A 5-fluorouracil-loaded floating gastroretentive hollow microsphere: development, pharmacokinetic in rabbits, and biodistribution in tumor-bearing mice

Figures & data

Figure 1 Absorption spectra of 5-fluorouracil (5-FU) in enzyme-free simulated gastric fluid (SGF) and enzyme-free simulated intestinal fluid (SIF).

Notes: (a) SGF; (b) SIF; (c) SGF spiked with excipients used for 5-FU hollow microspheres; (d) SIF spiked with excipients used for 5-FU hollow microspheres; (e) SGF spiked with 5-FU; and (f) SIF spiked with 5-FU.

Figure 2 Representative HPLC chromatograms of 5-fluorouracil (5-FU) in rabbit plasma: (A) blank plasma; (B) blank plasma spiked with 5-FU; and (C) plasma sample after oral administration of 5-FU hollow microspheres.

Abbreviation: HPLC, high-performance liquid chromatography.

Figure 3 Representative HPLC chromatograms of 5-fluorouracil (5-FU) in tumor-bearing mice biosamples: (A) blank tumor; (B) blank tumor spiked with 5-FU; and (C) tumor sample after oral administration of 5-FU hollow microspheres.

Abbreviation: HPLC, high-performance liquid chromatography.

Table 1 The effect of Span 80 concentration in the liquid paraffin on particle size, drug loading amount, and production yield of 5-fluorouracil hollow microspheresa

Span 80 concentration (%)	Particle size distribution			Drug loading (%)	Production yield (%)
	<450 µm (%)	450–600 µm (%)	>600 µm (%)
0.5	9.1±0.4	25.6±2.5	63.3±3.6	18.4±1.1	38.9±1.0
1.0	14.2±0.7	27.2±2.4	58.6±2.9	23.5±1.2	48.4±1.3
1.5	19.5±0.5	70.6±4.7	9.9±1.0	27.6±1.4	67.5±1.6
2.0	58.1±3.8	33.6±2.2	8.3±0.6	21.3±1.1	60.2±1.9

Note:

a Mean ± standard deviation.

Table 2 The effect of ether/ethanol volume ratio on particle size, drug loading amount, and production yield of 5-fluorouracil hollow microspheresa

Ether/ethanol (v/v)	Particle size distribution			Drug loading (%)	Production yield (%)
	<450 µm (%)	450–600 µm (%)	>600 µm (%)
0:10.0	–	–	–	–	0
0.5:10.0	19.5±2.1	60.1±2.5	20.4±2.1	21.4±1.3	58.4±1.5
1.0:10.0	18.1±1.6	62.9±4.2	19.0±1.7	26.7±1.5	71.1±2.3
1.5:10.0	20.0±2.4	61.2±3.7	18.8±1.9	20.9±1.2	32.2±1.2

Note:

a Mean ± standard deviation.

Abbreviation: v, volume.

Table 3 The effect of PVP/EC weight ratio on particle size, drug loading amount, and production yield of 5-fluorouracil hollow microspheresa

PVP/EC (w/w)	Particle size distribution			Drug loading amount (%)	Production yield (%)
	<450 µm (%)	450–600 µm (%)	>600 µm (%)
0.0:10.0	18.1±1.6	62.9±4.2	19.0±1.7	26.7±1.5	71.1±2.3
0.2:10.0	17.5±2.1	61.3±2.5	21.2±1.3	27.1±1.2	70.3±2.6
0.5:10.0	15.1±1.6	61.7±4.2	23.2±1.8	27.3±1.9	69.8±2.7
1.0:10.0	13.2±1.1	59.2±5.3	27.6±0.8	28.1±1.8	72.2±2.3
2.0:10.0	10.1±1.1	56.2±5.7	33.7±0.8	29.8±1.5	60.5±3.4

Note:

a Mean ± standard deviation.

Abbreviations: EC, ethyl cellulose; PVP, polyvinyl pyrrolidone; w, weight.

Figure 4 Effect of PVP/EC weight ratio on floating behavior of 5-fluorouracil hollow microspheres in simulated gastric fluid (A) and simulated intestinal fluid (B).

Note: Mean ± standard deviation.
Abbreviations: EC, ethyl cellulose; PVP, polyvinyl pyrrolidone.

Figure 5 Effect of PVP/EC weight ratio on in vitro release behavior of 5-fluorouracil hollow microspheres in simulated gastric fluid (A) and simulated intestinal fluid (B).

Note: Mean ± standard deviation.
Abbreviations: EC, ethyl cellulose; PVP, polyvinyl pyrrolidone.

Table 4 The particle size, drug loading amount, and production yield and floating efficiency of 5-fluorouracil hollow microspheresa

Batch no	Particle size distribution			Drug loading (%)	Production yield (%)	Floating efficiency (%)
	<450 µm (%)	450–600 µm (%)	>600 µm (%)
20120401	12.8±1.1	58.1±4.6	28.3±1.1	28.8±1.2	74.9±2.5	96.6±2.9
20120402	13.1±1.3	61.9±4.7	25.0±1.1	27.9±1.2	73.8±2.5	97.2±2.5
20120403	12.9±1.1	63.6±4.6	23.5±1.2	28.6±1.2	74.0±2.5	95.7±2.0

Note:

a Mean ± standard deviation.

Figure 6 Scanning electron microscopy photographs of 5-fluorouracil hollow microspheres (batch: 20120401).

Figure 7 Percentage cumulative release of three batches of 5-fluorouracil hollow microspheres in simulated gastric fluid (A) and simulated intestinal fluid (B).

Note: Mean ± standard deviation.

Table 5 Pharmacokinetic parameters of 5-FU after oral administration of 5-FU hollow microspheres and its solid microspheres and powder to rabbits at a dose of 50 mg/kg body weighta

	AUC(0–t) (mg/L* hours)	MRT(0–t) (hours)	Cmax (mg/L)	Tmax (hours)	t1/2 (hours)
5-FU hollow microspheres	12.53±1.65*	7.65±0.97*	1.64±0.21*	2.00±0.22*	15.43±2.12*
5-FU solid microspheres	7.80±0.83	3.61±0.41	2.25±0.26	1.00±0.15	2.25±0.22
5-FU powder	5.82±0.83	2.34±0.35	2.55±0.19	0.75±0.11	1.43±0.18

Notes:

a Mean ± standard deviation.

* P<0.01 vs 5-FU solid microspheres and powder as the controls.

Abbreviations: C_max, maximum plasma drug concentration; 5-FU, 5-fluorouracil; MRT, mean residence time; T_max, time to reach the maximum plasma drug concentration; t_1/2, elimination half-life; AUC, area under curve.

Figure 8 Plasma drug concentration–time curve after oral administration of 5-fluorouracil (5-FU) hollow microspheres and its solid microspheres and powder to rabbits at a dose of 50 mg/kg body weight.

Note: Each point represents the mean ± standard deviation.

Figure 9 Drug distribution in plasma, tumor, and main tissues including heart, liver, spleen, lung, kidney, and stomach in tumor-bearing mice after oral administration of 5-fluorouracil (5-FU) hollow microspheres as a test formulation and its solid microspheres and powder as controls in the sodium carboxymethyl cellulose suspension form at a dose of 72 mg/kg body weight.

Notes: These values are arithmetic mean ± standard deviation. Plasma, ng/mL; tumor and main tissues, ng/g.
Abbreviation: h, hours.