DESIGN AND EVALUATION OF SUSTAINED RELEASE MULTIPARTICULATE SYSTEM OF TIZANIDINE HYDROCHLORIDE

DESIGN AND EVALUATION OF SUSTAINED RELEASE MULTIPARTICULATE SYSTEM OF TIZANIDINE HYDROCHLORIDE

M. Thriveni ¹, A. Brahma Reddy ², D. Srinivas Reddy ¹, D. Vasavi Reddy*¹

Department of Pharmaceutics, Vaageswari College of Pharmacy ¹, Beside L.M.D Police Station, Thimmapur, Karimnagar Dist., 505481, Andhra Pradesh, India

Glukem Pharmaceuticals Pvt. Ltd ², Phase II, Cherlapally, Hyderabad, 500051, Andhra Pradesh, India

ABSTRACT: The aim of the present investigation is to formulate and evaluate Tizanidine hydrochloride sustained release pellets. Tizanidine hydrochloride is an immadazole α₂-adrenergic agonist used in the management of increase in muscle tone associated with spasticity. It has short biological half-life of 2- 2.5 hrs and is rapidly eliminated from the body. Sustained release dosage form of Tizanidine hydrochloride was developed for reduction in total amount of dose administration, to improve patient compliance, and increase efficiency in the treatment. The pellets were prepared by pan coating and fluidized bed coating technique (Wurster type) using hydroxy propyl methyl cellulose E₅ (HPMC E₅), Ethyl cellulose N-50, Eudragit L-100 as polymers and Isopropyl alcohol, Methylene dichloride as solvents. The pellets are filled in capsules and evaluated for weight variation, content uniformity, moisture content, lock length, disintegration and in-vitro dissolution tests and the results were found to be within the limits. A comparative study of dissolution profile of different batches with marketed product was performed. The optimized batch showed good similarity with the marketed product (Zanaflex Capsules). The dissolution data was fitted with various kinetic models, and the optimized formulation followed zero order kinetics by non-Fickian case-II diffusion process. Stability studies were conducted for 3 months according to ICH guidelines and found to have good results.

Tizanidine hydrochloride, Pellets, Sustained release, Pan coating, Wurster type

INTRODUCTION: Oral route is the most frequently used route of drug administration. Oral route dosage forms are usually indicated for systemic effects resulting from drug absorbance through various epithelia and mucosa of the gastro intestinal tract.

Comparing with other routes, the oral route is the most convenient and safest means of drug administration. Oral sustained release dosage forms are widely used for delivery of medicament. The dosage forms can be categorized into single and multiple units based on number of unit per dosage form.

The multiple unit dosage forms are preparation that consists of several mini reservoirs ¹. A multiple unit dosage form readily separates into sustained release units throughout the gastrointestinal tract after ingestion.

One of the multiple unit dosage forms is the pellets, which reduces variations in gastric emptying time and transit time, has less susceptible to dose dumping & provides less irritation from high local concentration of drugs ². Pellets are small, free flowing, spherical particulates manufactured by agglomeration of fine powders or granules and size ranging from 0.5 mm-1.5 mm.

The most important reason for the wide acceptance of multiple-unit products is the rapid increase in popularity of oral controlled-release dosage form. Controlled release oral solid dosage forms are usually intended either for delivery of the drug at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period of time. The above mentioned goals can be obtained through the application of coating materials mainly polymers, providing the desired function or through the formulation of matrix pellets to provide the desired effect ³.

Spasticity is characterized by increased muscle tone and dysfunctional muscle spasm resulting from unregulated brain impulse to the muscles caused by damage to the spinal cord or to portions of the brain that control voluntary movement ⁴.

Tizanidine HCl reduces spasticity by increasing presynaptic inhibition of motor neurons through agonist action at α₂-adrenergic receptor sites. It has short biological half-life (2-2.5 hrs) and it is rapidly eliminated from the body. For reduction in total amount of dose administration, to improve patient compliance, and improved efficiency in the treatment, we need to develop Tizanidine hydrochloride sustained release pellets. Tizanidine hydrochloride is centrally acting imidazole α₂-adrenergic agonist which is orally administered & indicated for the management of increased muscle tone associated with spasticity ⁵.

The main objective of the study is to compare the drug release profile of the best with the marketed product. It involves the preparation of sustained release pellets consisting of Tizanidine HCl with different polymer ratios and to perform preformulation studies for drug i.e., drug excipients compatibility studies by FTIR & DSC and to evaluate the drug release profile of Tizanidine HCl and to extend the drug release up to 12 hrs.

MATERIALS AND METHODS:

Materials: Tizanidine hydrochloride is a gift sample from Glukem Pharmaceuticals, Hyderabad. Sugar core of size range 20#24 were used as the initial core for drug loading in coating pan. Sustained release coating was done in fluidized bed coater, using HPMC E-5, Ethyl cellulose N-50, and Eudragit L-100 is obtained from Clariant Chemicals Pvt. Ltd, Mumbai. PVP K-30 is obtained from BASF Chemical Company in India.

Methodology: The formulation development involves the preformulation, drug loading and sustained release coating. Preformulation studies were conducted for pure drug and excipients. Drug and excipients compatibility studies were performed using Fourier transform infra-red spectroscopy (FTIR) and Differential scanning calorimetry (DSC).

Formulation Studies:

Drug Loading: According to the formula (Table 1) dispense all the materials as per manufacturing composition.Pulverize the drug i.e., Tizanidine hydrochloride, sugar powder, and talc.Add PVP K-30 in Isopropyl alcohol and stir well to get the clear solution.Transfer the basic core sugar pellets into coating pan, and then spray with the binder solution prepared above.Over wetting of the cores to be avoided as it may cause agglomeration.Add thepulverized powdermixture slowly by spraying the binder solution.The pellets are then dried in a tray dryer for about 45 min at a temperature 45-55^oC to attain the moisture content less than 2.5 %.The dried pellets are sized on a sifter to remove agglomerates, broken pellets and fine powder. These pellets are ready for coating ⁶.

Coating of Tizanidine hydrochloride pellets: According to the formula (Table 2) Coating solution was prepared by taking Isopropyl alcohol and Methylene dichloride into a stainless steel container and Hydroxyl propyl methyl cellulose (HPMC E-5), Ethyl cellulose N-50 and Eudragit L-100 were added at different concentrations.

Transfer the drug loaded pellets into the Fluidized bed coater and coated with the above prepared coating solution.Set the inlet temperature to 45-55^oC & bed temperature 37-42^oC.

Coat the drug loaded pellets with sustained release coating solution by bottom spray (Wurster type) with peristaltic pump 25-30 rpm and atomizing air pressure of 1.5 Kg/cm² till the coating solution was completed.Over wetting of drug coated pellets to be avoided as it may cause agglomeration. After complete quantity of the coating solution was consumed, reduce the fluidization for a brief post-drying period ⁶.

TABLE 1: DRUG LOADING COMPOSITION

TABLE 2: SUSTAINED RELEASE COATING COMPOSITION

 Evaluation of Pellets: The pellets were evaluated for flow properties, moisture content, size distribution and assay.

Bulk density and Tapped density: Accurately weighed quantity of the pellets (W), were taken into the graduated cylinder and the volume (V_o) was measured. Then the graduated cylinder was closed with the lid and set into the density determined apparatus. The density apparatus was set for 500 taps and after that, the volume (V_f) was measured. The bulk density and tapped density were calculated using the following formula ⁷:

Where, M = weight of the pellets, Vo = initial volume   Vf = final volume

Compressibility index: The compressibility of a material can be estimated from the tapped and bulk density measurements by using following formula ⁷:

Where, ρt = Tapped density and ρo = Bulk density

Hausner’s ratio: The Hausner’s ratio was calculated using the formula ⁷:

Where, ρt = Tapped density, ρo = Bulk density

Angle of repose: Accurately weighed quantities of pellets were poured into funnel and the height of funnel is adjusted to a height of 2.5 cm and the radius of the circle is measured by taking the diameter values of average of four values. The formula for calculating angle of repose is ⁷.The formula for calculating angle of repose is,

Where, h =Height of the funnel, r =Half of the diameter of circle

Moisture Content (% w/w): Take suitable quantity of Methanol in titration flask of Karl Fischer Titrator and titrate with Karl Fischer reagent upto end point. Grind the pellets to fine powder in a dry mortar, weigh accurately about 0.5 g of the sample, transfer quickly to the titration flask, and dissolve by stirring and titrate with Karl Fischer reagent upto end point ⁸.

Where, F = Factor of Karl Fischer reagent, V = Volume in ml of Karl Fischer reagent consumed for sample titration.

Size Distribution: Arrange the sample collector, 20 ASTM sieve, 16 ASTM sieve, Weigh and transfer around 100 g of the sample into 16 ASTM sieve and shake for 5 minutes. Collect the 16 ASTM retains (W₁₆) from 16 mesh and pass through 20 ASTM (W₂₀).The sample was collected and the % passed and % retained was calculated using formula ^[9].

Assay: Transfer an accurately weighed quantity of the powdered pellets equivalent to about 100 mg Tizanidine hydrochloride into a 100 ml volumetric flask, 60 ml of methanol was added & sonicated for 15 minutes and cool the solution to room temperature and dilute with methanol upto the mark. Transfer 10 ml of above solution to a 100 ml volumetric flask and make upto the mark with methanol. Then transfer the 10 ml of the above solution into a 100 ml volumetric flask and make up the volume to 100 ml with methanol, then absorbance was set to 320 nm in UV visible spectrophotometer. Using calibration curve the drugcontent was determined from absorbance values of pellets.

Evaluation of Capsules:

Weight variation test: Individual weights of 20 capsules were taken and the average weight was calculated by using the following formula ¹⁰.

Weight variation should not be more than 10%. Limits: Less than 300 mg ±10%, more than 300 mg ±7.5%

Lock length: It was tested by using Vernier callipers ¹¹.

Content uniformity: The amount of drug determined by assay is within the range of 85- 105% of the label claim for 9 out of 10 dosage forms and no formulation outside the range of 70 -125% of label claim.

Disintegration: : The capsules are placed in the basket rack assembly which is repeatedly immersed about 30 times per minute into a thermostatically controlled fluid at 37±2^oC and observed ¹².

In-vitro Dissolution Studies: The dissolution test was carried out for capsules by using USP type-I apparatus (basket type) in 0.1N HCl for first 2 hrs and then continued in 6.8 pH phosphate buffer up to 12 hrs. Capsules contain pellets equivalent to 6 mg of Tizanidine hydrochloride placed in a basket containing 900 ml of dissolution media maintained at 37±0.5^oC and rpm was set to 100. Samples of 5 ml were withdrawn at specified time intervals and replaced with fresh medium and analyzed for drug content by using U.V spectrophotometer at 320 nm.

In-vitro Release Kinetics: The dissolution data of optimized batch (F7) were fitted to various kinetic models like zero order, first order, Higuchi’s, Korsemeyer- Peppas model and Hixson Crowell to known the kinetics of drug release ¹³.

Comparison of dissolution profiles by stastical analysis: In order to compare the dissolution profiles, model-independent methods were used. The similarity factor (f2) provides a simple measure of similarity between pairs of dissolution profiles. The dissolution profiles of product were compared using the formula f2. The similarity factor is calculated using the following formula ¹⁴ (table 3):

n - number of dissolution time points, R_t - reference profile at the time point t, T_t- test profile at the time point t

TABLE 3: SIGNIFICANCE OF SIMILARITY FACTOR (f2)

Stability Studies: Stability studies were carried out for 3 months as per ICH guidelines for optimized formulation by placing at different temperatures and evaluated for the parameters assay, disintegration, moisture content, and dissolution ¹⁵.

Storage Conditions: The stability samples are stored ataccelerated: 40±2°C/75±5% RH, Intermediate: 30±2°C/65±5% RH, Long term: 25±2°C/60±5% RH.

RESULTS AND DISCUSSION: Attempts were made to sustain the release of Tizanidine hydrochloride by pelletization technology. The prepared pellets were optimized and characterized.

Drug-Excipients Compatibility Studies:

 FT-IR Studies: The FT-IR studies were carried out for pure drug alone and along with polymers. The results are summarized as follows.

FT-IR spectra of pure drug (Tizanidine hydrochloride) and individual polymers such as HPMC E-5, Ethyl cellulose N-50, and Eudragit L-100 were shown in the Fig. 1 and peaks were listed in Table 4. The peaks given in the Table 4 matches with that of the literature values for the functional groups present in Tizanidine hydrochloride. This result along with the results of melting point and UV scan confirms that the sample drug under consideration is Tizanidine hydrochloride only.

The peaks listed in the Table 4 for pure drug can be considered as characteristic peaks. The peaks for the drug in the presence of polymers were not affected and prominently observed in FT-IR spectra given in Fig. 1. This indicates that there is no interaction between Tizanidine hydrochloride and polymers and the drug was compatible with the formulation components.

FIGURE 1. A) PURE DRUG B) HPMC E5 C) ETHYL CELLULOSE N-50 D) EUDRAGIT L-100 E) OPTIMIZED PRODUCT

 TABLE 4: FTIR DATA OF TIZANIDINE HCl ALONG WITH POLYMERS

Differential Scanning Calorimetry (DSC) Studies: DSC studies for pure drug, and optimized formulation ‘F7’ was carried out. The thermo grams were shown in Fig. 2-A & 2-B respectively for pure drug and optimized formulation ‘F7’. Fig. 2-A indicates that the melting of drug has taken place at 289.9^oC. It was matching with the literature value 280-290^oC. Fig. 2-B indicates that the melting point of the blend (F7) is 270.5^oC. Further no more peaks were found in Fig. 2-B. This indicates that there is no interaction between drug and Excipients.

FIGURE 2:  DSC OF A) PURE DRUG B) OPTIMIZED PRODUCT

Evaluation of Pellets:

Flow Properties: The formulated pellets from batch F1-F9 have showed the range of Bulk density 0.64-0.76, Tapped density 0.81-0.89, Carr’s index was 10.7-21.9, Hausner’s ratio 1.10-1.28 and Angle of repose 20-25^o. It shows pellets have excellent flow properties. The results are shown in Table 5.

Moisture Content: It is determined by using the Karl-Fischer method and all formulations showed <5% moisture.

Size distribution: Initially the sugar core size is 20#24, after drug loading and coating the pellets sizes from F1-F9 batches falling in the range of 16#20.

TABLE 5: EVALUATION OF PELLETS (F1-F9)

All values are expressed as mean ± SD, n=3

Evaluation of Capsules: Capsules are evaluated for weight variation, content uniformity, moisture permeation, lock length, and disintegration. The results were listed in Table 6. All formulated batches showed the drug content within the range of 94.5-102.4%, Weight variation was found to be within the limits, lock length of the capsules were found to be in the range of 15.8-16.1 mm. Disintegration time for capsules found to be in the range of 198-239 sec.

TABLE 6: CAPSULES EVALUATION PARAMETERS

All values are expressed as mean ± SD, n=3

In-vitro dissolution studies: The dissolution profiles of formulated batches were compared with that of the marketed product. The F1 batch pellets were prepared by using HPMC E-5 at a concentration of 0.5% shows 99.9% drug release at the end of 4^th hr, and to control the drug release we prepared the pellets with the combination of polymers. From F2-F5 formulations were prepared by using the combination of HPMC-E5, and Ethyl cellulose N-50. Form F6-F9 formulations were prepared by using the combination of Eudragit L-100 and Ethyl cellulose N-50. F2 shows 99.5% drug release at the end of 10^th hr. The dissolution result of batch from F3-F6 does not match with the innovator product. The drug release profile was shown below in Fig. 3, 4, 5.

The F7 batch were prepared by using 2% of Ethyl cellulose N-50 and 2%  Eudragit L-100 match with the dissolution profile of marketed product and the release profile was shown in Fig. 6. Further increasing the concentration of polymers from F8-F9 the drug release was decreased.

Scanning Electron Microscopy: Scanning electron microscopy images of the optimized formulation were shown in Figure 7.

FIGURE 3: DISSOLUTION PROFILES OF F1 TO F3

FIGURE 4: DISSOLUTION PROFILES OF F4 TO F6

FIGURE 5: DISSOLUTION PROFILES OF F7 TO F9

FIGURE 6: DISSOLUTION PROFILES OF OPTIMIZED PRODUCT (F7) WITH MARKETED (ZANAFLEX)

FIGURE 7:  IMAGES OF SEM AT DIFFERENT MAGNIFICATIONS a) 30x, b) 33x, c) 40x, d) 43x, e) 50x, f) 70x, g) 75x, h) 80x, i) 85x, j)150x, k) 220x, l) 360x

Drug Release Kinetics: The regression values of optimized formulation were given in Table 7. The release kinetics followed zero order kinetics by non-Fickian case-II diffusion process & was shown in Fig. 8.

TABLE 7: DRUG RELEASE KINETICS OF FORMULATED PELLETS FOR OPTIMIZED BATCH (F7)

FIGURE 8: PLOT OF CUMULATIVE% DRUG RELEASE VS TIME FOR F7

TABLE 8: CHARACTERISTICS OF PELLETS FOR OPTIMIZED BATCH (F7)

Stability Studies: Stability studies were carried out as per ICH guidelines for F7 batch for 3 months of this product at long term: 25±2°C/60±5% RH, intermediate: 30±2°C/65±5% RH and accelerated: 40±2°C/75±5% RH storage conditions as shown in Fig. 9, 10, 11.

FIGURE 9: PLOT OF CUMULATIVE% DRUG RELEASE VS ROOT TIME FOR F7

FIGURE 10: PLOT OF LOG CUMULATIVE % DRUG RELEASE VS LOG TIME FOR F7

FIGURE 11: PLOT OF LOG % DRUG RELEASE VS TIME FOR F7

FIGURE 12: PLOT OF Q1/3-QT1/3 VS TIME FOR F7

There was no change observed in the assay, disintegration, moisture content, content uniformity, dissolution profiles were listed in Table 9.

 TABLE 9: EVALUATION PARAMETER VALUES AT DIFFERENT TEMPERATURE CONDITIONS

FIGURE 13: IN-VITRO DISSOLUTION PROFILE OF F7 AND MARKETED AT 25°C/60% RH

FIGURE 14: IN-VITRO DISSOLUTION PROFILE OF F7 AND MARKETED AT 30°C/65% RH

FIGURE 15: IN-VITRO DISSOLUTION PROFILE OF F7 AND MARKETED AT 40°C/75% RH

The aim of the present investigation was to design and evaluate sustained release multi particulate system of Tizanidine hydrochloride. The parameters like assay, weight variation, content uniformity, lock length, disintegration test and in-vitro dissolution studies were within the limits. The kinetics data of various models revealed that the formulation followed zero order kinetics by non-Fickian case-II diffusion process. Optimized batch (Formulation F7) complies with innovator product (Zanaflex capsules) and thus considered as an ideal formulation.

ACKNOWLEDGEMENTS: The authors are grateful to Mr. Susanta Kumar Hazra, Assistant Director, Glukem Pharmaceuticals, Hyderabad, for providing a gift sample of Tizanidine HCL. They are also indebted to Mrs. D. Vasavi Reddy and Mr. A. Brahma Reddy for their valuable support and suggestions for carrying out this research work.

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    How to cite this article:

    Thriveni M, Reddy AB, Reddy DS and Reddy DV: Design and Evaluation of Sustained Release Multiparticulate system of Tizanidine hydrochloride. Int J Pharm Sci Res 2013; 4(4); 1614-1625.

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