Ali, Tariq; Shoaib, Muhammad Harris; Yousuf, Rabia Ismail; Jabeen, Sabahat; Muhammad, Iyad Naeem; Tariq, Asfia

doi:10.1590/S1984-82502014000400016

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Articles • Braz. J. Pharm. Sci. 50 (4) • Oct-Dec 2014 • https://doi.org/10.1590/S1984-82502014000400016 linkcopiar

Use of hydrophilic and hydrophobic polymers for the development of controlled release tizanidine matrix tablets

O objetivo do presente estudo foi desenvolver matriz de de tizanidina de liberação controlada. As formulações foram projetadas usando o método do componente, central com a ajuda de software Design expert^(r), versão 7.0. Utilizou-se Avicel pH 101, no intervalo de 14-50%, como material de preenchimento, enquanto HPMC K4M e K100M, no intervalo de 25-55%, Etilcelulose 10 ST e 10FP, no intervalo de 15-45% e Kollidon SR, na faixa de 25-60% foram utilizados como agentes de liberação controlada, no planejamento de formulações diferentes. Vários parâmetros físicos, incluindo o fluxo de pó para as misturas e variação de peso, espessura, dureza, friabilidade, tempo de desintegração e liberação in vitro, foram testados para comprimidos. Ensaios dos comprimidos foram, também, realizados, tal como especificado em USP 35 NF 32. Avaliaram-se os parâmetros físicos de ambos, mistura em pó e comprimidos, como índice de compressibilidade, ângulo de repouso, variação de peso, espessura, dureza, friabilidade, tempo de desintegração e de ensaio, considerando-os satisfatórios para as formulações K4M2, K4M3, K4M9, K100M2, K100M3, K100M9, E10FP2, E10FP9, KSR2, KSR3 e KSR9. O estudo de dissolução in vitro foi realizado em 900 mL de HCl 0,1 N, tampão de fosfato pH 4,5 e meio 6,8, usando aparelho USP II. Os perfis de liberação in vitroindicaram que as formulações preparadas com Ethocel 10 padrão não foram capazes de controlar a liberação do fármaco, enquanto as formulações K4M2, K100M9, E10FP2e KSR2, com teor de polímero variando entre 40 e 55% apresentaram padrão de liberação controlada de fármaco no meio anteriormente mencionado. Observou-se cinética de liberação de fármaco de ordem zero para as formulações K4M2 , K100M9, E10FP2 e KSR2. Resultados do teste de similaridade (f ₂) para K4M2, E10FP2 e KSR2 foram comparáveis com a formulação de referência K100M9. Gráficos de superfície de resposta também avaliaram o efeito da variável independente sobre as respostas. Estudo de estabilidade foi realizado conforme as diretrizes do ICH e a vida de prateleira calculada foi de 24-30 meses para as formulações K4M2, K100M9 e E10FP2.

Tizanidina/liberação controlada; Hidroxipropilmetilcelulose/agente de liberação controlada; Etilcelulose/agente de liberação controlada; Kollidon SR./agente de liberação controlada; Comprimidos/liberação controlada

Formulation Code	Coded factor level		Factors Amount (% )		Factors Amount (mg)		Total Wt. of Tablet (mg)	Total wt. adjusted (mg)
Formulation Code	X 1	X 2	Factors Amount (% )		Factors Amount (mg)
HPMC K4M	HPMC K4M	Avicel PH 101	HPMC K4M	Avicel PH 101	HPMC K4M	Avicel PH 101
K4M 1	-1	-1	30.00	20.00	30.84	20.56	87.40	88
K4M 2	1	-1	50.00	20.00	51.40	20.56	107.96	108
K4M 3	-1	1	30.00	45.00	30.84	46.26	113.10	113
K4M 4	1	1	50.00	45.00	51.40	46.26	133.66	134
K4M 5	-1.414	0	25.86	32.50	26.58	33.41	95.99	96
K4M 6	1.414	0	54.14	32.50	55.66	33.41	125.07	125
K4M 7	0	-1.414	40.00	14.82	41.12	15.23	92.35	93
K4M 8	0	1.414	40.00	50.18	41.12	51.58	128.70	128
K4M 9	0	0	40.00	32.50	41.12	33.41	110.53	110
HPMC K100M	HPMC K100M	Avicel PH 101	HPMC K100M	Avicel PH 101	HPMC K100M	Avicel PH 101
K100M 1	-1	-1	30.00	20.00	30.84	20.56	87.40	88
K100M 2	1	-1	50.00	20.00	51.40	20.56	107.96	108
K100M 3	-1	1	30.00	45.00	30.84	46.26	113.10	113
K100M 4	1	1	50.00	45.00	51.40	46.26	133.66	134
K100M 5	-1.414	0	25.86	32.50	26.58	33.41	95.99	96
K100M 6	1.414	0	54.14	32.50	55.66	33.41	125.07	125
K100M 7	0	-1.414	40.00	14.82	41.12	15.23	92.35	93
K100M 8	0	1.414	40.00	50.18	41.12	51.58	128.70	128
K100M 9	0	0	40.00	32.50	41.12	33.41	110.53	110
Ethocel 10 Standard	Ethocel 10 ST	Avicel PH 101	Ethocel 10 ST	Avicel PH 101	Ethocel 10 ST	Avicel PH 101
E10ST 1	-1	-1	20.00	30.00	22.00	33.00	91.00	91
E10ST 2	1	-1	40.00	30.00	44.00	33.00	113.00	113
E10ST 3	-1	1	20.00	45.00	22.00	49.50	107.50	108
E10ST 4	1	1	40.00	45.00	44.00	49.50	129.50	130
E10ST 5	-1.414	0	15.86	37.50	17.45	41.25	94.70	95
E10ST 6	1.414	0	44.14	37.50	48.56	41.25	125.81	126
E10ST 7	0	-1.414	30.00	26.89	33.00	29.58	98.58	99
E10ST 8	0	1.414	30.00	48.11	33.00	52.92	121.92	122
E10ST 9	0	0	30.00	37.50	33.00	41.25	110.25	110
Ethocel 10 FP	Ethocel 10 FP	Avicel PH 101	Ethocel 10 FP	Avicel PH 101	Ethocel 10 FP	Avicel PH 101
E10FP 1	-1	-1	20.00	30.00	22.00	33.00	91.00	91
E10FP 2	1	-1	40.00	30.00	44.00	33.00	113.00	113
E10FP 3	-1	1	20.00	45.00	22.00	49.50	107.50	108
E10FP 4	1	1	40.00	45.00	44.00	49.50	129.50	130
E10FP 5	-1.414	0	15.86	37.50	17.45	41.25	94.70	95
E10FP 6	1.414	0	44.14	37.50	48.56	41.25	125.81	126
E10FP 7	0	-1.414	30.00	26.89	33.00	29.58	98.58	99
E10FP 8	0	1.414	30.00	48.11	33.00	52.92	121.92	122
E10FP 9	0	0	30.00	37.50	33.00	41.25	110.25	110
Kollidon SR	KSR	Avicel PH 101	KSR	Avicel PH 101	KSR	Avicel PH 101
KSR 1	-1	-1	30.00	15.00	33.00	16.50	85.50	86
KSR 2	1	-1	55.00	15.00	60.50	16.50	113.00	113
KSR 3	-1	1	30.00	45.00	33.00	49.50	118.50	118
KSR 4	1	1	55.00	45.00	60.50	49.50	146.00	146
KSR 5	-1.414	0	24.82	30.00	27.30	33.00	96.30	96
KSR 6	1.414	0	60.18	30.00	66.20	33.00	135.20	135
KSR 7	0	-1.414	42.50	8.79	46.75	9.67	92.42	92
KSR 8	0	1.414	42.50	51.21	46.75	56.33	139.08	139
KSR 9	0	0	42.50	30.00	46.75	33.00	115.75	116

Formulation code	Mass	Bulk Volume	Tapped volume	Bulk density	Tapped density	Haunser Ratio	Compressibility Index	Angle of repose	Flow properties according to
Formulation code	(g)	(mL)	(mL)	( g/mL)	(g/mL)		%	θ	USP 35
K4M 1	10.00	17.00	12.00	0.59	0.83	1.42	29.41	53.28	Poor
K4M 2	10.00	17.00	16.00	0.59	0.63	1.06	5.88	29.56	Excellent
K4M 3	10.00	19.00	16.00	0.53	0.63	1.19	15.79	36.32	Fair
K4M 4	10.00	20.00	14.00	0.50	0.71	1.43	30.00	49.83	Poor
K4M 5	10.00	20.00	16.00	0.50	0.63	1.25	20.00	38.39	Fair
K4M 6	10.00	20.00	14.00	0.50	0.71	1.43	30.00	53.99	Poor
K4M 7	10.00	17.00	12.00	0.59	0.83	1.42	29.41	54.21	Poor
K4M 8	10.00	18.00	12.00	0.56	0.83	1.50	33.33	58.18	V Poor
K4M 9	10.00	17.00	15.00	0.59	0.67	1.13	11.76	33.20	Good
K100M 1	10.00	17.00	11.00	0.59	0.91	1.55	35.29	60.79	V Poor
K100M 2	10.00	18.00	16.00	0.56	0.63	1.13	11.11	32.11	Good
K100M 3	10.00	20.00	17.00	0.50	0.59	1.18	15.00	33.28	Good
K100M 4	10.00	19.00	11.00	0.53	0.91	1.73	42.11	70.45	V V Poor
K100M 5	10.00	17.00	13.00	0.59	0.77	1.31	23.53	38.12	Fair
K100M 6	10.00	20.00	15.00	0.50	0.67	1.33	25.00	42.66	Passable
K100M 7	10.00	17.00	12.00	0.59	0.83	1.42	29.41	46.32	Poor
K100M 8	10.00	17.00	11.00	0.59	0.91	1.55	35.29	60.28	V Poor
K100M 9	10.00	18.00	17.00	0.56	0.59	1.06	5.56	27.19	Excellent
E10ST 1	10.00	24.00	16.00	0.42	0.63	1.50	33.33	61.24	V Poor
E10ST 2	10.00	23.00	19.00	0.43	0.53	1.21	17.39	38.13	Fair
E10ST 3	10.00	23.00	17.00	0.43	0.59	1.35	26.09	51.22	Poor
E10ST 4	10.00	22.00	15.00	0.45	0.67	1.47	31.82	58.54	V Poor
E10ST 5	10.00	23.00	15.00	0.43	0.67	1.53	34.78	64.87	V Poor
E10ST 6	10.00	24.00	21.00	0.42	0.48	1.14	12.50	34.25	Good
E10ST 7	10.00	24.00	18.00	0.42	0.56	1.33	25.00	43.30	Passable
E10ST 8	10.00	21.00	15.00	0.48	0.67	1.40	28.57	48.74	Poor
E10ST 9	10.00	22.00	18.00	0.45	0.56	1.22	18.18	37.34	Fair
E10FP 1	10.00	27.00	21.00	0.37	0.48	1.29	22.22	43.23	Passable
E10FP 2	10.00	28.00	24.00	0.36	0.42	1.17	14.29	32.12	Good
E10FP 3	10.00	29.00	24.00	0.34	0.42	1.21	17.24	37.75	Fair
E10FP 4	10.00	31.00	24.00	0.32	0.42	1.29	22.58	44.09	Passable
E10FP 5	10.00	31.00	22.00	0.32	0.45	1.41	29.03	53.37	Poor
E10FP 6	10.00	30.00	20.00	0.33	0.50	1.50	33.33	58.16	V Poor
E10FP 7	10.00	28.00	18.00	0.36	0.56	1.56	35.71	62.97	V Poor
E10FP 8	10.00	29.00	22.00	0.34	0.45	1.32	24.14	44.23	Passable
E10FP 9	10.00	31.00	26.00	0.32	0.38	1.19	16.13	37.32	Fair
KSR 1	10.00	19.00	14.00	0.53	0.71	1.36	26.32	51.55	Poor
KSR 2	10.00	19.00	18.00	0.53	0.56	1.06	5.26	27.19	Excellent
KSR 3	10.00	21.00	18.00	0.48	0.56	1.17	14.29	34.31	Good
KSR 4	10.00	22.00	16.00	0.45	0.63	1.38	27.27	47.5	Poor
KSR 5	10.00	18.00	15.00	0.56	0.67	1.20	16.67	39.25	Fair
KSR 6	10.00	22.00	15.00	0.45	0.67	1.47	31.82	57.86	V Poor
KSR 7	10.00	20.00	14.00	0.50	0.71	1.43	30.00	46.82	Poor
KSR 8	10.00	22.00	17.00	0.45	0.59	1.29	22.73	42.51	Passable
KSR 9	10.00	20.00	17.00	0.50	0.59	1.18	15.00	33.62	Good

Formulation code	Thickness (mm)	Hardness (kg)	Weight Variation (mg)	Friablity (%)	Disintegration time (hrs)	Assay (%)
K4M 2	3.96 ± 0.10	4.81 ± 0.52	108.23 ± 2.80	0.76	4.82	98.76
K4M 3	4.05 ± 0.12	4.20 ± 0.38	113.21 ± 2.80	0.91	4.18	97.25
K4M 5	3.67 ± 0.14	3.74 ± 0.70	96.98 ± 5.00	1.14	3.55	96.38
K4M 9	3.99 ± 0.12	4.69 ± 1.18	110.71 ± 4.06	0.94	4.30	98.05
K100M 2	4.01 ± 0.14	5.87 ± 0.68	109.30 ± 3.66	0.57	6.87	98.37
K100M 3	4.03 ± 0.16	4.30 ± 0.70	113.37 ± 4.78	0.85	4.95	97.82
K100M 5	3.97 ± 0.16	4.04 ± 1.12	95.74 ± 6.32	0.99	3.73	98.61
K100M 9	3.98 ± 0.08	5.57 ± 0.76	110.27 ± 4.00	0.63	6.58	98.87
E10ST 2	4.01 ± 0.15	8.04 ± 1.86	113.54 ± 3.71	0.76	1.42	96.81
E10ST 6	4.39 ± 0.18	8.53 ± 2.26	125.35 ± 4.53	0.69	2.10	97.32
E19ST 9	4.05 ± 0.13	7.96 ± 1.57	109.85 ± 3.82	0.97	1.38	96.18
E10FP 2	3.99 ± 0.08	12.92 ± 1.80	113.77 ± 3.74	0.30	5.72	98.79
E10FP 3	4.00 ± 0.10	11.75 ± 2.14	109.46 ± 4.5	0.95	3.68	96.32
E10FP 9	3.98 ± 0.14	12.57 ± 2.30	110.82 ± 5.38	0.47	5.13	98.24
KSR 2	4.24 ± 0.10	5.01 ± 0.74	113.30 ± 3.04	0.29	7.52	98.39
KSR 3	4.07 ± 0.14	4.24 ± 0.88	118.97 ± 3.98	0.84	4.25	96.51
KSR 5	4.04 ± 0.12	3.40 ± 0.78	96.82 ± 5.28	1.53	3.15	95.23
KSR 9	4.20 ± 0.12	4.20 ± 0.58	116.05 ± 4.04	0.63	6.27	97.27

	Zero order		First order		Higuchi		Korsmeyer-Peppas			Hixon-crowell
	r²	K₀(h ^-1 )	r²	K₁(h ^-1 )	r²	K_H(h ^-1/2 )	r²	n	K _kp (h ^-n )	r²	K _HC (h ^-1/3 )
0.1 N HCl
K4M 2	0.996	11.586	0.964	0.192	0.972	26.792	0.982	0.641	21.498	0.976	0.055
K4M 3	0.930	17.217	0.951	0.923	0.978	42.347	0.991	0.226	63.683	0.974	0.180
K4M 9	0.992	13.355	0.984	0.259	0.994	31.333	0.994	0.526	30.089	0.992	0.072
K100M 2	0.994	8.310	0.977	0.115	0.971	19.058	0.985	0.726	13.342	0.983	0.034
K100M 3	0.927	16.894	0.972	0.566	0.970	40.719	0.976	0.358	50.441	0.980	0.146
K100M 9	0.997	10.830	0.969	0.170	0.971	24.870	0.986	0.713	17.794	0.979	0.049
E10FP 2	0.996	11.653	0.978	0.195	0.983	26.959	0.990	0.642	21.589	0.987	0.056
E10FP 9	0.927	15.951	0.995	0.526	0.978	38.660	0.989	0.325	50.353	0.991	0.139
KSR 2	0.991	12.287	0.975	0.215	0.981	28.472	0.987	0.629	23.277	0.985	0.061
KSR 3	0.778	17.573	0.979	1.821	0.862	44.177	0.919	0.117	77.467	0.936	0.191
KSR 9	0.938	15.559	0.991	0.449	0.981	37.471	0.987	0.363	46.104	0.996	0.119
pH 4.5
K4M 2	0.997	11.257	0.971	0.182	0.975	25.919	0.988	0.686	19.373	0.982	0.052
K4M 3	0.941	16.764	0.959	0.732	0.982	40.997	0.991	0.257	58.960	0.965	0.171
K4M 9	0.990	13.075	0.986	0.250	0.993	30.579	0.994	0.554	28.138	0.993	0.069
K100M 2	0.997	7.971	0.982	0.108	0.973	18.242	0.988	0.749	12.322	0.988	0.033
K100M 3	0.944	16.422	0.981	0.487	0.981	39.311	0.984	0.401	45.674	0.987	0.127
K100M 9	0.996	10.326	0.969	0.156	0.968	23.606	0.987	0.761	15.623	0.979	0.046
E10FP 2	0.996	11.393	0.980	0.187	0.983	26.297	0.991	0.664	20.350	0.989	0.054
E10FP 9	0.937	15.397	0.998	0.425	0.983	36.938	0.990	0.392	43.513	0.997	0.113
KSR 2	0.989	11.920	0.973	0.202	0.976	27.493	0.985	0.673	20.987	0.982	0.057
KSR 3	0.784	16.026	0.997	0.825	0.879	39.806	0.927	0.202	61.979	0.981	0.171
KSR 9	0.944	13.861	0.999	0.318	0.987	33.152	0.991	0.411	37.952	0.996	0.085
pH 6.8
K4M 2	0.997	10.986	0.972	0.173	0.975	25.181	0.989	0.733	17.455	0.982	0.050
K4M 3	0.948	16.217	0.968	0.561	0.983	39.362	0.989	0.302	53.009	0.968	0.144
K4M 9	0.990	12.811	0.990	0.237	0.996	29.837	0.997	0.591	25.898	0.996	0.066
K100M 2	0.998	7.769	0.985	0.104	0.974	17.638	0.994	0.836	10.336	0.990	0.031
K100M 3	0.949	15.577	0.991	0.412	0.985	37.135	0.988	0.430	41.332	0.995	0.109
K100M 9	0.995	10.075	0.969	0.149	0.967	22.928	0.988	0.812	13.960	0.978	0.044
E10FP 2	0.994	11.092	0.982	0.179	0.984	25.538	0.992	0.689	19.001	0.989	0.051
E10FP 9	0.935	14.844	0.999	0.381	0.982	35.546	0.988	0.406	41.007	0.997	0.101
KSR 2	0.992	11.578	0.983	0.191	0.984	26.576	0.992	0.719	18.845	0.990	0.055
KSR 3	0.797	15.700	0.985	0.610	0.889	38.587	0.925	0.272	54.335	0.980	0.156
KSR 9	0.959	13.485	0.999	0.291	0.993	32.119	0.995	0.433	35.555	0.998	0.078

Comparision	f ₂			Dissolution Profile
Comparision	0.1 N HCl	pH 4.5	pH 6.8	Dissolution Profile
K100M9 and K4M2	69.28	65.69	65.80	Similar
K100M9 and K4M3	20.42	20.96	22.44	Dissimilar
K100M9 and K4M9	43.66	42.05	42.22	Dissimilar
K100M9 and K100M2	47.22	48.88	49.19	Dissimilar
K100M9 and K100M3	23.73	24.33	26.37	Dissimilar
K100M9 and E10FP2	66.04	60.97	59.94	Similar
K100M9 and E10FP9	26.00	27.33	28.24	Dissimilar
K100M9 and KSR2	55.27	53.27	54.19	Similar
K100M9 and KSR3	16.57	20.68	21.93	Dissimilar
K100M9 and KSR9	28.13	33.48	34.45	Dissimilar

Study Period	Test	Methocel K4M			Methocel K100M			Ethocel 10 FP		Kollidon SR
Study Period	Test	K4M 2	K4M 3	K4M 9	K100M 2	K100M 3	K100M 9	E10FP 2	E10FP 9	KSR 2	KSR 3	KSR 9
0 Month	Hardness (kg)	4.81 ± 0.52	4.20 ± 0.38	4.69 ± 1.18	5.40 ± 0.68	4.30 ± 0.70	5.57 ± 0.76	12.92 ± 1.80	12.57 ± 2.30	5.01 ± 0.74	4.24 ± 0.88	4.20 ± 0.58
	Friability (%)	0.76	0.91	0.94	0.57	0.85	0.63	0.30	0.47	0.29	0.84	0.63
	*DT (Hrs)	4.82	4.18	4.30	6.87	4.95	6.58	5.72	5.13	7.52	4.25	6.27
	Dissolution (%)	98.32	97.98	97.56	82.32	98.15	99.52	98.21	98.65	99.59	98.29	98.53
	Assay (%)	98.76	97.25	98.05	98.37	97.82	98.87	98.79	98.24	98.39	96.51	97.27
1 Month	Hardness (kg)	4.79 ± 0.61	4.15 ± 0.24	4.62 ± 0.94	5.36 ± 0.83	4.21 ± 0.78	5.55 ± 0.39	12.73 ± 1.75	12.49 ± 2.00	4.98 ± 0.83	4.20 ± 0.95	4.17 ± 0.62
	Friability (%)	0.77	0.91	0.94	0.68	0.9	0.65	0.38	0.54	0.35	0.87	0.69
	*DT (Hrs)	4.78	4.04	4.25	6.82	4.78	6.51	5.64	5.03	7.18	4.03	5.93
	Dissolution (%)	97.64	97.56	97.19	81.97	97.88	99.07	97.79	97.55	98.41	96.16	97.54
	Assay (%)	98.53	96.79	97.64	98.08	97.34	98.51	98.32	97.86	98.17	95.87	96.82
3 Month	Hardness (kg)	4.76 ± 0.64	4.04 ± 0.73	4.58 ± 0.96	5.21 ± 0.88	4.13 ± 0.93	5.45 ± 0.86	12.45 ± 1.14	12.34 ± 2.20	4.96 ± 0.61	4.18 ± 0.56	4.02 ± 0.39
	Friability (%)	0.81	0.93	0.97	0.63	0.94	0.69	0.42	0.63	0.42	0.93	0.78
	*DT (Hrs)	4.63	3.97	4.13	6.71	4.71	6.48	5.48	4.97	6.43	3.93	5.67
	Dissolution (%)	97.39	96.42	96.7	80.63	96.94	98.83	97.00	96.13	97.57	95.04	95.73
	Assay (%)	97.96	96.24	97.11	97.64	96.82	98.16	97.87	97.02	97.4	95.29	95.99
6 Month	Hardness (kg)	4.68 ± 0.86	3.93 ± 0.65	4.53 ± 1.02	5.14 ± 0.93	4.01 ± 0.82	5.36 ± 0.54	12.30 ± 1.11	12.11 ± 1.64	4.83 ± 0.56	4.00 ± 0.98	3.79 ± 0.65
	Friability (%)	0.87	0.97	0.99	0.69	0.97	0.74	0.55	0.78	0.59	1.08	0.85
	*DT (Hrs)	4.58	3.85	4.05	6.59	4.63	6.36	5.37	4.86	6.07	3.72	5.10
	Dissolution (%)	96.84	95.47	95.93	80.28	96.1	98.54	96.13	94.33	96.52	91.76	93.33
	Assay (%)	97.84	95.73	96.85	97.38	96.51	98.02	97.46	96.77	96.83	94.83	95.00
Shelf Life (Months)		26.680	18.896	21.712	29.450	19.775	30.347	24.172	17.053	21.900	13.551	16.209

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Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

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[t06TFN06] *DT = Disintegration time