Modulating drug release profiles by lipid semi solid matrix formulations for BCS class II drug – an in vitro and an in vivo study

Figures & data

Table 1. Dissolution data of immediate release SSM aceclofenac capsule formulations in pH 6.8 buffer.

Code	Carrier	Drug:carrier ratio	Q5 min (%)	Q15 min (%)	DE15	t100% (min)
F1	G 33/01	1:1	6.67	24.40	11.92	86.95
F2		1:2	9.81	41.93	16.83	55.92
F3		1:3	11.89	65.90	27.76	43.19
F4		1:5	16.41	69.08	33.60	35.08
F5	PEG 4000	1:1	1.73	13.76	4.64	106.79
F6		1:2	1.79	15.03	5.12	83.33
F7		1:3	1.83	20.88	6.83	66.36
F8		1:5	3.38	51.56	16.73	52.13
F9	PEG 6000	1:1	1.76	9.73	3.82	137.61
F10		1:2	1.89	10.95	4.26	101.52
F11		1:3	2.27	11.44	4.53	86.54
F12		1:5	2.20	16.74	6.30	70.47
F13	Polox	1:5	2.06	7.93	3.29	87.10
F14	G 44/14	1:1	8.33	32.83	14.10	125.22
F15		1:2	9.91	50.24	27.50	50.20
F16		1:3	11.64	70.78	31.58	42.49
F17		1:5	14.43	74.96	36.66	26.01
F18^a		1:6	13.32	99.91	42.20	19.73
F19^b		1:8	26.29	100.51	44.81	19.87
F20^c		1:6	48.57	99.75	63.19	18.68
F21^c		1:10	43.55	99.11	64.12	17.08
F22	G 50/13	1:1	0.90	3.88	1.75	>800
F23		1:5	1.72	7.40	2.91	>600

^aFilled in size “00” capsules.

^bFilled in size “000” capsules.

^cWithout capsule.

Remaining formulations filled in size “0” capsules.

Polox – Poloxamer 188 and G – Gelucire.

Table 2. Effect of excipients on Gelucire 44/14 based formulation (F18).

Formula	Excipients	% of additive	Q5min (%)	Q15min (%)	DE15	t100% (min)
A1	Docusate Na	0.5	74.18	101.15	73.60	14.74
A2		1.0	99.87	99.96	85.20	5.09
A3		1.5	26.96	78.52	39.11	19.60
A4	Tween 80	1	38.07	100.71	54.19	14.70
A5		5	82.71	100.37	81.00	5.80
A6		7.5	101.11	101.12	81.6	4.87
A7	Aerosil 200	1	62.88	96.47	65.81	17.58
A8	PVP K-30	10	30.06	85.48	44.29	19.06

Table 3. Dissolution data of aceclofenac sustained release SSM capsules.

Formula	G 50/13 (mg)	G 43/01 (mg)	G 44/14 (mg)	Q6 h (%)	Q12 h (%)	Q18 h (%)	Q24 h (%)
S1	200	–	–	78.42	100.11	^c	^c
S2	400	–	–	46.86	92.30	^c	^c
S3	–	200	–	7.21	9.89	11.92	13.74
S4	–	400	–	5.19	7.44	9.64	11.27
S5^a	400	200	–	81.84	101.84	^c	^c
S6	200	200	–	43.06	83.66	100.56	^c
S7^a	200	400	–	29.00	58.37	76.35	100.73
S8^b	200	600	–	27.54	56.57	68.67	80.04
S9^a	100	600	–	12.99	30.30	38.87	45.12
S10	–	100	200	40.89	94.30	100.70	^c
S11	–	200	200	41.65	79.28	99.69	^c
S12^a	–	300	200	39.20	64.15	89.76	101.58
S13	–	300	100	20.15	49.70	67.80	98.04
S14^a	–	400	100	14.79	46.63	64.07	81.70
S15^a	–	450	50	2.92	12.26	24.59	41.40
MT	–	–	–	35.84	66.33	82.55	102.56

^aFilled in size “00” capsules.

^bFilled in size “000” capsules.

^cNot determined as complete release occurred at earlier time points.

Remaining formulations filled in size “0” capsules

MT – marketed tablets and G – Gelucire.

Table 4. Semiquantitative solubility of Aceclofenac in different bases.

Carrier	1:1	1:2	1:3	1:5	1:6	1:8	1:10	1:15	1:20
G 44/14	_	_	_	_	+	+ +
G 50/13	_	_	NP	_	_	+	+ +
G 33/01	_	_	NP	_	NP	_	_	+	+ +
G 43/01	_	_	NP	_	NP	NP	_	NP	_
PEG 4000	_	_	+	+ +
PEG 6000	_	_	+	+ +
Polox 188	_	_	NP	+	NP	NP	++

_ insoluble, + sparingly soluble and + + soluble.

NP – not performed and G – Gelucire.

Figure 1. Release profiles of aceclofenac and marketed tablets in different pH. D-plain drug, MT – immediate release marketed tablets. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.

Table 5. Comparative studies of immediate release formulations in different media.

pH	Formula code	Q5 min (%)	Q15 min (%)	DE15	t100% (min)
0.1 N HCl in 2% SLS	Drug	12.66	21.98	14.41	286.01
	MT	41.13	68.19	44.35	83.71
	F18	16.77	81.25	39.22	22.10
	A2	48.23	98.24	64.28	16.78
	A5	68.92	97.53	70.73	16.93
pH 4.5	Drug	1.99	13.99	4.44	703.77
	MT	28.82	52.46	33.85	294.97
	F18	19.83	82.83	38.91	31.02
	A2	36.54	89.92	49.12	21.91
	A5	23.14	79.59	39.99	26.10
pH 6.8	Drug	84.13	101.48	78.84	9.42
	MT	73.54	101.34	74.94	9.48
	F18	13.32	99.91	42.20	19.73
	A2	99.87	99.96	85.20	5.09
	A5	82.71	100.37	81.00	5.80
pH 7.4	Drug	78.65	101.33	74.73	13.59
	MT	78.65	101.33	74.73	15.94
	F18	22.82	97.89	61.63	17.63
	A2	68.84	98.88	69.60	17.29
	A5	61.04	87.47	61.96	26.29

MT – marketed tablets.

Figure 2. Release profiles in pH 6.8 of drug:different SSM carriers (1:5). MT – immediate release marketed tablets, G – Gelucire. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.

Figure 3. Release profile of Gelucire 44/14-based SSM at different ratios in pH 6.8. MT – immediate release marketed tablets. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.

Figure 4. Effect of excipients on dissolution profile of Gelucire 44/14-based SSM (F18) in pH 6.8. MT – immediate release marketed tablets. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.

Figure 5. Dissolution profiles of sustained release Gelucires 50/13- and 43/01-based SSM formulations. MT – sustained release marketed tablets. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.

Figure 6. Dissolution profiles of sustained release Gelucires 43/01- and 44/14-based SSM formulations. MT – sustained release marketed tablets. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.

Table 6. Kinetic data of sustained release SSM capsules.

Formula	f2	Zero order Ko	First order K1	Higuchi (KH)	Peppas^a (n)
S1	24.3	9.46 (113)	0.22 (107)	36.78 (109)	0.73 (109)
S2	37.1	8.04 (104)	0.14 (125)	32.38 (123)	1.01 (105)
S3	12.6	0.49 (96)	0.01 (118)	2.90 (43)	0.51 (44)
S4	11.9	0.42 (67)	0.01 (96)	2.39 (12)	0.57 (5)
S5	24.8	13.56 (78)	0.21 (90)	42.23 (90)	1.13 (80)
S6	42.5	6.82 (108)	0.12 (134)	29.87 (131)	0.92 (104)
S7	56.3	4.11 (170)	0.08 (187)	23.21 (186)	0.86 (161)
S8	45.0	3.53 (183)	0.06 (152)	19.84 (171)	0.76 (166)
S9	22.1	1.97 (144)	0.03 (120)	11.22 (148)	0.80 (132)
S10	38.7	8.34 (85)	0.13 (117)	31.72 (117)	1.15 (85)
S11	46.7	6.66 (100)	0.11 (133)	29.02 (132)	0.96 (99)
S12	72.1	4.83 (142)	0.09 (161)	24.8 (156)	0.82 (123)
S13	43.9	3.99 (148)	0.06 (192)	21.62 (193)	0.99 (149)
S14	36.7	3.58 (145)	0.05 (178)	19.39 (188)	0.99 (146)
S15	16.1	1.71 (160)	0.02 (175)	8.617 (187)	1.96 (100)
MT	100	4.16 (175)	0.09 (180)	23.80 (169)	0.74 (144)

^an is reported for Peppas model. AIC values are reported in brackets.

MT – sustained release marketed tablets.

Figure 7. DSC scans of Gelucire-based immediate release SSM formulations. (a) Aceclofenac, (b) dummy A3 (Gelucire 44/14 +docusate sodium), (c) dummy A7 (Gelucire 44/14 + Tween 80) and (d) A3, (e) A7.

Figure 8. Percent inhibition by aceclofenac SSM formulations on carrageenan-induced rat paw edema. Each value represents mean ± SD (n = 6). Only positive SD bar is displayed for clarity.