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The object of this study was to develop a high dose pellet
dosage form for a drug with poor powder characteristics and low
density. The specific aims were to study the effects of the
physical modification of powder and manufacturing process on the
physical characteristics of the treated powder and so obtained
pellets, and their in vitro dissolution. Extrusion-
spheronization technology was chosen as a basic method since it
has been proved to be effective in the prodution of pellet with
a higher density. Etofibrate was selected as a model drug due to
its low bulk density andpoor flow characteristics. Etofibrate
was subjected to four different methods to modify its physical
characteristics. Among them, the processing method of melting
and then solidifying at -80 ℃ significantly improved the
density and flow characteristic of the powder. This was possible
due to the increase of the mean size and the density of the
powder. However, the increase of mean size leaded to the
eecrease of total surface area resulting in the decrease of
binding area of powder particles. Since that, the density of
pellet did not increase with the increase of powder density.
Furthermore, the yield of pellets decreased significantly. An
experimental design of central composite was employed to
quantitatively examine the influence of formulation factors and
manufacturing conditions on the pellet properties. The results
were analyzed by response surface methodology. Three formulation
factors and two spheronization conditions were simultaneously
examined. The results demonstrated that the use of powder with a
smaller mean size to prepare pellet was able to obtain pellets
with a higher density. Increasing the used amount of binder and
water could significantly increase the yield of pellets, but
they showed no influence on the density of pellets. Regarding
the manufacturing conditions, the effect of spheronization time
on the density of pellets was more profound than that of
spheronization speed. Especially, when the spheronization time
was increased, the density of pellets could be effectively
increased for most of formulations. As a result, one dose amount
of etofibrate could be filled into a zero size of capsule by the
simultaneous manipulation of powder characteristics and
manufacturing conditions.A controlled release pellet dosage form
of etofibrate was accomplished by coating etofibrate pellets
with a polymeric material. Further spheronization of such a
coated pellet under heating was conducted to examine its effect
on the properties of pellets and the curing effect on the
controlling membrane. It was found that secondary spheronization
could further improve the density of coated pellets. However,
both increasing the temperature and extending the spheronization
time tended to increase the chance for pellets to adhere to the
wall of machine resulting in a significant decrease of the
pellet yield. Additionally, the results of in vitro dissolution
showed that since the temperature could be employed was limited
by the melting point of etofibrate at no more than 49 ℃, the
short residence time of spheronization employed was not able to
effectively cure the coated polymeric membrane. Finally, the use
of ethylcellulose as a controlling material for etofibrate
pellets to sustain the release of etofibrate was demonstrated to
be effective. Among them, the in vitro drug release profile for
these pellets coated with 2.5% ethylcellulose was comparable to
that for the commercial product of Lipo-Merz Retard(. With a
higher coated amount (5.0 and 7.5%), the drug release time could
be further prolonged to 10 and 16 hours respectively.
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