Optimasi Formula Tablet Lepas Lambat Ranitidin HCl Dengan Sistem Floating dan Korelasi In Vitro-In Vivo
Teuku Nanda Saifullah Sulaiman, Prof. Dr. Achmad Fudholi, DEA., Apt.
2012 | Disertasi | S3 Ilmu FarmasiRanitidin HCl merupakan antagonis reseptor H2, digunakan secara luas dalam pengobatan tukak pada duodenum dan lambung, sindrom Zollinger- Ellison, gastroesophageal reflux disease dan erosive esophagitis. Sediaan konvensional ranitidin HCl dalam terapi sekresi tukak lambung memiliki bioavailabilitas yang rendah sehingga perlu dikembangkan bentuk sediaan sustained release ranitidin HCl yang bertahan lama di dalam lambung. Tujuan penelitian ini adalah untuk mengoptimasi formula tablet lepas lambat ranitidin HCl dengan sistem floating dan korelasi in vitro-in vivo Tablet floating ranitidin HCl diformulasi menggunakan sistem effervescent dengan metode granulasi basah. Simplex lattice design digunakan untuk optimasi formula sediaan tablet floating ranitidin HCl dengan variasi kadar Methocel K15M, natrium bikarbonat, dan asam sitrat. Granul dan tablet yang dihasilkan dilakukan uji sifat fisik granul dan tablet. Uji disolusi dilakukan dalam medium HCl 0,1N dan simulated gastric fluid (SGF) tanpa pepsin dengan alat USP tipe 2 dan Rossett-Rice test. Volume medium 900 ml, temperatur 37oC ± 0,5oC dan kecepatan pengadukan 75 rpm. Formula optimum (F18) diuji kemampuan absorpsi in vivo menggunakan kelinci. Formula optimum ditentukan berdasarkan superimposed contour plot berbagai parameter sifat alir granul, sifat fisik tablet dan pelepasan obat dengan menggunakan program Design Expert®. Data disolusi dianalisis dengan menggunakan beberapa parameter kinetika dan mekanisme pelepasan obat, antara lain: zero order, first order, Higuchi release, HixsonCrowell cube root, dan KorsmeyerPeppas untuk menentukan kinetika pelepasannya dan curve fitting dengan WinSAAM. Data hasil uji in vitro dan in vivo dilakukan analisis korelasi IVIVC. Berdasarkan superimposed contour plot diperoleh area formula optimum pada rentang 100145 mg Methocel K15M, 2080 mg natrium bikarbonat dan 2580 mg asam sitrat. Hasil uji disolusi menunjukkan bahwa perbedaan alat disolusi mempengaruhi profil disolusi ranitidin HCl dari tablet gastroretentive dalam medium HCl 0,1 N (nilai f2 kurang dari 50 %) tetapi tidak mempengaruhi kinetika dan mekanisme pelepasannya. Perbedaan medium disolusi tidak mempengaruhi profil disolusi ranitidin HCl dari tablet gastroretentive (nilai f2 lebih dari 50 %). Analisis data disolusi berbasis kompartemen diperoleh hasil pelepasan ranitidin HCl dari sediaan tablet gastroretentive mengikuti model tiga kompartemen. Hasil analisis korelasi IVIVC dari fraksi obat yang terdisolusi dan yang diabsorbsi diperoleh korelasi yang linear.
Ranitidine HCl is an H2 receptor antagonist drug, widely prescribed for gastric and duodenum ulcers, ZollingerElliso n syndro me, gastroesophageal reflux disease and erosive esophagitis. Conventional tablet of ranitidine HCl has a low bioavailability in the treatment of peptic gastric urcers, thearfore the development of a sustained release ranitidine HCl dosage forms with prolonged stomach retention time is required. The objectives of this research was to optimize the formula of ranitidine HCl sustained release tablet matrix with floating system and in vitroin vivo correlation. Floating tablet of ranitidine HCl was formulated by effervescent system using wet granulation method. Simplex lattice design method was applied to optimize the formula of ranitidine HCl by varying concentration of Methocel K15M, sodium bicarbonate and citric acid. Granules and tablets were tested its the physical properties. Dissolution test was performed in medium of 0.1 N HCl and simulated gastric fluid (SGF) without pepsin using USP type 2 and RossettRice test apparatus. Volume of dissolution medium was 900 ml, temperature 37 °C ± 0.5 ° C and stirring rate of 75 rpm. The optimum formula (F18) was tested for absorption using in vivo in rabbits. The optimum formula was determined by superimposed contour plot with various parameters; flowability of granules, physical properties of tablet and drug released using DesignExpert ® programe. Dissolution data were also analyzed using several kinetics dan mechanism of drug release parameters, such as: zero order, first order, Higuchi release, HixsonCrowell cube root, and Korsmeyer Peppas to determine releasing kinetics and curve fitting with WinSAAM. The data from dissolution and in vivo absorption were analysed based on in vitroin vivo correlation approach. Based on the superimposed contour plot obtained area of the optimum formula was ranges from 100145 mg Methocel K15M, 2080 mg sodium bicarbonate and 2580 mg citric acid. The results of dissolution test showed that differences of dissolution apparatus affected the ranitidine HCl dissolution profiles from gastroretentive tablets (f2 value less than 50%) but did not affect the kinetics and mechanism of release. The difference of dissolution medium did not affect the ranitidine HCl dissolution profile from gastroretentive tablets (f2 value more than 50%). Results of dissolution analysis using the compartmental based model indicated that the release of ranitidine HCl from gastroretentive tablet followed three compartments model. The results of IVIV correlation analysis from the fractions of absorbed and dissoluted drug showed a linear correlation.
Kata Kunci : ranitidin HCl, gastroretentive, simplex lattice design, disolusi, IVIVC
