CONTROLLED RELEASE FORMULATIONS OF ANTIRETROVIRAL (ARV) DRUGS USING POLYMETHACRYLATE POLYMERS
CONTROLLED RELEASE FORMULATIONS OF ANTIRETROVIRAL (ARV) DRUGS USING POLYMETHACRYLATE POLYMERS
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Date
2010-09
Authors
SANI-GWARZO, Mahmud
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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. Invitro
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
ix
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.
Description
A DISSERTATION SUBMITTED TO THE POSTGRADUATE
SCHOOL
AHMADU BELLO UNIVERSITY, ZARIA, NIGERIA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
AWARD OF THE
DOCTOR OF PHILOSOPHY IN PHARMACEUTICS
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL
MICROBIOLOGY,
AHMADU BELLO UNIVERSITY,
ZARIA, NIGERIA
Keywords
CONTROLLED RELEASE FORMULATIONS,, ANTIRETROVIRAL,, DRUGS,, POLYMETHACRYLATE POLYMERS.