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INTERNATIONAL JOURNAL OF RESEARCH ARTICLE PHARMACEUTICAL INNOVATIONS ISSN 2249-1031
1 | P a g e Volume 3, Issue 3, May ₋ June 2013 http://www.ijpi.org
DESIGN AND EVALUATION OF MODIFIED PULSINCAP OF TRAMADOL
HCL ACCORDING TO CIRCADIAN RHYTHM
Priyanka Modi*, Ghanshyam Patel, Dr. Ragin Shah,
Arihant School of pharmacy and bio- research institute, Gandhinagar, Gujarat
ABSTARCT
The objective was to design and evaluate modified pulsincap of Tramadol HCl according to
circadian rhythm using formaldehyde vapour for cross-linking to make capsule body water
insoluble and hydro gel plug to achieve a predetermined lag time for chronotherapy of
rheumatoid arthritis. The capsule body was made water insoluble by exposing the body to
formaldehyde vapour. A physical mixture of drug and excipients was filled in the treated
capsule body and hydro gel plug was fitted to the mouth of the treated body and the untreated
cap was fitted to the treated body which was coated with Eudragit S-100 to prevent variable
gastric emptying. Developed formulation was evaluated for in-vitro drug release in pH 1.2 (2
hrs), phosphate buffer pH 6.8 (3 hrs) and phosphate buffer pH 7.4. 32 full factorial design was
used for optimization. Formulation F1 and F5 both showed predetermined lag time of 6 hrs
but in formulation F1 less amount of SSG and HPMC K4M was used so it was selected as
optimized formulation showing the immediate release of the drug after the lag time of about 6
hrs.
Key words: modified pulsincap, chronotherapy, rheumatoid arthritis
INTRODUCTION
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.
To follow this principle one must have to
design the dosage forms so that it can be
given at the convenient time for example
bed time for the diseases with the drug
release in the morning.
Pulsincap is the one of the approaches for
pulsatile drug delivery. Pulsincap system
comprises of a water-insoluble capsule
body, soluble cap and hydro gel plug.
When this capsule came in contact with
the dissolution fluid, it dissolves and after
a lag time, the plug pushed itself outside
the capsule and rapidly releases the drug.
The length of the plug and its point of
insertion into the capsule controlled the lag
time. Pulsincap was studied in human
volunteers and was reported to be well
tolerated. [1-3]
Almost 20% people of the
total population of the world suffering
from arthritis. Rheumatoid arthritis is a
generic term that describes many different
*Corresponding Author
Priyanka Modi
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and usually painful conditions. It is based
on the circadian rhythm of the body
because peak pain occurs in early morning
and decreases as the time passes. These
will be possible by formulating pulsatile
delivery of drug, which release the drug
rapidly in early morning followed by
predetermined lag time and thus prevent
unusual exposure of drug to the patient. [4-
6]
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.
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 the
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. [7]
The capsule bodies of size ‘1’ were treated
with formaldehyde vapor to make capsule
body water insoluble. The amino group in
the gelatin molecular chain could react
with an aldehyde group of formaldehyde
by a schiff’s base condensation reaction to
produce a water insoluble body. The
concentrations of formaldehyde solution
and exposure time to capsule bodies were
optimized by solubility study of treated
capsule bodies. [8-10]
The physical mixture
of drug and excipients was filled in
formaldehyde treated capsule body and
fitted with hydro gel plug which was
compressed having diameter of 6 mm.
Then untreated cap was fitted on the body
and the entire capsule device was coated
with Eudragit S-100. After the cap opening
in the dissolution media, the hydrogel plug
came into contact with dissolution media
and it hydrated and started to swell and
after ejection of plug from the body, the
drug was released immediately.
In this study an attempt had been made to
develop modified capsule which will give
pulsatile release of Tramadol HCl for
arthritic pain.
MATERIAL AND METHODS
Materials
Tramadol HCl was obtained from Apex
pharma, Hyderabad. Sodium starch
glycolate, HPMC K4M, Na-alginate,
Eudragit S-100, Acetone were from S.D
Fine chemicals, Mumbai. Formaldehyde,
Sodium chloride, Potassium permanganate
was from Dow chemical’s Rajkot. All
other ingredients used were either
pharmaceutical or analytical grade.
Methods
Formaldehyde treatment and its
optimization
Formalin treatment has been employed to
modify the solubility of gelatin capsules.[8-
11] Hard gelatine capsule of size ‘1’ and 50
in number taken. Their bodies were
separated from the caps. 25 ml of 5%, 7%,
10% (v/v) formaldehyde was taken into
separate desiccators and a pinch of
potassium permanganate was added to it
respectively, to generate formalin vapours.
The wire mesh containing the empty
bodies of capsule was then exposed to
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formaldehyde vapours. The caps were not
exposed leaving them water-soluble. The
desiccators were tightly closed. The
reaction time was optimized by removing
capsule bodies at different time intervals
and dried at 50°C for 30 min to ensure
completion of reaction between gelatin and
formaldehyde vapors. The bodies were
then dried at room temperature to facilitate
removal of residual formaldehyde. These
capsule bodies were capped with untreated
caps and stored in a polythene bag.
Tests for Formaldehyde Treated Empty
Capsules
Various physical and chemical tests were
carried out simultaneously for
formaldehyde treated and untreated
capsules.
a) Physical tests
Identification attributes: The size ‘1’
capsule were one with a red cap and
white colored body. They were
lockable type, odourless, softy and
sticky when treated with wet fingers.
After formaldehyde treatment, there
were no significant changes in the
capsules. They were non-tacky when
touched with wet fingers.
Visual defect: In about 50 capsule
bodies treated with formaldehyde,
about five were found to be shrunk or
distorted.
Dimensions: Variations in dimensions
between formaldehyde, treated and
untreated capsules were studied. The
length and diameter of the capsules
were measured before and after
formaldehyde treatment, using dial
caliper.
b) Chemical test
Qualitative test for free
formaldehyde
Standard formaldehyde solution used is
formaldehyde solution (0.002 w/v) and
sample solution is formaldehyde treated
bodies (about 25 in number) were cut into
small pieces and taken into a beaker
containing distilled water. This was stirred
for 1 hrs with a magnetic stirrer, to
solubilise the free formaldehyde. The
solution was then filtered into a 50 ml
volumetric flask, washed with distilled
water and volume was made up to 50 ml
with the washings. 1ml of sample solution,
9 ml of water was added. One ml of
resulting solution was taken into a test tube
and mixed with 4 ml of water and 5 ml of
acetone reagent. The test tube was warmed
in a water bath at 40oC and allowed to
stand for 40 min. The solution was not
more intensely colored than a reference
solution prepared at the same time and in
the same manner using 1ml of standard
solution in place of the sample solution.
The comparison should be made by
examining tubes down their vertical axis.
Drug-excipient compatibility study
FTIR absorption spectra of pure drug,
physical mixture and pulsincap
formulation were recorded in the range of
400 to 4000 cm-1
by KBr disc method
using FTIR spectrophotometer.
Selection of core physical mixture and
hydrogel plug
In the present study for the preparation of
modified pulsincap the composition of
physical mixture and the type of hydrogel
plug. Here the effect of osmogen (NaCl)
and superdisintegrant (SSG) in core
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physical mixture was checked on the
immediate drug release after the lag time.
Hydrogel plug of two polymers HPMC
K4M and Na-alginate were selected. Both
are swellable hydrophilic polymers and
control the lag time. Eudragit S-100 was
selected for enteric coating of entire
capsule device. 5% w/v solution of
Eudragit S-100 in acetone was selected for
enteric coating which was suitable for
uniform dip coating.
Preliminary trial formulations of modified pulsincap
Table 1: Composition of preliminary formulation
Ingredients (mg) P1 P2 P3 P4 P5 P6
Tramadol HCl 50 50 50 50 50 50
MCC 150 100 100 150 100 100
NaCl - 50 40 - 50 40
SSG - - 10 - - 10
HPMC K4M plug 50 50 50 - - -
Na-alginate plug - - - 50 50 50
Total weight* (mg) 352.5
±6.2
349.4
±7.6
350.7
±6.9
355.5
±8.1
351.0
±7.2
357.9
±6.5
*Values are mean± S.D, n=10
Wt. of empty capsule =78 mg,
Avg. wt gain by 5% Eudragit S-100 coating solution= 7.53%
Evaluation of modified pulsincap
Lag time [12]
Lag time is the total time period after
which the plug is ejected out of the capsule
body and the drug releases immediately.
Lag time was determined visually using
phosphate buffer pH 6.8 and 7.4. For lag
time determinations USP paddle apparatus
was used. Capsules were tied with the
paddle by cotton thread; temperature was
maintained at 37°C at 50 rpm. Results of
preliminary trial formulations are
depicated in Table 9.
In-vitro release profile [9, 13]
Dissolution studies were carried out by
using USP XXIII dissolution test apparatus
(Basket) method. Capsules were placed in
a basket so that the capsule should be
immersed completely in dissolution media
but not float. 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.
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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.
Results of drug release study are shown in
Figure 4.
Optimization of variables using 32 full
factorial design [9, 14, 15]
A full factorial 32 design is used for
optimization procedure. It is suitable for
investigating the quadratic response
surfaces and for constructing a second-
order polynomial model, thus enabling
optimization of the modified pulsincap.
Table 2 summarizes the independent along
with their levels. The resulted formulations
are listed in Table 3. A statistical model
incorporating interactive and polynomial
term will be used to evaluate the response.
Y = β0 + β1X1+ β2X2 + β12X1X2 + β11X12
+ β22X22
Where, Y is the dependent variables.
Table 2: Coding of variable
Coded values Actual values
X1(conc. ratio of SSG and NaCl) X2 ( wt. of hydrogel plug in mg)
-1 10:90 40
0 20:80 50
+1 30:70 60
Dependent variables is
Y = Lag time
Table 3: Compositions of factorial formulations
Ingredients
(mg) F1 F2 F3 F4 F5 F6 F7 F8 F9
Tramadol
HCl 50 50 50 50 50 50 50 50 50
MCC 100 100 100 100 100 100 100 100 100
NaCl 45 40 35 45 40 35 45 40 35
SSG 05 10 15 05 10 15 05 10 5
HPMC K4M
plug 40 40 40 50 50 50 60 60 60
Total
weight*
(mg)
345.9
± 5.2
347.0
± 4.6
344.3
± 4.1
356.6
± 6.1
354.2
± 5.7
356.2
± 5.9
365.4
± 5.5
368.1
± 6.3
365.2
± 6.9
*Values are mean ± S.D where, n=10
Avg. wt gain by 5% Eudragit S-100 coating solution= 8.23 %
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Statistical analysis of the data
Statistical analysis of the factorial design
formulations was performed by multiple
regression analysis using Microsoft Excel
2007. 3D response plots were constructed
using Design expert 8.0 trial version
software
Result and Discussion
Optimization of formaldehyde
concentration & exposure time for cross-
linking
The solubility of the capsule bodies
checked and it was found that 10% v/v
formaldehyde solution and 6 hrs exposure
times was optimum in which capsule
bodies remained intact up to 12 hrs in all
the media (Table 4). So it was used in
cross-linking of capsule bodies. After
formaldehyde treatment of 100 capsule
bodies about 10 were found to be
distorted. Then they were subjected to
measurement of dimensions as shown in
Table 5.
Table 4: Solubility study of cross-linked capsule bodies
Formaldehyd
e conc.
(%v/v)
Time of
exposur
e
(hrs)
Observation in dissolution media
0.1 N HCl Phosphate buffer
6.8
Phosphate buffer
7.4
5 % 2 softened in 1 hr softened in 1 hr softened in 1 hr
4 softened in 2 hrs softened in 2 hrs softened in 2 hrs
6 softened in 4 hrs softened in 4 hrs softened in 4 hrs
7% 2 softened in 3 hrs softened in 3 hrs softened in 3 hrs
4 softened in 5 hrs softened in 5 hrs softened in 5 hrs
6 softened in 7 hrs softened in 7 hrs softened in 7 hrs
10% 2 softened in 9 hrs softened in 9 hrs softened in 9 hrs
4 Intact up to 10 hrs Intact up to10 hrs Intact up to10 hrs
6 Intact up to 12 hrs Intact up to12 hrs Intact up to 12 hrs
Table 5: Comparison of dimension of capsule bodies
Parameter Before treatment After treatment
Avg. capsule length (mm) 15.23 14.75
Avg. diameter of capsule body (mm) 6.5 6.1
Avg. length of capsule body (mm) 11.39 10.97
From the observations of the cross linked capsule bodies it was found that there was slight
decrease in the diameter and length after formaldehyde treatment.
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Qualitative test for free formaldehyde
The formaldehyde capsules were tested for
the presence of free formaldehyde. The
sample solution was not more intensely
colored than the standard solution inferring
that less than 20 µg free formaldehyde is
present in 25 capsules.
Drug- excipient compatibility study
FTIR spectrum of Tramadol HCl, physical
mixture and pulsincap formulation are
shown in Figure 1, 2 and 3 respectively.
From the FTIR spectra of physical mixture
and pulsincap formulation, it was found
that drug and excipients are compatible
with each other.
Figure 1: FTIR spectra of Tramadol HCl
Figure 2: FTIR spectra of physical mixture of Drug and excipients
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Figure 3: FTIR spectra of pulsincap formulation
Evaluation of hydrogel plug
Table 6: Evaluation of Hydrogel plug of trial formulations
Type of plug Thickness
(mm)
Friability (%) Swelling index (%)
( in 6 hrs)
pH 6.8 pH 7.4
HPMC K4M 2.40 ± 0.07 0.53 65.9 ± 1.2 64.2 ±1.5
Na-Alginate 2.42 ± 0.06 0.58 80.6 ± 2.1 81.8 ± 1.7
values are mean± S.D, n=3
The swelling index of Na-alginate was found to be more in comparison with the HPMC K4M
plug at the end of 6 hrs.
Evaluation of modified pulsincap formulations
Lag time
Table 7: Lag time of preliminary trial formulations
Batch Lag time (min.)
P1 460 ± 12
P2 447 ± 15
P3 365 ± 10
P4 416 ± 10
P5 405 ± 16
P6 320 ± 13
Values are mean ± S.D, n=3
Due to enteric coating by Eudragit S-100
pulsincap remained intact in 0.1N HCl But
starts to dissolve in phosphate buffer. It
was postulated that after the dissolution of
coating the cap starts to dissolve and fluid
enters the body because it was insoluble
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but permeable. After entering the body the
osmogen and superdisintegrant creates the
pressure on swollen plug and hence plug
ejected out of the body. From the results of
lag time of preliminary trial formulations,
it was found that there is no significant
effect of osmogen (NaCl) alone on the lag
time but in combination with the
superdisintegrant (SSG) it helps in ejection
of plug after lag time and releases the drug
immediately.
In vitro drug release study
Figure 4: In-vitro drug release study of preliminary formulations
From the drug release study it was also
found that sustaining capacity of HPMC
K4M plug is more than the Na-alginate
plug. From the result of lag time it was
observed that the P1-P6 had the lag time in
the range of 5-8 hrs. P3 formulation had
the lag time of about 6 hrs having the ratio
of NaCl to SSG was 80:20 (40 mg NaCl
and 10 mg SSG) and the HPMC K4M plug
of 50 mg weight. Hence it was used for the
setting of levels and factors for the 32 full
factorial designs.
Evaluation of modified factorial formulations
Lag time
Table 8: Lag time of factorial formulations
Batch Lag time (min)
F1 365 ± 09
F2 315 ± 11
F3 275 ± 10
F4 405 ± 15
F5 363 ± 13
F6 320 ± 10
F7 425 ± 12
F8 409 ± 14
F9 393 ± 10
Values are mean ± S.D, n=3
0
20
40
60
80
100
120
0 2 4 6 8 10% c
um
ula
tive
dru
g re
leas
e
Time (hrs)
P1
P2
P3
P4
P5
P6
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From the lag time determination study of the factorial formulations, it was found that as the
weight of the hydrogel plug increases the lag time also increases and as the amount of super
disintegrant increases the lag time decreases. From all the formulations F1 and F5 shows the
lag time of about 6 hrs.
In vitro drug release study of factorial formulations
Figure 5: In-vitro drug release study of factorial formulations
Pulsincap formulation of F1-F9 showed
distinct lag time as given in Figure 5. It
showed that lag time increases with
increase in weight of hydrogel plug and
decreases with increase in ratio of SSG
and NaCl. Upon contact with dissolution
media the hydro gel plug starts to swell
and due to pressure inside the capsule
body plug comes out. So both the
parameters affect the lag time and drug
release from the pulsincaps.
Formulations F1 (SSG to NaCl ratio 20:80
and HPMC K4M plug of 40 mg) and F5
(SSG to NaCl ratio 10:90 and HPMC K4M
plug of 50 mg) provides the desired lag
time of about 6 hrs.
Statistical analysis of the data
The fitted full model equation relating the
response Y (lag time) to the transformed
factor are shown in following equation.
Y= 362 – (35X1) + (44.83X2) + (13.75X1X2) +
(1X12) + (0.5X2
2)
The P value for X1, X2 and X1X2 was
found to be 0.00164, 0.00079 and 0.00394
respectively which is less than 0.05. Thus
X1, X2 and X1X2 has significant effect on
the dependent variable Y (Lag time) while
other term X12 and X2
2 were rendered
insignificant having P value greater than
0.05.
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9
%cu
mu
lati
ve d
rug
rele
ase
stu
dy
Time (hrs)
F1
F2
F3
F4
F5
F6
F7
F8
F9
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Table 9: Regression Statistics for Y (Lag time)
Regression Statistics for Y
Multiple R 0.9954
R Square 0.9909
Adjusted R Square 0.9757
Standard Error 7.854
Observations 9
Coefficients P- value
β0 = 362 9.31959E-06
β1 = - 35 0.00164
β2 = 44.83 0.00079
β12 = 13.75 0.03944
Β11 = 1 0.86858
Β22 = 0.5 0.9339
Table 9 shows the results of the analysis of variance (ANOVA), which was performed to
identify insignificant factors. The high values of correlation coefficient for lag time indicate a
good fit, i.e., good agreement between the dependent and independent variables. The
significance test for regression coefficients was performed by applying the student F test.
(Table 10)
Positive value of coefficient of X1 indicates that dependent variable (lag time) is directly
proportional to the X1 variable (weight of plug) and negative value of coefficient of X2
indicates that if there is increase in X2 variable (ratio SSG:NaCl), there is decrease in lag time
Table 10: Testing the model in portions
Lag time (Y)
DF SS MS F R2
Fcal = 0.0477
Regression
FM 5 20319.7 4063.93 59.66 0.9909
RM 3 20313.2 6771.06 160.58 0.9907
Fcri = 9.5520 Error
FM 3 204.33 68.11 - -
RM 5 210.83 42.17 - - DF = (2,3)
DF: degree of freedom, SS: sum of squares, MS: mean of squares, F: Fischer’s ratio, R2:
regression coefficient, FM: full model, RM: reduced model.
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So, the reduced model equation is as follows:
Y= 362 – (35X1) + (44.83X2) + (13.75X1X2)
The results for testing the model in portions are shown in Table 5.19. Since the calculated
value (F = 0.0477) is less than critical value, it may be concluded that the quadratic terms β11
and β22 do not contribute significantly to the prediction of lag time and therefore can be
omitted from the full model.
Figure 6: Contour plot showing relationship between two independent variables on lag
time
Figure 7: Response surface plot showing the influence of independent variables on lag
time.
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Figure 6 and 7 showed the countor plot
and response surface plot of ratio of SSG
to NaCl (X1) and plug weight (X2) versus
lag time respectively. It was also observed
that the X1 and X2 appear to favor the
preparation of modified pulsincap of
Tramadol HCl. It can say that the lag time
and drug release profile may be changed
by appropriate selection of the X1 and X2
levels. The area in contour plot (Figure
5.12) shows if we selected X1 and X2 in
this range we get the desired release
profile of Tramadol HCl modified
pulsincap.
CONCLUSION
Tramadol HCl was successfully
formulated as a modified pulsincap to
deliver drug after predetermine lag time of
6 hrs. Formulation F1 and F5 both gave
the lag time of about 6 hrs but the F1 (
Ratio SSG to NaCl 10:90 and plug weight
40 mg) was selected as optimized
formulation hence less amount of SSG and
HPMC K4M were used in that in
comparison with F5. 100 % drug was
released in 1 hr after the lag time in
optimized formulation which is necessary
in pulsatile release.
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