Thiolated polycarbophil/glutathione: Defining its potential as a permeation enhancer for oral drug administration in comparison to sodium caprate

Figures & data

Table 1.  Composition of dosage forms.

Dosage form	NaFlu	FD4	PCP-Cys	C10	GSH
i.v. solution	2.5 mg	—	—	—	—
i.v. solution	—	2.5 mg	—	—	—
Oral solution	2.5 mg	—	—	—	—
Oral solution	—	2.5 mg	—	—	—
Oral solution	2.5 mg	—	—	5 mg	—
Oral solution	—	2.5 mg	—	5 mg	—
Hydrogel	2.5 mg	—	5 mg	—	0.5 mg
Hydrogel	—	2.5 mg	5 mg	—	0.5 mg
Minitablet	2.5 mg	—	5 mg	—	0.5 mg
Minitablet	—	2.5 mg	5 mg	—	0.5 mg
Minitablet	2.5 mg	—	—	5 mg	—
Minitablet	—	2.5 mg	—	5 mg	—

Table 2.  Comparison of the apparent permeability coefficients of model compounds in the presence of indicated permeation enhancers. Indicated values are means ± SD (n ≥ 4).

Permeating compound	Permeation enhancer	Papp (× 10^−6 cm/s)	Enhancement ratio
FD4	—	1.38 ± 0.49 ^0	—
FD4	C10	4.12 ± 0.82 ^1	3.0
FD4	PCP-Cys	3.32 ± 0.80 ^2	2.4
NaFlu	—	8.77 ± 1.54 ^a	—
NaFlu	C10	20.06 ± 1.67 ^b	2.3
NaFlu	PCP-Cys	19.61 ± 5.13 ^c	2.2
C10	—	7.78 ± 0.96	—

1, 2 are not statistically different but differ significantly from 0. b, c are not statistically different but differ significantly from a.

Figure 1.  Cumulative transport of NaFlu in buffer (squares), of NaFlu with 1 % sodium caprate (diamonds), of NaFlu with 1 % PCP-Cys/0.5 % GSH (circles) and of sodium caprate (dashed line) across rat intestinal mucosa. Indicated values are means of at least three experiments ± standard deviation. 1,2 are not statistically different but differ significantly from 3.

Figure 2.  Cumulative transport of FD4 in buffer (squares), of FD4 with 1 % sodium caprate (diamonds), of FD4 with 1 % PCP-Cys/0.5 % GSH (circles) and of sodium caprate (dashed line) across rat intestinal mucosa. Indicated values are means of at least three experiments ± standard deviation. 1,2 are not statistically different but differ significantly from 3.

Figure 3.  Release of NaFlu (circles) and FD4 (squares) from PCP-Cys tablets in phosphate buffer. Indicated values are means of at least three experiments ± standard deviation.

Figure 4.  Cell viability according to reduction of MTT after 12 h incubation with 0.5 % PCP-Cys and 0.5 % sodium caprate. Indicated values are means of at least three experiments ± standard deviation.

Table 3.  Pharmacokinetic parameters after oral administration of NaFlu and FD4 with C10 and PCP-Cys as permeation enhancers.

	AUC0–6 (µg/mL min)	cmax (µg/mL)	tmax (min)	Fabs (%)
NaFlu + buffer (control)	137.3 ± 16.3	0.85 + 0.03	30	6.2^0
NaFlu + C10 (solution)	310.7 ± 182.4	1.00 ± 0.47	30	14.0^1
NaFlu + C10 (tablets)	674.2 ± 229.4	4.04 ± 0.94	30	30.3^2
NaFlu + PCP-Cys (hydrogel)	305.4 ± 141.8	1.37 ± 0.70	120	13.7^3
NaFlu + PCP-Cys (tablets)	674.1 ± 326.0	5.19 ± 3.14	120	30.3^4
FD4 + buffer (control)	88.0 ± 1.7	0.28 ± 0.03	60	2.8^a
FD4 + C10 (solution)	197.4 ± 22.8	1.06 ± 0.53	60	6.2^b
FD4 + C10 (tablets)	245.1 ± 51.6	1.62 ± 0.76	60	7.7^c
FD4 + PCP-Cys (hydrogel)	283.2 ± 98.7	1.83 ± 1.45	60	8.9^d
FD4 + PCP-Cys (tablets)	626.2 ± 49.7	3.22 ± 1.13	60	19.6^e

1, 2, 3, 4 differ significantly from 0. 1 and 3 are not significantly different and 2 and 4 are not statistically different. b, c, d, e are statistically different from a. b and d are not statistically different, but e differs significantly from c.

Figure 5.  Sodium fluoresceine plasma concentration-time profiles after administration of liquid formulations (A) and tablets (B) with 5 mg sodium caprate (squares) and 5 mg PCP-Cys/0.5 mg GSH (circles) in comparison to buffer control solution (diamonds). Indicated values are means of at least three experiments ± standard deviation.

Figure 6.  FD4 plasma concentration-time profiles after administration of liquid formulations (A) and tablets (B) with 5 mg sodium caprate (squares) and 5 mg PCP-Cys/0.5 mg GSH (circles) in comparison to buffer control solution (diamonds). Indicated values are means of at least three experiments ± standard deviation.