Formulation and Evaluation
of Once Daily Sustained Release Matrix Tablets of Terbutaline
Sulphate for the Treatment of Nocturnal Asthma
Mohd Abdul Hadi, A. Srinivasa Rao, P. Vineeth, Md. Azharuddin
Dept. of Pharmaceutics, Bhaskar Pharmacy College, (J.B.I.E.T), Moinabad,
R.R District, Hyderabad-500075, A.P. India.
ABSTRACT:
Terbutaline sulphate is a β2-adrenergic
agonist bronchodilator and used to treat bronchospasm
associated with lung diseases such as asthma, bronchitis, and emphysema.
Bioavailability of terbutaline sulphate
about 14.8 %. The drug half-life is 3-4 hrs. In nocturnal asthma, lung function
is usually highest at 4 PM and lowest at 4 AM, the latter time is generally
when asthma symptoms are most prevalent. Based on these findings drug delivery
and therapy should be modified to achieve an effective drug level at the
required time. This can be achieved by adapting a sustained drug delivery
system of a suitable drug which when administered during night releases the
drug till early morning hours. So, in order to improve bioavailability and
efficacy we have designed once a day sustained release tablets of terbutaline sulphate. The tablets
were prepared by wet granulation technique using HPMC K200M, Ethylcellulose and combination of both. The sustained release tablets were subjected
to preformulation studies, in- vitro drug
release, post-compression studies, kinetic studies and stability studies. FTIR
studies shown there was no interaction between drug and polymers. The percentage of drug
content from the tablets was determined by UV-Spectroscopy and ranged from 97.20±0.50
to 99.12±0.92.
The in-vitro percentage release of terbutaline
sulphate from the optimized tablets at the end of
24hrs was 99.69±0.91 %. The kinetic studies revealed that the drug was
released by first-order kinetics. The optimized formulation was subjected to
stability studies and shown there were no significant changes in drug content,
physicochemical parameters and release pattern.
KEYWORDS: Terbutaline sulphate,
Nocturnal asthma, Sustained drug delivery system, wet granulation technique,
HPMC K200M, Ethylcellulose.
INTRODUCTION:
Chronotherapeutic refers to a clinical practice of synchronizing drug
delivery in a manner consistent with the body's circadian rhythm including
disease states to produce maximum health benefit and minimum harm. Asthma is a
chronic obstructive lung disease characterized by airways, inflammation and
hyperactivity. In most patients, the condition worsens at night with acute
exacerbation being most common. Clinical and epidemiological studies verify
that asthma is several hundred folds more likely at night than during the day
with disturbance of sleep. The worsening of asthma at night commonly referred
to as nocturnal asthma (NA).
It is a variable exacerbation of the
underlying asthma conditions associated with increases in symptoms, need for
medication, airway responsiveness, and/or worsening of lung function.
Generally
a reduction in peak flow or forced expiratory volume in one second of at least
20% is implicit in this definition. Approximately two-thirds of asthmatics
suffer from night time symptoms. In a large study involving 8,000 asthmatics it
is observed that 70% awakened one night per week, 64% awakened 3 nights per
week and 39% had their sleep disturbed on a nightly basis. The patients who
self-characterized their asthma as mild, 26% has nightly awakenings and 53% of
asthma deaths occurred during the night time hours. A drug delivery system
administered at bed time but releasing drug during morning hours would be ideal
in this case. The possibility of deferring the drug release for a programmed
time interval after oral administration of the dosage form is to perform chronotherapy is quite appealing for those diseases the
symptoms of which recur mainly at night times or in the early morning, such
as asthma1, 2.
Terbutaline sulphate is a β2-adrenergic
agonist bronchodilator and used to treat bronchospasm
(wheezing, shortness of breath) associated with lung diseases such as asthma,
bronchitis, and emphysema. The main drawback of conventional Terbutaline sulphate formulation
is that it undergoes hepatic first pass metabolism. Thus, it shows plasma or
biological half- life 3 to 4 hrs, thereby decreasing bioavailability up to
14.8%. The present work describes such delivery system, which will improve the
biological half-life as well as bioavailability of Terbutaline
sulphate3-7. This makes Terbutaline sulphate a candidate for incorporation in sustained release
dosage form and was used as a model drug.
Objective:
The
objective is to formulate and evaluate a sustained drug delivery system of terbutaline sulphate which when
administered during night releases the drug till early morning hours and can be
used for the treatment of Nocturnal Asthma. To reduce the frequency of dosage
and to improve the half-life of terbutaline sulphate.
MATERIALS
AND METHODS:
Materials:
Terbutaline sulphate was obtained as a gift sample
by Franco Indian Pharmaceuticals Pvt Ltd., (Mumbai).
Microcrystalline cellulose (MCC), polyvinyl pyrrolidone
K-90 (PVP K-90) and magnesium stearate were purchased
from Rajesh chemicals, Mumbai. All other chemical and reagent were of
analytical grade.
Experimental Methods:
Preformulation studies:
Drug-excipient compatibility studies:
Assessment of possible incompatibilities between an
active drug substance and different excipients forms
an important part of the pre-formulation stage during the development of solid
dosage form. Therefore, the pure drug and the formulations mixed with polymers
were subjected to infra-red (IR) studies.
Fourier Transform Infrared
(FTIR) spectral analysis:
The compatibility of drugs and excipients used under experimental condition were studied.
The study was performed by taking 2 mg sample in 200 mg KBr
(Perkin Elmer, spectrum-100, Japan). The scanning range was 400 to 4000 cm-1
and the resolution was 1cm-1. This spectral analysis was employed to check the
compatibility of drugs with the excipients used8.
Micromeritic properties9:
Angle of repose:
The fixed funnel and free
standing cone methods employ a funnel that is secured with its tip at a given
height, h, which was kept 2cm above graph paper that is placed on a flat
horizontal surface. With r being the radius, of base of conical pile, angle of
repose can be determined by following equation:
Ө = tan-1
(h/r)
Where, Ө is the angle of
repose,
h is height of pile, r is radius
of base of the pile
Bulk density and tapped density:
\Both loose bulk density and tapped bulk
density were determined. A quantity of 2gm of granules from each formula,
previously light Shaken for the break of any agglomerates formed, was
introduced into the 10ml of measuring cylinder. After the initial volume was
observed, the cylinder was allowed to fall down its own weight from the hard
surface from a height of 2.5cm at 2 sec Intervals. The tapping was continued
until no further change in the volume was noted
LBD and TBD were calculated
using the following formulas:
LBD: Weight of the powder/volume of
the packing.
TBD: Weight of the powder/Tapped
volume of the packing.
Compressibility index:
The compressibility index of the
granules was determined by Carr’s Compressibility index.
Carr’s index (%) = [(TBD-LBD) *
100] / TBD
Where,
LBD: Weight of the powder/volume
of the packing.
TBD: Weight of the powder/Tapped
volume of the packing.
Hausner’s ratio:
Hausner’s ratio can be determined by the
following equation,
Hausner’s ratio = TBD / LBD
Where, TBD -Tapped bulk
densities & LBD- Loose bulk densities
Preparation of tablets10:
The tablets
were prepared by wet granulation technique using different polymers (HPMC K200M, Ethyl Cellulose, and HPMC
K200M-Ethyl cellulose combination) as shown in Table 1. Drug and polymers were
passed through 60 # sieve and then dry blend of drug were granulated with PVP
K-90 as a binder which was dissolved in isopropyl alcohol. The mass was dried
at 50°C and sized through 22 # sieve. Finally, magnesium stearate
were mixed as glidant, and then tablet blend weighing
200 mg was compressed using 8 mm round convex punches in a rotary tablet press
(Rimek mini press, model RSB-4, M/S: Karnavati engineering, Ahmedabad).
Table 1: Composition of Sustained release tablets of Terbutaline sulphate
|
Ingredients |
F1 |
F2 |
F3 |
F4 |
|
Terbutaline sulphate |
15 |
15 |
15 |
15 |
|
HPMC K 200M |
50 |
|
|
|
|
EC |
|
50 |
|
|
|
HPMC K 200M: EC |
|
|
25:25 |
20:40 |
|
Dibasic Calcium phospate anhydrous |
q.s |
q.s |
q.s |
q.s |
|
Magnesium stearate |
3 |
3 |
3 |
3 |
|
Aerosil |
3 |
3 |
3 |
3 |
|
Total |
150 |
150 |
150 |
150 |
Evaluation of physical properties of matrix tablet 9:
Hardness test:
The hardness of
the tablets was determined using Monsanto Hardness tester. It is expressed in
kg/cm2. Six tablets were randomly picked from each formulation and the mean and
standard deviation values were calculated.
Friability:
A friability
test was conducted on the tablets using a veego friabilator. Twenty tablets were selected from each batch
and any loose dust was removed with the help of a soft brush. The tablets were
initially weighed (Winitial) and transferred into friabilator. The drum was rotated at 25 rpm for 4 minutes
after which the tablets were removed. Any loose dust was removed from the tablets
as before and the tablets were weighed again (Wfinal).The
percentage friability was then calculated by,
F = 100 x (W initial-
Wfinal) / Winitial
% Friability of
tablets less than 1% is considered acceptable.
Weight variation:
The weight
variation test was conducted by weighing 20 randomly selected tablets
individually, calculating the average weight and comparing the individual
tablet weights to the average. The specification of weight variation is 10%.
Uniformity of thickness:
The tablet thickness
was measured using screw gauge.
Estimation
of Terbutaline sulphate11:
Preparation of standard calibration curve
of Terbutaline sulphate:
The
standard calibration curve was prepared using 6.8 phosphate buffer.
Standard
solution:
200
mg of Terbutaline sulphate
is dissolved in 100 ml of phosphate buffer (ph-6.8) to give a concentration of
2 mg/ml (2000μg/ml).
Stock
solution:
From
the standard solution pipette out 10 ml of solution into 100ml volumetric flask
and dilute it up to 100 ml with phosphate buffer (ph-6.8) to produce 200 μg/ml concentration. From this solution pipette out 1,
2, 3, 4, 5, 6, 7 and 8 ml into 10 ml volumetric flask and dilute them up to 10
ml with phosphate buffer (ph-6.8) to produce concentration as 20, 40, 60, 80, 100,
120, 140 and 160 μg/ml respectively. The
absorbance of prepared solution of TBS is measured at 278 nm in Shimadzu
UV/visible 1700 spectrophotometer against 6.8 phosphate buffer solution as
blank.
Estimation
of drug content11:
Drug
content of prepared tablet of each batch of the formulation was determined.
From each batch 20 tablets were taken, weighted and finely grounded. An amount
of powder equivalent to 5 mg of powder was accurately weighted and dissolved in
6.8 phosphate buffer. The resulting solution was suitably diluted and analysed on UV spectrophotometer Shimadzu 1601 at 278 nm.
Dissolution
testing11:
Dissolution
test of Terbutaline Sulphate
was performed in 6.8 phosphate buffer at 50 rpm using USP dissolution test
apparatus type II (paddle type). Five ml aliquots were withdrawn with a pipette
and replaced with 5 ml fresh dissolution medium at different time intervals.
The aliquots were passed through Whatman filter paper number 41 to remove any
suspended impurity which may interfere during spectroscopic estimation. The
absorbance of samples was taken on UV spectrophotometer (Shimadzu 1601) at 278
nm against blank and correspondingly concentration of the drug was determined
at various time intervals.
RESULTS AND DISCUSSION:
Drug excipients interaction studies:
Compatibility study:
Spectra of the pure drug, excipient
and physical mixture of drug and excipient were
recorded in between 400-4000 wave number (cm-1) (as shown in Figure 1). The FTIR spectral analysis showed that
there is no appearance or disappearance of any characteristic peaks of pure
drug glimepiride and in the physical mixture which
confirms the absence of chemical interaction between drug and polymers.
Micromeritic
properties:
Granules of all
the formulations were subjected for various pre-compressional evaluations such
as angle of repose, bulk and tapped density, compressibility index and
Hausner’s ratio. Results of all the pre-compressional parameters performed on
granules for formulations shown in Table 2. The bulk densities of granules were found
to be range between 0.437±0.14 to 0.445±0.67 g/cm3.Carr’s
index was found to be range between 13.38±0.56 to 14.48±0.73. The
angle of repose was found to be range between 22 ş.90’±0.41
to 24 ş.88’±0.20. The results
of Hausner’s ratio were found to be lesser than 1.25
which indicates better flow properties. The results of angle of repose (<30)
indicates good flow properties of the powder. This was further supported by
lower compressibility index values. These results indicate that granules were
of good flow properties.
Figure 1: IR Spectras
of 1) Terbutaline sulphate
2) Ethylcellulose
3) HPMC K 200 M 4) Formulation F1
Table 2: Evaluation of powder Blend
|
Powder Blend |
Angle of repose (°) |
Bulk Density (g/mL) |
Tapped Density (g/mL) |
Carr’s Index (%) |
Hausner’s ratio |
|
F1 |
23 ş.16’±0.16 |
0.437±0.14 |
0.511±0.30 |
14.48±0.73 |
1.17±0.53 |
|
F2 |
22 ş.90’±0.41 |
0.445±0.67 |
0.515±0.17 |
13.59±0.11 |
1.15±0.15 |
|
F3 |
24 ş.76’±0.32 |
0.440±0.33 |
0.508±0.12 |
13.38±0.56 |
1.15±0.44 |
|
F4 |
24 ş.88’±0.20 |
0.438±0.18 |
0.507±0.49 |
13.60±0.63 |
1.15±0.39 |
Table 3: Evaluation of Tablets
|
Formulation |
Weight Variation (mg) |
Hardness (kg/cm2) |
Thickness (mm) |
Friability |
Drug Content (%) |
|
F1 |
150±1.42 |
6.2±0.44 |
4.32±0.22 |
0. 40±0.10 |
99.12±0.92 |
|
F2 |
148±1.30 |
6.1±0.57 |
4.26±0.31 |
0. 63±0.18 |
98.20±0.26 |
|
F3 |
150±1.16 |
6.2±0.29 |
4.28±0.38 |
0. 53±0.25 |
97.20±0.50 |
|
F4 |
149±1.47 |
6.3±0.11 |
4.19±0.10 |
0. 33±0.19 |
98.92±0.44 |
Table
4: Data of In-Vitro Drug Release Studies of sustained-release matrix tablets of
Terbutaline sulphate
|
Time |
F1 |
F2 |
F3 |
F4 |
|
|
0 |
0 |
0 |
0 |
|
1 |
21.94±0.41 |
14.31±0.62 |
19.79±0.28 |
17.41±0.33 |
|
2 |
48.65±0.12 |
31.00±0.93 |
46.03±0.52 |
44.60±0.73 |
|
4 |
59.15±0.37 |
47.94±0.55 |
56.76±0.11 |
54.14±0.84 |
|
6 |
71.07±0.16 |
63.20±0.27 |
68.45±0.81 |
65.11±0.69 |
|
8 |
77.51±0.10 |
68.45±0.16 |
75.37±0.20 |
72.98±0.45 |
|
10 |
80.14±0.98 |
74.89±0.39 |
77.75±0.42 |
75.13±0.26 |
|
12 |
85.86±0.72 |
79.66±0.80 |
83.71±0.0.66 |
81.09±0.82 |
|
16 |
90.39±0.40 |
85.86±0.78 |
88.01±0.0.17 |
85.62±0.94 |
|
20 |
96.36±0.86 |
90.63±0.83 |
92.30±0.90 |
89.92±0.54 |
|
24 |
99.69±0.91 |
94.92±0.16 |
97.31±0.81 |
96.59±0.10 |
Evaluation of
prepared tablets:
The results of physical
evaluation of tablets were given in Table 3. The tablets of different
batches were found uniform with respect to hardness within the range of 6.1±0.57 to 6.3±0.11 kg/cm2.
Another measure of a tablet's strength is friability. Conventional compressed
tablets that lose less than 1% of their weight are generally considered
acceptable. Results of friability test were also has been found within limit.
In weight variation test, the pharmacopoeial limit for percentage deviation for
tablets of more than 250 mg is ±5% and all the formulations were found to
comply with the specifications given in I.P. for weight variation test. Good
uniformity in drug content was found among the formulations, and percentage of
drug content was more than 95%. All the tablet formulations showed acceptable
pharmaco technical properties.
In - vitro drug release study:
Tablets were prepared using plain
hydrophilic and plain hydrophobic as well as blend of Hydrophilic-hydrophobic
combination. From the results (as shown in Table 4 and Figure 2) of in vitro-dissolution study
it was found that Formulations F1 prepared with HPMC K200M polymer shown
99.69±0.91 % release at the end of 24hrs. Whereas, formulations F2 prepared
with ethylcellulose polymer released 94.92±0.16 % of
drug at the end of 24hrs respectively. This slow release is due to the
hydrophobic nature of ethylcellulose polymer which
retards release for longer period. But when, Formulation F3 and F4 was prepared
with combination of hydrophilic and hydrophobic polymer they released
97.31±0.81 and 96.59±0.10 % at the end of 24hrs respectively. Based on the
above results it was known that only formulations F1 shown a good release
profile at the end of 24hrs. It is due to the hydrophilic nature of HPMC K200M
polymer which increased the release profile.
Stability studies:
The results of accelerated stability
studies shown in Table 6 carried out according to ICH guidelines
indicated that the tablets did not show any physical changes (color
change, friability and hardness), assay and dissolution characteristics
during the study period.
Figure 2: In-vitro drug release profile of
Once daily sustained release matrix tablets of Terbutaline
sulphate
Table
5: Kinetic Values Obtained from Different Plots of Formulations F-1 to F-4
|
Formulations |
Zero
order (R) |
First
order (R) |
Higuchi’s
(R) |
Peppa’s |
|
|
(R) |
(N) |
||||
|
F-1 |
0.7324 |
0.9048 |
0.9279 |
0.5677 |
0.88 |
|
F-2 |
0.7998 |
0.9902 |
0.9579 |
0.6701 |
0.96 |
|
F-3 |
0.7359 |
0.9725 |
0.9290 |
0.5826 |
0.89 |
|
F-4 |
7539 |
0.9641 |
0.9365 |
0.6009 |
0.91 |
Table
6: Summary of physical properties of F-3 before and after accelerated stability
studies
|
Parameter |
Before
stability studies (Initial) |
After
stability studies |
||
|
After
1 month |
After
2 months |
After
3 months |
||
|
Thickness (mm) |
4.32±0.22 |
4.32±0.28 |
4.32±0.12 |
4.32±0.56 |
|
Hardness (kg/cm2) |
6.2±0.44 |
6.2±0.57 |
6.1±0.23 |
6.1±0.41 |
|
Friability (%) |
0. 40±0.10 |
0. 32±0.15 |
0. 29±0.11 |
0. 26±0.19 |
|
Drug content (%) |
99.12±0.92 |
99.02±0.92 |
98.87±0.11 |
98.75±0.51 |
|
In-vitro release study (at the end of 12 hours) |
99.69±0.91 %. |
99.27±0.46 %. |
98.98±0.62 %. |
99.81±0.38 %. |
|
Number
of trials (n) = 5 |
||||
CONCLUSION:
The study was undertaken with the aim to
Formulation and evaluation of once daily sustained-release matrix tablets of terbutaline sulphate using
various polymers. From the above results and discussion, it is concluded that
the formulation of sustained release tablet of terbutaline
sulphate containing HPMC K200M and Ethylcellulose which are taken as ideal or optimized
formulation for 24 hours release fulfills all the requirement of sustained
release tablet. Hence, the prepared tablet improves the half-life of drug and
reduces the frequency of dosage and can be successfully useful in the treatment
of nocturnal asthma.
ACKNOWLEDGEMENTS:
Authors thank to Franco Indian
Pharmaceuticals Pvt Ltd., Mumbai for providing
a gift sample of Terbutaline sulphate.
The authors are also thankful to Mr. Devilal,
Assistant professor, Bhaskar Pharmacy College,
R.R. District for their valuable suggestion in carrying out this
research work. The authors are also thankful to Mr. Joginpally
Bhaskar Rao Garu, Chairman, and Dr. A. Srinivasa
Rao, Principal, Bhaskar
Pharmacy College, Moinabad, R.R. District for
providing the research lab facilities to carry out this research work.
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Received on 02.12.2012
Modified on 20.12.2012
Accepted on 02.01.2013
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and Technology. 5(1):
January- February, 2013, 27-32