Development and in vivo evaluation of a new oral nanoparticulate dosage form for leuprolide based on polyacrylic acid

Figures & data

Table 1.  Composition of leuprolide dosage forms for in vivo studies containing 1 mg of leuprolide.

	PAA control tablet	PAA NP tablet	oral solution	i.v. injection	s.c. injection
PAA	13.3 mg	-	-	-	-
Leuprolide	1 mg	-	1 mg	1 mg	1 mg
NP	-	14.3 mg
Eudragit	+	+	-	-	-
Water	-	-

Table 2.  Characterization of leuprolide loaded nanoparticles.

	particle size ditribution [nm]	zeta potential [mV]
PAA/Pluronic NP	316.2 ± 133.4	-6.38

Figure 1.  Inter polymer complexation due to formation of hydrogen bonds between polyacrylic acid (A) and co-block-polymer Pluronic (B).

Figure 2.  Absorbance monitoring during particle formation between PAA/Pluronic F68 (line) and PAA/PVP (dotted line). Abbreviations: OD (optical density).

Figure 3.  Release of leuprolide from nanoparticle suspension: Release of unbound and encapsulated leuprolide (▪) and release of encapsulated leuprolide only (▴). Indicated values represent means (± S.D.) of at least three experiments.

Figure 4.  Release of leuprolide from nanoparticle tablets. Indicated values represent means (± S.D.) of at least three experiments.

Table 3.  Pharmacokinetic parameters of leuprolide dosage forms (* differs significantly from PAA control tablets with p<0.05). Abbreviations: F=absolute bioavailability, f=improvement ratio.

		AUC [ug*h/ml]	t1/2 [h]	cmax [ug/ml]	tmax [min]	F [%]	f
iv	solution	4.488	0.18	17.129	-	100	-
sc	solution	1.481	1.19	0.8659	60	33	-
oral	solution	0.011	0.91	0.0088	60	0.26	1
	PAA	0.006	2.85	0.0014	120	0.13	0.5
	PAA NP	0.025	2.80	0.0061*	120	0.55	2.2

Figure 5.  Plasma leuprolide levels [ng/ml] after administration of 1 mg of leuprolide to rats: PAA tablets (□), PAA NP tablets (▪), solution (Δ). Indicated values represent means of at least three experiments. Indicated values represent means (± S.D.) of at least three experiments. 1 differs from 2 and 3 p = 0.0001.

Figure 6.  Plasma leuprolide levels [μg/ml] after intravenous (▪) and subcutaneous (□) administration of 1 mg of leuprolide to rats. Indicated values represent means (± S.D.) of at least three experiments. 1 differs from 2 p = 0.0001.

Figure 7.  Chemical structure of leuprolide.