Ketotifen fumarate oral strips were formulated and evaluated. Hydroxypropyl methylcellulose was found to be the best film-forming polymer. Polyethylene glycol 400 was the best plasticizer. Decreasing HPMC concentration and increasing the hydrophilic surfactant tween 80 concentration led to faster disintegration and drug release. Formula F17 containing 61.64% HPMC, 21.14% PEG400 and 6.28% tween 80 showed the fastest disintegration time of 20.4 seconds and highest drug release of 74.77% within 2.1 minutes. The oral strips were stable for up to 3.5 years and could improve ketotifen fumarate bioavailability by avoiding

1. Formulation and In-Vitro
Evaluation of Ketotifen
Fumarate Oral Strips
1

2. 2

3. Introduction
3

4. 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
4

5. Lyophilized
systems
Fast-dissolve
technologies
Compressed
Oral thin
tablet-based
films (OTFs)
systems
5

6. Oral Strip
A thin film that is
prepared using
hydrophilic
polymers that
rapidly
dissolves on the
tongue or buccal
cavity
6

7.  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
7

8. Solvent
casting
Electrostatic
spinning Hot melt
method extrusion
Manufacturing
Methods
Semisolid
Rolling
casting
Solid
dispersion
extrusion
8

9. Drug Used in the Study
Ketotifen Fumarate
C19H19NOS.C4H4O4
Mwt.= 425.50
pKa= 8.75
Log P = 4.99
Oral bioavailability
4-(1-Methylpiperidin-4-ylidene) - of 50% due to
4Hbenzo [4, 5] cyclohepta [1, 2-b] hepatic first pass
thiophen-10(9H)-one monofumarate metabolism
9

10. 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
10

11. Chapter Two
Experimental
11

12.  Determination of melting point
 Determination of λ max
 Construction of calibration curves
 Fourier transform infrared spectroscopy (FTIR)
 Determination of pH- solubility profile
12

13. Preparation of Ketotifen Fumarate Oral Films
Heating
Add
stirring
KF ,plasticizer, surfactant,
Na saccharin, citric acid and
Dissolving mannitol
polymer in Cooling to
20 ml D.W room
temperature
Rest for 24 drying
Dispersion hours to
stirred for remove all
30 minutes the air
bubbles
casting
13

14. Composition of Ketotifen Fumarate Oral Films
Formulas
14

15. Formulation Variables Studied
 Type of film forming polymer
 Type of plasticizer
 Concentration of plasticizer
 Concentration of the selected polymer
 Type of surfactant
 Concentration of surfactant
15

16. Evaluation of Ketotifen Fumarate Oral Films
 Drug content uniformity
 Visual inspection
 Weight variation
 Thickness measurements
 Folding endurance
 Tensile testing of the films (tensile strength ,
elastic modulus , percent elongation , strain )
 Disintegration test ( in -vitro disintegration study
, in -vivo disintegration study)
 Surface pH measurement
16

17.  In –vitro dissolution study
 Comparison 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 study
 Drug polymer compatibility study
 FTIR spectroscopy
o Drug
o Blank polymer
o Physical mixture of polymer and the drug
17

18. Stability Studies
 Stability Studies (Effect of Humidity)
 F17 stored at humidity oven 40˚C /75 ± 5 % RH for
duration of three months
 Tested for various physical mechanical tests
Stability 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
18

19. Statistical analysis
 One way analysis of variance (ANOVA) test was
used, and (P <0.05) was considered to be statistically
significant
19

20. Results and Discussion
20

21. Characterization of Ketotifen Fumarate
 Determination 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
21

22. Construction of Calibration Curves
pH 1.2
pH 7.4 pH 6.8
22

23. Fourier Transform Infrared
Spectroscopy (FTIR)
3074.53
856.42
3100-3000
1651.12 1321.28 1255.7 790.84
FTIR spectra of pure ketotifen fumarate
23
powder

24. Determination of pH-Solubility Profile
pH Solubility of KF (mg/ml)
1.2 44.17
6.8 10
7.4 8.2
24

25. 25

26. Moderate
tensile
strength
High percent High
drug release %Elongation
Oral
Film
Short
disintegration High strain
time
Low elastic
modulus
26

27. Effect of type of polymer
Formula code In vivo DT(sec) Folding Strain T80%
endurance
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
27

28. 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 0.056
F10(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
28

29. Effect of type of plasticizers and their concentrations
Formula F6 F8 F9 F10 F12
code
T80% 4.8 7.0 4.1 9.3 3.0
D2min% 57.3 37.05 55.45 28.33 63.07
29

30. Effect of Concentration of Hydroxypropyl
methylcellulose
Formula In vivo DT Folding Tensile T80% D2min%
code ( sec) Endurance Strength
(MPa)
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
30

31. Effect of Type and Concentration of Surfactants
Formula In vivo DT Folding Strain T80% D2min%
code ( sec) Endurance
F17 20.4±1 >300 0.033 2.1 74.77
(tween 6.28%)
F18 38.6±1 >300 0.038 5.3 48.24
(span 6.28%)
31

32. Formula code In vivo Folding Strain T80% D2min%
DT(sec) Endurance
F16
24.6±2.5 >300 0.039 3.7 56.93
(Tween 2.28%)
F17
20.4±1 >300 0.033 2.1 74.77
(Tween 6.28%)
F19
29.4±3 >300 0.029 4.1 55.62
(0.0%surfactant)
32

33. Comparative Study
Formula source T80% D2min
F17 2.1 74.77
Zaditen® 3.6 51.82
Asmafort® 5.2 41.66
33

34. 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
34

35. Drug –Polymer Compatibility Study
FTIR spectra of pure ketotifen fumarate powder
35

36. FTIR spectra of hydroxypropyl
methylcellulose 36

37. FTIR spectra of the physical mixture of ketotifen
fumarate and hydroxypropyl methylcellulose
37

38. 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
38

39. 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
39

40. Conclusions
 The best film forming polymer was hydroxypropyl
methylcellulose
 Polyethylene Glycol 400 was the best plasticizer
 Decreasing 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
40

41.  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
41

42. Thanks For
Listening