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

Thanks For Listening

Thanks For Listening

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