Formulation and In-Vitro Evaluation of Ketotifen Fumarate
Oral Strips
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Chapter One
Introduction
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Fast- dissolving drug delivery systems were first developed in the late 1970s as an alternative to conventional dosage
forms for pediatric and geriatric patients who experience difficulties in
swallowing traditional oral solid-dosage forms
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Fast-dissolve
technologies
Lyophilized
systems
Compressed tablet-
based systems
Oral thin films
(OTFs)
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Oral Strip
A thin film that is prepared
using hydrophilic
polymers that rapidly
dissolves on the tongue or buccal
cavity
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Ingredients Active pharmaceutical ingredient (API) 1 - 30% Strip forming polymers 40 - 50% Plasticizers 0 -20% Surfactants Sweetening agents Saliva stimulating agents Flavoring agents Coloring agents Stabilizing and thickening agents
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Manufacturing
Methods
Solvent casting
Hot melt extrusion
Semisolid casting
Solid dispersion extrusion
Rolling
Electrostatic spinning
method
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Drug Used in the StudyKetotifen Fumarate
C19H19NOS.C4H4O4
Mwt.= 425.50
pKa= 8.75
Log P = 4.99
Oral bioavailability of
50% due to hepatic first
pass metabolism
4-(1-Methylpiperidin-4-ylidene) - 4Hbenzo [4, 5] cyclohepta [1, 2-
b] thiophen-10(9H)-one monofumarate
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Aim of the Study
This study aims to formulate ketotifen fumarate as oral dissolving films, to
improve the bioavailability by avoiding hepatic first-pass metabolism
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Chapter Two Experimental
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Characterization of Ketotifen Fumarate
Determination of melting pointDetermination of λ maxConstruction of calibration curvesFourier transform infrared spectroscopy (FTIR)Determination of pH- solubility profile
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Preparation of Ketotifen Fumarate Oral Films
Dissolving
polymer in 20 ml
D.W
Add KF ,plasticizer,
surfactant,Na saccharin, citric acid
and mannitol
Rest for 24 hours
to remove all the
air bubbles
Dispersion stirred
for 30 minutes
Cooling to room
temperature
drying
casting
Heating stirring
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Composition of Ketotifen Fumarate Oral Films Formulas
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Formulation Variables Studied
Type of film forming polymerType of plasticizerConcentration of plasticizerConcentration of the selected polymerType of surfactantConcentration of surfactant
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Evaluation of Ketotifen Fumarate Oral Films
Drug content uniformityVisual inspectionWeight variationThickness measurementsFolding enduranceTensile testing of the films (tensile strength ,
elastic modulus , percent elongation , strain )Disintegration test ( in -vitro disintegration
study , in -vivo disintegration study)Surface pH measurement
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In –vitro dissolution studyComparison of selected formula F17 with
traditional tablet (Zaditen® )and (Asmafort ®) for drug release profile in 0.1 N HCL as dissolution medium
In –vitro permeation studyDrug polymer compatibility studyFTIR spectroscopyo Drug o Blank polymero Physical mixture of polymer and the drug
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Stability StudiesStability Studies (Effect of Humidity)F17 stored at humidity oven 40˚C /75 ± 5 %
RH for duration of three monthsTested for various physical mechanical
testsStability study
(Accelerated Temperature Effect)
F17 stored in ovens at different temperatures of 40°C, 50 ° C, and 60 ° C for three months and analysis for drug
content
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Statistical analysis One way analysis of variance (ANOVA) test
was used, and (P <0.05) was considered to be statistically significant
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Chapter Three
Results and Discussion
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Characterization of Ketotifen FumarateDetermination of Melting Point
The melting point of ketotifen fumarate after drying was 190⁰C
Determination of λ max UV scan in 0.1N HCL (pH 1.2), phosphate buffers (pH
6.8) and (pH 7.4) showed λ max. at 300 nm
300 nm
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Construction of Calibration Curves
pH 1.2
pH 6.8pH 7.4
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Fourier Transform Infrared Spectroscopy (FTIR)
3074.53
1651.12790.84
856.42
3100-3000
1321.28 1255.7
FTIR spectra of pure ketotifen fumarate powder
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Determination of pH-Solubility Profile
pH Solubility of KF (mg/ml)
1.2 44.17
6.8 10
7.4 8.2
Evaluation of Ketotifen Fumarate Oral Films
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Oral Film
Moderate tensile strength
High %Elonga
tion
High strain
Low elastic
modulus
Short disintegration time
High percent
drug release
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Effect of type of polymerFormula
codeIn vivo DT(sec)
Folding endurance
Strain T80%
F1(HPMC 6cp) 30.0±1 110 0.047 5.2
F2(NaCMC) 90.0±3.1 2 Not available 4
F3(PVA) 110.0±5 >300 1.48 1.8
F4(Gelatin) Not available Not available Not available Not available
F5 (Xanthan) 60.0±3.3 Not available Not available 40
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Effect of type of plasticizers and their concentrations
Formula code In vivo DT(sec) Folding endurance
Strain
F1(Gly 17.14%) 30.0±1 110 0.047
F6(Gly 21.14%) 29.0±2.5 128 0.049
F7(Gly 13.14%) 32.0±4.1 35 0.021
F8(PEG 17.14%) 31.0±1 220 0.035
F9(PEG 21.14%) 30.2±2 ˃300 0.056F10(PEG 13.14%) 33.0±2.2 150 0.017
F11(PG 17.14%) 31.0±2.8 80 0.021
F12(PG 21.14%) 33.0±3.1 92 0.043
F13(PG 13.14%) 36.0±4 20 0.019
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Effect of type of plasticizers and their concentrations
Formula code
F6 F8 F9 F10 F12
T80% 4.8 7.0 4.1 9.3 3.0
D2min% 57.3 37.05 55.45 28.33 63.07
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Effect of Concentration of Hydroxypropyl methylcellulose
Formula code
In vivo DT
( sec)
Folding Enduran
ce
Tensile Strength
(MPa)
T80% D2min%
F9(68.64%) 30.2±2 >300 13.41 4.1 55.45
F14(64.64%) 28.6±1 >300 12.88 4.1 61.93
F15(70.97%) 33.0±1 >300 14.76 4.6 51.53
F16(61.64% ) 24.6±2.5 >300 11.83 3.7 65.93
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Effect of Type and Concentration of Surfactants
Formula code
In vivo DT
( sec)
Folding Enduranc
e
Strain T80% D2min%
F17(tween 6.28%)
20.4±1 >300 0.033 2.1 74.77
F18(span 6.28%)
38.6±1 >300 0.038 5.3 48.24
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Formula code In vivo DT(sec)
Folding Endurance
Strain T80% D2min%
F16(Tween 2.28%) 24.6±2.5 >300 0.039 3.7 56.93
F17(Tween 6.28%) 20.4±1 >300 0.033 2.1 74.77
F19(0.0%surfactant) 29.4±3 >300 0.029 4.1 55.62
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Comparative Study
Formula source T80% D2min
F17 2.1 74.77Zaditen® 3.6 51.82
Asmafort® 5.2 41.66
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In- vitro Permeation
Study
The results
indicated that
ketotifen fumarate
permeated through
the sheep sublingual
mucosa and hence
could possibly
permeate through the
human buccal
membrane also
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FTIR spectra of pure ketotifen fumarate powder
Drug –Polymer Compatibility Study
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FTIR spectra of hydroxypropyl methylcellulose
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FTIR spectra of the physical mixture of ketotifen fumarate and hydroxypropyl
methylcellulose
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Stability Studies( Effect of Humidity)
Properties Before storage After storage
Drug content% 98.10 97.5
Thickness(mm) 0.136±0.02 0.132±0.01
Tensile strength 11 10.8
Elongation % 3.31 2.77
Elastic modulus 332.32 389.89
Strain 0.033 0.027
Folding endurance ˃300 ˃300
In vivo DT(sec) 20.4±1 20.1±1
In vitro DT (sec) 22.74±1 21.5±2
Surface pH 5.9 6
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Stability Studies( Effect of Temperature)
Temperature(°C) K (week-1)
40 1.5×10-3
50 3.08×10-3
60 4.6×10-3
The estimated shelf life of the selected formula was found to be 167.7 weeks or about 3.5 years
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ConclusionsThe best film forming polymer was hydroxypropyl
methylcellulosePolyethylene Glycol 400 was the best plasticizerDecreasing the concentration of HPMC resulted in faster
disintegration and drug release rates of ketotifen fumarate oral films
The disintegration and the drug release rates were faster for films prepared with hydrophilic surfactant (tween 80) than that for films prepared with span 80
As the concentration of tween 80 is increased, both the disintegration and the drug release rates increased
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Amongst the nineteen formulas, the formula F17 which contain (61.64% w/w) of HPMC, (21.14% w/w) of PEG400, and (6.28%w/w) of tween 80 showed fastest disintegration time 20.4seconds, T80% 2.1 minutes, the D2 min % 74.77% and satisfactory mechanical properties
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Thanks For Listening
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