INTRODUCTION:

Topical formulations apply a wide spectrum of preparations both cosmetic and dermatological, to healthy or diseased skin^1,2. These formulations range in consistency from solid through semisolid to liquids. When gels and emulsions are used in a combined form, the dosage forms are referred to emulgel^3,4. As the name suggests they are the combination of emulsion/ microemulsion and gel.

Novel polymers with complex functions as emulsifiers and thickeners have been widely used due to their gelling capacity which allows the formulation of stable emulsion by decreasing surface and interfacial tension and also by increasing the viscosity of the aqueous phase. Oil/water and water/oil emulsions are used as vehicles to deliver various drugs to the skin⁵. Emulsion gels are gaining importance due to many reasons; they have better application property in comparison to classical formulation as creams and ointment, they have faster and more complete release of the drug from the vehicle to the skin, also they are convenient to apply on hairy skin due to the absence of greasiness and lack of residue upon application. They permit the incorporation of both aqueous and oleaginous ingredients, so hydrophobic or poorly water-soluble drugs as antifungal agents are easily incorporated in such type of vehicles through the proper choice of the oily phase⁶. Clotrimazole is an antifungal agent which inhibits the growth of pathogenic dermatophytes. It shares with Econazole, miconazole, first choice status for topical treatment of tineapedis, tineacruris and tineacorporis due to Candida albicans. It is effective for topical treatment of vulvovaginal and or pharyngeal candidacies^7,8,9 for skin care and the topical treatment of dermatological diseases, a wide choice of vehicles including solid, semisolids and liquid preparations is available to physicians and patients Emulgel or gellified emulsion is stable one and better vehicle for hydrophobic or water insoluble drugs as Clotrimazole. Also emulgels have a high patient acceptability since they possess the advantages of both emulsions and gels. Therefore, they have been recently used as vehicles to deliver various drugs to the skin.

Fig No-1: Anatomy of Skin

TOPICAL DRUG DELIVERY SYSTEM:

Topical drug delivery can be defined as the application of a drug directly to the skin to treat skin diseases or disorders with the intent of containing the pharmacological effect. Topical drug delivery is mainly used to remove the first pass metabolism and to get onset of action^10,11,12.

STRUCTURE AND PHYSIOLOGY OF SKIN:

The study of structure and physiology of skin is important for designing topical dosage form, because the topical preparations are meant to apply to the skin. The skin of an average adult body covers a surface area approximately 2m² and receives about one third of the blood circulating through the body and the skin¹³ surface contains 40-70 hair follicles and 200-300 sweat ducts on every square centimeter of the skin. The pH of the skin varies from 4-5.6 Sweat and fatty acids secreted from sebum influence the pH of the skin surface.

The skin contains four different layers¹⁴ like

1 Non-viable epidermis

2 Viable epidermis

3 Dermis

4 Subcutaneous connective tissue

EMULGEL AS A TOPICAL DRUG DELIVERY:

Over the last decades the treatment of illness has been accomplished by oral, sublingual, rectal, parenteral and topically. Topical drug delivery can be defined as the application of a drug containing formulation to the skin to treat cutaneous disease or disorder directly. This delivery is through by ophthalmic, rectal, and vaginal and skin^14,15,16. The topical drug delivery is used for both dermatological and cosmetic purpose. The main advantage of topical drug delivery system is to bypass first pass metabolism. One of the formulations in the topical drug delivery system is the EMULGELS. They also have a high ability to penetrate the skin. Emulgel for dermatological use has several favorable properties like thixotropic, greaseless, easily spreadable, easily removable, emollient, non staining, water soluble longer shelf life, bio friendly, transparent and pleasing appearance.

MATERIALS AND METHODS¹⁷:

Clotrimazole was purchased from Alapati Pharma. (Ongole, India). Carbopol 934, HPMC K4M, from Indian research products (Chennai, India). All other chemicals and reagents used were of laboratory or analytical grade.

METHODOLOGY:

Preformulationstudies:

Preformulation testing is an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. It is the first step in the rational development of dosage forms¹⁸.

I. Analytical tests for API:

a) Solubility analysis: Preformulation solubility analysis was done, which include the selection of suitable solvents to dissolve the drug and also excipients.

b) Melting point determination: It was done for the drug sample, as it is a first indication of purity of the sample.

II Drug excipient compatibility studies (FTIR):

Fourier Transformer Infrared Spectroscopy (FTIR) the possible incompatibilities between the active drug substance and different excipients form an important part of the Preformulation stage during the development of a dosage form. The use of FTIR technique allows pointing out the implication of the different functional groups of drug and excipients by analyzing the significant changes in the shape and position of the absorbance bands. In this method individual samples as well as the mixture of drug and excipients were ground mixed thoroughly with potassium bromide (1:100) for 3-5 min in a mortar and compressed into disc by applying pressure of 5 tons for 5 min in hydraulic press. The pellet was kept in the sample holder and scanned from 4000 to 400 cm^-1 in FTIR spectrophotometer. Then the characteristics peaks were obtained of all sample as well as mixtures¹⁹.

FORMULATION DEVELOPMENT:

I) Standard curve of clotrimazole:

i) Preparation of pH 7.4 phosphate buffer solution:

50 ml of 0.2 M potassium di hydrogen phosphate mixed with 39.1 ml of 0.2 M sodium hydroxide which gives 200ml of pH 7.4 Phosphate Buffer Solution.

ii) Preparation of standard solution of clotrimazole:

100 mg of Clotrimazole was accurately weighed and transferred in to 100 ml volumetric flask. 50 ml of methanol was added to it. Then the solution was makeup to the final volume with pH 7.4 phosphate buffer solution to give a final concentration of 1mg/ml.

iii) Preparation of working standad solution of clotrimazole: From the stock solution, different aliquots of 0.1, 0.15, 0.2, 0.25, 0.3, 0.35 ml were taken and dilute up to 10ml with buffer to give concentrations of 5µg/ml 10µg/ml, 15µg/ml, 20µg/ml, 25µg/ml, 30µg/ml, 35µg/ml of Clotrimazole respectively. The absorbance of each solution was measured by UV Visible Spectrophotometer at 262 nm using phosphate buffer solution pH 7.4 as blank. The graph of concentration versus absorbance was plotted.

PREPARATION OF EMULSION²⁰:

Preparation of aqueous phase: The aqueous phase of the Emulsion was prepared by dissolving Tween 80 in purified water. Preparation of Oil phase: Methyl Paraben and Propyl Paraben were dissolved in propylene glycol where as drug was dissolved in ethanol and both solutions were mixed with the aqueous phase. Both the oily and aqueous phases were separately heated to75ºC. Then the oil phase was added to the aqueous phase with continuous stirring until cooled to room temperature.

B. PREPARATION OF GEL PHASE:

The gel bases were prepared by dispersing different concentrations of polymers in distilled water separately with constant stirring at a moderate speed using mechanical shaker. The pH of all formulations was adjusted to 6-6.5 using triethanolamine (TEA).

C. PREPARATION OF EMULGEL:

The obtained emulsion was mixed with gel with gentle stirring to obtain the emulgel.

EVALUATION STUDIES FOR EMULGEL:

1. Physical Examination and p^H Determination:

The prepared Clotrimazole were inspected visually for their color, homogeneity, consistency and Ph values of 1% aqueous solutions of the prepared emulgels were measured by a pH meter. Experiments were carried out in triplicates.

2. Spreadability test:

A sample of 0.5 g of each formula was pressed between two slides (divided into squares of 5 mm sides) and left for about 5 minutes where no more spreading was expected. Diameters of spreaded circles were measured in cm and were taken as comparative values for Spreadability. The results obtained are average of three determinations.

3. Rheological Studies:

The viscosity of the formulated batches was determined using a cone and plate viscometer with spindle. The assembly was connected to a thermostatically controlled circulating water bath maintained at 25 °C. The formulation whose viscosity was to be determined was added to a beaker covered with thermostatic jacket. Spindle was allowed to move freely into the emulgel and the reading was noted.

4. Drug content determination:

The drug content of Clotrimazole emulgel was measured by dissolving a known weight of the emulgel formulation (one gram) in 100 ml methanol, appropriate dilutions were made and the resulting solution was then filtering using Millipore filter. Absorbance was measured at 262 nm using UV- spectrophotometer. Dug content was calculated using the slope and the intercept obtained by linear regression analysis of standard calibration curve. Experiments were carried out in triplicates.

5. In vitro release studies:

The in vitro drug release studies were carried out using a modified Franz diffusion (FD) cell. The formulation was applied on dialysis membrane which was placed between donor and receptor compartment of the FD cell. Phosphate buffer pH 7.4 was used as a dissolution media. The temperature of the cell was maintained at 37 °C by circulating water jacket. This whole assembly was kept on a magnetic stirrer and the solution was stirred continuously using a magnetic bead. A similar blank set was run simultaneously as a control. Sample (5 ml) was withdrawn at suitable time intervals and replaced with equal amounts of fresh dissolution media. Samples were analyzed Spectrophotometrically at 260 nm and the cumulative % drug release was calculated. The difference between the readings of drug release and control was used as the actual reading in each case.

RESULTS:

a) Preformulation studies of clotrimazole:

i) Drug excipient compatibility studies:

There is no change in major peak of Clotrimazole in the presence of Carbopol 934, HPMC K4M. So the drug and excipients are compatible with each other.

Fig 2: FTIR Structure of Clotrimazole+Carbopol940

Fig 3: FTIR structue of clotrimazole+HPMCK4M

Absorbance

Concentration (µg/ml)

Graph 1: Standard Curve of Clotrimazole

STANDARD CURVE OF CLOTRIMAZOLE:

Table 1: Data for Standard curve of Clotrimazole

S. No	Concentration(µg/ml)	Absorbance at 262nm (in pH 7.4 phosphate buffer)
1.	5	0.118
2.	10	0.235
3.	15	0.348
4.	20	0.471
5.	25	0.587
6.	30	0.696

Table 2: Physical examination of emulgel formulations:

S. No	Formulation code	Colour	Phase separation	Grittiness	Homogeneity	Consistency
1	F1	White	None	-	Excellent	Excellent
2	F2	White	None	-	Excellent	Excellent
3	F3	White	None	-	Excellent	Excellent
4	F4	White	None	-	Excellent	Excellent
5	F5	White	None	-	Excellent	Excellent
6	F6	White	None	-	Excellent	Excellent

Table 3: pH of emulgel formulations:

S. No	Formulation code	pH value
1	F1	6.5±0.01
2	F2	6.3±0.02
3	F3	6.2±0.1
4	F4	6.5±0.14
5	F5	6.4±0.12
6	F6	6.3±0.14

Graph No-2: Comparison of pH in different formulations from F1 to F6

Table No-4: Spreadability of emulgel formulations

S. No	Formulation code	Spreadability(cm)
1	F1	6.0±0.1
2	F2	5.8±0.2
3	F3	5.7±0.1
4	F4	5.9±0.05
5	F5	5.7±0.12
6	F6	5.5±0.15

Table no-5: Viscosity of emulgel formulations

S. No	Formulation code	Viscosity (cp)
1	F1	3337±0.13
2	F2	4528±0.15
3	F3	8129±0.19
4	F4	3529±0.12
5	F5	4693±0.10
6	F6	8232±0.12

Graph No-3: Comparison of Spreadability in different formulations from F1 to F6

Table no-6: Drug content of emulgel formulations

S. No	Formulation code	Drug Content (%)
1	F1	98.5±0.01
2	F2	97.2±0.11
3	F3	94.22±0.15
4	F4	97.65±0.12
5	F5	96.22±0.14
6	F6	92.17±0.01

Graph No-4: Comparison of Viscosity in different formulations from F1 to F6

Graph No- 5: Comparison of Drug Content in different formulations from F1toF6

Table No-7: In vitro drug release of emulgel formulations

S. No	TIME (hr)	F1	F2	F3
1.	1	8.05±0.11	7.56±0.14	6.02±0.01
2.	2	15.54±0.01	13.95±0.11	11.87±0.12
3.	3	24.92±0.11	20.57±0.14	15.85±0.14
4.	4	33.25±0.15	25.25±0.15	20.65±0.07
5.	5	42.98±0.02	36.65±0.02	27.87±0.06
6.	6	51.38±0.14	41.24±0.17	34.96±0.05
7.	7	53.11±0.13	45.45±0.13	39.78±0.10
8.	8	58.57±0.11	49.65±0.21	43.05±0.12

Table No-8: In vitro drug release of emulgel formulations F4 to F6

S. No	TIME (hr)	F4	F5	F6
1.	1	7.92±0.05	6.86±0.12	5.91±0.02
2.	2	14.23±0.12	11.99±0.11	9.25±0.05
3.	3	22.99±0.13	18.24±0.01	13.64±0.05
4.	4	30.93±0.14	23.22±0.10	18.54±0.01
5.	5	39.99±0.02	25.44±0.12	24.29±0.03
6.	6	47.02±0.03	31.55±0.14	30.15±0.05
7	7	50.85±0.04	37.99±0.01	35.54±0.04
8	8	54.98±0.02	47.29±0.23	42.12±0.02

Graph No- 6: in vitro drug release profile for different formulations from F1 to F6

DISCUSSION:

1. Physical Examination: The prepared emulgel formulations were white, viscous, creamy preparation with a smooth, homogeneous appearance with good consistency and without any gritty particles.

2. Measurement of pH: The pH of the emulgel formulations was in the range of 6.0 to 6.5 and there was no significant change in pH values as a function of time for all formulations which are considered acceptable to avoid the risk of irritation upon application to the skin because adult skin pH is 6.5

3. Spreadability: The observations for spreadability of all formulations are shown in the table. The spreadability of the formulation depends on its viscosity. The greater the viscosity the longer will be the time taken for spreading on the skin.

4. Determination of viscosity: The measurement of viscosity of the prepared Emulgel was done with a Brookfield Viscometer was used to determine viscosity (cp) of the formulations. The viscosity was measured at 10 rpm after 60 seconds. At each speed, the corresponding dial reading was noted. The viscosity of the emulgel was obtained.

5. Drug content determination: Drug content was calculated using the following equation, which was obtained by linear regression analysis of calibration curve. The drug content of all emulgel formulation is found within range 97% -102%.

Drug content= (concentration× dilution factor× volume taken) ×conversion factor

6. In vitro drug release studies: The Invitro diffusion studies of all formulations (F1 to F6) were conducted and the results are shown in Table No.12. The amount of drug released from different formulations F1, F2, F3, F4, F5 and F6 at the end of 8hrs were 58.57%, 49.65%, 43.05%, 54.98%, 47.29% and 42.12% respectively.

CONCLUSION:

Clotrimazole emulgel formulations were prepared by using polymers like Carbopol 934 and HPMC K4M showed acceptable physical properties, viscosity and drug release. HPMC K4M based emulgel in its low concentration i.e., F6 proved to be the optimized formulation, since it showed highest drug release i.e., 58.57 % in 8hrs. The release of Clotrimazole from the emulgel was observed as sustained release in a controlled manner. So, emulgel is one of the best topical drug delivery and it is very effective for loading of hydrophobic drugs.

REFERENCE:

1. Lawrence H. Block. Medicated Topicals, Ch.44 in Remington. In: Lippincott Williams and Wilkins, editors. The science and practice of pharmacy 21th ed. Philadelphia; 2006.

2. L.Lackman, H. A, Lieberman and J.L.Kanig, Theory and Practice of Industrial Pharmacy, Lea and Fibiger, Philadelphia Latest Edn.

3. Mohamed MI Topical emulsion- gel composition comprising diclofenac sodium. AAPS Journal 2004; 6(3).

4. Mohamed MI. Optimization of Cholrphensin emulgel formulation. AAPS Journal. 2004;6:(26).

5. Rieger MM, Lachmann L, Lieberman HA, Kanig JL. In: Lea and Fibiger, editors. The theory and the practice of industrial pharmacy 3rd ed. Philadelphia; 1986.

6. Shahin M, Abdel Hady S, Hammad M, Mortada N. Optimized formulation for topical administration of Clotrimazole using pemulen polymeric emulsifier: a conceptual framework. Drug development and industrial pharmacy.2011;37(5):559-568. Accessed 25 June 2010. Available: http://www.ncbi.nlm.nih.gov.pubmed/21128701

7. Steven P. Gelone. Anti- infectives, Ch. 90 in Remington. In: Lippincott Williams and Wilkins, editors. The science and practice of pharmacy 21 th ed. Philadelphia: Lippincott Williams and Wilkins; 2006.

8. The Merk Index. In: MaryadeleJ.O, Neil, editor. An encyclopaedia of Chemicals, Drugs and Biologicals 14 the d. NJ, USA: Merck and co; 2006.

9. Martindale. The complete drug references: Sean C Sweet man, editor. 36th ed. The pharmaceutical press; 2009.

10. Sunil Kumar Yadav, Manoj kumar Mishra, Anupamaa Tiwari, AshutoshShukla. “Emulgel: a new approach for enhanced topical drug delivery.” Int J Curr Pharma Res 2017; 9(1):15-19.

11. Date AA, Naik B, and Nagarsenker MS. Novel Drug Delivery Systems: Potential in improving topical delivery of antiacne agents. Skin Pharmacol Physol 19(1):2-16(2006).

12. Joshi M, Butola BS, Saha K. Advances in topical drug delivery system: micro to nanofibrous structures. J Menisci Nanotechnology 2014; 14:853-67

13. Tortora, G.J and Anagnodokas, Principles of Anatomy and Physiology, N.P Happer and Row Publishers N.Y.

14. Ross and Wilson, Anatomy and Physiology in the health and illness.

15. A.S. Panwar, N. Upadhyay, M. Bairagi, S. Gujar, G.N. Darwhekar, D. K. Jain. “Emulgel: A Review.” Asian J Pharmacy and life Sci 2011; 1(3): 333-343.

16. Joshi Bhaibav et al; ‘’Clarithromycin Emulgel for topical delivery’’: International Journal of Drug Development and Research 2012: vol. 4 Issue 3. ISSN 0975-9344.

17. Snehal P. Mulye, et al; ‘’Formulation and Evaluation of Indomethacin Emulgel’’. Der Pharmacia Sinica; 2013, 4(5):31-45.

18. Joshi Bhaibav et al; ‘’Clarithromycin Emulgel for topical delivery’’: International Journal of Drug Development and Research 2012: vol. 4 Issue 3. ISSN 0975-9344.

19. Monika Rao et al; ‘’Optimization of Metronidazole Emulgel”. Journal of Pharmaceutics; 2013;2013;501082.

20. Dalia Abd El Rhman et al; ‘’ Formulation and evaluation of Fluconazole Emulgel”. International Journal of Pharmacy and Pharmaceutical sciences; 2012, 4(5): 176-183.

Received on 27.07.2020 Modified on 07.09.2020

Asian J. Pharm. Tech. 2021; 11(1):41-47.

DOI: 10.5958/2231-5713.2021.00007.6