formulation of mometasone furoate emulgel

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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


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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%


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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


Fig. 9 Showing Chromatogram of Mometasone Furoate

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Confirmation tests of Mometasone Furoate ( IP 2014)


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


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


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


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


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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








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.

formulation of mometasone furoate emulgel

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