Jornal de Farmacêutica Molecular e Pesquisa de Processos Orgânicos

Abstrato

Pharmacokinetic Evaluation of Diclofenac Matrix Tablets Employing Cross Linked Starch-Urea

K.P.R Chowdary1 , Veer Reddy. K *2, Bhaskara Reddy Nallamilli2

ABSTRACT
Modified starches are promising and having
good potential as release retardants and rate
controlling polymers for controlled release. The
controlled release properties of modified starches,
generally based on solvent-activation have been
intensively investigated. Aim: this aimed to research
the in vivo performance of the new polymer (Cross
linked starch-urea or CLSU) within the formulation of
controlled release dosage forms. Methods: Diclofenac
matrix tablets employing CLSU were prepared by
gelatinizing potato starch within the presence of urea
and salt . 15 mg strength of diclofenac matrix tablets
(B) were formulated employing CLSU and pure drug
(A) were tested for in vivo pharmacokinetic evolution.
Plasma drug concentration of Diclofenac decided by
HPLC method. From the time Vs plasma
concentration data various pharmacokinetic
parameters like peak concentration (Cmax), time at
which peak occurred (Tmax), area under the curve
(AUC), elimination rate constant (kel), biological halflife
(t1/2), percent absorbed to varied times and
absorption rate constant (Ka) were calculated in each
case as per known standard methods. Results: The
absorption rate constant (Ka) was found to be 0.152h-
1 for A and 0.817 h-1 for B, and MRT was increased
from 9.68 h for A to 14.05 h for B. Tmax raised to 6 h
for B from 3 h for A. Based on AUC0 α the relative
bioavailability of the diclofenac from CLSU was
found to be 124.9% compared to diclofenac pure drug
(100%). Conclusion: Thus the results indicated that
starch urea cross-linked with salt may be a promising
matrix former for controlled release.
Controlled drug delivery is a topic of current interest
in pharmaceutical technology and industry. In the last
two decades, controlled release dosage forms have
made significant progress in terms of clinical efficacy
and potential compliance. Controlled release drug
delivery systems are those formulations designed to
release a lively ingredient at rates, which differ
significantly from their corresponding conventional
dosage forms. The controlled release drug delivery
systems are aimed toward controlling the speed of
drug delivery, sustaining the duration of therapeutic
activity and / or targeting the delivery of the drug to a
tissue. Drug release from these systems should be at a
desired rate, predictable and reproducible.
The formation of cross-linked starches with calcium
salts is known in polymer chemistry. As the cross-linked
polymers generally swell in water and aqueous fluids
and form gelatinous matrices suitable for controlled
release, it is thought worthwhile to investigate starch
urea cross linked with calcium chloride for its
application in controlled release.
Diclofenac sodium known as diclofenac is a widely used
non-steroidal anti-inflammatory analgesic and antipyretic
drug. Controlled release formulation is needed
for diclofenac because of its short biological half-life9 of
2.0 h. The drug also causes10 gastro intestinal
disturbances, peptic ulceration with bleeding if present
in large concentration in gastrointestinal tract. Hence,
diclofenac is a suitable drug for oral sustained and
controlled release and it would be advantageous to slow
down its release in gastrointestinal tract not only to
prolong its therapeutic action but also to minimize
possible side effects of diclofenac.
from M/s Micro Labs Ltd., Pondicherry, Methanol,
Potassium dihydrogen phosphate, caustic soda , urea,
salt were procured from Qualigens fine chemicals Ltd.
Potato starch was procured from Loba Chemie.
Crosslinked starch urea (prepared in the laboratory) and
all other chemicals used in the study were of analytical
grade
Preparation of Cross-linked starch urea polymer: Potato
starch (9 parts) was dispersed in purified water (10
parts) to make starch slurry. Urea (1 part), salt (1 part)
were dissolved in purified water (40 parts) and therefore
the solution was heated to boiling. While boiling, the
starch slurry was added and mixed. Mixing while
heating was continued for 20 minutes to form CLSU
polymer. The mass formed was spread on to a stainless
steel plate and dried at 850C for 6-8 h. The dried
polymer was powdered and skilled mesh No. 120.
Preparation of matrix Tablets: Matrix tablets of 15mg
diclofenac were prepared employing 50% CLSU. The
drug and matrix material were mixed in mortar and the
binder, water-alcohol (1:1) solution was added and mixed thoroughly to form dough mass. The mass was
skilled mesh No.12 to get wet granules. The dried
granules were passed through mesh No.24 to break
aggregates. Passed granules were blended with talc
2% and magnesium stearate 2% in a closed polythene
bag. The tablets granules were compressed in to
tablets on rotary multi-station punching machine
Pharmacokinetic evaluation was done on diclofenac
matrix tablets (B) formulated employing CLSU as
compared to diclofenac pure drug (A) with a view to
guage the discharge retarding and rate controlling
efficiency of CLSU in vivo. When the diclofenac
matrix tablets formulated employing CLSU were
administrated orally at the same dose of 15 mg, the
plasma concentrations were found to be lower than
those observed with the diclofenac pure drug (Fig. 1)
indicating slow absorption of diclofenac from the
matrix tablets. A Cmax of 2.9 ± 0.6 μg/ml
wasobserved at 6.0 h following the oral administration
of matrix tablets. The absorption rate constant (Ka)
was found to be 0.152 h-1 . The plasma concentrations
were stabilized and maintained within a narrow range
for longer periods of time in the case of matrix tablets
(Fig. 1). The mean duration (MRT) was increased
from 9.68 h for diclofenac pure drug to 14.05 h with
the matrix tablets. The MRT value indicated longer
stay of drug within the body when administered as
matrix tablets. Based on AUC0 α the relative
bioavailability of diclofenac from CLSU urea matrix
tablets was found to be 124.9 that when compared to
diclofenac pure drug (100 %). The elimination rate
constant (Kel) for diclofenac was found to be 0.1274
h-1 and the corresponding half- life was found to be
5.44 h following the oral administration of diclofenac.
The mean residence time (MRT) was found to be 9.68
h. The adsorption rate constant (Ka) was found to be
0.8172 h-1 . A Cmax of 4.7 ± 1.4 μg/ml was observed
at 3.0 h after oral administration of diclofenac pure
drug.
The pharmacokinetic evaluation, thus, indicated that
diclofenac from the matrix tablets formulated
employing CLSU was released slowly and absorbed
slowly over longer periods of time in vivo resulting in
the maintenance of plasma concentrations within a
narrow range over longer periods of time. As such
CLSU exhibited good release retarding and rate
controlling effect in vivo in the pharmacokinetic
evaluation.
Keywords: Diclofenac, Matrix tablets, Cross-linked
Starch-Urea, Controlled drug delivery