Brain targeting by intranasal drug delivery (INDD): a combined effect of trans-neural and para-neuronal pathway

Figures & data

Table 1. Radiolabeling stability in normal saline (0.9% w/v) and rat serum.

	Percentage stability of ^99mTc-NEROP
Time (h)	0.9% NaCl	Rat serum
0.5	95.15 ± 1.31	96.23 ± 2.33
1	98.76 ± 1.25	97.49 ± 1.46
2	97.93 ± 1.64	97.66 ± 3.59
3	98.12 ± 1.58	98.11 ± 1.85
4	98.45 ± 1.96	97.58 ± 1.68
5	98.57 ± 1.44	97.34 ± 2.56
22	97.98 ± 2.72	97.15 ± 3.79
24	98.04 ± 1.56	96.19 ± 4.15

Ropinirole nanoemulsion radiolabeled with technetium (^99mTc-NE_ROP).

Table 2. Partitioning potential of the optimized formulation in chloroform/water and chloroform/phosphate buffer (pH 5.6 and 7.4) mixture showing the impact of droplet size on its lipophilicity.

	%Ropinirole partition in chloroform layer
Partitioning medium	NEROP1	NEROP2	NEROP3	NEROP4	NEROP5	NEROP6**	NEROP7	Soln^ROP
Distilled water–chloroform	81.49 ± 3.59	73.66 ± 11.14	72.51 ± 3.64	77.94 ± 6.40	90.30 ± 2.62	95.67 ± 2.00	55.62 ± 8.81	8.38 ± 3.13
Phosphate buffer (5.6)–chloroform	83.12 ± 6.49	72.84 ± 7.73	70.36 ± 9.16	76.46 ± 7.93	88.53 ± 4.15	94.39 ± 3.93	56.97 ± 6.49	10.54 ± 2.95
Phosphate buffer (7.4)–chloroform	81.85 ± 8.75	65.79 ± 7.89	68.19 ± 5.34	71.81 ± 11.27	89.81 ± 2.91	95.09 ± 2.99	61.78 ± 3.21	13.46 ± 2.11

Decreasing order of droplet size of different formulations (Mustafa et al., 2012): NE_ROP7 ≥ NE_ROP2 ≥ NE_ROP3 ≥ NE_ROP4 ≥ NE_ROP1 ≥ NE_ROP5 ≥NE_ROP6.

Decreasing order of partition co-efficient of different formulations: NE_ROP6 ≥ NE_ROP5 ≥ NE_ROP1 ≥ NE_ROP4 ≥ NE_ROP3 ≥ NE_ROP2 ≥ NE_ROP7.

Decreasing order of surface charge of different formulations (Mustafa et al., 2012): NE_ROP6 ≥ NE_ROP7 ≥ NE_ROP4 ≥ NE_ROP2 ≥ NE_ROP3 ≥NE_ROP1 ≥ NE_ROP5.

The statistical significant difference for each formulation was calculated by student's t-tests: *p < 0.05, **p < 0.005.

Figure 1. Gamma scintigraphic imaging showing impact of neuronal and non-neuronal pathway in nose to brain targetin after administering ^99mTc-NE_ROP with different strengths of lidocaine as a nerve blocking agents. Here, treatment group (A) represent ^99mTc-NE_ROP with lidocaine (0% v/v), group (B) ^99mTc-NE_ROP with lidocaine (0.1% v/v), group (C) ^99mTc-NE_ROP with lidocaine (0.2% v/v) and group (D) ^99mTc-NE_ROP with lidocaine (0.3% v/v).

Table 3. Comparative systemic to brain counts of intranasally administered ^99mTc-CSNE_ROP containing nerve blocking agents.

Specifications	Brain/systemic ratio (in terms of radioactivity counts)
Lidocain (%v/v)	5 min	10 min	15 min	30 min	45 min	60 min
^99mTc-CSNEROP
0	16.95 ± 1.89 × 10^−2	25.65 ± 6.75 × 10^−2	34.03 ± 15.4 × 10^−2**	19.96 ± 3.27 × 10^−2	7.27 ± 2.04 × 10^−2	3.16 ± 0.67 × 10^−2
0.25	9.51 ± 2.56 × 10^−2*	8.24 ± 1.92 × 10^−2	7.96 ± 2.6 × 10^−2	8.19 ± 6.62 × 10^−2	2.69 ± 1.36 × 10^−2	1.29 ± 0.43 × 10^−2
0.5	6.154 ± 1.99 × 10^−2	4.64 ± 0.96 × 10^−2	5.25 ± 0.97 × 10^−2	5.09 ± 1.48 × 10^−2	2.14 ± 0.53 × 10^−2	1.26 ± 0.31 × 10^−2
1.0	0.74 ± 0.22 × 10^−2	0.94 ± 0.26 × 10^−2	0.91 ± 0.18 × 10^−2	0.107 ± 0.44 × 10^−2	0.039 ± 0.02 × 10^−2	0.021 ± 0.014 × 10^−2

The gamma scintigraphic study for determining the qualitative distribution profile was done using New Zealand white rabbit. Here, ^99mTc-CSNE_ROP represents chitosan-coated ropinirole nanoemulsion radiolabeled with technetium.

The statistical significant difference at each time point was calculated by student's t-tests: *p < 0.05, **p < 0.005.

Table 4. Quantitative estimation of ropinirole in brain and blood after intranasal administration of CSNE_ROP containing lidocain as an olfactory nerve blocker.

		Concentration (ng/g)
Lidocain (%v/v)	Sampling time (h)	0.5 h	1 h	6 h	24 h
0	Blood	202.29 ± 8.33 × 10^−3**	180.78 ± 11.48 × 10^−3	83.89 ± 9.12 × 10^−3	21.83 ± 4.36 × 10^−3
	Brain	18.96 ± 2.53 × 10^−3**	14.74 ± 1.08 × 10^−3	6.58 ± 1.03 × 10^−3	1.56 ± 0.91 × 10^−3
0.25	Blood	155.61 ± 11.24 × 10^−3	134.11 ± 9.77 × 10^−3	68.21 ± 3.49 × 10^−3	18.34 ± 2.95 × 10^−3
	Brain	12.39 ± 1.81 × 10^−3*	10.03 ± 3.01 × 10^−3	4.71 ± 0.85 × 10^−3	0.82 ± 0.06 × 10^−3
0.5	Blood	141.46 ± 7.22 × 10^−3	134.96 ± 6.29 × 10^−3	51.68 ± 3.75 × 10^−3	16.55 ± 1.92 × 10^−3
	Brain	10.56 ± 2.19 × 10^−3	8.13 ± 0.95 × 10^−3	2.3 ± 0.59 × 10^−3	0.38 ± 0.10 × 10^−3
1.0	Blood	109.76 ± 8.79 × 10^−3	82.03 ± 4.21 × 10^−3	38.79 ± 5.26 × 10^−3	11.91 ± 2.14 × 10^−3
	Brain	9.33 ± 2.62 × 10^−3	6.58 ± 2.05 × 10^−3	1.15 ± 0.06 × 10^−3	0.16 ± 0.05 × 10^−3

The radioactivity was measured per gram of organ, while in LC-MS/MS data aere shown in nanogram per gram (ng/g) sample (mean ± SD, n = 3). Any significant difference at each time point was calculated according to the Student’s t-tests: *p < 0.005, **p < 0.001.