Trans-nasal zolmitriptan novasomes: in-vitro preparation, optimization and in-vivo evaluation of brain targeting efficiency

Figures & data

Table 1. Design parameters and constraints for full factorial design (2³).

Independent variables	Level of variables
X1: Type of SAA	Span® 60 (S 60) Span® 80 (S 80)
X2: Type of FFA	Oleic Acid Stearic Acid
X3: Ratio of FFA: SAA	1:1 2:1
Responses	Constraints
Y1: E.E (%)	Maximize
Y2: Particle size (nm)	Minimize
Y3: PDI	Minimize
Y4: ZP (mV)	Maximize
Y5: ZT release after 2 h (%)	Maximize

Table 2. Experimental runs independent variables (formulation variables) of the 2³ full factorial experimental design.

	Factors (Independent variables)			Dependent variables
Run	X1: Type of SAA	X2: Type of FFA	X3:Ratio of FFA:SAA	Y1:E.E (%)	Y2: Particle size (nm)	Y3:PDI	Y4:ZP (mV)	Y5: ZT release after 2h (%)
R1	S 60	Oleic acid	1:1	98.31 ± 1.75	656.56 ± 79.32	0.468 ± 0.14	−63.77 ± 1.12	46.29 ± 0.92
R2	S 60	Oleic acid	2:1	48.05 ± 5.50	368.60 ± 77.98	0.540 ± 0.11	−68.10 ± 10.18	38.05 ± 1.24
R3	S 60	Stearic acid	1:1	99.30 ± 0.65	494.96 ± 89.10	0.895 ± 0.09	−64.63 ± 5.39	45.08 ± 3.37
R4	S 60	Stearic acid	2:1	88.83 ± 1.16	482.36 ± 35.11	0.930 ± 0.09	−50.97 ± 1.97	55.71 ± 2.37
R5	S 80	Oleic acid	1:1	71.12 ± 3.09	201.03 ± 8.98	0.315 ± 0.04	−51.57 ± 2.20	38.88 ± 1.32
R6	S 80	Oleic acid	2:1	33.41 ± 1.75	242.00 ± 53.89	0.396 ± 0.04	−54.27 ± 1.97	29.81 ± 0.48
R7	S 80	Stearic acid	1:1	92.94 ± 1.04	149.90 ± 10.92	0.477 ± 0.10	−55.57 ± 1.04	48.43 ± 1.64
R8	S 80	Stearic acid	2:1	87.01 ± 1.66	199.90 ± 98.89	0.563 ± 0.00	−54.63 ± 2.65	55.75 ± 2.06

N.B.: Drug concentration was kept constant 2 mg/ml in all formulations.

Data are mean values (n = 3) ± S.D.

Figure 1. Line charts showing the effects of (a) type of SAA (X₁) and the FAA (X₂) on the E.E (%) of ZT-loaded novasomes, (b) type of SAA (X₁) and the FAA (X₃) on the E.E (%) of ZT-loaded novasomes, (c) type of SAA (X₁) on the particle size of ZT-loaded novasomes, (d) type of SAA (X₁) and the ratio of FAA: SAA (X₃) on the particle size of ZT-loaded novasomes, (e) type of SAA (X₁) and the type of FAA(X₂) on the PDI of ZT-loaded novasomes.

Figure 2. Line charts showing the effects of (a) type of SAA (X₁) and the FAA (X₂) on the ZP of ZT-loaded novasomes, (b) type of SAA (X₃) on the ZP of ZT-loaded novasomes.

Figure 3. Release profiles of ZT from different ZT-loaded novasomes and ZT solution.

Figure 4. Line charts showing the effects of (a) type of SAA (X₁) and the FAA (X₂) on the ZT (%) released after 2h from ZT-loaded novasomes, (b) type of FAA (X₂) and the ratio of FAA: SAA (X₃) on the ZT (%) released after 2h from ZT-loaded novasomes.

Figure 5. TEM image of optimized R7 dispersion.

Figure 6. DSC thermographs of (a) stearic acid, (b) ZT, (c) cholestrol, (d) Span® 80 and (e) lyophilized (R7).

Figure 7. XRD spectra of the samples.

Figure 8. ZT concentration in (a) brain, (b) blood of Wister albino male mice at different time of intervals following of IV ^99mTc-ZT solution in IN ^99mTc-R7 novasomes, mean ± SD n = 3.

Table 3. Compartmental distribution of ^99mTc-ZT (I.V) and ^99mTc-R7 (I.N) at different time intervals in Swiss albino mice (mean n = 3 ± S.D.).

		Distribution of ZT in blood and brain compartments (%/g) at different time intervals (h)
Formulation and route of administration	Organ/tissue	0.25	0.5	1	2	4	6	24
^99mTc-ZT/I.V. administration	Blood	10.18 ± 1.33	8.34 ± 1.16	2.21 ± 034	2.09 ± 0.20	1.83 ± 0.20	1.47 ± 0.19	0.61 ± 0.37
	Brain	0.28 ± 0.04	0.29 ± 0.03	0.07 ± 0.03	0.05 ± 0.01	0.03 ± 0.00	0.03 ± 0.02	0 ± 0.00
	Brain/blood	0.02 ± 0.00	0.03 ± 0.00	0.03 ± 0.00	0.02 ± 0.00	0.01 ± 0.00	0.01 ± 0.01	0.02 ± 0.02
^99mTc-R7/I.N. administration	Blood	0.23 ± 0.09	0.22 ± 0.03	0.18 ± 0.02	0.17 ± 0.07	0.17 ± 0.05	0.15 ± 0.05	0.14 ± 0.04
	Brain	1.26 ± 0.58	1.14 ± 0.17	0.73 ± 0.12	0.59 ± 0.07	0.54 ± 0.15	0.51 ± 0.13	0.35 ± 0.07
	Brain/blood	5.39 ± 0.83	5.14 ± 1.31	3.93 ± 0.33	3.87 ± 1.98	3.26 ± 0.30	3.41 ± 0.90	2.36 ± 0.57

N.B. The mice were administered with 100 mCi ^99mTc-zolmitriptan formulations and the radioactivity was measured in percent per g of tissue of the administrated dose. Each value is the mean of three estimations.

Table 4. Pharmacokinetic parameters for ZT in mice blood and brain after I.V administration ^99mTc-ZT and I.N administration of the ^99mTc-R7.

	I.N.		I.V.
Pharmacokinetic parameters	Brain	Blood	Brain	Blood
AUC(0–24) observed (h. %/g)	11.26	3.72	0.78	34.39
AUC(0–∞) (h. %/g)	23.29	16.31	0.89	45.58
t1/2 (h)	26.05	62.31	9.46	12.61
MRT(0–∞) (observed) (h)	36.38	90.45	9.35	15.75
Cmax (%/g)	1.27	0.23	0.29	10.18
Tmax (h)	0.50	0.25