Paliperidone microemulsion for nose-to-brain targeted drug delivery system: pharmacodynamic and pharmacokinetic evaluation

Figures & data

Table 1. Composition of PALI-ME and PALI-MME.

Ingredients	PALI-ME^a (% w/w)	PALI-MME^a (% w/w)
Oleic acid	4.00	4.00
[Caprylocaproyl polyoxylglycerides: polyoxyl 40 hydrogenated castor oil (1:1)]:[diethylene glycol monoethyl ether] (3:1)	30.00	30.00
Water	66.00	66.00

^aThe formulations contain PALI 5 mg/mL; PALI-MME additionally contains 0.5% w/w of polycarbophil as mucoadhesive agent.

Table 2. Characterization parameters of optimized PALI-ME and PALI-MME (n = 3).

Formulation	% Assay	pH	Globule size (nm) ± SEM	PDI ± SEM	Zeta potential (mV) ± SEM	Viscosity (cp)
PALI-SOL	99.56 ± 1.85	5.91 ± 0.04	–	–	–	–
PALI-ME	99.89 ± 2.66	5.98 ± 0.05	20.01 ± 1.28	0.117 ± 0.034	−36.59 ± 2.03	77 ± 3.64
PALI-MME	99.12 ± 2.28	5.85 ± 0.18	27.31 ± 1.86	0.241 ± 0.049	−38.65 ± 2.39	96 ± 5.11

Table 3. Pharmacodynamic study (apomorphine-induced compulsive behavior) of PALI formulation in normal mice (n = 6).

Formulation and routeof administration	Dose (mg/kg of BW)	Average score forstereotype behavior^a
Distilled water (control)	–	2.57 ± 0.26
PALI-MEi.v.	2	1.42 ± 0.34
PALI-SOLi.n.^b	2	1.07 ± 0.18
PALI-MEi.n.^b	2	0.89 ± 0.11
PALI-MMEi.n.^b	2	0.45 ± 0.09
Haloperidole (positive control)	1	0.00 ± 0.00

^aValues are expressed as mean ± SEM of six estimations.

^bThe mice were administered with 5 µL of PALI formulation per nostril.

Table 4. Pharmacodynamic study (spontaneous motor activity) of PALI formulation in normal mice (n = 6).

Formulation and route of administration	Locomotor counts^a
Control	911 ± 45
PALI-MEi.v.	592 ± 61.8
PALI-SOLi.n.^b	518 ± 21.5
PALI-MEi.n.^b	438 ± 27
PALI-MMEi.n.^b	375 ± 19.2

^aValues are expressed as mean ± SEM of six estimations.

^bThe mice were administered with 5 µL of PALI formulation per nostril.

Figure 1. (A) PALI concentration in rat blood at different time intervals in the following: ^99mTc-PALI-ME (IV), ^99mTc-PALI-ME (IN), ^99mTc-PALI-MME (IN) and ^99mTc-PALI-SOL (IN) administrations. (B) PALI concentration in rat brain at different time intervals in the following: ^99mTc-PALI-ME (IV), ^99mTc-APLI-ME (IN), ^99mTc-PALI-MME (IN) and ^99mTc-PALI-SOL (IN) administrations.

Table 5. Compartmental distribution of ^99mTc-PALI-ME (IV), ^99mTc-PALI-ME (IN), ^99mTc-PALI-MME (IN), and ^99mTc-PALI-SOL (IN) at different time intervals in normal wistar rats^a.

	Distribution of PALI in blood and brain compartments at different sampling time points
Formulation and route of administration	Organ/tissue	30 min	60 min	120 min	240 min	480 min
PALI-SOLi.n.	Blood	0.49 ± 0.04	0.38 ± 0.03	0.23 ± 0.05	0.16 ± 0.03	0.05 ± 0.02
	Brain	0.25 ± 0.04	0.14 ± 0.03	0.10 ± 0.06	0.06 ± 0.03	0.04 ± 0.03
PALI-MEi.n.	Blood	0.69 ± 0.08	0.55 ± 0.03	0.35 ± 0.04	0.22 ± 0.04	0.09 ± 0.03
	Brain	0.52 ± 0.07	0.45 ± 0.06	0.24 ± 0.03	0.11 ± 0.02	0.05 ± 0.04
PALI-MMEi.n.	Blood	0.78 ± 0.07	0.65 ± 0.02	0.54 ± 0.04	0.34 ± 0.05	0.15 ± 0.06
	Brain	0.64 ± 0.04	0.55 ± 0.04	0.41 ± 0.07	0.24 ± 0.05	0.13 ± 0.03
PALI-MEi.v.	Blood	1.40 ± 0.05	0.99 ± 0.03	0.88 ± 0.04	0.55 ± 0.11	0.17 ± 0.02
	Brain	0.38 ± 0.01	0.41 ± 0.06	0.22 ± 0.05	0.09 ± 0.03	0.03 ± 0.01
PALI-SOLi.n.	Brain/blood	0.51 ± 0.99	0.37 ± 0.87	0.43 ± 1.05	0.40 ± 1.15	0.79 ± 1.65
PALI-MEi.n.	Brain/blood	0.75 ± 0.83	0.82 ± 1.71	0.70 ± 0.72	0.49 ± 0.43	0.54 ± 1.61
PALI-MMEi.n.	Brain/blood	0.82 ± 0.52	0.84 ± 2.62	0.75 ± 1.63	0.71 ± 1.00	0.86 ± 0.42
PALI-MEi.v.	Brain/blood	0.27 ± 0.22	0.41 ± 2.00	0.25 ± 1.11	0.16 ± 0.33	0.17 ± 0.65

^aThe rats were administered with 100 µCi ^99mTc-PALI and the radioactivity was measured in percent per gram of tissue of the administered dose. Each value is the mean ± SEM of four estimations. Radioactivity was measured at 0 min and all the measurements were performed using 0 min sample of corresponding tissue/organ as blank sample.

Table 6. Pharmacokinetics of ^99mTc-PALI-ME (IV), ^99mTc-PALI-ME (IN), ^99mTc-PALI-MME (IN) and ^99mTc-PALI-SOL (IN) at different time intervals in normal wistar rats^a.

Formulation and route of administration	Organ/tissue	Cmax (%/g)	Tmax (h)	AUC0 → t (h %/g)	AUCt → ∞ (h %/g)	Kel (L/h)	T1/2 (h)
PALI-SOLi.n.	Blood	0.49 ± 0.11	0.5 ± 0.19	1.4 ± 0.43	1.56 ± 0.63	0.27 ± 0.09	2.5 ± 1.20
	Brain	0.25 ± 0.08	0.5 ± 0.12	0.63 ± 0.25	0.88 ± 0.32	0.17 ± 0.04	4.03 ± 1.31
PALI-MMEi.n.	Blood	0.78 ± 0.21	0.5 ± 0.35	2.94 ± 1.03	3.84 ± 0.49	0.21 ± 0.07	3.28 ± 0.89
	Brain	0.64 ± 0.16	0.5 ± 0.21	2.29 ± 0.87	2.89 ± 0.81	0.21 ± 0.03	3.27 ± 1.03
PALI-MEi.n.	Blood	0.69 ± 0.13	0.5 ± 0.27	2.1 ± 0.56	2.46 ± 0.72	0.23 ± 0.08	3.07 ± 0.92
	Brain	0.52 ± 0.08	0.5 ± 0.18	1.34 ± 0.49	1.51 ± 0.66	0.31 ± 0.05	2.2 ± 0.77
PALI-MEi.v.	Blood	1.4 ± 0.34	0.5 ± 0.16	4.57 ± 1.32	5.18 ± 1.29	0.27 ± 0.04	2.5 ± 0.64
	Brain	0.41 ± 0.12	1.0 ± 0.47	1.11 ± 0.76	1.19 ± 0.62	0.32 ± 0.07	2.14 ± 0.48

^aThe rats were administered with 100 µCi ^99mTc-PALI and the radioactivity was measured in percent per gram of tissue of the administered dose. Each value is the mean ± SEM of four estimations.

Table 7. Brain targeting efficiency and direct nose-to-brain transport following intranasal administration of ^99mTc-PALI-ME, ^99mTc-PALI-MME and ^99mTc-PALI-SOL.^a.

Formulation and route of administration	Brain targeting efficiency (DTE, %)	Direct nose-to-brain transport (DTP, %)
PALI-MMEi.n.	320.69 ± 9.5	68.82 ± 6.0
PALI-MEi.n.	262.71 ± 5.0	61.93 ± 5.5
PALI-SOLi.n.	185.27 ± 4.5	46.02 ± 3.0

^aParameters derived using values of four different estimation estimations and each value is mean ± SEM.

Figure 2. Gamma scintigraphy of anteroposterior (AP) views of rabbit following intravenous administration of ^99mTc-PALI-ME (A), intranasal administration of ^99mTc-PALI-SOL (B), ^99mTc-PALI-ME (C) and ^99mTc-PALI-MME (D). Rabbits were administered 100 µCi radioactivity by intravenous and intranasal administration.