Evaluation of physicochemical and microbiological stability of liquid preparation from tizanidine hydrochloride tablets - a Hospital concern

Tizanidine hydrochloride is a centrally acting skeletal muscle relaxant, used in the management of spasticity. This drug is commercially available only as tablets, which highlights the need to develop oral liquid formulations. In the hospital environment, this aspect is circumvented by the preparation of suspensions, to allow administration to children and adults with impaired swallowing, but there are no data regarding their stability. The purpose of this study was to evaluate the physicochemical andmicrobiological stability of liquid dosage forms prepared in the hospital environment from tizanidine hydrochloride tablets, applying high performance liquid chromatography (HPLC) and microbiological analysis. A simple and stability-indicating HPLC method was developed and validated for specificity, linearity, limits of detection and quantification, precision, accuracy and robustness. The liquid formulations were placed in amber PET and glass bottles, which were stored under three different conditions: at room temperature, under refrigeration and at 40 ºC. The liquid formulations were analyzed and demonstrated chemical stability for 56 days, allowing their use for long periods. However, the determination of microbiological stability showed that these formulations are prone to microbial contamination, which has dramatically reduced its stability to 7 days, in both bottles and at all evaluated temperatures

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

The aim of the present study was to develop tizanidine controlled release matrix. Formulations were designed using central composite method with the help of design expert version 7.0 software. Avicel pH 101 in the range of 14-50% was used as a filler, while HPMC K4M and K100M in the range of 25-55%, Ethylcellulose 10 ST and 10FP in the range of 15 - 45% and Kollidon SR in the range of 25-60% were used as controlled release agents in designing different formulations. Various physical parameters including powder flow for blends and weight variation, thickness, hardness, friability, disintegration time and in-vitro release were tested for tablets. Assay of tablets were also performed as specified in USP 35 NF 32. Physical parameters of both powder blend and compressed tablets such as compressibility index, angle of repose, weight variation, thickness, hardness, friability, disintegration time and assay were evaluated and found to be satisfactory for formulations K4M2, K4M3, K4M9, K100M2, K100M3, K100M9, E10FP2, E10FP9, KSR2, KSR3 & KSR9. In vitro dissolution study was conducted in 900 ml of 0.1N HCl, phosphate buffer pH 4.5 and 6.8 medium using USP Apparatus II. In vitro release profiles indicated that formulations prepared with Ethocel 10 standard were unable to control the release of drug while formulations K4M2, K100M9, E10FP2 & KSR2 having polymer content ranging from 40-55% showed a controlled drug release pattern in the above mentioned medium. Zero-order drug release kinetics was observed for formulations K4M2, K100M9, E10FP2 & KSR2. Similarity test (f 2) results for K4M2, E10FP2 & KSR2 were found to be comparable with reference formulation K100M9. Response Surface plots were also prepared for evaluating the effect of independent variable on the responses. Stability study was performed as per ICH guidelines and the calculated shelf life was 24-30 months for formulation K4M2, K100M9 and E10FP2.

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 vitro indicaram 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.

Design and evaluation of tizanidine buccal mucoadhesive patches.

Mucoadhesive buccal dosage forms are becoming more popular and patient acceptable dosage forms. By this route advantages are many as the dose can be reduced, avoidance of first pass metabolism and liver toxicity, etc. The Tizanidine has first pass metabolism because of this the patient has to take more dose and two to three times in a day. To overcome this problem mucoadhesive patches of tizanidine are prepared and evaluated. Tizanidine is a non-selective, α-two adrenergic agonist receptor and used as muscle relaxant. The oral bioavailability of Tizanidine is 40%, because of first pass metabolism. The polymers used are polyvinyl alcohol and polyvinyl pyrolidine. FTIR and UV spectroscopic methods reveal that there is no interaction between tizanidine and polymers. The patches evaluated for various parameters and results are satisfied. In vitro release studies in phosphate buffer (pH, 6.6) exhibited drug release in the range of 71.68 to 97.27% in 90 min. The release of tizanidine from the patches followed first order, Higuchi’s model and mechanism diffusion rate limited. In vivo buccal absorption studies in rabbits showed 68.85% of drug releases from polyvinyl alcohol patch while it 67.52 to 88.31% within 90 min in human volunteers. Good correlation among in- vitro release and in- vivo studies observed.

Effect of Combination of Baclofen, Tizanidine and Eperisone on Moderate to Severe Spasticity after Spinal Cord Injury / 中国康复理论与实践

@#Objective To investigate the effect of combination of baclofen, tizanidine and eperisone on moderate or severe spasticity after spinal cord injury. Methods 18 inpatients with moderate (n=2) or severe (n=16) spasticity after spinal cord injury were treated with combination of 2 or 3 kinds of drugs for 2 months, and followed up for at least 4 months with modified Ashworth scale (MAS). Their blood pressure, blood and urine routine, liver and kidney function were observed. Results Among the 16 cases of severe spasticity (MAS≥3), MAS reduced 3 grades in 3 cases, 2 grades in 12 cases, 1 grade in 1 case, with alleviation of phantom pain. For the cases of moderate spasticity (MAS=2), the MAS reduced 1 grade with alleviation of phantom pain. Slightly drowsiness was observed in 2 cases. No hepatic or renal dysfunctions was found. Conclusion Combination of baclofen, tizanidine and eperisone is effective on moderate or severe spasticity after spinal cord injury with limited side-effects.

Efficacy of three antispasmodics on limb spasticity in patients after stroke: A comparative analysis / 中国脑血管病杂志

Objective: To compare and evaluate the efficacy and adverse reactions of tizanidine, baclofen and eperisone for treatment of limb spasticity in patients after stroke. Method: One hundred and three patients with stroke were enrolled in this prospective, randomized, controlled study. They were randomly divided into 4 groups: Tizanidine (n = 30), baclofen (n = 25), eperisone (n = 22) and control (n = 26) groups. The muscular tone, motor function and daily live activities (ADL) were evaluated with the modified Ashworth scale (MAS), Fugl-Meyer ssessment (FMA) and modified Bathel index (BI) respectively 4 and 12 weeks before and after the medication. Results: Circled digit oneTwelve weeks after the medication, the MAS scores of the upper and lower limbs of the patients were decreased in the 3 treatment groups as compared to the control group (P 0.05). Circled digit twoThe FMA scores of the upper limbs in patients of the 4 groups showed that there were no significant differences before and after the treatment (P > 0.05 all); the FMA scores of the lower limbs in patients of the 4 groups after the 12-week treatment were significantly higher than those before treatment. The average increased scores were 5 ± 3, 6 ± 5, 5 ± 4, and 4 ± 4, respectively (P 0.05). Circled digit threeCompare to the scores before the treatment, the MBI showed that there were significant differences in the average scores in the 4 groups 12 weeks after the treatment (P 0.05). Circled digit fourBlood, urine, liver and renal function tests of all patients were in the normal range before and after treatment. 10% and 8% of patients in the tizanidine and baclofen groups experienced drowsiness; 6.7%, 8%, and 4.5%. of patients in the tizanidine, baclofen, and eperisone groups had gastrointestinal discomfort; 6.7% and 8% of patients in the tizanidine and baclofen groups had blood pressure drop; and 22.7% of patients in the eperisone group had generalized weakness. The symptoms were relieved in all patients after reduce or stop the medication. Conclusion: Tizanidine, baclofen and eperisone have obviously effects for reducing muscular tone and relieving spasticity. Their therapeutic effects has no differences, but the three medicines did not show significant effect on functional recovery.

Quantitative Assessment of the Effect of Tizanidine on Spasticity in Stroke Patients

OBJECTIVE: The aims of this study were to evaluate quantitatively the effect of tizanidine on spasticity reduction and to evaluate the effective and tolerable dosage of it in stroke patients. METHOD: A prospective, randomized controlled study was carried out. 24 stroke patients were included and randomly assigned to a control and experimental group. In experimental group, tizanidine was medicated from starting dose of 3 mg/day and titrated up by 3 mg/day increments every 3 days to a maximal dose of 15 mg/day. In both group assessment of spasticity was done by clinical and biomechanical-neurophysiological methods one day before medication (baseline), on 9th and 15th days after medication. Biomechenical-neurophysiological assessment was done through isokinetic dynamometer and BIOPAC system. RESULTS: In control group, no significant changes were found in the degree of spasticity between each assessment. In experimental group, most of the parameters that determine the degree of spasticity revealed the significant reduction of spasticity on the post-medication assessment compared with the baseline assessment (p<0.01). The degree of spasticity reduction was increased with the increase of dosage. The incidence of adverse effect was also increased with the increase of dosage, but tolerable within the dosage of 15 mg/day. CONCLUSION: Tizanidine was effective in reducing spasticity in stroke patients. Its efficacy and adverse effects were dosage-related.