Presented by,Mr. Sumeet P. SonajeM. Pharm (IV Sem.)(Pharmaceutics)Seat No. 1035
Guided by,Mr. S. B. GondkarM. Pharm (Pharmaceutics)
R.G. SAPKAL COLLEGE OF PHARMACY, ANJANERI, NASHIK
FORMULATION AND EVALUATION OF FLURBIPROFEN
LOADED EMULGEL
Contents2
Need and Objectives
Summary and Conclusion
Literature Survey
Plan of Work
References
Future Outcomes
Marketed Products
Drug and Polymer Profile
Material and Equipment's
Preformulation and Formulation
Evaluation
Introduction
Why Transdermal Drug Delivery System ?
Transdermal drug delivery system is recognized as one of the most important and reliable alternative to the oral and parenteral drug delivery system. Skin act as reservoir system for drug.
TDDS includes the patches, gels, microemulsion, nanoparticles, liposomes, niosomes, emulgel etc.
The NSAID’s, antifungals, antivirals drugs can be given through the TDDS.
Advantages of TDDS: Avoidance of first pass metabolism. Convenient and easy to apply. Avoidance of gastro-intestinal incompatibility. A relatively large area of application in comparison with buccal or nasal
cavity.
3
Introduction
Anatomy and Physiology of Skin:
4
Fig. : Structure of skin
5Human skin consist of three layers,
(1) Epidermis
Epidermis has five layers,
Stratum corneum (horny layer)
Stratum lucidum
Stratum granulosum (granular cell layer)
Stratum spinosum (spinous or prickle cell layer)
Stratum basale (basale or germinativum cell layer)
(2) Dermis
(3) Hypodermis
Skin as Permeability Barrier
An important element in transdermal drug delivery system is the skin itself. It act as permeability barrier against the transdermal absorption of various chemicals and biologicals agents. Like all other epithelium systems of the body, the prime function of the skin is to keep water and other vital substances in the skin and restricted the entry of foreign substances.
The permeability barrier of skin is constituted of three major layers that include: Stratum corneum ( 10 µm thick) Viable epidermis (100 µm thick) Papillary epidermis (100-200 µm thick)
Components of stratum corneum:
6
Components % Gross biochemical
compositionsCell membranes 5 Lipids and nonfibrous proteins
Cell contents 85 Lipids ( 20%)
α – proteins (50%)
β – proteins (20%)
Nonfibrous proteins (10%)
Intercellular materials 10 Lipids and nonfibrous proteins
Mechanism of Percutaneous Absorption
Fig. : Mechanism of percutaneous absorption
7
Methods of Drug Penetration
Chemical enhancement :- Eg. Sulfoxides, Azone, Fatty acids, Alcohols.
Physical enhancement :- - Ultrasound
- Iontophoresis
8
Fig. :- Schematic presentation of emulgel penetration through skin
Physiological factors - Skin thickness - Lipid content - Density of hair follicles - Density of sweat glands - Skin pH - Blood flow - Hydration of skin - Inflammation of skin
Physicochemical factors - Partition coefficient - Molecular wt. ( < 400 dalton ) - Degree of ionization - Effect of vehicles.
9 Factors Affecting Topical Absorption
Rheumatoid Arthritis
Inflammation is an important nonspecific defence reaction to tissue injury caused by pathogen or wound.
The five cardinal signs of inflammation are redness, swelling, heat, pain, loss of function.
Rheumatoid arthritis is an autoimmune disease that causes chronic inflammation of the joints.
10
Emulgel
Definition:-
When gel and emulsion are used in combined form the dosage form are referred as ‘Emulgel’.
11
The use of transparent gel has expanded both in cosmetics and in pharmaceutical preparations. Gels are relatively newer class of dosage form created by entrapment of large amount of aqueous liquids in a network of colloidal solid particle.
In spite of many advantages of gels a major limitation is in the delivery of hydrophobic drugs. So to overcome this limitation emulgels are prepared and with their use the hydrophobic drugs are delivered.
The presence of gelling agent in the water phase converts a classical emulsion into an emulgel.
Both o/w and w/o emulsions are used as vehicles to deliver various drugs to the skin. Emulsion itself is a controlled release system where entrapped drug particles in
internal phase pass through the external phase to the skin and slowly get absorbed. Internal phases act as reservoir of drug and slowly release drug in a controlled way through the external phase to the skin. Gel forms cross linked network where it captures small drug particles and provides its release in a controlled manner.
12
Due to its bioadhesive property it prolongs the contact period of medication over the skin. Since emulgel possesses the property of both emulsions and gel, it acts as dual control release system.
Depending on the type of emulsion used to prepare emulgel, they are referred as macroemulgel, microemulgel, nanoemulgel.
Various categories of drug such as NSAIDS, antifungal, antibacterial, antiviral etc. are used for preparation of emulgel.
13
Ideal Properties of Emulgel
being greaseless,
easily spreadable,
easily removable,
emollient,
non-staining,
longer shelf life, bio-friendly,
pleasing appearance.
14
Advantages15
Hydrophobic drugs can be easily incorporated into gels using emulsions.
Better stability.
Better drug loading capacity.
No intensive sonication.
Controlled release, medication can be terminated when needed.
Avoidance of first pass metabolism.
Disadvantages16
Drug of large particle size not easy to absorb through the skin.
Skin irritation or allergic reaction on contact dermatitis.
Occurrence of bubble during formation of emulgel.
Rational
Because, many widely used topical agents like ointments, creams, lotions have many disadvantages. They are sticky in nature causing uneasiness to the patient when applied, have lesser spreading coefficient so applied by rubbing and they also exhibit the problem of stability.
17
Need for Study
Flurbiprofen belongs to the class II of the BCS system of drugs and oral administration of Flurbiprofen is associated with severe gastric irritation therefore to overcome this problem emulsion based gel form was formulated.
Flurbiprofen is hydrophobic in nature therefore it reports a problem of solubility in water this can be solved by adding drug in oil phase of emulsion.
Emulgel overcomes the problems associated with emulsion (i.e. stability) and gel (i.e. syneresis) alone.
Emulgel are alternative to the solid dispersion gel.
18
19To overcome the limitation of conventional oral and
parenteral route of drug administration.
To improve the patient compliance..
To formulate Emulgel of Flurbiprofen for topical drug delivery system.
To eliminate the drawbacks of emulsion and gel by formulating in an Emulgel.
In-vitro drug release permeation studies through the suitable membrane models using modified Franz-Diffusion
cell.To predict stability of the formulation by conducting
stability studies.
Objectives
Plan of Work20
1. Literature survey
2. Selection of drug and polymer
3. Procurement of drug and polymer
4. Preformulation study of drug Organoleptic property Melting point Solubility UV spectroscopy FTIR Drug – Polymer compatibility study
5. Formulation development of emulgel
6. Optimization of emulgel
7. Evaluation of Emulgel Appearance pH Viscosity Drug content Spreadability Swelling Index In- vitro diffusion study Ex- vivo diffusion study Skin irritation study Ex -vivo bioadhesive strength Stability study
8. Data Analysis
9. Result and Conclusion
21
Literature Survey
Sr . No.
Author Topic Polymer
1 Khullar R et. al.(Saudi Pharmaceutical
Journal, 20, 2012)
Formulation and evaluation Mefenamic acid emulgel for topical drug delivery.
Carbopol 940 , liquid parrafin ,tween 20 ,span 20 , PG ,ethanol , methyl paraben , ethyl paraben, clove oil , mentha oil, water etc.
2 Jain A et. al. (Der Pharmacia Sinica, 1(3),
2010)
Development and characterization of Ketoconazole emulgel for topical drug delivery.
Carbopol 940 carbopol 934 , liquid parrafin ,tween 20 ,span 20 , PG ,ethanol , methyl paraben , propyl paraben, Glutaraldehyde, water etc.
3 Bachav Y et. al. (International Journal of
Pharmaceutics, 365, 2009)
Microemulsion based vaginal gel of Clotrimazole : formulation , in -vitro evaluation and stability studies.
Carbopol, cremophor , chlorocresol ,water, tween 20 , span 20, PG etc.
22
Sr. no.
Author Topic Polymer
4 Patil P et. al. (Indian Drugs, 49(11), 2012)
Evaluation of wound healing activity of Silver Sulfadiazine emulgel (1%) in the rat burn wound model and its skin irritation study.
Poloxamer 407, Lecithin, Sepineo P600, Tween 80, Span 60, calcium hydroxide, methyl paraben, propyl paraben, coconut oil, lavender oil etc.
5 Patil S et. al. (WJPPS, 3(4),
2014)
Novel cosmeceutical herbal emulgel for skin care.
Cucurbita pepo oil, carbopol 940, liquid paraffin, tween 20, span 20, propylene glycol, methyl paraben, clove oil, water etc.
6 Varma VN et. al. (Saudi
pharmaceutical Journal, 2014)
Calcipotriol delivery into the skin as emulgel for effective permeation.
Carbopol, Kollicream 3C, Kolliphor CS, liquid paraffin, propylene glycol, PEG, IPA, strong ammonia, fragrance, water etc.
23 Literature Survey
Sr. no.
Author Topic Polymer
7 Sushil Raut et. al. (RJPT, 5(1), 2012)
Comparative evaluation of Zidovudine loaded hydrogel and emulgel.
AZT, Tween 20, Span 20, Carbopol 940, Methyl paraben, Propyl paraben, Liquid paraffin, PG, Ethanol, TEA etc.
8 Singla Vikas et. al. (International Pharmaceutica
Sciencia, 2(3), 2012)
Development and evaluation of topical emulgel of Lornoxicam using different polymer bases.
Lornoxicam, Carbopol 940 and 934, HPMC K4M, Tween 20, Span 20, Liquid paraffin, PG, Methyl paraben, Propyl paraben, Mentha oil, Water etc.
9 Mahant Sheefali et. al. (Scientia
Pharmaceutica, 80, 2012)
Formulation and characterization of Benzoyl Peroxide gellified emulsion.
Carbopol 940, Benzoyl Peroxide, Almond oil, Wheat germ oil, Sesame oil, Jojoba oil, tween 20, Span 60, PG, MP, PP, Water, Disodim EDTA, BHT etc.
24 Literature Survey
Sr. no.
Author Topic Polymer
10 Ganapathi Jeevaprakash et. al. (IJPIR, 2(1),
2012)
Efficient formulation and evaluation of Flurbiprofen transdemal gel compared with marketed gel by using water soluble polyacrylamide polymer.
Polyacrylamide polymer, Isopropyl alcohol, Sodium metabisulphite, Glycerine, Propylene glycol, Cocodiethanolamide etc.
11 Charoo Naseem Ahmad et. al. (Colloids and
Surfaces B: Biointerfaces, 65, 2008)
Improvement in bioavailability of transdermally applied Flurbiprofen using tulsi and turpentine oil.
Methocel, Tulsi oil, Turpentine oil, PG, IPA etc.
12 Rajesh S. et. al.(International Journal of
Pharmaceutics, 356, 2008)
Permeation of Flurbiprofen polymeric films through human cadaver skin.
PVP, PVA, PEG 400, DMSO, Dimethyl formamide etc.
25 Literature Survey
Sr. no.
Author Topic Polymer
13 Chandra Dinesh et.al. (AJPR, 3(6),
2013)
Formulation and evaluation of proniosomal gel of Flurbiprofen.
Lecithin, Brij 93, Cholesterol etc.
14 Idrees MA et.al. (DARU, 19(6),
2011)
Enhance transdermal delivery of Flurbiprofen via microemulsion: effects of different types of surfactants and cosurfactants.
Oleic acid, Tween 80, PG, Ethanol, IPA, IPM, Tween 20 etc.
15 Perioli Luana et.al. (International
Journal of Pharmaceutics,
356, 2008)
Rheological and functional characterization of new antiinflammatory delivery systems designed for buccal administration.
Pemulen 1621, Compritol 888 ATO etc.
26 Literature Survey
Drug Profile
Sr. No. Properties Flurbiprofen
1 IUPAC Name (2RS)-2-(2-Fluorobiphenyl-4-yl)propanoic acid
2 Molecular Formula C15H13FO2
3 Molecular Weight 244.3
4 Description White or almost white, crystalline powder.
5 Solubility Practically insoluble in water, freely soluble in ethanol and in methylene chloride. Dissolves in aqueous NaOH and Carbonates.
6 Melting Point 114°C - 117°C
27
Sr. No. Properties Flurbiprofen
7 Dose 150 – 200 mg daily in divided doses.
8 UV 247 nm
9 CAS Number 5104-49-4
10 Category Anti-inflammatory, Analgesics, Antipyretic.
11 Half life 4 – 5 hours
12 Log P 4.2
13 Mode of Action Flurbiprofen is a non-selective COX inhibitor and inhibits the activity of both COX-1 and COX-2.
14 BCS Class II ( Low solubility, High permeability )
15 Storage condition Preserve in tight container.
28
Pharmacokinetics
Flurbiprofen
Absorbtion Flurbiprofen is rapidly and almost completely absorbed following oral administration.
Bioavailability 96 %
Distribution 0.12 L/kg
Protein binding 99 %
Metabolism Hepatic (Hydroxylation, Conjugation)
Excretion Renal
29
Marketed Products of Flurbiprofen30
Brand Name Dosage Form Mfg. Company
Brugel Gel Abbott
Cadiflur Eye Drops Cadila (Le Sante)
Flurofen Tablet Sanofi Aventis
Froben SR Capsule Abbott
Relyonflurbi Transdermal Patch Indocoar
Justification for Selection of Drug
Nature of Flurbiprofen is hydrophobic. Flurbiprofen possess analgesic-anti-inflammatory effect in addition to antipyretic
action. Suitable for formulation of emulgel. Molecular mass of Flurbiprofen is less than 600 Daltons i.e. 244.3 Solubility of Flurbiprofen in water is less and oil solubility is high. Log P of Flurbiprofen is 4.2 Half life is 3-4 hrs. so required frequent dosing i.e. patient incompliance.
31
Excipients Profile
(1) Transcutol – PDefinition Highly purified diethylene glycol monoethyl ether.
CAS 111-90-0
Synonyms Carbitol, Solvolsol, Dioxitol, Transcutol.
Chemical formula C6H14O3
IUPAC Name 2-(2-ethoxyethoxy) ethanol
Molecular weight 134.17356
Appearance Colourless limpid liquid.
32
Odour Faint
Description Transcutol–P is a hydrophilic/lipophilic high purity solubilizer, with broad API compatibility and a broad spectrum of use in creams and lotions to aqueous gels.
Use Dermal drug delivery: Solvent, oil. Dermal drug delivery: Solubilizer for actives. Dermal drug delivery: Absorption enhancer for cutaneous
application.
Storage Store the product in its original packaging sealed tightly, protected from light and moisture. Special temperature storage conditions are not required.
33
(2) Sepineo P 600
INCI Name Acrylamide/ Sodium Aryloyldimethyl taurate copolymer and Isohexadecane and Polysorbate 80.
Physical State Liquid (Emulsion)
Colour Opaque, White, Yellow tint
Odour Faint odour
pH 5 to 7 (Conc. (% w/w) 2%)
Solubility Dispersible in cold water
Viscosity Dynamic (1500 to 5000 cp) at 250C
Description Thickening power Emulsifying power Stabilizing power
34
Sepineo P 600 Benefits
Ready to use fluid form. Very easy to handle at room temperature Thickens over a large pH range Stabilizes and thickens O/W emulsions Gel-Cream texture Good skin tolerance
Sepineo P 600 Doses Gel application = thickening power up to 5 % Cream application = stabilizing power 0.5 % to 2 % Gel- Cream application = emulsifying power up to 5 %
35
Material and Equipment's36
Sr. No.
Instruments Manufacturer
1 UV- visible Spectrophotometer Jasco- V630, Japan.
2 FTIR Spectrometer Cary 630, Agilent Technologies, USA.
3 Brookfield Viscometer DV II+ pro, Brookfield Engineering Laboratories, Inc, USA.
4 Digital pH Meter Systronics, Ahmadabad.5 Magnetic Stirrer DBK Instruments, Mumbai.
6 Franz Diffusion Cell Lab. made assembly
7 Melting point apparatus Analab Scientific Instruments Pvt. Ltd. India.
Sr. No. Instruments Manufacturer
8 Assembly for Bioadhesive strength measurement
Lab. made assembly
9 Sonicator PCI Analytics 1.5 L
10 Centrifuge Eltek
11 Spreadability apparatus Lab. made assembly
12 Electronic analytical balance AY220 Shimadzu corporation Kyoco, Japan.
37
Experimental Work38
Organoleptic Properties
Properties Observation Reported Standards
Appearance Crystalline powder Crystalline powder
Color White White or almost white
Melting Point Determination
Sr. No. Observation Reported Standards
1 114-119 0C 114-117 0C
Preformulation Study of Drug
Solvents Solubility
Distilled Water Practically insoluble
Dichloromethane soluble
0.1 N NaOH soluble
Methanol soluble
0.1 N HCL soluble
Acetone soluble
Ethanol soluble
Phosphate buffer pH 6.8 soluble
Phosphate buffer pH 7.0 soluble
Phosphate buffer pH 7.4 soluble
39Solubility Determination in Solvents
Oils Solubility (mg/ml)
Castor oil 72.91
Oleic acid 78.71
Propylene glycol 148.36
Transcutol - P 341.33
40 Solubility Determination in Oils
Oleic acid Castor oil Propylene glycol
Transcutol - P0
50
100
150
200
250
300
350
400
78.71 72.91
148.36
341.33
Solubility
Oils
Solu
bilit
y (m
g/m
l)
41Determination of λ max
Media λ max observed
Methanol 247 nm
Sr. no. Conc. (ppm) Abs.
1 2 0.1858
2 4 0.3595
3 6 0.4966
4 8 0.6566
5 10 0.7979
1 2 3 4 5 6 7 8 9 10 110
0.10.20.30.40.50.60.70.80.9
f(x) = 0.076065 x + 0.04289R² = 0.99869051292518
CC of Flurbiprofen in Methanol
Concentration (ppm)
Abs
orba
nces
UV Analysis
UV Analysis42
Determination of λ max
Media λ max observed
0.1 N NaOH 247 nm
Sr. no. Conc. (ppm) Abs.
1 2 0.2514
2 4 0.4101
3 6 0.5497
4 8 0.6825
5 10 0.8463
1 2 3 4 5 6 7 8 9 10 1100.10.20.30.40.50.60.70.80.9
f(x) = 0.07311 x + 0.10934R² = 0.998780196576725
CC of Flurbiprofen in 0.1 N NaOH
Concentration
Abso
rban
ces
UV Analysis43
Determination of λ max
Media λ max observed
PBS pH 7.0 247 nm
Sr. no. Conc. (ppm) Abs.
1 2 0.1929
2 4 0.341
3 6 0.5129
4 8 0.691
5 10 0.8798
1 2 3 4 5 6 7 8 9 10 110
0.10.20.30.40.50.60.70.80.9
1
f(x) = 0.08619 x + 0.00637999999999994R² = 0.998077850817249
CC of Flurbiprofen in PBS pH 7
Series1Linear (Series1)
Concentration (ppm)
Abso
rban
ces
IR Analysis44
400600800100012001400160018002000240028003200360040001/cm
25
30
35
40
45
50
55
%T
3070.78
3010.98
2928.04
2717.79
2623.28
2536.48
2337.80
1898.02
1838.22
1695.49
1622.19
1572.04
1465.95
1415.80
1315.50
1265.35
1217.12
1136.11
1072.46
960.58
866.07 839.06
765.77
688.61
623.03
580.59
453.29
f lurbiprofen
Sr.
No
.
Functional Groups Observed
Ranges (cm-1)
Standard
Ranges (cm-1)
1. Aromatic C-H
stretch
3070.78 3150-3050
2. C-X Fluoride (F) 1217.12 1400-1000
3. C=O Carboxylic
acid
1695.49 1725-1700
4. CH3 Bend of Alkane 1465.95 1450 and 1375
5. C=C Alkene 1622.19 1680-1600
45
Sr. No.
Functional Group
Pure Drug
Physical mixture
Standard Value
1 Aromatic C-H stretch
Yes Yes 3150-3050
2 C-X Fluoride (F) Yes Yes 1400-1000
3 C=O Carboxylic acid
Yes Yes 1725-1700
4 CH3 Bend of Alkane
Yes Yes 1450 and 1375
5 C=C Alkane Yes Yes 1680-1600
Drug- Excipients Compatibility Study
Formulation
Ingrediants Property
Flurbiprofen Active Pharmaceutical Ingredient
Transcutol – P As Oil and Penetration Enhancer
Sepineo P600 As Gelling agent, Emulsifying agent and Stabilising agent
Propylene Glycol Cosolvent, Humectant
Methyl Paraben Antimicrobial Preservative
Propyl Paraben Antimicrobial Preservative
BHT Antioxidant
Distilled Water Vehicle
46
Method of Preparation
Step 1: Preparation of gel using gelling agent and water by constant stirring.
Step 2: Preparation of emulsion.
Step 3: Incorporation of emulsion into gel.
Flow diagram showing emulgel preparation,
47
48
Emulsion
Preparation of Gel
32 Factorial Design
Independent VariablesLevels
Low Medium High
X1 = Transcutol – P 1.5 2.5 5.0
X2 = Sepineo P 600 0.25 0.5 1.0
Dependent Variables Goal
Y1 = % CDR 100 %
Y2 = Viscosity _
49
Composition of 32 Factorial Design for Emulsion50
Preparation of Gel
Ingrediants ( % w/w ) QuantitySepineo P 600 0.35
Distilled Water q.s. 50
51
Fig. : Emulgel formulations
Evaluation of Formulations52
Batch code Colour Phase separation Homogeneity
F1 White No Homogenous
F2 White No Homogenous
F3 White No Homogenous
F4 White No Homogenous
F5 White No Homogenous
F6 White No Homogenous
F7 White No Homogenous
F8 White No Homogenous
F9 White No Homogenous
Physical Parameters
Viscosity (cp)
Batch Spindle RPM Viscosity (cp)
F1 LV 4 20 503.9
LV 4 40 422.9
LV 4 60 399.2
LV 4 100 387.5
F2 LV 4 20 2519
LV 4 40 1815
LV 4 60 1490
LV 4 100 1200
53
Batch Spindle RPM Viscosity (cp)
F3 LV 4 20 6599
LV 4 40 4274
LV 4 60 3469
LV 4 100 2543
F4 LV 4 20 1500
LV 4 40 975
LV 4 60 659.9
LV 4 100 407
Viscosity (cp)
Batch Spindle RPM Viscosity (cp)
F5 LV 4 20 7558
LV 4 40 4274
LV 4 60 3529
LV 4 100 2471
F6 LV 4 20 12357
LV 4 40 7453
LV 4 60 5649
LV 4 100 3875
54
Batch Spindle RPM Viscosity (cp)
F7 LV 4 20 3749
LV 4 40 2624
LV 4 60 2050
LV 4 100 1530
F8 LV 4 20 6209
LV 4 40 3809
LV 4 60 2589
LV 4 100 1686
Viscosity (cp)
Batch Spindle RPM Viscosity (cp)
F9 LV 4 20 13715
LV 4 40 8293
LV 4 60 6359
LV 4 100 5359
Marketed LV 4 20 18530
gel LV 4 40 11814
LV 4 60 8750
LV 4 100 4990
55
10 20 30 40 50 60 70 80 90 100 1100
2000400060008000
100001200014000160001800020000
F1 F2 F3 F4F5 F6 F7 F8F9 Marketed Gel
RPM
Visc
osity
(cps
)
pH Determination
Sr. No. Formulation Observed pH ( ± S.D.)
1 F1 6.67 ± 0.085
2 F2 6.53 ± 0.170
3 F3 6.81 ± 0.066
4 F4 6.33 ± 0.052
5 F5 6.55 ± 0.1014
6 F6 6.80 ± 0.05
7 F7 6.74 ± 0.070
8 F8 6.45 ± 0.096
9 F9 6.92 ± 0.0503
10 Marketed Product 6.3 ± 0.085
56
Spreadability
Batch Code Spreadability ( gm.cm/sec)F1 14.33 ± 0.050F2 16.65 ± 0.315F3 18.78 ± 0.130F4 15.20 ± 0.075F5 17.86 ± 0.2968F6 32.26 ± 0.1101F7 22.14 ± 0.1662F8 31.01 ± 0.1205F9 38.49 ± 0.1417
Marketed Product 30.25 ± 0.1662
57 It is calculated by the following formula, S = M × L / T Where, M = wt. tied to upper slide L = length of glass slides T = time taken to separate the slides
Swelling Index
Formulation code Time (Min.) Swelling Index (%)At 30 min. 113.33
F1 At 60 min. 119.33
At 90 min. 121.56
At 30 min. 88.88
F2 At 60 min. 100.0
At 90 min. 111.0
At 30 min. 77.77
F3 At 60 min. 86.66
At 90 min. 102.22
At 30 min. 91.11
F4 At 60 min. 100
At 90 min. 120
58
Swelling Index
Formulation code Time (Min.) Swelling Index (%)At 30 min. 106.66
F5 At 60 min. 113.33
At 90 min. 113.33
At 30 min. 80
F6 At 60 min. 88.88
At 90 min. 95.55
At 30 min. 108.88
F7 At 60 min. 113.33
At 90 min. 115.55
At 30 min. 88.88
F8 At 60 min. 97.77
At 90 min. 113.33
59
Swelling Index
Formulation code Time (Min.) Swelling Index (%)At 30 min. 73.33
F9 At 60 min. 80
At 90 min. 86.66
At 30 min. 70.88
Marketed Gel At 60 min. 82.15
At 90 min. 87.22
60
Drug Content
Batch Code Drug Content ( % )
in methanol at 247 λmax.
F1 99.87 ± 0.1167F2 99.20 ± 0.1026F3 98.12 ± 0.1609F4 100.24 ± 0.1250F5 98.45 ± 0.1001F6 98.35 ± 0.0655F7 100.77 ± 0.1026F8 98.33 ± 0.0953F9 99.55 ± 0.07
Marketed Product 100.4 ± 0.1532
61
In–vitro Drug Release Time(hrs)
F1(%) F2(%) F3(%) F4(%) F5(%) F6(%) F7(%) F8(%) F9(%) Marketed Product
0 min 0 0 0 0 0 0 0 0 0 0
0.25 6.10±0.0025 1.58±0.0015 4.88±0.020 3.49±0.015 2.06±0.05 2.069±0.015 4.63±0.0034 1.58±0.019 1.56±0.0025 6.32±0.05
0.5 17.59±0.0025 3.55±0.002 7.33±0.026 10.72±0.020 10.70±0.020 10.70±0.020 10.41±0.0024 4.84±0.022 2.70±0.0020 20.07±0.019
0.75 30.44±0.0020 8.57±0.055 10.86±0.025 28.94±0.015 28.93±0.015 20.92±0.020 20.57±0.052 6.14±0.025 5.65±0.0025 41.31±0.020
1 51.46±0.0025 27.86±0.0020 27.95±0.057 35.97±0.010 34.34±0.020 26.13±0.020 26.15±0.019 10.82±0.031 10.53±0.026 59.63±0.0047
2 68.13±0.057 40.79±0.025 40.88±0.020 45.82±0.030 41.25±0.020 35.69±0.020 34.31±0.026 20.24±0.036 16.86±0.034 78.63±0.072
3 81.01±0.007 57.94±0.020 58.03±0.020 63.77±0.015 55.95±0.015 38.78±0.020 58.07±0.025 36.66±0.025 28.04±0.035 90.72±0.042
4 94.35±0.003 67.03±0.0025 65.71±0.020 66.09±0.079 60.43±0.015 52.52±0.021 70.37±0.035 41.94±0.028 36.80±0.015 95.53±0.022
5 96.89±0.03 77.46±0.013 70.18±0.010 77.79±0.020 64.77±0.020 54.70±0.029 81.48±0.072 62.25±0.022 46.15±0.042 96.31±0.024
6 98.88±0.0025 84.29±0.0030 74.66±0.0047 95.43±0.015 69.75±0.025 56.14±0.036 90.02±0.032 78.44±0.062 52.38±0.028 98.06±0.035
7 99.76±0.0025 94.44±0.025 80.06±0.025 97.54±0.020 75.00±0.020 59.78±0.032 96.84±0.018 85.65±0.032 57.54±0.068 99.65±0.020
8 99.80±0.0020 98.07±0.015 84.92±0.0020 99.49±0.015 77.92±0.015 62.13±0.018 97.79±0.032 92.86±0.052 57.58±0.020 99.71±0.015
62
In-vitro Drug Release Profile of the Formulations63
0 1 2 3 4 5 6 7 8 90
20
40
60
80
100
120
In-vitro drug release
%CDR f1 %CDR f2
%CDR f3 %CDR f4
%CDR f5 %CDR f6
%CDR f7 %CDR f8
%CDR f9 % CDR Mktd. Gel
Time (Hrs.)
% C
DR
Data Analysis : Layout of Design
FormulationFactor 1
A: Transcutol- P (%)
Factor 2
B: Sepineo P 600
(%)
Response1:
%Drug Release
(%)
Response2:
Viscosity (cp)
F1 1.5 0.25 99.80 587.9
F2 1.5 0.5 98.07 1692
F3 1.5 1.0 84.92 3755
F4 2.5 0.25 99.49 755.8
F5 2.5 0.5 77.92 3839
F6 2.5 1.0 62.13 6371
F7 5.0 0.25 97.79 2363
F8 5.0 0.5 92.86 3143
F9 5.0 1.0 57.58 7222
64
(1) % CDR
Final Equation in Terms of Actual Factors : % drug release = +117.03692 – 2.43564 * Transcutol-P – 41.33524 * Sepineo P600
ANOVA for % drug release
65
Source Sum of Square
df Mean square
F value P- valueProb > F
S. D. R2
Model 1610.71 2 805.35 9.01 0.0156 9.45 0.7503 Signific
ant
A –
Transcutol P
115.68 1 115.35 1.29 0.2986
B- Sepineo
P600
1495.03 1 1495.03 16.73 0.0064
Counter Plot (% CDR)
66
Perturbation Plot
3-D Response Surface Plot (% CDR)67
(2) Viscosity
Final Equation in Terms of Actual FactorsViscosity = -1890.21238 + 560.03846 * Transcutol-P + 6022.78095 * Sepineo P600
ANOVA for Viscosity
ANOVA for Viscosity:
68
Source Sum of
Squares
df Mean
Square
F Value p- Value
Prob> F
S. D. R2
Model 3.786E+007 2 1.893E+007 23.80 0.0014 891.78 0.8881 Signific
antA –Transcutol-
P
6.116E+006 1 6.116E+006 7.69 0.0323
B- Sepineo
P600
3.174E+007 1 3.174E+007 39.91 0.0007
Countor Plot (viscosity)
69
Perturbation Plot
3-D Response Surface Plot (viscosity)70
Solution for Optimized Batch
Sr. No. Conc. of Transcutol-
P (%w/w)
Conc. of Sepineo
P 600 (%w/w)
%CDR viscosity
(cps)Desirability
1. 2.5 0.25 99.49 755.8 1
71
Composition of Optimized Batch
Sr. No. Ingrediants Quantity (%)1 Flurbiprofen 1
2 Transcutol – P 2.53 Sepineo P 600 0.254 Propylene glycol 2.55 Methyl paraben 0.0156 Propyl paraben 0.0057 BHT 0.058 Distilled water q.s. 50
Ex-vivo Drug Release
Time (hrs.)
Optimized Batch Marketed Product
0 0 0
0.25 1.58 ± 0.2650 5.30 ± 0.3611
0.5 9.20 ± 0.1053 11.02 ± 0.2032
0.75 24.18 ± 0.2122 19.89 ± 0.1056
1 38.56 ± 0.7856 25.61 ± 0.4122
2 44.23 ± 0.4306 32.60 ± 0.2581
3 53.06 ± 0.5029 43.09 ± 0.1326
4 58.98 ± 0.3092 57.96 ± 0.5941
5 61.31 ± 0.2389 62.91 ± 0.1152
6 65.20 ± 0.3579 67.13 ± 0.096
7 69.55 ± 0.1966 75.03 ± 0.1020
8 71.59 ± 0.1128 81.33 ± 0.08599
72
Ex-vivo Drug Release Profile73
0 1 2 3 4 5 6 7 8 90
10
20
30
40
50
60
70
80
90
Optimized Batch Marketed Product
Time (hrs.)
% d
rug
relea
se
Drug Release Kinetics of Formulation
Formulation
Code
Zero order First order HiguchiKorsmeyer
Peppas
R2 R2 R2 R2 n
F4 0.9415 0.9866 0.9487 0.9514 0.8591
74
Parameters for Korsmeyer – Peppas Equation
n 0.8591
k 0.5648
It was performed by using the PCP Disso V3. Software
This study approved by IAEC no. 06 under the guidelines of CPCSEA. The skin irritation study was performed on female albino wister rats weight between 145 to 185 gm. The study was carried out by using 9 rats.
Control Standard Marketed Formulation
75 Skin Irritation Study
Groups Parameters No. of ratsGroup I Control -
Group II Standard (Formalin) 3
Group III Test 3
Group IV Marketed formulation 3
Skin Irritation Study (continue)76
Marking of
Rats
Hours Erythema Edema
1 (Head) 48 0 0
2 (Middle) 48 0 0
3 (Tail) 48 0 0
M
H
T
Results
Results after 48 hrs.
Bioadhesive Strength Determination
Bioadhesion strength is performed to evaluate the ability of emulgel formulation to adhere onto skin for longer duration of time where it can release medicament for prolonged period and thus provide sustained release type of drug release.
77
Formulation
code
Bioadhesion strength
(Newton))
F4 0.044 N
Stability Study
From the stability studies of the optimized batch, it was found that the formulation did not show any change in physical appearance, clarity and other parameters were also found to be within limits.
78
Sr. No. Observations
Stability testing interval days
Before stability testing 3 month 6 month
1 Appearance White cream like White cream like White cream like
2 pH 6.72 6.49 6.55
3 Drug content 99.49 99.95 98.56
4
Viscosity
At 20 rpmAt 40 rpmAt 60 rpm
At 100 rpm
1520 cp960 cp721 cp466 cp
1535 cp986 cp768 cp490 cp
1565 cp1012 cp787 cp531 cp
Marketed Comparison
Brand Name
Drug
Manufacturer
Quantity ( gm )
BRUGEL Flurbiprofen Abbott 30 gm
79
Marketed Products
Product Name Drug Manufacturer
Voltaren emulgel™ Diclofenac diethyl ammonium
Novartis Pharma
Miconaz-H-emulgel™ Miconazole nitrate,Hydrocortisone
Medical Union Pharmaceuticals
Diclomax Emulgel™ Diclofenac diethyl amine Torrent Pharma
80
Conclusion
Following conclusions can be came forward after performing present study:
1) Amongst all formulations, emulgel prepared with Transcutol-P (2.5%), Sepineo P600 (0.25%) was better with respect to overall product qualities.
2) Emulsion system provides solubalization of hydrophobic drug, thus imparts in enhancing availability of drug in the formulation.
3) When emulgel was compared with the marketed gel, drug release from the emulgel was found to be increased and prolonged. Additionally its permeation and appearance was found to be more acceptable.
4) The formulation followed Korsmeyer-Peppas kinetic model of drug release.
5) In-vitro diffusion studies showed good percent drug release for more than 8 hrs.
6) The formulated emulgel showed no irritation after performing skin irritation study using wistar albino female rat is model.
Thus, results of the current study clearly indicate that Flurbiprofen emulgel can be a good alternative to the conventional dosage form. However, further clinical studies are needed to assess the utility of this system. By considering all above points it was concluded that, the objective of the present research study were achieved successfully.
81
Future Outcomes
The future trends in innovations of drug delivery systems will continue to bring together different technological disciplines and formulation aspects to create novel technologies.
The futuristic disciplines for emulgel may be, Use of natural polymers as gelling agents for emulgel preparation. Accessing the stability study for natural polymers. Emulgels can be used in case of drugs which are having short half-life. The use of nanosponges, microemulsion and nanoemulsion in emulgel for enhancing the
performance of emulgels. Selection of packaging material for emulgels.
82
Papers Communicated
Review Paper
1) Gellified emulsion: A new born formulation for topical delivery of hydrophobic drugs. WJPPS, Vol. 3, Issue 1, 2013, 233-251.
2) A review on Atrigel by using Biodegradable Polymers: A Depot and Innovative system for Controlled and Sustained release drug delivery system. Inventi Rapid: NDDS, Vol. 2014, Issue 4, 2014, 1-9.
83
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