Comparative study of nisoldipine-loaded nanostructured lipid carriers and solid lipid nanoparticles for oral delivery: preparation, characterization, permeation and pharmacokinetic evaluation

Figures & data

Table 1. Composition of nisoldipine-loaded NLCs, SLNs and suspension formulation.

	Formulation code
Formulation ingredients	N1	N2	N3	N4	N5	Solid lipid nanoparticles	NS
Organic phase
Nisoldipine (mg)	10	10	10	10	10	10	10
Oleic acid (mL)	0.05	0.06	0.05	0.06	0.06	–	–
Dynasan-114 (mg)	75	75	100	100	125	100	–
Egg lecithin (mg)	75	75	75	75	75	75	–
Chloroform : methanol (1:1) (mL)	10	10	10	10	10	10	–
Aqueous phase
Polaxomer-188	1.5%	1.5%	1.5%	1.75%	2%	1.75%	–
Na CMC	–	–	–	–	–	–	50
Double distilled water (mL)	10	10	10	10	10	10	–

Table 2. Physical characters – size, PDI, ZP, drug content and EE of ND-NLCs and SLNs formulations (mean ± SD, n = 3).

Formulation code	Size (nm)	PDI	ZP (mV)	Assay (mg)	EE (%)
N1	265.9 ± 4.69	0.283 ± 0.007	–22.6 ± 2.47	9.91 ± 0.21	82.71 ± 0.31
N2	252.7 ± 3.84	0.261 ± 0.008	–24.6 ± 2.74	9.89 ± 0.18	84.23 ± 0.10
N3	210.8 ± 2.47	0.287 ± 0.005	–23.9 ± 2.34	9.91 ± 0.12	91.38 ± 0.21
N4	110.4 ± 2.95	0.202 ± 0.006	–29.4 ± 2.05	9.97 ± 0.20	97.07 ± 2.27
N5	193.8 ± 4.33	0.248 ± 0.004	–27.2 ± 3.71	9.90 ± 0.09	93.56 ± 0.30
Solid lipid nanoparticles	105.2 ± 3.81	0.233 ± 0.004	–25.3 ± 2.84	9.94 ± 0.23	90.53 ± 3.24

Figure 1. In-vitro drug release of ND from ND-NLCs, ND-SLNs and NDS in 0.1 N HCl followed by pH 6.8 phosphate buffer (mean ± SD, n = 3).

Table 3. Effect of storage at refrigerated and room temperature on size, PDI, ZP, assay and EE of optimized NLCs (N4) formulation for 3 months (mean ± SD, n = 3).

	Size (nm)		PDI		ZP (mV)		Assay (mg)		EE (%)
Time	At 4 °C	At 25 °C	At 4 °C	At 25 °C	At 4 °C	At 25 °C	At 4 °C	At 25 °C	At 4 °C	At 25 °C
Initial	111.3 ± 2.5	109.2 ± 1.8	0.201 ± 0.006	0.203 ± 0.007	–29.4 ± 2.3	–29.8 ± 1.8	9.97 ± 0.21	9.98 ± 0.22	97.3 ± 1.4	97.4 ± 2.7
15 days	110.6 ± 3.2	113.9 ± 3.7	0.206 ± 0.02	0.207 ± 0.05	–29.4 ± 2.6	–28.9 ± 2.1	9.92 ± 0.84	9.91 ± 0.43	96.9 ± 2.0	95.8 ± 2.4
30 days	112.7 ± 4.1	115.8 ± 2.9	0.205 ± 0.04	0.211 ± 0.06	–29.3 ± 2.1	–28.4 ± 2.7	9.94 ± 0.36	9.90 ± 0.45	96.1 ± 1.8	95.1 ± 1.7
45 days	112.5 ± 2.7	116.6 ± 2.5	0.208 ± 0.01	0.218 ± 0.02	–28.6 ± 1.9	–28.1 ± 1.8	9.97 ± 0.32	9.89 ± 0.53	95.9 ± 1.4	94.8 ± 1.3
60 days	114.9 ± 3.1	118.7 ± 3.0	0.212 ± 0.04	0.223 ± 0.04	–28.8 ± 3.1	–28.0 ± 2.4	9.90 ± 0.41	9.91 ± 0.67	95.0 ± 2.1	94.1 ± 2.5
90 days	118.7 ± 2.9	121.3 ± 3.4	0.221 ± 0.03	0.234 ± 0.07	–28.2 ± 2.4	–27.2 ± 2.8	9.89 ± 0.24	9.88 ± 0.71	95.9 ± 1.6	93.6 ± 2.3

Figure 2. Drug permeation profiles of ND from ND-NLCs, ND-SLNs and NDS by in-situ absorption studies in rat intestine (mean ± SD, n = 3).

Table 4. Release coefficients and kinetic parameters of drug permeation studies of nisoldipine from ND-NLCs, SLNs and NDS formulation across rat intestine (mean ± SD, n = 3).

Formulation	Keff (nm^2/min)	Peff (mL/min/cm) × 10^–2	Ka (h)	ER
N4	983.7 ± 41.8	2.95 ± 0.025*^,**	0.796	2.89
SLNs	879.6 ± 36.5	2.36 ± 0.018*	0.771	2.31
NDS	408.8 ± 23.4	1.02 ± 0.015	0.489	–

*p < .001 indicates statistically significant compared to NDS. **p < .05 indicates statistically significant compared to SLNs.

SLNs: optimized nisoldipine solid lipid nanoparticle; NDS: nisoldipine suspension; N4: optimized nisoldipine nanostructured lipid carrier.

K_eff: elimination coefficient; P_eff: permeability coefficient; K_a: absorption rate constant; ER: enhancement ratio.

Figure 3. DSC thermograms of (A) pure nisoldipine, (B) pure lipid, (C) physical mixture of ND and lipid (1:1 ratio), (D) lyophilized ND-NLCs and (E) lyophilized ND-SLNs.

Table 5. Degree of crystallinity of pure drug, physical mixture and lyophilized NLCs and SLNs formulation.

Compound	Melting temperature (°C)	Enthalpy (J/g)	Crystallinity (%)
Pure drug	158.85	545.84	100
PM	65.83	487.67	89.34
Lyophilized NLCs	64.81	136.68	25.04
Lyophilized solid  lipid nanoparticles	64.73	156.89	28.74

Figure 4. XRD spectra of (A) pure nisoldipine, (B) pure lipid, (C) physical mixture of ND and lipid (1:1 ratio), (D) lyophilized ND-NLCs and (E) lyophilized ND-SLNs.

Figure 5. SEM images of optimized ND-NLCs at different magnifications.

Figure 6. Pharmacokinetic (PK) profiles of nisoldipine in rat serum following oral administration of ND-NLCs (N4), optimized SLNs and NDS formulation (mean ± SD, n = 6).

Table 6. Pharmacokinetic parameters of nisoldipine after oral administration of ND-NLCs, SLN and NDS in rats (mean ± SD, n = 6).

Parameter	SLNs	NDS	N4
Cmax (µg/mL)	11.94 ± 1.16**	7.01 ± 1.03	12.27 ± 1.65**
tmax (h)	4.00 ± 0.00*	3.00 ± 0.00	4 ± 0.00*
AUCtot (µg h/mL)	89.02 ± 3.16**	39.72 ± 1.99	97.73 ± 3.81**^,***
thalf (h)	15.26 ± 1.75**	8.58 ± 1.07	17.77 ± 1.82**
MRT (h)	14.22 ± 2.01**	9.53 ± 0.88	16.78 ± 1.73**

*p < .01 and **p < .001 indicate statistically significant compared with NDS; ***p < .01 indicates statistically significant compared with SLNs.

SLNs: optimized nisoldipine solid lipid nanoparticles; NDS: nisoldipine suspension; N4: optimized nisoldipine nanostructured lipid carrier.