Preparation and evaluation of dual-mode floating gastroretentive tablets containing itraconazole

Figures & data

Figure 1. A conceptional image of dual-mode floating GRT (DF-GRT).

Table 1. Compositions of tablets containing ITR-SD (unit: mg/tablet).

	IRT	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11
ITR-SD	300	300	300	300	300	300	300	300	300	300	300	300
Starch	235	150	150	150	150	150	150	264	264	264	264	150
HPMC 4,000 cP	–	150	150	150	–	–	–	–	–	–	30	–
HPMC 15,000 cP	–	–	–	–	150	–	–	–	–	–	–	–
HPMC 100,000 cP	–				–	150		–	–	–	–	150
HEC	–	–	–	–	–	–	150	–	–	–	–	–
HPMC 50 cP	–	–	–	–	–	–	–	30	30	30	–	–
CCS	60	–	–	–	–	–	–	–	7	15	15	–
NaHCO3	–	–	60	120	120	120	120	–	–	–	–	120
Citric acid	–	–	30	60	60	60	60	–	–	–	–	60
Camphor^b	–	–	–	–	–	–	–	100 (14.3)	100 (14.2)	100 (14.0)	100 (14.0)	100 (11.3)
Magnesium stearate	5	5	5	5	5	5	5	5	5	5	5	5
Total	600	605	695	785	785	785	785	599^a	606^a	614^a	614^a	785^a
Floating mechanism^c	–	–	GG	GG	GG	GG	GG	LD	LD	LD	LD	DM

ITR: itraconazole, SD: solid dispersion, HPMC: hydroxypropylmethyl cellulose, HEC: hydroxyethyl cellulose, CCS: croscarmellose sodium.

^aTotal weight after sublimation.

^bRepresented as amount (% weight fraction).

^cGG: gas generation by NaHCO₃ and citric acid, LD: low density by camphor sublimation, DM: dual mode (combined effect of gas generation and low density).

Table 2. Formulations to evaluate effect of camphor amount on hardness and density of LD-GRT (unit: mg/tablet).

	L1	L2	L3	L4	L5	L6
ITR-SD	300	300	300	300	300	300
Starch	247	247	247	247	247	247
Camphor^a	50 (8.3)	60 (9.8)	70 (11.3)	80 (12.7)	100 (15.4)	200 (26.7)
Mg. stearate	3	3	3	3	3	3

^aRepresented as amount (% weight fraction).

Figure 2. DSC thermograms of (A) ITR-SD, (B) physical mixture, (C) HPMC, (D) raw ITR substance and (E) citric acid.

Figure 3. XRD patterns of (A) ITR-SD, (B) physical mixture, (C) HPMC, (D) raw ITR substance and (E) citric acid.

Figure 4. Release profiles of IRT and GG-GRT with various amount of gas-generators (n = 3, Mean ± SD) Key •: F1 (without gas generators), ○: F2 (60 mg of NaHCO₃ and 30 mg of citric acid), ▾: F3 (120 mg of NaHCO₃ and 60 mg of citric acid), △: IRT.

Table 3. Physical properties and release rate of tablets containing ITR-SD.

					Release rate constant^c
	Tablet hardness (N)	Density (g/cm^3)	Buoyancy^a	Lag time^b	r^2	k
F1	151.7 ± 6.5	1.095 ± 0.012	NF	NF	0.8937	1.0957
F2	144.3 ± 5.5	1.105 ± 0.005	O	O	0.9380	7.9204
F3	148.7 ± 3.1	1.106 ± 0.006	O	O	0.9511	8.5779
F4	153.3 ± 4.2	1.108 ± 0.006	O	O	0.9500	8.4973
F5	148.3 ± 6.4	1.113 ± 0.005	O	O	0.9540	8.4494
F6	144.7 ± 2.5	1.112 ± 0.007	X	O	0.9717	10.9050
F7	97.7 ± 5.9	0.908 ± 0.011	O	X	0.8937	1.0957
F8	99.7 ± 3.2	0.913 ± 0.007	O	X	0.9143	1.6507
F9	100.7 ± 4.7	0.921 ± 0.009	X	X	0.9567	6.5603
F10	103.3 ± 6.5	0.928 ± 0.011	O	X	0.9371	3.0984
F11	108.3 ± 7.4	0.937 ± 0.012	O	X	0.9497	8.8277

^aO: floated throughout a in vitro release test, X: floated but sank before end of a in vitro release test, NF: not floated.

^bO: required lag time (3–5 min) to float, X: floated on the medium without any lag time, NF: not floated.

^cAnalyzed using Higuchi model.

Figure 5. Release profiles of GG-GRT with various cellulose-derived polymers (n = 3, Mean ± SD) Key •: F3 (HPMC 4,000 cP), ○: F4 (HPMC 15,000 cP), ▾: F5 (HPMC 100,000 cP), △: F6 (HEC).

Figure 6. Effect of amount of camphor on density (A) and hardness (B) of LD-GRT (n = 3, Mean ± SD).

Figure 7. Release profiles of LD-GRT (F8-F10) and DF-GRT with both gas-generators and camphor (F11) (n = 3, Mean ± SD) Key •: F7 (30 mg of HPMC 50 cP without CCS), ○: F8 (30 mg of HPMC 50 cP and 7 mg of CCS), ▾: F9 (30 mg of HPMC 50 cP and 15 mg of CCS), △: F10 (30 mg of HPMC 4000 cP, 15 mg of CCS) and ▪: F11 (DF-GRT).

Figure 8. (A) Images of DF-GRT (F11) during in vitro dissolution test. (B) A diagram of GRT (F11) during dissolution test.

Figure 9. (A) Surface and (B) cross-sectional SEM images of DF-GRT (F11) (magnification: ×25, scale bar: 1 mm).

Figure 10. Representative chromatograms of (A) camphor standard solution (1 μg/mL) and (B) sample solution (F11).

Figure 11. Mean plasma concentration of ITR versus time profiles after oral administration in mini pig model. Key •: IRT, ○: DF-GRT (F11) (n = 6, Mean ± SE).

Table 4. Pharmacokinetic parameters for IRT and FD-GRT (F11) containing ITR-SD in the miniature pig model (n = 6, Mean ± SE).

	IRT	FD-GRT
Cmax (ng/mL)	88.99 ± 12.44	124.30 ± 26.12
tmax (h)^a	5.5 (4–16)	16.0 (8–24)
AUC (ng·h/mL)	1609.55 ± 380.26	2195.51 ± 644.85
t1/2 (h)	7.11 ± 1.45	7.28 ± 1.67
MRT (h)	14.22 ± 2.10	20.28 ± 1.39^b

^aRepresented as median (range).

^bSignificantly different compared to IRT (p < 0.05).