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RESEARCH ARTICLE e-ISSN: 2454-7867
Swapna G* et al. Int J Trends in Pharm & Life Sci. 2015: 1(4); 457-470 457
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International Journal of Trends in Pharmacy and Life Sciences Vol. 1, Issue: 4, 2015: 457-470
FORMULATION AND IN-VITRO EVALUATION OF IVABRADINE BUCCAL
TABLETS Garika Swapna*, Sharadha Srikanth, Uma Maheswar Rao
CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad – 501401
E.Mail: [email protected]
ABSTRACT
The main objective of the present study was to formulate and evaluate Ivabradine
mucoadhesive buccal tablets by direct compression technique. Ivabradine is a novel medication used for the
symptomatic management of stable angina pectoris and it has short half -life (2 hrs) with a bioavailability of
40% orally. The drug identity was confirmed by UV spectroscopy. The polymers used to sustain the drug
release are Guar gum, Xanthum gum, HPMC K4M and Carbopol934. The compatibility studies between the
drug and the polymer were studied using the FTIR spectroscopy and were found to be compatible.
Preformulation parameters like tapped density, bulk density, Carr’s index, Hausner’s ratio, compressibility
index, angle of repose are studied and the results were found to be within the limits. Using the above
polymers formulations f1 to f12 were manufactured by direct compression technique and the tablets were
evaluated for their thickness, hardness, friability, weight variation and content uniformity test. The in vitro
drug release studies were performed in Phosphate buffer of pH6.8 using USP type-II dissolution apparatus.
From the dissolution studies it was found that f2 formulation containing HPMC K4M was best since it
release minimum amount of drug (9.8%) initially and maximum drug (99.6%) at the end of 8hrs.The f2
formulation was subjected to stability studies for about 3months as per ICH guidelines and found to be
stable.
Key words: Ivabradine, mucoadhesive buccal tablets, direct compression, angina pectoris
*Corresponding Author:
Garika Swapna CMR College of Pharmacy,
Kandlakoya (V), Medchal Road,
Hyderabad – 501401
E.Mail: [email protected]
INTRODUCTION
Buccal delivery refers to drug release which can occur when a dosage form is placed in the outer
vestibule between the buccal mucosa and gingival.
Advantages of mucoadhesive buccal drug delivery:
Drug administration via the oral mucosa offers several advantages.
a. Flexibility in physical state, shape, size and surface.
b. Ease of administration and termination of therapy in emergency.
c. Permits localization of the drug for a prolonged period of time.
d. Administered to unconscious and trauma patients.
e. Offers an excellent route for the systemic delivery of drugs which bypasses first pass metabolism, there
Received: 25/09/2015
Revised: 28/10/2015
Accepted: 31/10/2015
RESEARCH ARTICLE e-ISSN: 2454-7867
Swapna G* et al. Int J Trends in Pharm & Life Sci. 2015: 1(4); 457-470 458
by offering a greater bioavailability.
f. Significant reduction in dose can be achieved, thereby reducing dose dependent side effects.
Disadvantages of buccal drug delivery system:
Drug administration via buccal mucosa has certain limitations,
a) Drugs which irritate the oral mucosa have a bitter or unpleasant taste or odor cannot be administered
by this route.
b) Drugs, which are unstable at buccal pH, cannot be administered by this route.
c) Only drugs with small dose requirements can be administered [1].
Ivabradine is a novel medication used for the symptomatic management of stable angina pectoris. Ivabradine
acts by reducing the heart rate via specific inhibition of the If funny channel, a mechanism different from
beta-blockers and calcium channel blockers, two commonly prescribed anti-angina drugs. Ivabradine is a
cardio tonic agent [2].
MATERIALS AND METHODOLOGY
Materials:
Ivabradine was obtained as a gift sample from Chandra labs, HYD, HPMC K4M, Carbapol Xanthan gum
were obtained from Merck specialties private limited, Guar gum, Mg.sterate, Mannitol, Aspartame , are
purchased from SD Fine Chem [3].
Methodology:
Calibration curve of Ivabradine in pH 6.8 Phosphate buffer:
Ivabradine (100mg) was dissolved in small quantity of phosphate buffer and volume was made up to
100 ml in volumetric flask using Phosphate buffer pH 6.8. From this stock solution 10 ml was withdrawn
and is diluted to 100ml in volumetric flask which gives the concentration of 100µg/ml. From this stock
solution aliquots were withdrawn in volumetric flask to give concentrations 2µg/ml, 4µg/ml, 6µg/ml,
8µg/ml and 10µg/ml. Absorbance of each solution was measured at 286 nm using Shimadzu UV- 1700 UV-
Vis double beam spectrophotometer with Phosphate buffer pH 6.8 as a reference standard [4].
Compatibility Studies:
To investigate any possible interactions between the drug and excipients used, the FT-IR
spectra of pure Ivabradine and its physical mixture with different excipients were carried out using
thermo Electron Corporation (Nicolet IR 200 FTIR) spectrophotometer. The samples were prepared
as KBr (potassium bromide) disks compressed under a pressure of 150 lbs. The wave number range is
selected in between 500 - 3500cm-1.
Method: 1 mg of drug is mixed with the 100 mg of Spectroscopic grade of KBr and triturated for
uniform mixing. The thin and transparent pellet is prepared by applying 150 lbs pressure. The
prepared pellet is exposed to IR beam and spectra are recorded by using FT-IR [5].
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Formulation of Mucoadhesive Tablets of Ivabradine:
Direct compression method was employed to prepare buccal tablets of Ivabradine using HPMC
K4M, Carbapol, Xanthan gum and Guar gum as polymers. All the ingredients including drug, polymer and
excipients were weighed accurately according to the batch formula and were passed through #60 to get
uniform particle size. The drug and all the ingredients except lubricants were taken on a butter paper with
the help of a stainless steel spatula and the ingredients were mixed in the order of ascending weights and
blended for 10 min in a porcelain mortar. After uniform mixing of ingredients, lubricant was added and
again mixed for 2 min. The prepared blend (150mg) of each formulation was compressed by using 8mm
punch on a single stroke, multi-station tablet punching machine. The buccal tablets containing 7.5 mg
Ivabradine were prepared using different polymers in varying ratios [6].
Table 1: formulation Of Mucoadhesive Tablets of Ivabradine
Ingredients F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9 F-10 F-11 F-12
Ivabradine 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5
HPMC
K4M
5% 10% 15% --- --- --- --- --- --- --- --- ---
Carbopol --- --- --- 5% 10% 15% --- --- --- --- --- ---
Xanthum
gum
--- --- --- --- --- --- 5% 10% 15% --- --- ---
Guar gum --- --- --- --- --- --- --- --- --- 5% 10% 15%
Aspartame 1 1 1 1 1 1 1 1 1 1 1 1
Mannitol q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s
Magnesium
Stearate
4 4 4 4 4 4 4 4 4 4 4 4
Characterization of Tablets:
Thickness: The thickness of the tablets was measured by Vernier calipers. It is expressed in mm [7].
Hardness: Tablets require a certain amount of strength or hardness and resistance to friability, to withstand
mechanical shocks of handling in manufacture, packing and shipping. The hardness of tablet was measured
by Monsanto hardness tester. The tablets from each batch were used for hardness studies and results are
expressed in Kg/cm2
[7].
Weight variation test: Ten tablets were selected at randomly from the lot and weighed individually to
check for weight variation [7].
Friability: It was performed in Roche friabilator where the tablets were subjected to the combined effect of
abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm dropping the tablets at a distance
of six inches with each revolution. Pre weighted samples of 20 tablets were placed in the Friabilator, which
RESEARCH ARTICLE e-ISSN: 2454-7867
Swapna G* et al. Int J Trends in Pharm & Life Sci. 2015: 1(4); 457-470 460
is then operated for 100 revolutions. The tablets are then dusted and reweighed. Conventional compressed
tablets that loose less than 0.5 to 1 % of their weight are generally considered acceptable [7].
Twenty tablets were taken and triturated well. The quantity equivalent to 50mg of Ivabradine was dissolved
in 100ml of phosphate buffer pH 6.8 solutions on rotary shaker overnight. The solution was centrifuged and
supernatant was collected. The absorbance was measured using UV-Visible spectrophotometer at 286nm.
Microenvironment pH study: The microenvironment pH of the tablets were determined by the method
proposed by Battenberg, et al, 1991.The tablets were allowed to swell for 2hours in 2ml of pH 6.8 phosphate
buffer (pH 6.8+0.05) in specially fabricated glass tubes and microenvironment pH was measured by placing
the pH electrode in contact with the surface of the tablet and allowing it to equilibrate for 1 minute [8].
Swelling Study: The swelling properties of the tablets were evaluated by determination of percent of
swelling. Each tablet was weighed (W1) and placed in Petri dish with 5ml of PB PH6.8 and incubated at 37
0c
for predetermined times. After placing the formulation for specified time, the tablets were wiped off to
remove excess of surface water by using filter paper and weighed (W2).
%𝐬𝐰𝐞𝐥𝐥𝐢𝐧𝐠 𝐢𝐧𝐝𝐞𝐱 =(W2) − (W1)
W1× 100
Where, W 1=Initial weight of the tablet. W2= Weight of tablet after swelling time interval [8].
Determination of the Ex-Vivo Residence Time: The ex vivo residence time was found using a locally
modified USP disintegration apparatus. The disintegration medium was composed of 800 ml pH 6.8
phosphate buffer maintained at 37°C. The sheep buccal tissue was tied with thread to the central stand. The
buccal tablet was hydrated with 0.5ml of pH 6.8 phosphate buffer and then the hydrated surface was brought
in contact with the mucosal membrane. The tissue was allowed to run in such way that the tablet completely
immersed in the buffer solution at the lowest point and was out at the highest point. The time taken for
complete erosion or dislodgment of the tablet from the mucosal surface was noted [9].
In Vitro Drug Release Study: In vitro drug release study of mucoadhesive tablets were performed using
standard USP dissolution apparatus type II. The bowls of the dissolution apparatus was filled with 900ml of
phosphate buffer pH 6.8 and maintained at a temperature of 37±0.50C. The protocol of the dissolution
apparatus was settled for automatic 5ml sample withdrawal and replacement of fresh media at predetermined
time interval the dissolution apparatus was covered with the black colour polythene cover to protect the
solution from light. The collected samples were filtered through the 0.45μm 59millipore filter. The samples
were analyzed for drug release using double beam UV spectrophotometer at 286nm [9].
% Friability= (initial weight-final weight/initial weight) x100
RESEARCH ARTICLE e-ISSN: 2454-7867
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Drug Release Kinetics:
To examine the release mechanism of Ivabradine from the prepared buccoadhesive tablets, the results were
analyzed according to the following equation:
𝐌𝐭
𝐌∞ =k.t
n
Where Mt /M∞ is the fractional drug released at time t, k is a kinetic constant incorporating structural and
geometrical characteristics of drug / polymer system [device], and n is the diffusion exponent that
characterizes the mechanism of drug release. It is known that for non-swelling tablets, drug release can be
generally expressed by the Fickian diffusion mechanism, for which n=0.5, whereas for most erodible
matrices, a zero order release rate kinetics is followed, for which n = 1. For non-fickian release, the n value
falls between 0.5 and 1.0 (0.5< n< 0.89) whereas in the case super case II transport n > 0.89.
Data of the in-vitro release was fit in to different equations and kinetic models to explain the release kinetics
of Ivabradine from buccal tablets. The kinetic models used were zero-order equation (eq.1), first order
equation (eq.2), Higuchi equation (eq.3), and Korsmeyer-peppas equation (eq.4).
Zero Order Kinetics: A zero-order release would be predicted by the equation.
At = A0-k0t ------------ (1)
First Order Kinetics: A first-order release would be predicted by equation
Log C = log C0 – Kt/ 2.303 ------------ (2)
Higuchi’s Model: Drug released from the matrix devices by diffusion has been described by
following Higuchi’s classical diffusion equation.
Q = [Dε / τ (2 A - εCs) Cst] 1⁄2 ------------ (3)
Korsmeyer and Peppas Model: The release rates from the controlled release polymeric matrices can be
described by the equation proposed by the Korsemeyer et al [10].
Q = K1tn
Stability studies: Stability studies were performed data temperature of 400
Cat 75% RH, over a
period of three months (90days) for the optimized buccal tablet. Sufficient number of tablets (15)
were packed in amber colored screw capped bottles and kept in stability chamber maintained at
400±1
0C & 75% RH. Samples were taken at monthly intervals for drug content estimation. At the
end of three months period, dissolution test and drug content studies were performed to determine
the drug release profiles and drug content [10].
RESEARCH ARTICLE e-ISSN: 2454-7867
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RESULTS AND DISCUSSION
Preformulation Studies:
These tests were performed as per the procedure and the results are illustrated in the following table no.9
Table 2: Table showing the description of Ivabradine (API)
The results were found as per specifications.
Solubility: It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane.
Melting Point: This test is performed as per procedure and the result was illustrated in the following
table.no10.
Table 3: showing the melting point of API’s
Material Melting Point Melting Point Range
Ivabradine 1370c 135-140
0c
The Result was found to be within limit.
Calibration Curve of Ivabradine:
Table 4: calibration curve data
S.No Concentration (μg/ml) Absorbance(nm)
1 0 0
2 1 0.165
3 2 0.325
4 3 0.471
5 4 0.627
6 5 0.789
Test Description
Colour A white to off white colour crystalline powder
Odour Odourless
RESEARCH ARTICLE e-ISSN: 2454-7867
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Fig.1: Calibration curve plot of Ivabradine in 6.8 phosphate buffer
Compatibility Studies:
Fig.2: Ft-Ir Spectra of Ivabradine Pure Drug
Fig.3: FT-IR Spectra of Ivabradine optimized
Drug-excipient compatibility study indicates that the all used excipients in the optimized formulation are
compatible with the drug based on FT-IR spectra.
y = 0.1565x + 0.005 R² = 0.9997
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 1 2 3 4 5 6
abso
rban
ce
concentration μg/ml
RESEARCH ARTICLE e-ISSN: 2454-7867
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Characterization of Blend:
Table 5: Physical Properties of Pre-compression Blend
Formulations Angle of
repose ( ° )
Bulk
Density
(g/mL)
Tapped
Density
(g/mL)
Carr’s
Index
(%)
Hausner’s
ratio
Flow
property
F1 30.250 0.342 0.386 11.39896 1.128655 Good
F2 30.430 0.358 0.412 13.1068 1.150838 Good
F3 22.870 0.326 0.334 2.39521 1.02454 Excellent
F4 22.450 0.334 0.348 4.022989 1.041916 Excellent
F5 24.370 0.442 0.499 11.42285 1.128959 Excellent
F6 29.410 0.321 0.334 3.892216 1.040498 Good
F7 22.880 0.326 0.333 2.39531 1.02464 Excellent
F8 30.130 0.360 0.414 13.1071 1.1509 Good
F9 24.300 0.447 0.500 11.42687 1.1311 Excellent
F10 22.870 0.326 0.334 2.39521 1.02454 Excellent
F11 22.450 0.334 0.348 4.022989 1.041916 Excellent
F12 30.430 0.358 0.412 13.1068 1.150838 Good
Physical Evaluation of Buccoadhesive Tablets:
Table 6: Physical Evaluations of Buccoadhesive Tablets
F.Code Hardness
(kg/cm2)
Thickness
(mm)
Weight
(mg)
Friability
(%)
Drug content
(%)
F1 6.50 ±0.44 2.52±0.17 150.8±1.48 0.36 98.25±1.37
F2 6.60±0.31 2.57±0.25 149.4±0.54 0.39 99.48±0.80
F3 6.72±0.40 2.54±0.80 148.6±0.41 0.43 99.12±2.47
F4 6.86±0.55 2.50±0.20 148.8±1.64 0.12 100.22±0.88
F5 6.34±0.57 2.65±0.66 150.6±1.14 0.54 100.24±1.25
F6 6.49±0.30 2.63±0.25 148.2±0.83 0.58 99.53±1.87
F7 6.51±0.32 2.57±0.81 148.7±0.46 0.36 99.50±0.60
F8 6.53±0.35 2.58±0.80 148.9±0.64 0.39 99.32±0.87
F9 6.52±0.31 2.57±0.82 148.9±0.44 0.43 99.58±0.60
F10 6.76±0.55 2.30±0.20 149.8±1.64 0.12 99.22±0.88
F11 6.44±0.57 2.45±0.66 151.6±1.14 0.18 100.24±1.0
F12 6.59±0.30 2.33±0.25 149.2±0.83 0.26 100.53±1.0
Microenvironment pH study:
Table 7: Results of Microenvironment pH study
F.Code Surface pH
F1 6.4
F2 6.6
F3 6.2
F4 6.6
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F5 6.5
F6 6.3
F7 6.5
F8 6.4
F9 6.6
F10 6.3
F11 6.6
F12 6.9
Swelling Index:
Table 8: Results of Percent swelling Index
Time
(min)
Formulation code %
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
10 20.8 24.6 30.4 14.8 18.3 20.7 20.1 21.3 18.4 30.4 24.6 20.7
15 48.1 51 56.2 30.1 35.3 38.5 46.2 55.2 56.7 56.2 51 38.5
30 59.6 63.8 67.5 50.4 54.4 60.6 68.5 76.5 67.9 67.5 63.8 60.6
60 76.45 79.4 85.6 65.8 70.7 74.4 88.3 99.6 85.6 85.6 79.4 74.4
Mucoadhesion time:
Table 9: Effects of polymers on Mucoadhesion time
Formulation Code Mucoadhesion time (hr)
F1 6
F2 8
F3 9
F4 5
F5 7
F6 >9
F7 6
F8 7
F9 9
F10 5
F11 6
F12 6
RESEARCH ARTICLE e-ISSN: 2454-7867
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In-Vitro drug Release Study:
Table 10: Cumulative drug release of formulation F1-F12
Fig.4: In-Vitro Drug Release for Formulation F1, F2, F3
Fig.5: In-Vitro Drug Release for Formulation F4, F5, F6
0
20
40
60
80
100
120
0 2 4 6 8 10
CU
MU
LATI
VE
% D
RU
G
REL
EASE
TIME IN HRS
F1
F2
F3
0
20
40
60
80
100
0 5 10
CU
MU
LATI
VE
% D
RU
G
REL
EASE
TIME IN HRS
F4
F5
F6
%CDR
Tim
e
(hrs)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
0 0 0 0 0 0 0 0 0 0 0 0 0
1 17.6 9.8 7.2 21.3 20.6 19.8 21.3 20.6 19.8 29.6 30.1 25.4
2 39.8 17.2 15.0 34.9 30.4 25.1 34.9 30.4 25.1 35.9 39.6 35.1
3 52.31 23.80 20.9 48.6 42.6 33.6 48.6 42.6 33.6 59.6 45.8 49.5
4 70.61 45.6 33.8 52.1 54.1 48.2 52.1 54.1 48.2 72.4 61.5 64.5
5 86.3 60.1 58.0 74.8 68.7 56.1 74.8 68.7 56.1 92.1 72.8 79.2
6 98.2 70.8 65.1 98.5 85.9 68.5 97.3 77.4 68.5 100.
5
90.5 88.1
7 -- 89.0 79.3 -- 99.6 74.2 -- 85.9 74.2 -- 99.9 100.
2
8 -- 99.6 86.7 -- -- 90.6 -- 98.6 80.6 -- -- --
RESEARCH ARTICLE e-ISSN: 2454-7867
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Fig.6: In-Vitro Drug Release for Formulation F7, F8, F9
Fig.7: In-Vitro Drug Release for Formulation F10, F11, F12 Drug Release Kinetics:
Fig.8: Zero order kinetic graph for formula F2
Fig.9: Higuchi kinetic graph for formula F2
0
20
40
60
80
100
0 5 10
CU
MU
LATI
VE
% D
RU
G
REL
EASE
TIME IN HRS
F7
F8
F9
0
20
40
60
80
100
120
0 5 10
%C
DR
Time in hrs
F10
F11
F12
y = 12.725x - 5.1333 R² = 0.9842
-20
0
20
40
60
80
100
120
0 5 10
%
C
D
R
TIME IN HRS
ZERO ORDER
y = 36.232x - 19.878 R² = 0.8587
-40
-20
0
20
40
60
80
100
120
0 1 2 3
%
C
D
R
SQUARE ROOT OF TIME
HIGUCHI PLOT
RESEARCH ARTICLE e-ISSN: 2454-7867
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Fig.10: Peppas kinetic graph for formula for F2.
Fig.11: First Orders Kinetic Graph for Formula F2
Discussion: In-vitro drug release data of all the buccal tablet formulations was subjected to goodness of
fittest by linear regression analysis according to zero order, first order, Higuchi’s and Korsmeyer-Peppas
models to ascertain the mechanism of drug release. From the above data, it can be seen the formulation,
F2have displayed zero order release kinetics (‘r2 value of 0.9842).From Peppas data; It is evident that the
drug is released by non-Fickian diffusion mechanism. This is because as the proportion of polymers in the
matrix increased the rewash an increase in the amount of water uptake and proportionally greater swelling
leading to a thicker gel layer. Zero-order release from swellable hydrophilic matrices occurs as a result of
constant diffusion path lengths.
Ex-Vivo Drug Permeation Studies for F2:
Table 11: Ex-vivo drug permeation studies for F2
y = 1.6729x + 0.5685 R² = 0.8286
0
0.5
1
1.5
2
2.5
0 0.2 0.4 0.6 0.8 1
L
O
G
%
C
D
R
LOG TIME
PEPPAS
y = -0.1558x + 2.2060 R² = 0.8441
0
0.5
1
1.5
2
2.5
0 2 4 6 8 10
L
O
G
%
D
R
U
G
R
E
M
A
I
N
I
N
G
TIME IN HRS
FIRST ORDER
Time (hr) F2
1 9.03
2 13.8
RESEARCH ARTICLE e-ISSN: 2454-7867
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Fig.12: Graph showing permeation studies of formulation F2
Discussion: The drug permeation was slow and steady, 84.01% of drug could permeate through the
buccal membrane in 8 hours.
Stability Studies:
Table 12: Stability studies of Ivabradine buccoadhesive tablet (F2) at room temperature
Time
Colour
Assay Cumulative % drug
release
Surface PH
25±20c
and
65±5%R
H
40±20c
and
75±5%R
H
25±20c
and
65±5%R
H
40±20c
and
75±5%R
H
25±20c
and
65±5%R
H
40±20c
and
75±5%R
H
First day White 99.48 99.48 97.6 98.6 6.6 6.6
30 days White 99.40 99.30 99.1 97.9 6.6 6.6
60days White 99.31 99.2 97.2 97.1 6.6 6.6
90 days White 98.5 98.0 98 97.8 6.6 6.6
Results from stability studies indicate that the formulated Ivabradine Bucco adhesive tablets are stable for a
period of 3 months under 2 different conditions at 25±20c and65±5%RH and 40±2
0c and 75±5%RH. There
were no remarkable changes were observed during the period of storage.
0
10
20
30
40
50
60
70
80
90
0 5 10% D
RU
G P
ERM
EATE
D
TIME IN HRS
F2
3 26.18
4 35.27
5 44.89
6 58.76
7 70.04
8 84.01
RESEARCH ARTICLE e-ISSN: 2454-7867
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CONCLUSION
It can be concluded that Ivabradine can certainly be administered through the oral mucosa. The
designed Bucco adhesive tablets can overcome the disadvantage of extensive first pass effect and low oral
bioavailability of Ivabradine. This increased and predictable availability of Ivabradine from designed
formulation may result in substantial dose reduction of the dosage form when the drug is administered
through oral mucosa so that it will be economical to the patient. Further work is recommended to support its
efficacy claims by pharmacokinetic and Pharmacodynamics studies in human beings.
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