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Design and Evaluation of Novel Dosage Form of Rifampicin and Isoniazid with Improved Functionality
| Content Provider | Semantic Scholar |
|---|---|
| Author | Gohel, Mukesh C. Sarvaiya, Krishnakant G. Nagori, Stavan A. |
| Copyright Year | 2010 |
| Abstract | The aim of present investigation was to develop a novel dosage form of rifampicin and isoniazid to minimize degradation of rifampicin in acidic medium and to modulate the release of rifampicin in the stomach and isoniazid in intestine. Gastroretentive tablets of rifampicin were prepared by direct compression using polyethylene oxide, calcium carbonate and ascorbic acid. The powder blend and tablets of rifampicin were characterized. Isoniazid tablets, prepared by direct compression using dicalcium phosphate, were enteric coated using hydroxypropylmethylcellulose (HP-55S) and characterized. Two tablets each of rifampicin and isoniazid were put into a hard gelatin capsule (size 00) and characterized for in vitro drug release and in vitro drug degradation studies. Rifampicin was released over 4 h from the novel dosage form. Less than 8% of isoniazid was released from novel dosage form before reaching to intestinal pH 7.4. Complete drug release of isoniazid was observed within 90 m at pH 7.4. The degradation of rifampicin to 3-formyl rifampicin SV (3FRSV) in presence of isoniazid was arrested (less than 0.21% degradation of rifampicin at the end of 120 m) from novel dosage form because of the minimization of physical contact between the two drugs and controlled release of rifampicin in acidic medium. Key words-Rifampicin, Gastroretentive tablets, Isoniazid, Hydroxypropylmethylcellulose phthalate, Degradation, Modified dissolution apparatus INTRODUCTION Tuberculosis is a common and deadly infectious disease caused by mycobacterium, mainly Mycobacterium tuberculosis. Isoniazid is a first-line antitubercular drug. It inhibits the synthesis of mycolic acid in the mycobacterium cell wall. It is never used alone to treat active tuberculosis because of quick resistance to body. The chief adverse reactions associated with isoniazid therapy include rashes, hepatitis, sideroblastic anemia and peripheral neuropathy. Rifampicin, a novel antitubercular drug, inhibits DNAdependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins. Rifampicin is lipophilic in nature and thus is ideal candidate to treat the meningitis form of tuberculosis, which requires distribution to the central nervous system and penetration through the blood-brain barrier. The chief adverse reaction associated with rifampicin therapy is hepatitis. Combination product of isoniazid and rifampicin are widely prescribed for treatment of tuberculosis. However, major problem of such products is degradation of rifampicin in presence of isoniazid in acidic media 1-2 because of formation of hydrazone. Rifampicin is well absorbed from the stomach because of its high solubility between pH 1-2 whereas isoniazid is well absorbed from 3 all three segments of the intestine. The basic intention of formulation chemist is to develop bioavailable dosage form. Bioavailability not only depends on solubility and permeability of drugs but it also can be manipulated by properly choosing formulation ingredients. The drug should be released at a site of absorption at a rate which is equal to the absorption rate. The present work was undertaken to prevent degradation of rifampicin in presence of isoniazid in 22 Indian Journal of Pharmaceutical Education and Research Received on 22/12/2008; Modified on 24/03/2009 Accepted on 21/07/2009 c APTI All rights reserved acidic medium by formulating novel solid dosage form (tablets within a capsule) comprising of gastro-retentive modified release rifampicin tablets and enteric coated isoniazid tablets. MATERIALS AND METHODS Materials: Rifampicin and isoniazid were received as gift from Sunij Pharma Ltd. (India). Polyethylene oxide (PEO WSR N80), hydroxypropylmethylcellulose phthalate (HP55S) and dicalcium phosphate dihydrate (DCP) were received as gift from Cadila Pharmaceuticals Ltd. (India). Calcium carbonate, chloroform, acetone and isopropyl alcohol were procured from S.D. Fine Laboratory (India). Anhydrous sodium sulphate was procured from Laser Laboratories (India). Ascorbic acid was purchased from Dewang Corporation (India). Empty hard gelatin capsules were gifted by Capsule Corporation of India (India). Methods: Rifampicin floating matrix tablets were prepared by direct compression method. Rifampicin (75% w/w), polyethylene oxide (15% w/w), ascorbic acid (1.5% w/w), calcium carbonate (8% w/w) and magnesium stearate (0.5% w/w) were geometrically mixed and compressed to tablet of 200 mg average weight and 70 N crushing strength, by direct compression method on single station tablet machine (Cadmach, India). The powder blend of rifampicin matrix tablet was characterized for angle of repose and Carr's index while the tablets were characterized for percentage friability and in vitro drug release. The composition of rifampicin tablets was selected on basis of preliminary studies carried out by varying concentration of polyethylene oxide and calcium carbonate from 10-20% w/w and 3-13 % w/w respectively (data not shown). The core tablets of isoniazid, with average weight of 230 mg and 80 N crushing strengths were prepared by direct compression. Isoniazid (3 g), DCP (1.5 g) and magnesium stearate (0.1 g) were geometrically mixed in motar and pestle. The composition of isoniazid core tablets was selected on basis of preliminary studies carried out by varying ratio of isoniazid and dicalcium phosphate dihydrate from 1:0.2-1:0.5. The tablets of isoniazid were coated with dispersion of HP-55S using conventional coating pan (Manesty model number 354255). Three batches were formulated with different weight gain (batch A1-3%, A2-6% and A3-9% respectively) to achieve enteric effect. The dissolution criteria were arbitrarily selected as not more than 10% of the drug release should occur in 120 m at pH 1.5. The coated tablets (batches A1-A3) were characterized for enteric test and in vitro drug release. The coating dispersion contained HP-55S (3.5% w/v), dibutyl phthalate (10% w/w of polymer), magnesium stearate and titanium dioxide (1% w/w of polymer) and blend of acetone and isopropyl alcohol blend (1:1, quantity sufficient). Two gastro-retentive tablets of rifampicin and two enteric coated isoniazid tablets (batch A3) were filled in a “00” size hard gelatin capsules to formulate novel dosage form (Fig. 1) and evaluated for in vitro drug release and in vitro drug degradation. EVALUATION: The angle of repose was measured using the fixed height 4-5 funnel method. Carr's index was found by adding 2 g of sample to 10 ml measuring cylinder. After noting the initial volume, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 second intervals. The tapping was continued until no further change in volume was noted. Friability was carried out in USP friabilator (Electrolab, Model EF2, India). Lag time to float and duration of floating was measured by adding samples into 900 ml of 0.1 N hydrochloric acid maintained at 37 ± 0.5o C. Enteric test was performed using phosphate buffer (pH 6.8) following storage of the tablets in 0.1N HCl (pH 1.5) for 2 h. The results are depicted in Table 1. The in vitro drug release and in vitro degradation study was carried out using modified dissolution apparatus along USP dissolution test apparatus-II (Electrolab, Model TDT 06T, India). The modified dissolution apparatus contained a modified glass beaker (Fig. 1) filled with 75 ml of hydrochloric acid (pH 1.5). Hydrochloric acid was added from the top at a flow rate of 2 ml/m. The dissolution media in modified dissolution apparatus was maintained at 37 ± 0.5° C and rotated at 75 rpm (Remi magnetic stirrer, India). After 2 h, isoniazid tablets were removed from modified dissolution apparatus and transferred to USP dissolution test apparatus containing 900 ml of phosphate buffer (pH 7.4, 37 ± 0.5° C). The Indian J.Pharm. Educ. Res. 44(1), Jan-Mar, 2010 |
| File Format | PDF HTM / HTML |
| Volume Number | 44 |
| Alternate Webpage(s) | http://www.ijper.org/sites/default/files/IJPER_44_1_3.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
