Журнал молекулярной фармацевтики и исследований органических процессов

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Development and Study of an Erodible Matrix Drug Delivery Platform for SustainedRelease of Non-Steroidal Anti-Inflammatory Drugs Using Melt Granulation Process

Hilsana Achulatla*, Vinay U. Rao and M. Sudhakar

ABSTRACT
The aim of developing the platform was to possess
a generalunderstanding on how an erodible matrix
system modulates drugdelivery rate and extent and the
way it are often optimized to give adelivery system
which shall release the drug as per a common target
product profile (TPP). Mefenamic Acid (one of the
NSAID’s) is ready by using Melt Granulation Process.
Commonly used waxeslike Cetostearyl alcohol and
octadecanoic acid were used singly an incombination
to realize a TPP of not 15 to 35% in 1 hour and not
lessthan 80% Q in 24hours. Full factorial design of
experiments wasfollowed for optimization of the
formulation. Dissolution profile ofthe NSAID is taken
and recorded. Market available brands of thesame
NSAID is taken for dissolution profile. The results
arerecorded. The two recorded results are then
compared and verifiedwith the USP standards.
A simplest and most widely usedmethod of controlling
drug delivery is byincorporating drug in the polymer
matrix.Thus, drug dissolution and drug diffusion
through the polymer are important phenomena in
controlling the releasecharacteristics of the
formulation. The present work deals with developing a
waxmatrix drug delivery platform for
controlleddelivery of Mefenamic Acid which is a Non-
Steroidal Anti-inflammatory Drug (NSAID).Even
though a number of Non-SteroidalAnti-inflammatory
drugs (NSAID’s) areavailable with different
chemistries, theyshare common solubility
characteristics thatthey are relatively more soluble in
alkalineenvironment and practically insoluble inacidic
environment.
The present work deals withdeveloping a wax matrix
drug delivery platform for controlled delivery
ofMefenamic Acid. It is used to treat pain.Since
hepatic metabolism plays a significantrole in
Mefenamic acid elimination, patientswith known liver
deficiency may be prescribed lower doses. Mefenamic
aci isa competitive inhibitor of COX-1 andCOX-2,
which are responsible for the firstcommitted step in
prostaglandin biosynthesis. Decreasing the activity
ofthese enzymes thus reduces the productionof
prostaglandins, which are implicated ininflammation
and pain processesThe full factorial design
ofexperiments was conducted in order tostudy the
effect of combination of polymerson the in vitro drug
release. Factorialdesign is an effective tool to obtain
anopposite mathematical model withminimum
experiments for optimization offormulation design.
Factorial design allowsall the factors to be varied
simultaneously,thus enabling the evaluation of the
effects ofeach variable at each level and showinginterrelationship
among them. Mostimportant variables
which affect the systemfunction are selected and
systemicexperiments are then performed. Thenumber
of independent variables selecteddecides the number of
experiments that areto be performed
Mefenamic Acid tablet was preparedin two ways using
the direct compressionmethod. In the first way three
grades ofHPMCwere taken (k4, k15 and k100
m),magnesium stearate was used as lubricantand
Lactose as diluent. In the second way,Cetostearyl
alcohol, Stearic acid, sugar(diluent) and Magnesium
stearate (lubricant)were used.Mefenamic acid, HPMC
and lactosewere mixed and then Magnesium
Stearatewas added as lubricant and the wholemixture
was punched into tablets with anaverage weight of 750
mg using Cadmachtableting machine. This was
repeated for allthe three grades of HPMC.Cetostearyl
alcohol was heated at ahigh temperature and after 24
hours mixedwith Mefenamic acid, Stearic acid
sugar.Magnesium stearate was added to thatmixture
and the whole mixture was punchedinto tablets with an
average weight of 750mg using Cadmach tableting
machine.The
in vitr dissolution study of thecompressed matrix tablet
of Mefenamic acidwas carried out in 900ml of pH 7.4
phosphate buffer maintained at 37 ± 0.5°C.The drug
release at various time intervalswere analyzed
spectrophotometrically at285 nm (Lab India UV
3000+ UV/Visiblespectrophotometer, Japan).Aliquots
of 5 mlwas withdrawn at specified time interval andthe content of Mefenamic acid wasdetermined at 285nm
spectrophotometrically.An equal volume of fresh
dissolutionmedium, maintained at the
sametemperature, was added after withdrawingeach
sample to maintain the volume. Theabsorbance values
were transformed toconcentration by reference to a
standardcalibration curve obtained experimentally
(r2values in all the buffer was 0.98). Thedissolution
studies were performed intriplicate and mean values
was plotted versustime.
The target dissolution profile parameters of a
sustained-release productwere set as follows: After 1
h: 15-35 %; After5 h: 45-65%; After10 h: 65-85%;
after 16h:75-95%; and after 24h: not less than 80%
In the present study the effects ofvariables on the
release of Mefenamic acidfrom erodible matrix drug
platform had beenstudied using Factorial design. The
design ofexperiment has become a rapid,
systematicand reliable screening tool to identify
andquantitatively define the significant
factorsinfluencing the drug release. The derived
polynomial equations and contour plots aidsin
predicting the values of independentvariables for
preparation of optimumcontrolled release matrix tablet
of Mefenamicacid with the desired release profile
matchingthe targeted dissolution profile
Keywords: NSAIDs, Controlled delivery, Target
product profile, Melt granulation