	Chitosan hydrogel loaded with PV powder (O2)	Chitosan hydrogel loaded with optimized PV-LO-SNEDDs (O3)	Marketed PV 1% cream
Cmax (ng/mL)	919 ± 112	2400 ± 290	1346 ± 205
Tmax (min)	60 ± 30	30 ± 15	60 ± 15
AUC 0–t (ng/mL h)	3011.1 ± 222.1	7413.2 ± 698.3	4134.2 ± 543.4
AUC0–inf (ng/mL h)	3922.1 ± 285.2	9564.5 ± 299.1	5611.2 ± 633.2
Kel (h^−1)	0.655 ± 0.09	0.534 ± 0.05	0.605 ± 0.06