INTRODUCTION:
Circadian rhythms are self-sustaining, endogenous
oscillations that occur with a periodicity of about 24
Hours. Interestingly, the term circadian is derived
from the Latin circa which means "about" and dies
which can be defined as "a day”. Normally, circadian
rhythms are synchronized according to internal
biologic clocks related to the sleep-wake cycle. Our
circadian rhythm is based on sleep-activity cycle and
is influenced by our genetic makeup and thereby
affects our body’s function throughout day and night
(24-hour period).1,5 Circadian rhythm regulates many
body functions in humans like metabolism,
physiology, behavior, sleep pattern, hormone
production.There are number of conditions which
show circadian pattern and advantage could be taken
by timing and adjusting the administration of drugs
according to the circadian rhythm of the disease.
Diseases, such as cardiovascular, asthma,cancer,
peptic ulcer, arthritis etc follow the body’s circadian
rhythm. Coordination of biological rhythms and
medical treatment is called chronotherapy while
chronotherapeutics is the discipline concerned with
the delivery of drugs according to inherent activities
of a disease over a certain period of time. A major
objective of chronotherapy in the treatment of several
diseases is to deliver the drug in higher concentrations
during the time of greatest need according to the
circadian onset of the disease or syndrome.8,10
Pulsatile drug delivery system is the type of drug
delivery system, where the delivery device is capable
of releasing drug after predetermined time-delay (i.e.
lag time). These systems are gaining lot of interest and
attention these days. These systems have a peculiar
mechanism of delivering the drug rapidly and
completely after a "lag time," i.e., a period of "no drug
release. 1,2
Press coated tablets gained wide interest claiming
some advantages over regular and (pan) coated
tablets, such as to protect hygroscopic, light-sensitive
or oxygen-labile drugs from environmental
atmospheric ill effects or decomposition of acid-labile
drugs by gastric fluids; to separate incompatible drugs
from each other; to achieve a sustained release in that
the drug in the core is embedded in waxes or fats
constituting a depot; to protect the gastric mucosa
from irritation by certain drugs by using enteric
coating material in the outer press-coating granules; or
to achieve intermittent release by incorporating one
portion of drug in the core and the other in the coat,
separated by a film-coat or a second press-coat.
However, common drawbacks of the press-coating
technique are the multi step processes involved, and
the requirement for reliable and reproducible central
positioning of the core tablet within press-coated
tablet (PCT), a major challenge for large scale
industrial manufacturing. The lag time of drug release
from PCTs depends upon the thickness and the
composition of the barrier layer. Generally speaking,
the thicker the barrier layer, the longer the lag time.
The aim of the present investigation was to develop
and evaluate an alternative, simple, orally applicable
one pulse drug delivery system based on a presscoated tablet preparation. Recent studies in the area of
oral controlled drug delivery include novel
approaches, which prolong the GRT and
Chronotherapeutic delivery system which release the
drug in a pulsatile fashion, is recently gaining much
attention worldwide. Pulsatile drug delivery system
are characterized by two release phases, a first phase
with no or little drug being released, followed by a
second phase, during which the drug is released
completely within a short period of time after the lag
time.4,6
Rheumatoid arthritis is a chronic inflammatory
autoimmune disorder. The cardinal signs of
rheumatoid arthritis are stiffness, swelling and pain of
one or more joints of the body characteristically most
severe in the morning. Rheumatoid arthritis shows a
marked circadian variation in its symptoms . A group
of British volunteers self-assessed the pain and
stiffness of affected finger joints every 2 to 3 h daily
for several consecutive days. They also measured the
circumference of the arthritic joints to gauge the
amount of their swelling, and they performed grip
strength tests to determine the effect of the arthritic
condition on the hands [11, 12]. Ratings of the
severity of joint pain swelling and stiffness were about
3 times higher between 08:00 and 11:00 am than at
bedtime. In contrast, hand strength was lower by as
much as 30% in the morning than at night. This is
typical of rheumatoid arthritis sufferers [13-15]. The
symptoms of rheumatoid arthritis are always worse in
the morning. Taking long-acting Non Steroidal
Antiinflammatory Drugs (NSAIDs) like flubiprofen,
ketoprofen and indomethacin at bedtime optimizes
their therapeutic effect and minimizes their side
effects.2,5,7
12-hour sustained-release NSAIDs that are taken
twice a day must include a night or bedtime ingestion
time to ensure adequate control of the prominent
morning symptoms of rheumatoid arthritis. If the
arthritic condition is severe, synthetic corticosteroids
are often of benefit. Morning once-a-day dosing of
these medicines is least likely to cause side effects
especially if they are taken for a long period of time.
Splitting the daily dose of medicine into several small
ones for ingestion with meals and at bedtime or taking
the entire daily dose at night is not recommended
unless absolutely necessary. The risk of severe side
effects from these medications increases when they
are taken more than 8 to 9 h after the customary time
of awakening, after 15:00 pm for most people. The
later in the day these medications are taken, the
greater the risk of side effects. If the relief from the
morning symptoms of rheumatoid arthritis sufferers is
not attained by a once-day morning schedule, an
increase in the morning dose is recommended. The
results of one study suggest an early afternoon once-aday treatment schedule might be beneficial for those
people who fail to get significant relief from the
morning pain and stiffness of rheumatoid arthritis
when taking medicine in the morning.3,4,9
Tramadol hydrochloride is a synthetic analgesic with
half life of 5-6 hrs and has a modest affinity for the μ
receptor. Its additional effect on the descending
inhibitory pathways relies on inhibition of serotonin
and norepinephrine re-uptake.The dose of tramadol is
50-100mg dailynby oral route in divided doses.It’s
half life is 5.5-7 hours. Thus it gives dual mode of
analgesic action. It doesn’t only provide analgesia
over a wide range of pathologies but it has significant
advantages like no respiratory depression or cardiac
side effects. It is BCS class-I drug having good
absorption throughout the GIT. The most common
side effects of Tramadol HCl are nausea and vomiting
which can be prevented by pulsatile delivery. Hence it
best suits for this approach..5,9,16
MATERIALS AND METHODS:
Materials:
Tramadol HCl was obtained as gift sample from Gen
Pharma,Pune. Cross-carmellose sodium (Ac-Di-Sol),
and magnesium stearate was purchased from Signet
Chemical Corporation (Mumbai,India). HPMC K4M
was
obtained from Lupin
Pharmaceuticals
(Aurangabad), microcrystalline cellulose (MCC,
Avicel PH-102), ethylcellulose (Ethocel) were gifted
by Cipla Pharma R & D (Mumbai, India).The colorant
Erythrocin red was obtained as a gift from Flamingo
Pharmaceuticals (Mumbai, India). All other chemicals
used were of analytical grade.
Method:
Formulation of core tablets by direct
compression:
The inner core tablets were prepared by using direct
compression method. As shown in Table 1 powder
mixtures ofTramadol HCl, microcrystalline cellulose
(MCC, Avicel PH-102), cross-carmellose sodium
(Ac-Di-Sol) and erythrocin red ingredients were dry
blended for 20 min. followed by addition of
Magnesium Stearate. The mixtures were then further
blended for 10 min., 100mg of resultant powder blend
was manually compressed using KBr hydraulic press
at a pressure of 1 ton, with a 9mm punch and die to
obtain the core tablet.
Table 1:Formulation table for core tabets of Tramadol HCl
INGREDIENTS
QUANTITY
Tramadol HCl
50mg
Microcrystalline cellulose
q.s.
Croscarmellose Sodium
25%
Magnesium Stearate
50%
Erythrocin Red
1%
Total weight of tablet
100mg
Formulation of mixed blend for barrier
layer:
As given in the Table 2 the various formulation
compositions containing HPMC K4 M and
Ethylcellulose. A1 to A7 different compositions were
weighed,and dry blended for about 10 min. and used
as press-coating material to prepare press-coated
pulsatile tablets (A1-A7) respectively by direct
compression method.
Preparation of press- coated tablets by
direct compresssion method:
The core tablets were press- coated with 4000mg of
powder mixture to produce corresponding PCT
formulations (A1-A7).200mg of barrier layer material
was weighed and transferred into 13mm die then the
core tablet was placed manually at the centre. The
remaining 200mg of the barrier layer wae added into
the die and compressed at a pressure of 5 tons for 2
min using KBr hydraulic press.
Table 2: Composition of the barrier layer
FORMULATION
HPMC K4 ETHYLCELLULOSE
BATCH CODE
M (%)
(%)
A1
100
0
A2
87.5
12.5
A3
75
25
A4
50
50
A5
25
75
A6
12.5
87.5
A7
0
100
Evaluation study:
Evaluation of powder mixtureThe PM was evaluated for angle of repose, loose bulk
density, tapped bulk density, void volume, bulkiness
and compressibility index.
Table 3:Evaluation of powder mixture
PARAMETER
OBSERVATION
Angle of repose
240
Loose bulk density(LBD)
0.4166 gm/cm3
Tapped bulk density(TBD)
0.4545 gm/cm3
Void volue
0.20 ml
Buikiness
2.400 cm3/gm
Compressibility Index(%)
8.3388%
Evaluation of core tabletThe core tablets of Tramadol HCl were evaluated for
thickness, hardness, average weight, friability and invitro drug release study.
Table 4:Evaluation Parameters
PARAMETER
Thickness
Hardness
Average weight
Friability
of core tablet
OBSERVATION
0.102±0.115 cm
4.50±0.25 kg/cm2
99.16 mg
0.7415%
RESULTS AND DISCUSSION:
Drug- excipient compatibility studyFTIR spectrum of Tramadol HCl, physical mixture
and press coated formulation are shown in Figure 1, 2
and 3 respectively. From the FTIR spectra of the
drug,excipients and press coated formulation, it was
found that drug and excipients are compatible with
each other.Also there is no interaction or chemical
change in the final formulation.
Evaluation of press coating barrier layer used for
direct compressionThe PM was evaluated for angle of repose, loose bulk
density, tapped bulk density, void volume, bulkiness
and compressibility index.The results are shown in
table 6.
Evaluation of press coated tabletsThe core tablets of Tramadol HCl were evaluated for
thickness, hardness, average weight, friability and invitro drug release study.
Table 5: Evaluation of press coated tablets
Batc Thickness
Avera
Hardness
h
(cm)
ge
(kg/cm2)
weight
(mg)
A1
0.303±0.11
498.16
10.50±1.81
A2
0.310±0.10
505.31
10.45±1.21
A3
0.302±0.14
497.08
10.66±1.32
A4
0.301±0.10
505.24
10.75±1.22
A5
0.305±0.10
500.21
9.94±2.34
A6
0.306±0.12
499.39
9,97±2.25
A7
0.311±0.13
497.25
9.98±3.21
Friability(%)
Figure 1: FTIR spectra of Tramadol HCl
0.6913±0.25
0.7004±0.14
0.6443±0.14
0.653±0.24
0.7544±0.13
0.7543±0.25
0.7454±0.15
In-vitro Drug release study of press coated
tablets of Tramadol HCl:
Dissolution studies were carried out by using USP
XXIII dissolution test apparatus USP II paddle
method method. In order to simulate the pH changes
along the GI tract, three dissolution media with pH
1.2, 6.8 and 7.4 were sequentially used referred to as
sequential pH change method. When performing
experiments, the pH 1.2 medium (0.1 N HCl) was first
used for 2 hrs (since the average gastric emptying
time is 2 hrs) then removed and the fresh pH 6.8
phosphate buffer was added. After 3 hrs (average
small intestinal transit time is 3 hrs) the medium was
removed and fresh pH 7.4 dissolution medium was
added for subsequent hrs. 900ml of the dissolution
medium was used at each time. Rotation speed was
100 rpm and temperature was maintained at 37± 0.5
°C. 5 ml of dissolution media was withdrawn at
predetermined time intervals and fresh dissolution
media was replaced. The withdrawn samples were
analyzed at 270 nm, by UV absorption spectroscopy.
Figure 2: FTIR spectra of Drug(Tramadol HCl) and
excipients
Figure 3: FTIR spectra of press coated formulation
Table 6: Evaluation of press coating barrier layer
Batch
A1
A2
A3
A4
A5
A6
A7
Angleof
repose (ɵ)
20.32
18.24
18.67
19.82
22.99
25.64
23.82
LBD
(gm/cm3)
0.4162
0.4166
0.4438
0.4002
0.4002
0.4028
0.4166
TBD
(gm/cm3)
0.4545
0.4763
0.4545
0.4544
0.4347
0.4763
0.4544
Void volume
(ml)
0.20
0.30
0.10
0.30
0.20
0.40
0.20
Carr’s Index(%)
Bulkiness
(cm3/gm)
2.4004
2.4004
2.4005
2.7
2.7
2.7
2.4004
8.3488
12.4973
4.3566
11.9914
7.9825
15.9804
8.3365
In- vitro drug release study of Press coated tablets of Tramadol Hydrochloride:
The results of in-vitro drug release studies of different batches are depicted in Figure 4:
120
100
80
A1
A2
% Cumulative drug 60
release
A3
A4
40
A5
A6
20
A7
0
0
100
200
300
400
500
600
700
Time (min)
Figure 4: Cumulative percentage release of Tramadol HCl from the Batches A1-A7
Table 7: Lag Times for drug release from the press coated
tablets of batches A1- A7
Batch
A1
A2
A3
A4
A5
A6
A7
HPMC K4M (%):
Ethylcellulose (%)
100:0
87.5:12.5
75;25
50:50
25:75
12.5:87.5
0:100
Lag time
(hours)
9
7
9
9
6
5
3
Formulation A5 showed the desired lag time of 6
hours. Also the drug release followed the required
conditions for pulsatile drug release for
chronotherapeutic drug delivery of Tramadol
hydrochloride for the treatment of rheumatic arthritis.
order, first order, Higuchi model, Hixon Crowell and
Korsemeyer-Peppas models in order to describe the
kinetics of drug release. Drug release from optimized
formulations fitted well into zero-order kinetics,
confirming that the release from formulations is close
to the desired release profile and drug load
dependent.18
140
% cumulative drug release
The lag times of the batches A1- A7 are depicted in
table 7.
120
100
80
60
y = 0.191x + 2.333
R² = 0.940
40
20
0
0
Curve fitting analysis:
Dissolution data of the optimized formulation (batch
A5) was fitted to various mathematical models as zero
200
400
600
800
Time(min)
Figure 5: Zero order drug release plot of optimized batch A5
7
³√% cumulative drug release
2.5
Log % drug retained
2
y = -0.0018x + 1.5105
R² = 0.2548
1.5
1
0.5
0
0
200
400
600
800
6
5
4
3
y = 0.0072x + 1.0962
R² = 0.7271
2
1
0
0
200
Time(min)
400
600
800
Time(min)
Figure 6: First order drug release plot of optimized batch
A5
Figure 8:Hixon-Crowell plot of optimized batch A5
2.5
120
% cumulative drug release
80
60
y = 5.3186x - 24.003
R² = 0.7486
40
20
0
0
10
20
30
log % cumulative drug release
2
100
y = 0.8174x - 0.409
R² = 0.6564
1.5
1
0.5
0
0
1
2
3
-0.5
-20
-40
-1
Square root of time
Figure 7: Higuchi diffusion plot of optimized batch A5
Log time
Figure 9: Korsmeyers-Peppas plot of optimized batch A5
Stability studies:
CONCLUSION:
The optimized batch A5 was charged for stability
studies. There was no change in physical appearance,
color, drug content and the drug release pattern.
Formulations were analyzed at the end of 3 months
for the assay and dissolution studies. In vitro
dissolution profile showed that there was no
significant change in the release rate of the drug from
The aim of this study was to explore the feasibility of
press coaed tablets of Tramadol HCl to treat
rheumatoid arthritis.Batch A5 which contained 25%
HPMC K4M and 75% ethylcellulose showed the
desired lag time of 6 hours.Formulated tablets gave
satisfactory results for various evaluation parameters
like tablet hardness, friability, weight variation,
Thickness, content uniformity, and in-vitro drug
release. Drug release profiles are fitted to kinetic
models like zero order, first order, Higuchi model,
Hixon-Crowell and Korsemeyer-Peppas models. It
was found that the formulation best fitted to zero
optimized tablets at the end of 3 months.The barrier
layer was found to remain stable and did not degrade.
order drug release model. Stability studies were
conducted for optimized formulation at different
conditions and the formulation is found stable in all
theconditions. It was concluded that the Batch A5 is
optimized because the drug release was found to fit
the principle for chronotherapeutic release.
11.
12.
ACKNOWLEDGEMENT:
The authors are grateful to Rajarambapu College Of
Pharmacy, Kasegaon, for providing necessary
facilities to carry out the research work and to Gen
Pharma, Pune for providing gift sample of the drug.
13.
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