Design and Optimization of New Enteric Nanoparticles of Ceftriaxone for Oral Delivery: In vitro and in vivo Assessments

Figures & data

Table 1 2³ Full Factorial Design Levels and Independent Variables

CPP		Units	Minimum	Maximum	Coded Low	Coded High
XA	CH concentration	%w/v	0.1%	0.2%	−1	+1
XB	SH concentration	%w/v	0.1%	0.2%	−1	+1
XC	CTX concentration	%w/v	0.2%	0.4%	−1	+1

Table 2 Formulations and CQAs Values of CTX-Loaded NPs as Claimed by 2³ Full Factorial Design

Formula Code	CPP			CQAs
	XA	XB	XC	*R1	*R2	*R3	*R4	*R5	*R6
F1	–	–	–	694±15.13	0.6±0.02	21.57±1.96	57±2	46.33±3.51	46.1±1.15
F2	+	–	–	258.77±0.57	0.1±0.0	30.1±1.57	83±3	68.77±1.1	64.67±2.08
F3	–	+	–	770.77±37.44	0.6±0.02	9.05±0.71	50.33±2.52	38±2	37±2
F4	+	+	–	522.90±29.07	0.51±0.06	24.57±1.27	74.67±1.27	61.13±0.32	55±2
F5	–	–	+	1465.33±42.7	0.87±0.03	12.93±2.08	43.33±3.51	33.33±3.79	27.33±2.08
F6	+	–	+	750±30	0.27±0.05	22.37±1.18	62.67±2.52	53.33±4.51	30.33±1.53
F7	–	+	+	812.67±40.5	0.71±0.02	8.23±0.85	29±3.61	18.33±3.06	27.67±3.06
F8	+	+	+	712.77±37.69	0.4±0.05	18.6±0.15	53±1.15	49.67±2.52	25±1.15

Notes: *Mean of three determinations ± SD. R1: PS, R2: PDI, R3: ZP, R4: %EE, R5: %DC and R6: %Yield.

Abbreviations: CPP, critical process parameters; CQAs, critical quality attributes; X_A, CH concentration; X_B, SH concentration; X_C, CTX concentration.

Figure 1 Contour plots elucidating the effect of the independent variables (CH concentration (X_A) and SH concentration (X_B)) on PS (A and B) and % EE (C and D) at the minimum and maximum levels of CTX concentration (X_C), respectively.

Figure 2 Three dimensional surface plots elucidating the effect of the independent variables (CH concentration (X_A) and SH concentration (X_B)) on PS (A and B) and % EE (C and D) at the minimum and maximum levels of CTX concentration (X_C), respectively.

Figure 3 TEM image of F2- NPs (see Table 1 for F2 composition).

Figure 4 FT-IR spectra of (A) CTX, (B) CH, (C) SH, (D) physical mixture of CH: SH: CTX (2:1:2) and (E) F2-NPs.

Figure 5 DSC thermograms of (A) CTX, (B) CH, (C) SH, (D) physical mixture of CH: SH: CTX (2:1:2) and (E) F2-NPs.

Table 3 Parameters of F2-NPs Flow Properties (See Table 2 for F2 Composition)

Parameters of F2-NPs Flow Properties
(°)	Vo (cc)	Vf (cc)	BD	TD	HR
32.2 ± 0.98	6.102±0.00	5.4±0.2	0.327±0.00	0.370±0.01	1.13± 0.04

Note: All values are expressed as mean of three determinations ± S. D.

Abbreviations: , angle of repose; V_o, bulk volume; V_f, tapped volume; BD, bulk density; TD, tapped density; HR, Hausner’s ratio.

Table 4 PS, PDI, ZP and % DC of Dry F2-NPs, Stored at Different Storage Condition (See Table 2 for F2 Composition)

Temp/Humidity	Month	PS	PDI	ZP	% DC
Refrigerated conditions 5 ± 3°C	0	258.77±0.57	0.1±0.0	30.1±1.57	68.77 ± 1.1
	1	259.42±1.3	0.1±0.02	31.02±1.1	68.55 ±1.2
	2	258.41±2.1	0.1±0.05	31.1±0.5	68.45 ± 0.9
	3	257.23±3.2	0.1±0.08	31.2±0.4	68.1 ± 0.80
Ambient conditions 25 ± 2°C/40 ± 5% RH	0	258.77±0.57	0.1±0.0	30.1±1.57	68.77 ± 1.1
	1	260.01±1.4	0.15±0.00	29.8±1.2	68. 35±1.13
	2	262.05±1.6	0.16±0.01	29.3±1.1	68.1 ±1.23
	3	263.1±1.2	0.17±0.01	28.9±1.5	67.9 ± 1.01
Accelerated stability study conditions 40 ± 2°C/75 ± 5% RH	0	258.77±0.57	0.1±0.0	30.1±1.57	68.77 ± 1.1
	1	*484.6±5.4	*0.34±0.15	*22.5±1.2	*65.45 ± 1.21
	2	*671.9±3.6	*0.59±0.55	*15.7±2.3	*63.21 ± 0.98
	3	*718.6±6.9	*0.99±0.11	*8.9±2.1	*60.4 ± 1.43

Notes: Each measurement was mean of three determinations ± SD *significant at p < 0.05 monthly vs initial.

Abbreviations: PS, particle size; PDI, poly dispersity index; ZP, zeta potential; DC, drug content.

Figure 6 In vitro release of CTX from pure drug and F2-NPs in: (A) pH of 6.8 and (B) pH of 7.4. Each point represents the mean ± SE (n=3).

Table 5 Kinetic Analysis of the Drug Release Data of F2-NPs (See Table 2 for F2 Composition)

	Coefficient of Determination (R^2)
Kinetic model	Zero order	First order	Higuchi	Korsmeyer–Peppas
pH 6.8	0.9587	0.9915	0.9830	0.9852	*n= 0.6902	Non-Fickian
pH 7.4	0.940	0.9412	0.9852	0.9654	*n =0.5362	Non-Fickian

Note: *Significant at p < 0.05 compared to the results of the previous CTX tablets³.

Table 6 Pharmacokinetic Parameters After Oral Administration of Enteric-Coated Hard Gelatin Capsules Loaded with F2-NPs (See Table 2 for F2 Composition)

Pharmacokinetic Parameters	Enteric-Coated Hard Gelatin Capsules (F2-NPs)
(μg h/mL)	769.6 ±4.24*
AUC 0-∞ (μg h/mL)	868.11 ± 26.76*
F	0.92 ± 0.01*
AUMC 0-∞ (μg h^2/mL)	5872.51 ± 331.56*
MRT (h)	6.76 ± 0.23*
C max (µg/mL)	93.23 ± 5.0*
T max (h)	4*
MAT (h)	3.1 ± 0.17*
Kabs(h ^−1)	0.32 ± 0.01*
T1/2 abs (h)	2.15 ± 0.12*

Notes: Each value represents the mean ± SEM (n = 6). Oral dose (50mg/kg). *Significant at p < 0.05 compared to the results of the previous CTX tablets³.

Figure 7 Mean plasma concentration-time profile in male New Zealand white rabbits after oral administration of the enteric-coated HGCs loaded with F2-NPs equals to 50 mg of CTX. Each point represents the mean ± SE (n=6).

Maghrabia AE, Boughdady MF, Meshali MM. New perspective enteric-coated tablet dosage form for oral administration of ceftriaxone: in vitro and in vivo assessments. AAPS PharmSciTech. 2019;20(306):1–12. doi:10.1208/s12249-019-1512-y

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