Development and characterization of gastroretentive sustained-release formulation by combination of swelling and mucoadhesive approach: a mechanistic study

Figures & data

Table 1 Composition of gastroretentive formulations of acyclovir

Ingredients	Function	Quantity (% w/w) per tablet in batch number
		AGR-1	AGR-2	AGR-3	AGR-4	AGR-5	AGR-6	AGR-7	AGR-8	AGR-9	AGR-10	AGR-11
Acyclovir	Drug	72.50	72.50	72.50	72.50	72.50	72.50	72.50	72.50	72.50	72.50	72.50
Carbomer	Mucoadhesive release-controlling polymer	7.50	10.00	15.00	–	–	7.50	5.00	2.50	5.00	3.50	10.00
Polyethylene oxide	Mucoadhesive release-controlling polymer	–	–	–	5.00	10.00	2.50	5.00	7.50	–	–	–
Sodium alginate	Mucoadhesive release-controlling polymer	–	–	–	–	–	–	–	–	5.00	3.50	3.50
Microcrystalline cellulose	Diluent	11.89	9.39	4.39	14.39	9.39	9.39	9.39	9.39	9.39	12.39	5.89
Povidone K30	Binder	3.00	3.00	3.00	3.00	3.00	3.00	3.00	3.00	3.00	3.00	3.00
Colloidal silicon dioxide	Glidant/charge dissipant	0.75	0.50	0.50	0.50	0.50	0.50	0.50	0.50	0.50	0.50	0.50
Magnesium stearate	Lubricant	0.50	0.75	0.75	0.75	0.75	0.75	0.75	0.75	0.75	0.75	0.75
Isopropyl alcohola	Granulation solvent	qs	qs	qs	qs	qs	qs	qs	qs	qs	qs	qs
Total tablet weight (mg)		1,000	1,000	1,000	1,000	1,000	1,000	1,000	1,000	1,000	1,000	1,000

Note:

a Note: Evaporates during processing.

Abbreviation: qs, quantity sufficient.

Figure 1 Comparison of simulated steady state plasma concentration profiles of the IR and GR formulations of acyclovir along with target drug release profile.

Abbreviations: GR, gastroretentive sustained-release; IR, immediate-release; h, hours.

Table 2 Results of drug–excipient compatibility study of acyclovir

Excipient	Ratio	Physical observation (initial and 30 days)				Percentage impurity (guanine)
		Initial	60°C (glass vial)	40°C, 75% RH (LDPE bag)	40°C, 75% RH (glass vial)	Initial	60°C (glass vial)		40°C, 75% RH (LDPE bag)		40°C, 75% RH (glass vial)
							15 days	30 days	15 days	30 days	30 days
None (drug alone)	–	White powder	NC	NC	NC	0.27	0.27	0.26	0.27	0.28	0.27
Microcrystalline cellulose (Avicel PH 101)	1:0.3	White powder	NC	NC	NC	0.27	0.26	0.26	0.26	0.28	0.27
Carbomer (Carbopol 974P)	1:0.3	White powder	NC	Soft lumps	NC	0.27	0.27	0.26	0.41	0.55	0.27
Polyethylene oxide (Polyox WSR 303)	1:0.3	White powder	NC	NC	NC	0.25	0.26	0.26	0.27	0.28	0.30
Sodium alginate (Keltone HVCR)	1:0.3	Off-white powder	NC	NC	NC	0.27	0.26	0.26	0.26	0.27	0.27
Povidone (Plasdone K30)	1:0.1	White powder	NC	NC	NC	0.26	0.27	0.27	0.27	0.29	0.27
Magnesium stearate	1:0.1	White powder	NC	NC	NC	0.27	0.27	0.26	0.26	0.27	0.27
Colloidal silicon dioxide (Aerosil 200)	1:0.1	White powder	NC	NC	NC	0.26	0.27	0.27	0.26	0.28	0.27

Abbreviations: LDPE, low-density polyethylene; NC, no change; RH, relative humidity.

Table 3 Characterization of acyclovir

Serial number	Parameter	ACV powder
1	Angle of reposea	41.6°±0.3°
2	Bulk density	0.58 g/mL
3	Tapped density	0.96 g/mL
4	Compressibility index	39.74%
5	Hausner’s ratio	1.65

Note:

a Data represented as mean ± SD (n=3).

Abbreviations: ACV, acyclovir; SD, standard deviation.

Table 4 In-process characterization of different batches of acyclovir gastroretentive tablets

Batch number	Average weight (mg) (n=20)	Weight variation (%) (n=20)	Hardness (kp) (n=5)	Thickness (mm) (n=5)	Friability (%) (n=10)
AGR-1	996	−1.69 to 2.26	17.8 to 22.7	6.20 to 6.34	0.07
AGR-2	1,002	−2.20 to 2.80	16.0 to 23.8	6.35 to 6.46	0.07
AGR-3	999	−2.36 to 1.99	15.8 to 23.8	6.33 to 6.75	0.09
AGR-4	1,005	−1.74 to 1.32	17.8 to 20.8	6.02 to 6.12	0.06
AGR-5	1,007	−1.64 to 1.37	19.6 to 22.6	5.94 to 6.03	0.10
AGR-6	996	−1.52 to 2.18	17.7 to 21.8	6.14 to 6.28	0.07
AGR-7	1,001	−1.88 to 1.85	18.9 to 22.1	6.02 to 6.27	0.08
AGR-8	998	−1.19 to 1.81	17.4 to 22.4	6.09 to 6.28	0.10
AGR-9	1,001	−1.88 to 1.85	18.9 to 22.1	6.02 to 6.27	0.05
AGR-10	996	−1.52 to 2.18	17.7 to 21.8	6.14 to 6.28	0.05
AGR-11	992	−2.80 to 2.52	18.1 to 21.9	6.16 to 6.27	0.11

Abbreviation: AGR, acyclovir gastroretentive sustained-release.

Figure 2 In vitro drug release profiles of gastroretentive tablets of acyclovir.

Abbreviations: Data are represented as mean ± standard deviation (n=3).

Table 5 Similarity factor and splitting behavior of acyclovir gas-troretentive tablets

Batch number	Polymer composition	Similarity factor (f2)	Splitting during drug release
AGR-1	Carbomer 7.5%	66	No
AGR-2	Carbomer 10%	41	No
AGR-3	Carbomer 15%	59	Yes
AGR-4	Polyethylene oxide 5%	48	No
AGR-5	Polyethylene oxide 10%	35	No
AGR-6	Carbomer 7.5%; polyethylene oxide 2.5%	85	No
AGR-7	Carbomer 5%; polyethylene oxide 5%	54	No
AGR-8	Carbomer 2.5%; polyethylene oxide 7.5%	29	No
AGR-9	Carbomer 5%, sodium alginate 5%	54	Yes
AGR-10	Carbomer 3.5%; sodium alginate 3.5%	58	Yes
AGR-11	Carbomer 10%; sodium alginate 3.5%	26	No

Abbreviation: AGR, acyclovir gastroretentive sustained-release.

Table 6 Mathematical modeling and drug-release kinetics of acyclovir gastroretentive formulations

Batch number	Carbomer: polyethylene oxide	R^2					n	Drug-transport mechanism
		Zero order	First order	Higuchi	Korsmeyer–Peppas	Hixson–Crowell
AGR-6	75:25	0.8846	0.9911	0.9624	0.9648	0.9897	0.55	Anomalous transport (non-Fickian)
AGR-7	50:50	0.9189	0.9988	0.9786	0.9768	0.9915	0.75
AGR-8	25:75	0.9999	0.9518	0.9784	0.9987	0.9797	0.87

Abbreviation: AGR, acyclovir gastroretentive sustained-release.

Figure 3 Swelling index of gastroretentive tablets of acyclovir.

Abbreviations: Data are represented as mean ± standard deviation (n=3).

Figure 4 Matrix erosion of gastroretentive tablets of acyclovir.

Abbreviations: Data are represented as mean ± standard deviation (n=3).

Figure 5 Relative size of optimized GR formulation.

Abbreviation: GR, gastroretentive sustained-release.

Figure 6 Detachment forces of different batches of gastroretentive and conventional acyclovir tablets in mucoadhesion study.

Note: Data are represented as mean ± standard deviation (n=3).

Figure 7 X-ray radiography photographs of rabbit administered with IR hours (A) and 8 hours (B) with optimized GR formulation (AGR-6).

Abbreviations: IR, immediate-release; GR, gastroretentive sustained-release; AGR acyclovir gastroretentive sustained-release.

Table 7 Pharmacokinetic parameters of acyclovir after administration of GR and IR formulations

Parameter	GR formulation (AGR-6)	IR formulation	Ratio of GR to IR (%)
tmax (hours)	4±0.1	1.5±0.2	267
Cmax (ng/mL)	292.6±7.5	295.4±5.9	99
AUCt (ng × h/mL)	3,100.7±94.8	1,152.9±48.1	269
AUCinf (ng × h/mL)	3,526.1±107.3	1,350.2±69.8	261
MRT (hours)	7.0±0.3	3.3±0.2	212

Note: Data represented as mean ± SD (n=3).

Abbreviations: AGR, acyclovir gastroretentive sustained-release; AUC_inf, area under the concentration–time curve from time 0 to infinity; AUC_t, area under the concentration–time curve from 0 to t; C_max, peak plasma concentration; GR, gastroretentive sustained-release; IR, intermediate-release; MRT, mean residence time; SD, standard deviation; t_max, time to C_max; GR, gastroretentive sustained-release.

Figure 8 Mean plasma concentration profiles of IR and optimized GR formulation (AGR-6).

Abbreviations: Data are represented as mean ± standard deviation (n=3).

Table 8 Stability data of optimized batch of acyclovir gastro-retentive sustained-release formulation (AGR-6)

Parameter	Initial	After 1 month	After 2 months	After 3 months
Assay (%)	99.8	100.2	99.9	99.7
Guanine content (%w/w)	0.32	0.40	0.39	0.40
Water content (%w/w)	5.7	5.9	5.8	5.8
Drug-release similarity factor (f2)	–	87	84.8	91.4

Abbreviation: AGR, acyclovir gastroretentive sustained-release.