Emulgel ppt

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.


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.


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.


Sr. no.


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.


Sr. no.


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.


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



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


0.1 N NaOH 247 nm


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


PBS pH 7.0 247 nm


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









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


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)


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


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)


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


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


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

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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.

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Health & Medicine

Emulgel ppt