CONTROLLED RELEASE FORMULATIONS OF ANTIRETROVIRAL (ARV) DRUGS USING POLYMETHACRYLATE POLYMERS
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Ahmadu Bello University Zaria
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
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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.