formulation of mometasone furoate emulgel
TRANSCRIPT
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Formulation and Evaluation of Emulgel for topical delivery of
Mometasone Furoate MINOR PROJECT – 2015
SPPSPTM, Mumbai External Seminar
25-04-15 Name of the Student: Aman Dube
ROLL NO: 4Programme and Specialization: M Pharm (QUALITY ASSURANCE) + MBA
Name of the Guide: Dr. DEEPALI KADUSKAR
PLAN OF WORKSr.no. Objective Duration in
weeks1 Literature & patent search 12 Listing & procurement of materials 13 Characterization of API & excipients 24 Formulation of Emulgels 25 Characterization of Emulgels 16 Permeability studies 17 Animal studies 18 Stability studies 29
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Data compilation & preparation
Patent and Publication
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111 Presentation & thesis submission 1
Total 152
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Aim & Objectives
• To formulate and develop emulgel containing Mometasone Furoate with
non-irritating components that can be applied to efficiently treat
inflammatory skin diseases such as psoriasis, eczema, cutaneous lupus
erythematosusand vitiligo for topical delivery.
• To prove the potential of emulgel over other conventional formulations by
formulating a formulation which will reduce the side effects like local
irritation and erythema with ease of application when formulated as an
emulgel.
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Drug Profile - Mometasone Furoate I.P
► Batch No: MMF/M/023/14► Manufacturing Date: Dec 2014► Expiry Date: Nov 2019► Therapeutic Category: Medium-potency synthetic
corticosteroid with anti-inflammatory, antipruritic, and vasoconstrictive properties
► BCS Class II► CAS Number: 105102-22-5► Mol wt.: 521.4► Dose: 220µg to 440µg► Trade names: Elocon , Elomex, Novasone , Nasonex► Routes: Topical, Inhalation
Fig 1. Showing structure of Mometasone Furoate
Ref: Indian Pharmacopoeia 2014 Pg. no – 2243, 2244, Vol 2
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Pharmacopoeial Characterization of Mometasone Furoate
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FT-IR of Mometasone Furoate (IP 2014)
Fig. 2 Showing IR spectra of Mometasone Furoate Batch No: MMF/M/023/14
Fig. 3 Showing Reference spectra of Mometasone Furoate as per IP 2014
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Peaks observed
Range cm-1 Functional group
751.81 700-900 (s) S-OR esters
1006.68 1000-1110(s,b) Si-OR
1106.27 1100-1200(s) P=O phosphine oxide
1171.98 1100-1200(s) P=O phosphate
1383.46 1350-1450(s) Sulphates
1305.46 1350-1450(s) Sulphates
1457.73 1465 -CH2
1696.53 1660-1500 nitro
1648.35 1650 amine
3565.62 3200-3600(s) -OH alcohols
9,21-dichloro-11ß-hydroxy-16α-methyl-3,20-dioxopregna-1,4dien-17-ylfuran-2-carboxylate
6-CARBON RING A B C5–CARBON RING DKETONE OXYGEN AT POSITION 321-CHLORO 17(2’FUROATE) AT POSITION 17
Table. 1 Showing IR interpretation of Mometasone Furoate
Batch No: MMF/M/023/14
Fig. 4 Structure of Mometasone Furoate Fig. 5 Steroid Nucleus
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TLC of Mometasone Furoate (USP 2014) Batch No: MMF/M/023/14
Fig. 6 Showing TLC of Mometasone Furoate
► Sample: 10 mg/ml Mometasone Furoate in methanol
► Adsorbent : 0.25 mm layer of chromatographic silica gel
► Mobile phase: Chloroform and ethyl acetate (3:1)
► Detection : Observed under UV chamber at 254nm
► Rf value: 0.64
Ref: USP 2014 Pg. No 3871
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UV calibration of Mometasone Furoate ( IP 2014)
0 2 4 6 8 10 12 140
0.1
0.2
0.3
0.4
0.5
0.6
0.7
f(x) = 0.0519785714285714 x − 0.0499666666666666R² = 0.990833122911064Concentration
(µg/ml)
Absorbance
2 0.0491 4 0.146 6 0.2963 8 0.3592 10 0.4522 12 0.5805
Table. 2 Showing Absorbance's at different concentrations at λ max- 248.95
Fig. 7 UV spectra of Mometasone Furoate showing λ max at 248.95
Fig. 8 Showing Linearity Curve of Mometasone Furoate I.P
Batch No: MMF/M/023/14
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Assay of Mometasone Furoate ( IP 2014)
• Procedure:• Dissolve 50.0 mg in 100 ml 95 percent
ethanol• Dilute 2.0 ml of this solution to 100.0
ml with alcohol R.• Measure the absorbance at the
maximum at 249 nm. • Calculate the content of
C27H30Cl2O6 taking the specific absorbance to be 481.
• Results:• Absorbance – 0.4839• A=abc• A= A 1% 1cm*b*c• 0.4839= 481*1*c• C= 0.0010 g/100ml• C=10.06 ppm• Assay= 100.6%
Batch No: MMF/M/023/14
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HPLC of Mometasone Furoate ( IP 2014)• Isocratic System• Sample: 10mg /10 ml in methanol• Stationary phase: C18 Column ( 25cm x 4.6mm)• Mobile phase: Acetonitrile: water (50:50)• Flow rate: 1ml/min• Injection Vol: 20 µl• λ max – 254nm• Retention time: 7.63 min which is comparable to
Thula et al, Stability indicating HPLC method for simultaneous estimation of Mometasone Furoate and Formoterol Fumarate in combined dosage form, Pharmacophore 2014, Vol. 5 (2), 219-230
Batch No: MMF/M/023/14
Fig. 9 Showing Chromatogram of Mometasone Furoate
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Confirmation tests of Mometasone Furoate ( IP 2014)
Batch No: MMF/M/023/14
Test Performed Acceptance Criteria
Observation
Test for chloride(Impurity test)
White curdy ppt. White curdy ppt.
Test for fluorescence No fluorescence No fluorescence observed
Loss on drying NMT 0.5 % Complies
Heavy Metal Test 0.67 g complies with 30 ppm
Complies
Fig. 10 Showing test for chlorides
Fig. 11 Showing test for heavy metals
Table 3: Showing tests for Mometasone Furoate as per IP 2014
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Pharmacopoeial Characterization of Excipients
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Characterization of Carbopol 934 IP
Fig. 12 Showing IR Spectra of Carbopol 934
Peaks observed
Range cm-1 Functional group
605.78 700–610 (b, s) –C≡C–H: C–H bend Alkynes
800.02 1000–650 (s) =C–H bend-alkenes
1244.31 1320–1000 (s) C–O stretch-alcohols, carboxylic acids, esters, ethers
1717.87 1760–1690 (s) C=O stretch-carboxylic acids
3177.49 3300–2500 (m) O–H stretch -carboxylic acids
Fig. 13 Structure of Carbopol 934 which is a Polymer of acrylic acid cross linked with allyl ether of pentaerythritol
Table. 4 Showing IR Interpretation of Carbopol IP
IP 2014 Pg. No 1275-76
Test Observation Limit
Loss on drying 2% is lost NMT 3%
Table. 5 Specific test for Carbopol
Batch No: C11Z/1611/1402/13
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Characterization of Methyl paraben IP
Fig. 14 Showing IR Spectra of Methyl paraben Fig. 15 Showing Reference spectra of methyl paraben as per IP 2014
Fig. 16 Structure of methyl paraben Ref : IP 2014 Pg. No 2204
Batch No: 0466000500
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Peaks observed
Range cm-1 Functional group
3308.41 3500–3200 (s,b) OH-alcohols, phenols
1682.7 1760–1665 (s) C=O stretch
2963.28 3100–3000 (s) C-H aromatic
2963.28 3000–2850 (m) C-H stretch
1278.88 1320–1000 (s) C-O - alcohols, carboxylic acids, esters, ether
Tests Observation Limits as per IP 2014
Acidity 1 drop of 0.1 M NaOH changes colour
Not more than 0.1 ml of 0.1 M NaOH is required to change the colour
On boiling 10mg with 10ml of water , cool add 0.05ml ferric chloride
Reddish violet color obtained
A reddish violet color is produced
Table. 6 Showing IR Interpretation of Methyl paraben
Characterization of Methylparaben IP
Table. 7 Tests as per IP
Batch No: 0466000500
Ref : IP 2014 Pg. No 2204
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Characterization of HPMC 4cps IP
Fig. 17 Showing IR Spectra of HPMC
Batch No: 109Z/0209/1808/13
Fig. 18 Showing structure of HPMC
Peaks (cm-1 ) Functional group3465.87 O-H alcohols, phenols
2934.25 C-H, alkanes
1640.29 C=O
943.38 O-H. COOH
610.09 alkynes
Tests Observation Limits Loss on drying 9% lost NMT 10%
Heavy metals 1g complies complies
Chlorides 5ml complies complies
Ref: IP 2014 Pg. no 1920-21
Table. 8 Showing IR interpretation of HPMC
Table. 9 Tests as per IP 2014
Characterization of Sorbitan Oleate IP 2014)
Figure no.19 :- FTIR spectra of Sorbitan Oleate as performed Figure no.20 :- Reference FTIR of Sorbitan Oleate IP 2014
Ref: http://www.chemicalbook.com/SpectrumEN_1338-43-8_IR2.htm
Batch no. 1112/0411/0401/13
Peaks observed Range cm-1 Functional group
3416.28 3500–3200 (s,b) O-H
1249.93 1320–1000 (s) C-O
1442.60
1400-1500
C-C
2916.90 3000–2850 (m) C-H stretch
1158.70 1320–1000 (s) C-O-C ether
Table no. 10: IR interpretation of Sorbitan Oleate IP 2014
Characterization of Sorbitan Oleate IP 2014
Fig.21 : Structure of Sorbitan Oleate IP 2014
Reference : IP 2014
Batch no. 1112/0411/0401/13
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Characterization of Isopropyl alcohol IP
Fig. 22 Showing IR Spectra of Isopropyl alcohol
Batch No: 10767210-8
Fig. 23 Structure of Isopropyl alcohol
Peaks (cm-1 ) Functional group3423.83 O-H alcohols. phenols
2926.78 C-H alkanes
1684.07 C=O, carbonyls
794.30 C-H, aromatics
670.35 alkynes
Tests Observation LimitsWater insoluble matter
No opalescence Complies
Acidity Pink color Complies
Table. 11 showing IR interpretation of Isopropyl alcohol
Table. 12 Tests as per IP 2014
Ref: IP 2014 Pg. No 2010-11
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Characterization of Propylene Glycol
Fig. 24 Showing IR Spectra of Propylene glycol
Fig. 25 Structure of Propylene glycol
Batch No: HO9A/1009/0608/31
Peaks (cm-1 ) Functional Groups
3422.19 O-H alcohols, phenols
2927.32 C-H alkanes
1683.15 C=O
1049.96 C-N
670.28 alkynes
Table. 13 Showing IR interpretation of propylene glycol
Ref: IP 2014 Pg. No 2852
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Characterization of Light liquid Paraffin
Fig. 26 Showing IR Spectra of Liquid Paraffin
Batch No: A11A/0910/2812/13
Ref: IP 2014 Pg. No 2435
Peaks (cm-1 ) Functional Groups
3447.43 O-H alcohols, phenols
2926.76 C-H alkanes
1458.13 C-C alkenes
1376.99 alkanes
721.18 Alkyl halides
Test Observation Limits as per IP 2014Acidity Pink color
developsComplies
Table. 14 Showing IR interpretation of liquid paraffin
Table. 15 Tests as per IP 2014
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Method of Formulation of Emulgel
OIL PHASE WATER PHASE
EMULSION EITHER O/W or W/O
EMULSION INCORPORATED IN GEL
• Castor oil• Clove oil• Liquid
Paraffin• Propylene
glycol
• Water• Alcohols
• Carbopol 934• HPMC
• Isopropyl myristate• Menthol
Emulsification
Fig. 27 Showing Flowchart for Emulgel preparation Ref: Singla et al ( 2012), Emulgel: a new platform for topical drug delivery, IJPBS, Vol 3, Issue 1
Mometasone Furoate Emulgel Trials
Fig.28 Batch MFE/SPTM01/15
Fig.29:Batch MFE/SPTM02/15
Fig.30:iBatch MFE/SPTM03/15
Fig.31:Batch MFE/SPTM04/15
Fig.32:Batch MFE/SPTM05/15
Fig.33:Batch MFE/SPTM06/15
Fig.34:Batch MFE/SPTM07/15
Fig.35:Batch MFE/SPTM08/15
Fig.36:Batch MFE/SPTM09/15
Fig.37:Batch MFE/SPTM10/15
Ingredients Batch No Category Quantity Mometasone Furoate I.P MMF/M/023/14 Active Ingredient 0.1%Carbopol 934 C11Z/1611/1402/13 Gelling agent 1 %Light liquid paraffin A11A/0910/2812/13 Oil phase 7.5%Span 80 1112/0411/0401/13 Surfactant 1%Tween 80 8467-6908-2 Emulsifier 0.5%Propylene glycol HO9A/1009/0608/31 Co solvent 5Methyl paraben 0466000500 Preservative 0.03%Propyl paraben V 310005 Preservative 0.01%Ethanol XK-13-201-00185 Solvent 2.5%Triethanolamine 1006-7210-8 pH balancer q.sWater q.s
Mometasone Furoate Emulgel Optimized – MFE/SPTM10/15
Batch size – 10ml
Table 16. Showing Composition of optimized formulation
Evaluation of emulgel -MFE/SPTM10/15
• ASSAY:
Take 1gm of gel and dissolve in 25 ml of methanol.
This solution was sonicated for 30 mins in order to get complete solubility of drug.
After completely dissolution filter the solution and make suitable dilutions.
After suitable dilution drug absorbance was recorded by using UV- visible spectrophotometer at λ max 249 nm
Assay – 91.41%
Evaluation of emulgel-MFE/SPTM10/15
Fig 38 Emulsion globules at 100x magnification Fig 40 Emulsion globules at 400x magnification Fig 39 Emulsion globules at 100x magnification
Fig 41 Emulsion globules at 100x magnification Fig 42 Emulgel globules at 400x magnification
Oil Phase
Aqueous phase
Staining agent: Amaranth red
Evaluation of emulgel- MFE/SPTM10/15
Parameters Observation
Clarity Clear
Homogeneity Excellent
Spreadability Excellent
Parameters Acceptance criteria
Observation
pH 5-7 6.0
Assay 90-110 % 91.47
Texture Smooth shiny and lustrous
Consistency Excellent
Phase separation
No
Fig.43 TLC of emulgel & Std drug
Table 17 Showing evaluation of various parameters
In vitro release of emulgel - MFE/SPTM10/15
Time (min) Release (%)n=2
15 16.73±0.725
30 23.9±0.41
60 27.37±0.08
120 29.365±0.145
240 35.34±0.22
300 39.33±1.49
360 47.92±0.16
420 54.265±0.325
480 59.73±1.81
Franz diffusion cellMedium: Ethanol: water(2:1)Membrane: Cellophane
Table 18 Showing In vitro release of emulgel
0 100 200 300 400 500 6000
10203040506070
In vitro release of emulgel
Series1 Series3
Time (in mins)
% R
elea
seFig. 44 % Release of emulgel
Release profiles of emulgel - MFE/SPTM10/15
0 100 200 300 400 500 6000
20
40
60
80
f(x) = 0.0807584848484848 x + 18.9343409090909R² = 0.963455519039921
Chart Title
Time (min)
% C
umul
ative
rele
ase
0 100 200 300 400 500 6000
1
2
3f(x) = 0.00332084848484848 x + 1.38558686868687R² = 0.919880784229033
Chart Title
Time (min)
Log
cum
rele
ase
0 5 10 15 20 250
10203040506070
f(x) = 2.06343977999306 x + 9.08257942293199R² = 0.925915494749961
Chart Title
Root T
Cum
rele
ase
%
1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.80123
f(x) = 1.09694240816367 x − 0.20578155393737R² = 0.964469038269102
Chart Title
Log Time (min)
Log
cum
rele
ase
Fig 45 Zero order release
Fig 48 Peppas modelFig 47 First order release
Fig 46 Higuchi model
Permeability of emulgel-MFE/SPTM10/15
Time (min) Permeation (%)n=2
15 14.24±0.26
30 22.66±0.215
60 27.97±0.7
120 28.23±1
240 32.26±0.055
300 35.68±0.3
360 40.52±0.175
420 46.37±0.675
480 50.54±0.215
Franz diffusion cellMedium: Ethanol: water(2:1)Membrane: Rat skinTable 19. Showing ex vivo permeation of emulgel
0 100 200 300 400 500 6000
102030405060
Chart Title
Time (mins)
% P
ERM
EATI
ON
Fig. 49 % Permeation of emulgel
Permeability of Elocon©(Batch:34140252)
Time (min) Permeation (%)n=2
15 11.99±0.69530 18.76±0.29560 21.33±0.4
120 23.99±1.84240 26.87±2.245300 31.34±1.995360 34.59±1.91420 37.93±1.64480 40.40±1.785
Franz diffusion cellMedium: Ethanol: water(2:1)Membrane: Rat skinTable 20. Showing ex vivo permeation of Elocon
0 100 200 300 400 500 6000
10
20
30
40
50
Chart Title
Time (mins)
% P
erm
eatio
n
Fig. 50 % Permeation of Elocon
Comparability study
0 100 200 300 400 500 6000
10
20
30
40
50
60
EMULGEL ELOCON
Time (min)
% R
elea
se
Fig. 51 Showing % permeation of emulgel & Elocon
0 100 200 300 400 500 6000
10
20
30
40
50
60
70
Cellophane Rat skin
Time (min)
% R
elea
se
Fig. 52 Showing % permeation through Cellophane & Rat skin
Skin irritation test
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
Control 0 0 0 0 0 0 0
Gel base 0 0 0 0 0 0 0
(Emulgel) 0 0 0 0 0 0 1
0- no erythema, 1- slight erythema. 2-patchy erythema, 3-severe erythema
Fig. 53 Control at 7th day Fig. 54 Gel base at 7th day Fig. 55 Test at 7th day
Table 21. Scoring for skin irritation in rats
Stability studies
Time (days) pH Assay (%)
n=2
5 5.7 91.69±0.03
10 5.8 89.765±0.245
15 6.1 89.925±0.175
20 6.1 89.945±0.115
25 6.0 89.867±0.077Percentage degradation- 1.84%
40⁰C / 75% RH
Table. 22 Stability of Optimized Emulgel
Conclusion
• Since emulgel is helpful in enhancing Spreadability, adhesion, viscosity and extrusion, this novel drug delivery will become popular. • Moreover, they will become a solution for loading hydrophobic drugs in water
soluble gel bases for the long term stability.• In this study, topical emulgels of Mometasone Furoate were formulated and
permeation of optimized formulation F10 was found to be greater than marketed cream Elocon• Thus Mometasone Furoate emulgel can be used for treatment of inflammatory
skin diseases with better patient compliance
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References
• Azazuddin et al, Recent expansions in an emergent novel drug deliverytechnology: Emulgel, Journal of Controlled Release 171 (2013) 122–132
• Khullar et al., Formulation and evaluation of mefenamic acid emulgelfor topical delivery, Saudi Pharmaceutical Journal (2012) 20, 63–67
• A.S Panwar et al., Emulgel: a review, Asian Journal of Pharmacy and Life Science ISSN 2231 – 4423Vol. 1 (3), July-Sept, 2011
• Madan JR, Khude PA, Dua K. Development and evaluation of solid lipid nanoparticles of mometasone Furoate for topical delivery. Int J Pharma Investig 2014;4:60-4
• Naga Sravan Kumar Varma, V. et al., Calcipotriol delivery into the skin as emulgel for effective permeation. Saudi Pharmaceutical Journal (2014)
• Kasliwal, N., Derle, D., Negi, J., Gohil, J., 2008. Effect of permeation enhancers on the release and permeationkinetics of meloxicam gel formulations through rat skin. Asian J. Pharm. Sci. 3 (5), 193–199.
• Gupta, G.D., Gaud, R.S., 2005. Release rate of tenoxicam from acrypol gels. Ind. Pharm., 69–76.