CONTROLLED RELEASE FORMULATIONS OF ANTIRETROVIRAL (ARV) DRUGS USING POLYMETHACRYLATE POLYMERS

ABSTRACT

To improve patient compliance and ensure better success in the management of HIV, spansule technology was employed to formulate controlled release dosage drug. Generic forms of seven of the most commonly used Anti-retro viral (ARV) drugs (didanosine, indinavir, lamivudine, nelfinavir, nevirapine, stavudine and zidovudine) and their clinically approved  combinations  were  used  in  this  study.  Calculated daily dose was divided into one loading and four maintainace doses. Granules of the drugs, prepared using wet granulation  method,  were divided into five batches and spray coated with various grades of polymethacrylate polymers (Eudragit brand). Using different combinations/ratios, each ARV drug and their  combinations  were  filled into capsules of sizes 00 to 000. Parameters such as  solubility, disintegration, coating thickness and  dissolution  were  determined.  In- vitro testing for drug release was conducted to  mimic  various  pH conditions of the G.I.T using disodium hydrogen orthophosphate and potassium  dihydrogen  phosphate  buffers.  Spectrophotometric  method was used to determine drug release. To serve  as  control,  conventional forms of the seven ARVs obtained from a major manufacturer were tested for drug release.

Conventional didanosine achieved a maximum drug release of 25% within ten minutes, as against 97% of the spansule controlled release capsule, over a period of ten hrs. In contrast, drug released from the conventional indinavir formulation produced 100% drug release within fourty minutes, while the formulated spansule released only 19% of  the drug. Similarly lamivudine conventional formulation released 90% in ten min, while the  controlled  release  spansule  formulation  took  eight  hours to reach the same level. Similar results were obtained with nelfinavir, nevirapine, stavudine and zidovudine. Drug release pattern of the binary mixture of stavudine with didanosine and the triple (combinations nevirapine + zidovudine + didanosine;  stavudine  +  lamivudine  + nevirapine and zidovudine + lamivudine + nevirapine) were generally similar to each individual component release profile. It was observed that the release  pattern of  each  component was  not  affected  by the  presence of other components in the formulations.

Except for indinavir, all other sustained release coatings were able to maintain drug levels for extended period of time.

Generally granules coated with polymethacrylate, Eudragit L 100 released their drug content at pH >5 very quickly, while granules coated with Eudragit S 100 released their drugs predominantly at pH >7.5, akin to the small intestinal pH; formulations containing Eudragit RL, RS and NE released their drug contents gradually over time.

The spansule formulations containing polymethacrylate polymers as controlled release agents could  reduce  pill  burden  of  HIV/AIDS  therapy, as dosage regimen compliance is improved from four times daily dosing to once daily dosing.