Nasal administration of metoclopramide from different dosage forms: in vitro, ex vivo, and in vivo evaluation

Figures & data

Table 1.  Compositions of the formulations.

Code of formulation	Parmaceutical form	MTC [mg-(%w/v)]	NaCMC [mg-(% w/v)]	BZC Sol 5 mg/100 ml (μl)	0.9% NaCI solution (ml)	Distilled water (ml)	HPβCD (mg )
S1	Solution	1600 (2.67)	120 (0.05)	240	60*	—	—
S2	Solution	1600 (2.67)	240 (0.1)	240	60*	—	—
S3	Solution	1600 (2.67)	360 (0.15)	240	60*	—	—
G1	Gel	1250 (1.25)	1200 (0.5)	400	—	100*	—
G2	Gel	1250 (1.25)	1600 (1)	400	—	100*	—
G3	Gel	1250 (1.25)	2000 (1.5)	400	—	100*	—
P1	Powder	20	20	—	—	2	—
P2	Powder	40	20	—	—	2	—
P3	Powder	20	40	—	—	2	—
EP2	Powder	40	20	—	—	2	3.16

BZC: Benzalconium chloride; q.s.: Quantum sufficit; *: q.s. to make % w/v. The weight/weight ratio of HPβCD used in powder formulation is 5%. The final concentration of BZC in the solution and gel formulations is 0.02%.

Table 2.  Polymer content, viscosity, and drug release parameters (by using cellulose membrane at the end of a 4-h period) of the formulations.

Code of formulation	Polymer content* (mg)	Viscosity** (cps)	Spindle number	Amount of MTC released (%)	Jss (μg/cm^2h)	Kp (cm/h)
S1	0.15	6.52 ± 0.54	2	34.76 ± 1.81	162.02 ± 3.84	81.01 ± 1.92
S2	0.30	13.51 ± 0.32	2	32.38 ± 2.59	139.64 ± 4.51	69.82 ± 2.26
S3	0.45	26.54 ± 1.21	2	29.55 ± 1.64	127.33 ± 5.53	63.67 ± 2.77
G1	1.92	1760 ± 59	3	22.75 ± 0.72	110.11 ± 3.29	55.06 ± 1.15
G2	2.56	5100 ± 77	4	19.23 ± 0.96	97.96 ± 6.33	48.98 ± 3.16
G3	3.20	6950 ± 62	4	16.82 ± 0.07	90.57 ± 1.54	45.26 ± 0.77
P1	2			22.45 ± 0.57	102.46 ± 1.22	51.23 ± 0.61
P2	1			26.02 ± 0.59	115.21 ± 3.65	57.61 ± 1.83
P3	4			12.25 ± 1.12	66.78 ± 1.78	33.39 ± 0.89
EP2	1			26.90 ± 1.93	119.88 ± 2.21	59.94 ± 1.11

* Polymer content of the formulation to apply 2 mg of MTC to the donor compartment of modified horizontal diffusion chamber (calculated according to Table 1). ** Measurements were done at 23 ± 1°C with the spindle speed of 10 rpm. Note: Each reading is an average of five determinations ± SD.

Table 3.  The kinetic parameters of the release of MTC from the formulations by using cellulose membrane.

Code of formulation	Zero order		First order		Higuchi		Hixon Crowell
	K0	r	K1	r	K2	r	K3	r
S1	0.175	0.995	0.107	0.999	0.0015	0.981	0.027	0.998
S2	0.162	0.991	0.098	0.998	0.0013	0.987	0.025	0.996
S3	0.146	0.994	0.086	0.999	0.0011	0.983	0.022	0.997
G1	0.119	0.994	0.067	0.998	0.0006	0.979	0.017	0.997
G2	0.099	0.997	0.055	0.996	0.0004	0.949	0.001	0.997
G3	0.089	0.995	0.048	0.994	0.0003	0.937	0.001	0.994
P1	0.112	0.994	0.063	0.998	0.0006	0.985	0.017	0.997
P2	0.129	0.992	0.075	0.997	0.0009	0.988	0.019	0.996
P3	0.064	0.998	0.038	0.997	0.0002	0.951	0.008	0.998
EP2	0.134	0.991	0.078	0.995	0.0009	0.985	0.021	0.994

K₀: Zero order rate constant (mg/h); K₁: First order rate constant (h⁻¹); K₂: Higuchi square root rate constant; K₃: Hixson-Crowell rate constant (mg/h cm²).

Figure 1.  Comparison of ex vivo drug release from different dosage forms (S3 solution, G2 gel, P2 and EP2 powder) prepared with NaCMC by using nasal mucosa (S3-G2, S3-P2, G2-P2, P2-EP2: p < 0.05).

Table 4.  Drug release parameters of the formulations in ex vivo experiments by using nasal mucosa and the mean scoring^a values from the light microscopy study subsequent to the transport study of formulations.

Code of formulation	Amount of MTC released %	Jss (μg/cm^2h)	Kp (cm/h)	Scoring 0–5^a
S3	5.82 ± 0.28	32.28 ± 0.83	16.14 ± 0.42	3
G2	3.09 ± 0.12	21.47 ± 0.77	10.74 ± 0.39	1
P2	5.25 ± 0.19	29.54 ± 0.66	14.77 ± 0.33	4
EP2	6.01 ± 0.19	33.29 ± 0.78	16.65 ± 0.39	4

Each reading is average of three determinations ± SD. ^a Where 0 = no damage, equal to control, 1 = less than 25% epithelial cells lost, 2 = less than 50% epithelial cells lost, 3 = less than 75% epithelial cells lost, 4 = only basal cells left, 5 = all epithelial and basal cells lost.

Figure 2.  Comparison of in vitro and ex vivo release of MTC from different dosage forms (S3 solution, G2 gel, P2 and EP2 powder) by using cellulose membrane and nasal mucosa at the end of 4 h period.

Figure 3.  Images from the histological evaluation of nasal mucosa; control (a), solution (b; S3), gel (c; G2), powder (d; P2) and powder + HPβCD (e; EP2).

Figure 4.  Mean sera concentration-time profiles in sheep after oral, IV, and intranasal administations of different formulations at a dose of 0.4 mg/kg applied to five sheep (G2-S3, P2, EP2: p < 0.05; P2-EP2: p < 0.05).

Table 5.  Pharmacokinetic parameters after intravenous, oral and nasal administration of MTC in sheep (n = 5).

Code of formulation	tmax (h)	Cmax (ng/ml)	AUC0–4 (ng.h/ml)	ka(h)	ke(h)	F (%)
S3	0.55 ± 0.06	14.95 ± 3.02	33.38 ± 6.31	5.75 ± 0.59	0.29 ± 0.02	16.71 ± 3.72
G2	1.05 ± 0.08	46.20 ± 9.97	84.08 ± 13.68	4.06 ± 0.74	0.34 ± 0.05	42.08 ± 5.53
P2	0.66 ± 0.15	23.55 ± 4.92	49.09 ± 5.41	3.32 ± 0.41	0.52 ± 0.08	24.57 ± 3.86
EP2	0.94 ± 0.07	27.52 ± 4.01	60.43 ± 5.29	1.97 ± 0.32	0.54 ± 0.09	30.24 ± 3.61
ORAL	1.15 ± 0.16	59.29 ± 11.58	113.19 ± 17.64	1.37 ± 0.44	0.51 ± 0.06	56.65 ± 6.01
V	5 ± 00	114.54 ± 9.78	199.81 ± 20.02	—	0.29 ± 0.03	100

Each value represents the mean ± SD (n = 5). k_a = Absorption constant; k_e = Elimination constant.