FORMULATION AND EVALUATION OF NASAL IN-SITU GEL FOR ANTIMIGRAINE DRUG

1. Submitted by
R. RAJAGURU.M. Pharm. (Ph D)
Junior Research Scientist
CSIR- CLRI, CDRI
1

2. INTRA NASAL DRUG DELIVERY SYSTEM
 The nasal route is an alternative to drug administration, and provides a
direct access to the systemic circulation.
 Many drugs have better bioavailability by nasal route than the oral route.
Mechanism of drug absorption
 Drug passes through the mucous membrane of the nasal cavity. Mainly two
mechanism involved.
 The first mechanism – it involves an aqueous route of transport.
 Second mechanism – it involves transport of drugs through lipoidal route.
2

3. 1. Hepatic first – pass metabolism is absent
2. Reduced dose concentration.
3. Quick onset of action.
4. Rapid drug absorption.(high permeability, neutral pH)
5. Improved patient compliance and comfort.
6. Ease of administration.
1. Absorption surface area is less when compared to GIT.
2. Once the drug administered can not be removed.
3. Nasal irritation.
3
DEMERITS
MERITS

4. ANATOMY AND PHYSIOLOGY OF NOSE
1. Surface area = 150cm(each cavity 75cm )
2. Mucosal secretion =15-20ml
(each cavity 7.5ml)
3.pH = 5-6.7 in children
5.5-6.5 in adult
NASAL SECRETION
water = 95%
mucin = 2%
proteins = 1%
lipids = 1%
4

5. Nasal drug administration pathway
5

6. In-situ
ADVANTAGES OF NASAL IN-SITU GEL
 Increase residence time.
 Reduced dosing frequency.
 cost effective.
6
Solution Gel

7. IN- SITE FOARMING HYDROGEL
POLYMER
pH sensitive polymers
- carbomer
- polymethacrilic acid
Temperature sensitive
polymers
-poloxamer
-chitosan
Ion sensitive polymers
-Gelrite
-Alginate
7

8. Commercial formulations of in situ polymeric system
Timoptic – XE (Timolol maleate)
cytorynTM
ReGel
8

9. Summary of the reported studies investigated as Nasal In-situ
gel
Polymer Gelling agent Drug
poloxamer HPMC Diltiazem hydrochloride
Poloxamer Propylene glycol Metoprolol succinate
carbopol HPMC Felodipine
Sodium alginate HPMC K4M Metoprolol tartarate
Pluronic acid F127 Xanthium gum Rizatriptan benzoate
9

10. Formulation aspects of in-situ nasal gel
Active pharmaceutical ingredients.
Gelling agent(carbopol, polaxomer, gelrite).
Viscosifying agents(HPMC, PEG).
Preservatives(parabens, benzalkonium chloride, benzyl
alcohol).
Antioxidants(metabisulfite, tocopherol).
Humectants (glycerin, sorbitol, mannitol).
10

11. DRUG PROFILE
Drug Name: OHC-X
Available dosage form:
1.Tablet - 2.5mg, 5mg
2.Nasal spray – 5mg
3.ODT - 2.5mg, 5mg
solubility: Highly soluble
11

12. NEED FOR STUDY….?
REDUCE DOSE FREQUENCY
 For tablet twice a day
 For Nasal spray – not exceed 10 mg/day (transient
improvement of migraine, another dose administered at
least 2 hours after the previous dose)
12

13. POLYMER PROFILE
carbomer (pH sensitive polymer)
 Synthetic high molecular weight polymers of acrylic acid cross linked with
allylether.
 Used as a gelling agent – 0.5-2.0%
 Carbomer grade used: Carbopol -940
HPMC- K4M
 Hydroxymethylated and 2-hydroxypropylated cellulose
 Viscosifying agent
13

14. OBJECTIVES OF PROPOSED STUDY
 To improve bioavailability by formulating pH
sensitive in-situ nasal gel.
 To reduce the mucociliary clearance by using
mucoadhesive polymer , thereby increase the contact
time with nasal mucosa.
14

15. Plan of work
Evaluation of in situ forming gel
Formulation of in situ forming gel
Preformulation study
15

16. Formulation of Nasal In situ gel of OHC-
X(2.5mg/0.2ml)
BATCH F-1 F-2 F-3 F-4 F-5 F-6 F-7 F-8 F-9
OHC-X (g) 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25 1.25
Carbopol 940
(%W/V)
0.25 0.25 0.25 0.50 0.50 0.50 0.75 0.75 0.75
HPMC K4M
(%W/V)
0.3 0.4 0.5 0.3 0.4 0.5 0.3 0.4 0.5
Benzalkonium
chloride (%W/V)
0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
Distilled water(ml) 100 100 100 100 100 100 100 100 100
16

17. PREPARATION
Benzalchonium chloride was added
Final volume was made by adding required amount of distilled water
Zolmitriptan added to the mixer
The resultant solution was thoroughly mixed
Carbopol 940 and HPMC K4M in distilled water with continuous stirring
Using magnetic stirrer
Allowed to hydrate overnight
17

18. Preformulation study
18
Wavelength determination
20 ml of PBS ( pH 6.4 )
Stock solution
Dilution 10 ml 20 mlUV-Spectrophotometer range
200-400 nm
Calibration curve
2.5 mg Drug
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 10 20 30 40
Absorbance
Concentration

19. 19
Drug content determination
pH measurement
In-vitro gelation study
Rhelogical study
Determination of gel strength
In-vitro release study
Short term stability study
EVALUVATION OF STUDY

20. 20
UV spectrum of OHC-X
UV spectrum of placebo
Maximum absorbance of OHC-X at 283nm

21. CALIBRATION CURVE OF OHC-X WITH
PHOSPHATE BUFFER SOLUTION pH 6.4
21
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 5 10 15 20 25 30 35
Absorbance
Concentration
Calibration curve of OHC-X with phosphate buffer solution
Y intercept = 0.0063; Slop m = 0.0202; R2 = 0.999
Stock solution: 10mg
drug + 100ml PBS (pH
6.4)
 Conc: 4 to 32µg/ml
 Wavelength:283nm

22. DRUG CONTENT OF FORMULATED IN-SITU
FORMING GELS
S.No Batch No Absorbance (12.5mg(1ml) of gel) Mean Percentage
drug content
1 F1 0.4929 0.4899 0.4901 0.4909 98.3
2 F2 0.4932 0.5110 0.4950 0.4997 100.1
3 F3 0.5283 0.4999 0.4511 0.4931 98.8
4 F4 0.4812 0.4932 0.4832 0.4859 97.3
5 F5 0.5123 0.4734 0.4844 0.4900 98.2
6 F6 0.4998 0.4789 0.4722 0.4836 96.9
7 F7 0.4945 0.4855 0.4967 0.4922 98.6
8 F8 0.4987 0.5134 0.5190 0.5103 102.2
9 F9 0.4719 0.4894 0.4812 0.4808 96.3
22

23. pH of the in-situ formulations
S.No Batch No
pH of the formulation Mean
1 2 3
1. F1 5.4 5.1 5.0 5.2
2. F2 5.2 5.2 5.4 5.3
3. F3 5.6 5.5 5.6 5.6
4. F4 5.2 5.3 5.3 5.3
5. F5 5.7 5.4 5.6 5.6
6. F6 5.0 5.2 5.1 5.1
7. F7 5.4 5.6 5.3 5.4
8. F8 5.2 5.2 5.3 5.2
9. F9 5.4 5.4 5.3 5.4
23

24. In-Vitro Gelation Study of In-situ formulation
S.No Batch code No gelation Slow gelation
Immediate
gelation which
remains for 2-3
hrs
Immediate stiff
gelation, which
remains for
extended period
of time
1. F1 -
2. F2 -
3. F3 +
4. F4 +
5. F5 ++
6. F6 ++
7. F7 +++
8. F8 +++
9. F9 +++
24
200µL formulation +7ml of PBS
scale ranging between – and +++.

25. Viscosity of in-situ forming gel system
S.No Sample code Liquid viscosity in
centipoise (cP) at
100rpm
Gel viscosity in centipoises
(cP) at 100rpm
Spindle no 61 Spindle no 63
1. F5 7.15 530
2. F6 9.06 595
3. F7 10.50 710
4. F8 11.10 830
5. F9 13.21 890
25

26. Comparative viscosity profile of F5 to F9
26
0
200
400
600
800
1000
1200
F5 F6 F7 F8 F9
ViscositycP
Formulation Code

27. MEASUREMENT OF GEL STRENGTH(sec)
27
BEAD
SOLUTION
BEAD
GEL

28. Gel Strength measurement
S.No Formulation code
Gel strength
(seconds)
1. F5 25.00
2. F6 28.14
3. F7 32.21
4. F8 39.45
5. F9 42.13
28
GEL STRENGTH
GEL FORMULATION

29. IN-VITRO RELEASE STUDY
29
Bead
Donor compartment
Receptor compartment
Membrane

30. IN-VITRO RELEASE STUDY OF F5
Time (min)
Cumulative percentage of drug released
F5 F6 F7 F8 F9
30 46.89 37.28 27.79 17.40 6.15
60 60.52 49.71 38.24 31.11 12.48
120 72.05 68.58 51.26 37.96 15.80
180 92.80 89.67 65.49 49.17 27.79
240 98.70 92.52 78.96 56.76 35.48
300 - 96.44 85.25 61.58 45.46
360 - - 95.36 79.34 54.19
30

31. Comparative in vitro release profile of F5-F9
31
0
20
40
60
80
100
120
0 50 100 150 200 250 300 350 400
Cumulative%ofdrugrelease
Time in minutes
F5
F6
F7
F8
F9

32. Coefficients (r2) data analysis of OHC-X
Formulation
code
Zero order
r2
First Order
r2
Higuchi
model
r2
Korsmeyer –
peppas
r2
F7
0.924 0.918 0.972 0.929
32
y = 0.2587x + 15.197
R² = 0.9248
0
20
40
60
80
100
0 100 200 300 400
cumulative%drugrelease
Time (mts)
Zero order
Zero order
Linear (Zero order)
y = 0.052x + 3.1475
R² = 0.9188
0.000
5.000
10.000
15.000
20.000
0 100 200 300 400
LogCumulative%drugremaining
time (mts)
First order
First order
Linear (First order)

33. 33
y = 13.762x - 5.4786
R² = 0.9725
0
10
20
30
40
50
60
70
80
90
100
0.000 2.000 4.000 6.000 8.000
cumulative%drugreleased
SQRT of Time
Higuchi
Higuchi
Linear (Higuchi)
y = -97.664x + 208.04
R² = 0.9296
0
10
20
30
40
50
60
70
80
90
100
0.000 0.500 1.000 1.500 2.000 2.500
logcumulative%drugrelease
log time
Kors-peppas
Kors-peppas
Linear (Kors-
peppas)

34. 34
y = 0.1889x + 0.1156
R² = 0.9849
0.000
0.500
1.000
1.500
2.000
2.500
0 5 10 15
CBR(Wo)-CBR(Wt)
Time (mts.)
Hixson
hixson
Linear (hixson)

35. stability testing – Appearance data (60% ±5% and 75% ±5% or
25oC±0.5oC and 40oC±0.5oC)
Formulation
code
Appearance
0 day 15 day 30 day
F5
Colorless Clear
viscous solution
Colorless Clear viscous
solution
Colorless Clear viscous
solution
F6
Colorless Clear
viscous solution
Colorless Clear viscous
solution
Colorless Clear viscous
solution
F7
Colorless Clear
viscous solution
Colorless Clear viscous
solution
Colorless Clear viscous
solution
F8
Colorless Clear
viscous solution
Colorless Clear viscous
solution
Colorless Clear viscous
solution
F9
Colorless Clear
viscous solution
Colorless Clear viscous
solution
Colorless Clear viscous
solution
35

36. stability testing – pH data (60% ±5% and 75% ±5% or 25oC±0.5oCand
40oC±0.5oC)
Formulation
code
pH
0 day 15 day 30 day
F5 5.6 5.4 5.5
F6 5.1 5.2 5.1
F7 5.4 5.6 5.6
F8 5.2 5.1 5.3
F9 5.4 5.6 5.5
36

37. stability testing – 15th day sampling in-vitro gelation study
(60% ±5% and 75% ±5% or 25oC±0.5oCand 40oC±0.5oC)
Batch code No gelation Slow gelation
Immediate
gelation which
remains for 2-3
hrs
Immediate stiff
gelation, which
remains for
extended period
of time
F5 - - ++ -
F6 - - ++ -
F7 - - - +++
F8 - - - +++
F9 - - - +++
37

38. Stability testing – 30th day sampling in vitro gelation study (60% ±5% and
75% ±5% or 25oC±0.5oCand 40oC±0.5oC)
Batch code No gelation Slow gelation
Immediate
gelation which
remains for 2-3
hrs
Immediate stiff
gelation, which
remains for
extended period
of time
F5 - - ++ -
F6 - - ++ -
F7 - - - +++
F8 - - - +++
F9 - - - +++
38

39. Solution to gel transition
39

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40
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