Development of an extended release naproxen sodium matrix tablet and evaluation of the effects of various fillers and additives on drug release kinetics.

摘要

Hydroxypropyl methyl cellulose (HPMC) has been used as a hydrophilic matrix system in extended release formulations. Limited work has been performed and published on hydroxypropyl cellulose (HPC) as a hydrophilic matrix system. This work is intended to develop an extended release naproxen sodium tablet using either hypromellose or hydroxypropyl cellulose as rate controlling polymers and to elucidate the effect of water insoluble (microcrystalline cellulose) and water soluble fillers (lactose monohydrate) as well as insoluble additives (corn starch and pregelatinized starch) on the rate and mechanism of drug release from the matrix.;The naproxen sodium-hypromellose formulation with drug to polymer ratio 1:0.38 when prepared by dry blending yielded an extremely poor flow (Hausner ratio: 1.65) and very low bulk density (0.33 g/mL) whereas upon granulation with IPA, it yielded a bulk density of 0.41g/mL and Hausner ratio of 1.38 which shows the improvement in the physical properties as compared to that of dry blend. Hence, the hypromellose matrix formulations for naproxen sodium tablets were prepared by wet granulation with isopropyl alcohol (IPA). The percent naproxen release from the tablets with drug to polymer ratio of 1:0.38 and microcrystalline cellulose (26% w/w) as filler after 4, 8 and 12 hours were 35%, 59% and 78%. Similarly, the percent naproxen sodium release from tablets with drug to polymer ratio of 1:0.38 and lactose monohydrate (26% w/w) as filler were 43%, 63% and 83%. The results demonstrated that there was no significant difference (F2 value = 59.28) between the release rates from the hypromellose formulations with lactose monohydrate (soluble) or microcrystalline cellulose (insoluble) as fillers.;The wet granulation approach with IPA when applied to hydroxypropyl cellulose (HPC) blend yielded a rubbery mass after drying. Hence, the hydroxypropyl cellulose formulations for naproxen sodium with drug to polymer ratio of 1:0.38 were prepared by dry blending process by adding microcrystalline cellulose or lactose monohydrate at 26% w/w. The final blend of hydroxypropyl cellulose tablets with drug to polymer ratio of 1:0.38 prepared by dry blending yielded a bulk density of 0.42 g/mL and Hausner ratio of 1.50. The percent naproxen sodium release from the HPC tablets with drug to polymer ratio of 1:0.38 and microcrystalline cellulose (26% w/w) after 4, 8 and 12 hours were 51%, 81% and 99% as compared to 50%, 89% and 97% from HPC tablets with drug to polymer ratio of 1:0.38 and lactose monohydrate (26% w/w) as filler. This demonstrated that there no significant difference (F2 value = 72.06) between the release rates from hydroxypropyl cellulose formulations with lactose monohydrate (soluble) or microcrystalline cellulose (insoluble) as fillers.;The release rate from reference formulation with naproxen sodium (51.6% w/w), hydroxypropyl cellulose (20% w/w) and microcrystalline cellulose (26% w/w) as filler was significantly affected when corn starch and pregelatinized starch were added as additives at 1%, 5% and 10% levels. The percent naproxen sodium release after 4, 8 and 12 hours from the tablets with corn starch (10% w/w) as additive were 48%, 76%, 90 % and with pregelatinized starch (10% w/w) as additive were 43%, 68% and 89% as compared to 51%, 81% and 99% from the reference formulation. The comparatively higher retarding effect of pregelatinized starch on the drug release can be attributed to the presence of approximately 20% of gelatinous (gum) part in it which acts synergistically with the gel formed by hydroxypropyl cellulose.;The percent naproxen sodium release form hydroxypropyl cellulose tablets with corn starch (1%, 5% and 10% w/w) and pregelatinized starch (1%, 5% and 10% w/w) as additives to the reference formulation were applied to various kinetic models like Higuchi equation, Power law. First order release equation and Hixson Crowell equation. The Higuchi constant 'k' value obtained from tablets with corn starch (10% w/w) and pregelatinized starch (10% w/w) were 29.642 and 27.141 respectively as compared to 30.173 from reference formulation. The release exponent 'n' of power law from tablets with corn starch (10% w/w) and pregelatinized starch (10% w/w) were 0.6651 and 0.6841 respectively as compared to 0.6935 of reference formulation. The comparative decrease in the higuchi constant 'k' and increase in value of release exponent 'n' from the power law for dissolution rate from the formulations with the increasing amount of corn starch and pregelatinized starch as additives to the reference formulation indicates that the release rate of naproxen sodium decreases with the increase in amount of insoluble additives. The 'n values' obtained upon application of dissolution values to Power law equation with r2 value ranging from 0.9925 to 0.9962 indicates that the naproxen sodium release from the formulations with insoluble additives at different levels is by anomalous path indicating existence of two mechanisms, drug diffusion and polymer relaxation.Thus it can be inferred that naproxen sodium release rate from the hydrophilic matrix can be modulated by varying the amount of insoluble additives in the formulation.