Phospholipid microemulsion-based hydrogel for enhanced topical delivery of lidocaine and prilocaine: QbD-based development and evaluation

Figures & data

Table 1. Quality Target Product Profile (QTPP) for EMLP-loaded MEs.

QTPP Elements	Target	Justification
Dosage form	ME	Selection of phospholipid based ME helps in the enhanced dermal delivery
Dosage type	Rapid release	Faster release leading to enhanced therapeutic effects
Dosage strength	5%	2.5% dose of Lido and Prilo each incorporated in a single formulation of ME
Route of administration	Topical	Recommended route for local anesthesia of skin
Ex vivo permeation	Higher flux and skin retention	Required for achieving higher drug levels in the skin for enhanced anesthetic action
Packaging	Aluminium tubes	The EMLP loaded ME gel can be easily incorporated in aluminium tubes for improved patient compliance, portability and manufacturing ease
Stability	At least 6 months at various storage temperatures	To maintain therapeutic potential of the drug during storage period

Table 2. Critical Quality Attributes (CQAs) for EMPL-loaded ME and their justifications.

Quality Attributes of the Drug Product	Target	Is this a CQA?	Justification
Physical attributes
Color	Transparent	No	Physical attributes of the formulation were not considered as critical, as these are not directly linked to the efficacy and safety.
Odor	No unpleasant order
Appearance	Acceptable to patients
Assay and content uniformity	100%			No	Albeit assay and content uniformity tend to affect safety and efficacy of formulations, yet the MEs being considered as the homogenous dispersions containing drug present in solubilized in the blend of lipidic excipients, these variables were regarded as moderately critical.
Globule size	Less than 100 nm	Yes*	Smaller globule size of ME will facilitate in better permeation and retention of the drugs within the dermal layers; hence was regarded as highly critical.
Flux	High	Yes*	Essential parameter to access the topical delivery potential of the formulation for enhanced therapeutic efficacy. Thus, it was considered as highly critical.
Cumulative drug permeation	High	Yes*	Permeation property of the drug formulations is highly responsible for attaining meaningful pharmacodynamic effects; hence was taken up as highly critical.
Skin retention	High	Yes*	High skin retention is important for topical anesthesia, wherein the pain sensitive nerve endings (target site) are located in the dermis region of the skin. Hence was regarded as highly critical.

*CQAs considered as critical.

Figure 1. Fish-bone diagram.

Table 3. Initial risk assessment for ME formulation containing EMLP.

	Risk estimation matrix
Drug product CQAs	Conc. of IPM	Conc. of Tween 80	Conc. of Labrasol/Lauroglycol 90	Ratio of PL: Ethanol	Water	ME stirring time	ME stirring speed	Temperature
Globule Size	High	High	Med	Med	Med	Med	Med	Low
FluxL	High	High	High	High	Med	Low	Low	Low
FluxP	High	High	High	High	Med	Low	Low	Low
Q5L	High	High	High	High	Med	Low	Low	Low
Q5P	High	High	High	High	Med	Low	Low	Low
SRL	High	Med	Med	High	Med	Low	Low	Low
SRP	High	Med	Med	High	Med	Low	Low	Low

Flux_L: Flux of Lido; Flux_P: Flux of Prilo; Q_5L: Amount of Lido release from ME in 5 h; Q_5P: Amount of Prilo release from ME in 5 h; SR_L: Skin retention time for Lido; SR_P: Skin retention time for Prilo; PL: Phospholipon 90G®; Conc: Concentration.

High: High-risk parameter; Med: Medium-risk parameter; Low: Low-risk parameter.

Figure 2. Pseudo-ternary phase diagrams of MEs composed of oil (IPM), S_mix (Tween 80: CS: Labrasol®) and water at various S_mix ratios (A) 1:1:0.5 (B) 1:1:1 (C) 1:2:1 (D) 2:1:1.

Figure 3. Pseudo-ternary phase diagrams of MEs composed of oil (IPM), S_mix (Tween 80: CS: Laurogycol 90®) and water at various S_mix ratios (A) 1:1:0.5 (B) 1:1:1 (C) 1:2:1 (D) 2:1:1.

Table 4. Experimental runs of D-optimal mixture design and their responses.

					Y2 (mg cm^−2)		Y3 (%)		Y4(µg cm^−2h^−1)
Runs	X1 (%)	X2 (%)	X3 (%)	Y(nm)	Prilo	Lido	Prilo	Lido	Prilo	Lido
1	10.000	50.000	40.000	71.5	0.17	0.19	0.99	0.89	9.13	9.80
2	10.000	70.000	20.000	305	0.13	0.16	0.78	0.70	8.09	5.86
3	9.850	60.025	30.125	203	0.12	0.13	0.89	0.82	3.33	2.67
4	10.000	70.000	20.000	304	0.13	0.16	0.78	0.70	8.09	5.86
5	10.000	70.000	20.000	305	0.13	0.16	0.78	0.70	8.09	5.86
6	10.000	30.000	60.000	44.8	0.52	0.56	1.07	0.91	10.46	9.39
7	9.8000	70.000	20.200	298	0.12	0.15	0.76	0.74	7.98	5.65
8	10.000	30.000	60.000	44.8	0.52	0.56	1.071	0.91	10.46	9.39
9	10.000	30.000	60.000	46	0.52	0.56	1.071	0.91	10.46	9.39
10	9.950	40.025	50.025	100	0.70	0.83	0.51	0.49	8.65	9.58
11	9.900	30.100	60.000	57	0.51	0.55	1.00	0.89	10.06	9.31
12	9.850	40.125	50.025	103	0.71	0.81	0.50	0.48	8.76	8.98
13	10.000	50.000	40.000	73	0.17	0.19	0.99	0.89	9.13	9.8

Table 5. Model summary statistics of the measured responses.

	Polynomial coefficients for response variable
		Y2		Y3		Y4
Coefficient code	Y1	Prilo	Lido	Prilo	Lido	Prilo	Lido
β1	−397.70	+155.01	+146.31	+16.74	+13.45	+2318.11	+343.607
β2	+302.13	+0.12	+0.15	+0.78	+0.69	+8.06	−1.489
β3	+46.62	+0.52	+0.56	+1.17	+0.99	+10.42	−2.396
β4	+837.57	−266.19	−250.58	−21.01	−16.44	−3902.11	−5.862
β5	+902.64	−264.73	−247.43	−24.37	−19.17	−3951.18	−5.852
β6	−412.11	−0.62	−0.71	+0.021	+0.21	+0.35	+0.023
β7	−7903.80	+241.43	+221.15	−114.39	−101.29	+3346.96	+0.054
β8	+1458.16	−120.52	−112.63	+50.11	+42.06	−1646.27	−0.027
β9	+4848.01	−119.41	−109.15	+25.59	+22.59	−1728.03	−0.027
β10	–	–0.79	+0.23	–	–	−6.03	−1.957
R^2	0.9984	0.9996	0.9970	0.9910	0.9924	0.9888	0.9995

Figure 5. Overlay plot depicting the location of optimized microemulsion formulation in the design space.

Figure 6. TEM image of optimized ME formulation.

Figure 7. Photograph showing the images of microemulsion formulations (a) M_OPT-NMP and (b) M_OPT-NMP gel.

Figure 8. Texture analysis: (a) M_OPT gel and (b) M_OPT-NMP gel formulations.

Table 6. Rheological characteristics of the developed ME gel formulations.

Formulations parameters	MOPT Gel	MOPT-NMP Gel
*n	0.376	0.555
*K (Pa)	53.074	42.26
*η0 (Pa.sec)	65.82	46.95
Yield value (Pa)	81.71	49.80
Gel strength (kg)	24.532	17.674
Work of spreading (kg.sec)	8.814	6.319
Stickiness (kg.sec)	1.248	1.161
Extrudability (kg)	9.802	9.197

*K: consistency index (Pa); n: power-law exponent; η₀: viscosity (Pa.sec).

Table 7. Chemical stability of Lido and Prilo in the M_OPT-NMP gel formulations after 6 months of storage at various conditions. Values are means of three experiments ± SD.

	Percent drug remaining (%)
	5 ± 3 °C		25 ± 2 °C		40 ± 2 °C
Time (months)	Prilo	Lido	Prilo	Lido	Prilo	Lido
0	100.26	100.04	100.26	100.04	100.26	100.04
1	99.89	99.87	99.76	99.85	98.89	99.12
3	99.43	99.65	99.32	99.53	96.34	98.34
6	98.65	99.39	98.60	99.34	94.95	97.27
Drug loss (%)	1.61	0.65	1.66	0.70	5.31	2.77

Figure 9. Cumulative permeation amount versus time curves of ME and the reference formulations (a) prilocaine (b) lidocaine (mean + SD); n = 3.

Table 8. Permeation parameters (mean±SD) of lidocaine and prilocaine through rat skin from ME formulations and commercial formulation (n = 3).

	Prilocaine		Lidocaine
Formulations	Flux (µg cm^−2 h^−1)	Permeability Coefficient × 10^−3	Flux (µg cm^−2h^−1)	Permeability Coefficient × 10^−3
CC	10.82	0.48	11.56	0.33
MOPT	26.86	1.16	34.08	1.40
MOPT-NMP	11.55	0.50	18.20	0.75
MOPT Gel	18.29	0.79	18.84	0.80
MOPT-NMP Gel	34.89	1.50	57.14	2.39

Figure 10. Skin absorption of lidocaine and prilocaine from various formulations (mean ± SD); n = 3.

Figure 11. Tail-flick test comparison of control gel, M_OPT-NMP gel and commercial cream (CC). The data represent the mean ± SD (n = 5).

Table 9. Comparison of % analgesic effect of M_OPT-NMP gel and CC*.

Time (minutes)	5	10	15	20	25	30	35	40	45
CC	1.57	7.81	16.40	22.66	14.84	12.50	6.25	3.90	–
MOPT-NMP gel	11.63	20.93	38.76	50.39	44.19	27.91	17.05	10.85	7.75

*CC: commercial cream.

Figure 12. Photomicrographs of skin histology sections treated with (a) Control (b) M_OPT-NMP gel treated (c) M_OPT-NMP treated.