Nanovesicles of nitrendipine with lipid complex for transdermal delivery: pharmacokinetic and pharmacodynamic studies

Figures & data

Table I. Formulation of lipid components (lipid drug ratio = 3:1).

S. No.	Formulation code	Cer 2	SA	CS	BA	OA
1.	NOV-1	3	2.5	1	1.5	0.5
2.	NOV-2	3	2.5	1	1.5	1.0
3.	NOV-3	3	2.5	1	1.5	1.5
4.	NOV-4	3	2.5	1	1.5	2.0
5.	NOV-5	3	2.5	1	1.5	2.5

Drug: lipid ratio 1:3.

Cer 2, ceramide; SA, stearic acid; BA, behenic acid; OA, oleic acid; CS, cholesteryl sulfate; NOV, nitrendipine ceramide vesicle prepared with oleic acid.

Figure 1. (A) SEM photograph of NOV-5. (B) TEM photograph of NOV-5. (C) Particle size distribution analysis report of NOV-5.

Table II. Nanovesicles and corresponding gels: physicochemical parameters.

Formulation code	Size* (nm)	PDI*	ζ potential* (mV)	Entrapment efficiency* (%)	Practical yield (%)	Viscosity† (Cps)
NOV-1	89.9 ± 1.9	0.173 ± 0.008	−35 ± 1.3	76.4 ± 3.1	62.1	17,123 ± 1.26
NOV-2	94.3 ± 1.1	0.160 ± 0.009	−37 ± 1.1	79.9 ± 1.4	64.6	17,276 ± 3.19
NOV-3	98.5 ± 2.3	0.154 ± 0.001	−38 ± 1.4	85.4 ± 1.4	66.3	17,895 ± 2.25
NOV-4	107.8 ± 2.6	0.197 ± 0.009	−39 ± 0.9	88.3 ± 2.5	69.6	18,157 ± 3.87
NOV-5	113.3 ± 1.7	0.186 ± 0.008	−41 ± 1.2	93.77 ± 1.9	73.8	18,279 ± 2.8

All data expressed as mean ± S.D.; n = 3. p ≤ 0.05.

*Determinations performed on nitrendipine ceramide oleic acid vesicles (NOV).

†Viscosity determined on corresponding carbopol gels.

Figure 2. In vitro drug release profile for nanovesicle formulations in 24 h. Data presented as mean ± SD; (n = 3); p ≤ 0.01.

Table III. Physicochemical characterization of nitrendipine ceramide oleic vesicles (NOV-5) after stability studies.

Days	Storage conditions	Size (nm)	Entrapment efficiency (%)	In vitro % cumulative drug release (in 24 h)
0th day	25 ± 2 °C & 60 ± 5% RH	113.3 ± 1.7	93.77 ± 1.9	68.9 ± 2.1
	40 ± 2 °C & 75 ± 5% RH	113.3 ± 1.7	93.77 ± 1.9	68.9 ± 2.1
30th day	25 ± 2 °C & 60 ± 5% RH	114.1 ± 0.9	93.13 ± 1.3	69.1 ± 1.3
	40 ± 2 °C & 75 ± 5% RH	115.2 ± 1.1	92.19 ± 1.7	70.08 ± 2.6
60th day	25 ± 2 °C & 60 ± 5% RH	114.9 ± 1.3	92.8 ± 1.1	70.3 ± 1.8
	40 ± 2 °C & 75 ± 5% RH	116.2 ± 1.9	91.04 ± 1.4	71.98 ± 1.4
90th day	25 ± 2 °C & 60 ± 5% RH	116.6 ± 1.5	91.32 ± 1.1	70.93 ± 2.8
	40 ± 2 °C & 75 ± 5% RH	119.2 ± 1.7	89.43 ± 1.18	73.58 ± 3.3

RH, relative humidity.

All data expressed as mean ± S.D.; n = 3; p ≤ 0.05.

Figure 3. Cumulative amount of drug permeated per unit area through human skin in 24 h. Data presented as mean ± SD; (n = 6); p ≤ 0.05.

Table IV. Flux, permeability coefficient and diffusion parameters of NOVG formulations.

S. No.	Formulation code	Flux (μg/cm^2/h)	Lag time (h)	Permeability coefficient (cm/h)	Diffusion coefficient (cm^2/h × 10^−3)
1.	NCG	0.0236	3.4	1.18 × 10^−5	1.02 × 10^−3
2.	NOVG-1	4.88	2.5	2.44 × 10^−3	1.4 × 10^−3
3.	NOVG-2	7.53	2.3	3.765 × 10^−3	1.5 × 10^−3
4.	NOVG-3	14.27	1.2	7.135 × 10^−3	2.91 × 10^−3
5.	NOVG-4	20.41	1.0	1.0205 × 10^−2	3.5 × 10^−3
6.	NOVG-5	24.72	0.4	1.236 × 10^−2	8.75 × 10^−3

NCG, nitrendipine carbopol gel.

Figure 4. Drug concentration in various strata of skin; SC, stratum corneum; VED, viable epidermis; D, dermis; RC, receiver chamber. Data presented as mean ± SD; (n = 6); p ≤ 0.05.

Figure 5. Plasma drug concentration profiles of NOVG-5, NOS and NCG. Data presented as mean ± SD; (n = 6); p ≤ 0.05.

Table V. C_max, t_max and AUC_0→24 values for NOS, NCG and NOVG formulations.

Formulation code	Cmax (μg/mL)	Tmax (h)	AUC (μg h/mL)
NCG	0.02	6	0.1753
NOS	7.4	2	100.4
NOVG-5	41.81	12	783.4

NOS, nitrendipine oral suspension (5 mg/kg); NCG, 1 mg equivalent nitrendipine carbopol gel; NOVG, 1 mg equivalent nitrendipine oleic acid vesicle carbopol gel.

All data expressed as mean ± S.D.; n = 6 (p ≤ 0.05).

Table VI. Antihypertensive effect of NOVG-5 and NCG in comparison to oral route.

		Mean blood pressure (mm Hg)
Group	Treatment	Initial	1 h	2 h	4 h	6 h	8 h	12 h	24 h
I	Negative control	90.4	92.1	91.6	93.2	94.3	92.4	91.5	92.3
II	Toxic control	181.23	181.72	181.92	180.94	180.43	181.04	180.07	180.11
III	Placebo	181.5	172.6	171.8	170.5	173.6	181.6	182.2	181.8
IV	Oral (NOS)	182.67	140.9	94.2	99.78	118.27	129.27	145.67	180.86
V	NCG	179.27	174.82	170.36	169.38	155.83	173.54	174.3	176.7
VI	NOVG-5	179.56	119.4	90.4	93.5	92.7	91.1	94.3	98.3