Development of a chitosan based double layer-coated tablet as a platform for colon-specific drug delivery

Figures & data

Figure 1 Stepwise illustration of DL-CDDS as a platform for colon targeting.

Notes: (A) In the stomach, the outermost enteric coating layer inhibits drug release; (B) in the small intestine, the inner CTN-dispersed polymeric subcoating layer impedes drug release; (C) in the colon, water infiltrates the core tablet and dissolves CA, resulting in microclimate acidification and pore generation to some extent; (D) in the latter part of the colon, under the influence of microflora, such as CTNase, a number of microporous channels are formed by enzymatic CTN digestion, thus facilitating drug release.
Abbreviations: DL-CDDS, double layer-coated colon-specific drug delivery system; CTN, chitosan; CTNase, chitosanase.

Table 1 Composition of various DL-CDDS formulations

Ingredient (mg/tablet)	CA-free DL-CDDS						CA-supplemented DL-CDDS
	CA0-CTN0/EE10	CA0-CTN1/EE9	CA0-CTN3/EE7	CA0-CTN0/EE21	CA0-CTN3/EE18	CA0-CTN6/EE15	CA15-CTN3/EE18	CA15-CTN6/EE15	CA30-CTN3/EE18	CA30-CTN6/EE15
Core tablet
LXP	60	60	60	60	60	60	60	60	60	60
Lactose	145	145	145	145	145	145	130	130	115	115
L-HPC	25	25	25	25	25	25	25	25	25	25
Povidone	8	8	8	8	8	8	8	8	8	8
Croscarmellose sodium	7	7	7	7	7	7	7	7	7	7
Colloidal silicon dioxide	1	1	1	1	1	1	1	1	1	1
Magnesium stearate	4	4	4	4	4	4	4	4	4	4
CA	–	–	–	–	–	–	15	15	30	30
Subtotal	250	250	250	250	250	250	250	250	250	250
Subcoatinga
EE	10.8	9.3	7.8	21.6	18.6	15.6	18.6	15.6	18.6	15.6
CTN	0	1.5	3	0	3	6	3	6	3	6
Triethyl citrate	0.6	0.6	0.6	1.2	1.2	1.2	1.2	1.2	1.2	1.2
Talc	3.6	3.6	3.6	7.2	7.2	7.2	7.2	7.2	7.2	7.2
Subtotal	15	15	15	30	30	30	30	30	30	30
Enteric coatingb	15	15	15	15	15	15	15	15	15	15
Total	280	280	280	295	295	295	295	295	295	295

Notes:

a CTN/EE subcoating was further modified with EC addition, designated as CTN/EC/EE coating;

b the layered enteric coating was maintained with 6% of the core tablet weight, composed of EL, triethyl citrate, and talc (6:0.5:1 in weight ratio).

Abbreviations: CA, citric acid; CTN, chitosan; DL-CDDS, double layer-coated colon-specific drug delivery system; EC, ethyl cellulose; EE, Eudragit E100; EL, Eudragit L100-55; L-HPC, low-substituted hydroxypropyl cellulose; LXP, loxoprofen sodium; CA0, citric acid-free tablet; CA15, CA 15 mg; CA30, CA 30 mg.

Table 2 Variables used in the 2-LFD method

Variables	Levels
Formulation variables	Low	Center	High
X1 : EE:EC ratio (w/w)	1:2	1:1	2:1
X2 : Subcoating weight (mg)	7.5	18.75	30
Response variables	Minimum	Target	Maximum
Y1: DEcolon (SCF) (%)	–	25	50
Y2: DEcolon (CTNase-SCF) (%)	50	75	–
Y3: CRDcolon (hours)	5	15	–

Abbreviations: CRD, controlled-release duration; CRD_colon, CRD in the colon; CTNase, chitosanase; DE, dis solution efficiency; DE_colon, DE in the colon; EC, ethyl cellulose; EE, Eudragit E100; 2-LFD, two-level factorial design; SCF, simulated colonic fluid.

Table 3 Physical properties of core tablets

Core tablet	Diameter (mm)	Thickness (mm)	Weight (mg)	Drug content (%)	Hardness (kg/cm^2)	Friability (%)
CA0	8.92±0.02	3.85±0.01	250.2±0.6	100.3±0.15	7.7±0.3	0.11±0.04
CA15	8.91±0.04	3.91±0.07	251.3±1.1	101.8±0.95	8.1±0.1	0.06±0.04
CA30	8.91±0.03	3.87±0.04	250.9±0.7	99.96±0.56	8.4±0.5	0.08±0.02

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

Abbreviations: CA0, citric acid-free tablet; CA15, CA 15 mg; CA30, CA 30 mg.

Figure 2 Dissolution characteristics of various formulations.

Notes: (A) Effect of amount of enteric coating; (B) effect of amount of CTN/EE subcoating; (C) effect of amount of CA in core tablet and presence of CTNase in SCF. Error bars denote standard deviation (n=3).
Abbreviations: CA, citric acid; CTN, chitosan; CTNase, chitosanase; EE, Eudragit E100; LXP, loxoprofen sodium; SCF, simulated colonic fluid; SGF, simulated gastric fluid; SIF, simulated intestinal fluid; CA0, citric acid-free tablet; CA15, CA 15 mg; CA30, CA 30 mg.

Figure 3 Comparison for dissolution efficiency of various formulations.

Notes: *P<0.05. Error bars denote standard deviation (n=3).
Abbreviations: CA, citric acid; CTN, chitosan; CTNase, chitosanase; DE, dissolution efficiency; DE_colon, DE in the colon; EE, Eudragit E100; SCF, simulated colonic fluid; CA0, citric acid-free tablet; CA15, CA 15 mg; CA30, CA 30 mg.

Table 4 Experimental design and responses observed from randomized runs in the 2-LFD method

Mixture number	Formulation composition		Response measured
	X1 (w/w)	X2 (mg)	Y1 (%)	Y2 (%)	Y3 (hours)
1	1:2	7.5	23.5	59.1	14
2	2:1	7.5	91.4	98.4	12.3
3	1:2	30	0.5	2.7	18.5
4	2:1	30	26	45	15
5	1:2	7.5	25.4	60.7	13.2
6	2:1	7.5	96.2	100	11.8
7	1:2	30	0.5	2.9	18.8
8	2:1	30	27.6	44.5	15.5
9	1:2	7.5	23.4	60.1	13.2
10	2:1	7.5	93.6	97.6	12.5
11	1:2	30	0.7	3.4	18
12	2:1	30	24.7	43.4	15.5
13	1:1	18.75	28.9	45.1	14
14	1:1	18.75	26.7	44.8	14.5
15	1:1	18.75	27.1	44.6	14.6

Notes: X₁, polymer composition; X₂, amount of subcoating; Y₁, dissolution efficiency in simulated colonic fluid; Y₂, dissolution efficiency in chitosanase-supplemented simulated colonic fluid; Y₃, controlled-release duration in the colon.

Abbreviation: 2-LFD, two-level factorial design.

Table 5 Estimated effects and coefficients

Terms	Regression coefficient	Standard-error coefficient	t-Value	P-value
DEcolon (SCF) (%; Y1)a
Constant	36.13	0.4191	86.19	0.000
X1	23.79	0.4191	56.76	0.000
X2	−22.79	0.4191	−54.38	0.000
X1·X2	−11.02	0.4191	−26.31	0.000
DEcolon (CTNase-SCF) (%; Y2)b
Constant	51.48	0.224	229.86	0.000
X1	20	0.224	89.29	0.000
X2	−27.83	0.224	−124.27	0.000
X1·X2	0.65	0.224	2.9	0.016
CRDcolon (h; Y3)c
Constant	14.86	0.1075	138.22	0.000
X1	−1.09	0.1075	−10.16	0.000
X2	2.03	0.1075	18.84	0.000
X1·X2	−0.46	0.1075	−4.26	0.002

Notes: X₁, polymer composition; X₂, amount of subcoating.

a R²=99.86%, predicted R²=97.92%, adjusted R²=97.39%;

b R²=99.96%, predicted R²=98.79%, adjusted R²=99.94%;

c R²=97.96%, predicted R²=94.46%, adjusted R²=97.14%.

Abbreviations: CRD, controlled-release duration; CTNase, chitosanase; DE, dissolution efficiency; DE_colon, DE in the colon; SCF, simulated colonic fluid.

Figure 4 Normal probability plots of the standardized residual (A) and Pareto charts of the standardized effect (B).

Notes: X₁, polymer composition; X₂, amount of subcoating; Y₁, dissolution efficiency in simulated colonic fluid; Y₂, dissolution efficiency in chitosanase-supplemented simulated colonic fluid; Y₃, controlled-release duration in the colon.

Figure 5 Main effect plot (A) and interaction plot (B).

Notes: X₁, polymer composition; X₂, amount of subcoating; Y₁, dissolution efficiency in simulated colonic fluid; Y₂, dissolution efficiency in chitosanase-supplemented simulated colonic fluid; Y₃, controlled-release duration in the colon.

Figure 6 Dissolution profile of the optimized DL-CDDS.

Note: Error bars denote standard deviation (n=3).
Abbreviations: CTNase, chitosanase; DL-CDDS, double layer-coated colon-specific drug delivery system; LXP, loxoprofen sodium; SCF, simulated colonic fluid; SGF, simulated gastric fluid; SIF, simulated intestinal fluid.