Formulation and Evaluation of Naproxen Emulgel for Topical Delivery

 

Rohini Reddy*1, Shanthi Priya1, Ganesh Akula3, Suddagoni Santhosh4, Albert Jaswanth4

1Department of Pharmaceutics, Surabhi Dayakar Rao College of Pharmacy,

Rimmanaguda, Gajwel, Siddipet, Telangana - 502312

3Department of Pharmaceutical Chemistry, Surabhi Dayakar Rao College of Pharmacy,

Rimmanaguda, Gajwel, Siddipet, Telangana - 502312

4Department of Pharmacology, Surabhi Dayakar Rao College of Pharmacy,

Rimmanaguda, Gajwel, Siddipet, Telangana - 502312

*Corresponding Author E-mail: rohinishimmula@gmail.com

 

ABSTRACT:

Topical conveyance of medications can be accomplished by fusing drug into the gel network for viable conveyance of medications. NSAIDs are non-steroidal medications having superb mitigating and pain-relieving action however NSAIDs produces GIT ulceration, liver and kidney inconvenience particularly if there should be an occurrence of oral organization. Hydrophilic polymers like carbopol-940 and HPMC K100 were used in an attempt to develop topical Emulgel formulations of Naproxen Evaluation tests for visual appearance, pH, consistency, spreadability test, in vitro prescription arrival of, in vivo medication release were performed. In vitro drug release ponders were finished by using Franz spread cell utilizing dialysis layer. The impacts of polymer, oil, surfactant and co surfactant piece on the rate of In vitro and in vivo medication discharge from the gel definitions were inspected through rodent stomach skin mounting on Franz dispersion cell at 37 ± 0.5oC. No conspicuous changes in physicochemical properties of definition were seen after its presentation to quickened states of temperature (40 ± 2oC) and mugginess conditions (75 ± 5% RH). Spreadability, pH and thickness esteems were observed to be marginally changed yet were tantamount with beginning qualities and the strength of the detailing was observed to be unaffected. The gel detailing, (F4) was observed to be reasonable for topical application dependent on in-vitro assessment and in-vivo pervasion thinks about. The optimized formulation, F4 was found to have great patient consistence on account of its simplicity of spreadability and the treatment was observed to be improved as the penetrability of the medication was enhanced.

 

KEYWORDS: Naproxen, Carbopol940, HPMC, Emulgel, Spreadability.

 

 


INTRODUCTION:

NSAIDs work by reducing the production of prostaglandins. Prostaglandins are chemicals that promote inflammation, pain and fever. They additionally secure the overlay of the stomach and digestive tract from the harming strike of corrosive advance blood thickening by initiating blood platelets1,2. Prostaglandins also affect kidney function. The enzymes that manufacture prostaglandins are known as enzyme (COX).

 

There are 2 kinds of COX enzymes. COX-1 and COX-2. Both chemicals produce prostaglandins that advance irritation, torment and fever, anyway just COX−1 produces prostaglandins that actuate platelets and ensure stomach and intestinal covering. NSAIDs square COX chemicals and lessen creation of prostaglandins. In this manner, aggravation, torment and fever are decreased. Since the prostaglandins that ensure stomach and advance blood coagulating likewise are diminished, NSAIDs can cause ulcer in the stomach and digestive system and increment the danger of dying3-5. Floating system is an effervescent or non-effervescent in nature. In effervescent, gas generating excipients for example bicarbonate salts were used that can form CO2 in presence of gastric acid6. The topical drug delivery system is generally used where these systems of drug administration fails or in local skin infection like fungal infection. Topical drug delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorder. Gels are relatively newer classes of dosage form created by entrapment of large amounts of aqueous or hydro alcoholic liquid in a network of colloidal solid particles. Gel formulations generally provide faster drug release compared with ointments and creams7.

 

MATERIALS AND METHODS:

Naproxen, active pharmaceutical ingredient was procured from local vendor. Carbopol 940 (Loba Chemie Pvt. Ltd., Mumbai, India), HPMC (Qualigens Fine Chemicals, Mumbai, India), Propylene glycol (Prime laboratories, Hyderabad), Tween 20, span 20(S.D Fine chemicals, Hyderabad, India), sodium hydroxide (S.D Fine chemicals, Hyderabad, India), potassium dihydrogen orthophosphate (S.D Fine chemicals, Hyderabad, India) were procured and used in this investigation. the entire chemicals of analytical grade and double distilled water used throughout the experiment8-12.

 

Formulation and development of emulgel:

Naproxen Emulgel was set up by the technique detailed by Mohammad et al (2004) with minor modification. Different plans were readied utilizing fluctuating measure of oil, surfactant and co-surfactant. The preparation of emulsion was same in all the formulations13-15. The gel stage in the details was set up by scattering Carbopol 940 in decontaminated water in purified water in case of carbopol based gel and by dispersing HPMC in purified water in case of HPMC based gel with steady mixing at a moderate speed utilizing mechanical shaker, at that point the pH was acclimated to 6– 6.5 utilizing tri ethanol amine (TEA).The oil period of the emulsion was set up by dissolving range 20 in light fluid paraffin while the watery stage was set up by dissolving tween 20 in refined water. Methyl and propyl parabens were disintegrated in propylene glycol, and mixed with the oil phase. And then drug was dissolved in the oil phase containing oil surfactant and co-surfactant. Both the slick and fluid stages were independently warmed to 70–80ºC, at that point the sleek stage was added to the watery stage with persistent mixing until it got cooled to room temperature. The acquired emulsion was blended with the gel in 1:1 proportion with delicate mixing to get the emulgel. The creation of various details has been examined in Table 1.

 

Evaluation of Emulgel:

Gels were evaluated for their clarity, pH, viscosity, spreadability, skin irritation test, anti-inflammatory activity, drug content, in vitro diffusion studies by using standard procedure.

 

Physical appearance:

The prepared emulgel formulations are inspected visually for their colour and phase separation and consistency.

 

Determination of pH:

2.5g of gel was precisely gauged and scattered in 25mL of refined water. The pH of scattering was estimated by utilizing advanced pH meter104 (Digital potentiometer 101)

 

Homogeneity:

All developed gels were tested for homogeneity by visual examination after the gels have been set in the holder for their appearance and nearness of any aggregate16.

 

Drug content estimation:

The naproxen emulgel of 100mg was dissolved in 50mL of phosphate buffer pH 7.4. The volumetric flagon containing gel arrangement was shaken for 2 h on mechanical shaker so as to get total solvency of medication. This solution was filtered and estimated spectrophotometrically at wavelength 273nm. Tests were carried out in triplicate and mean value of the three observed values was noted along with standard deviation value17.


 

Table 1: Composition of Formulations

Ingredients (in %w/w)

FORMULATION CODE

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

Naproxen

10

10

10

10

10

10

10

10

10

10

Carbopol-940

0.5

0.5

0.5

0.5

0.5

-

-

-

-

-

HPMC

-

-

-

-

-

2.5

2.5

2.5

2.5

2.5

Light liquid paraffin

7.5

10

12.5

10

10

7.5

10

12.5

10

10

Tween 20

1.6

1.6

1.6

1.2

0.8

1.6

1.6

1.6

1.2

0.8

Span 20

2.4

2.4

2.4

1.8

1.2

2.4

2.4

2.4

1.8

1.2

Propylene glycol

6

6

6

7

8

6

6

6

7

8

Methyl paraben

0.03

0.03

0.03

0.03

0.03

0.03

0.03

0.03

0.03

0.03

Propyl  paraben

0.01

0.01

0.01

0.01

0.01

0.01

0.01

0.01

0.01

0.01

Purified water up to

100

100

100

100

100

100

100

100

100

100

 


 

 

Measurement of viscosity:

Viscosity of the gels was determined using a Brookfield digital viscometer. It is an instrument used for measuring the viscosity of plastisols and other liquids of thixotropic nature. The instrument estimates the shearing weight on shaft pivoting at an unequivocal, consistent speed while submerged in the example. The level of axle slack is shown on a pivoting dial. This perusing is increased by a transformation factor dependent on shaft measure and rotational speed, gives an incentive for thickness in centipoises. By taking measurements at different rotational speeds, an indication of the degree of thixotrophy of the sample is obtained18.

 

Determination of spreadability:

Principle:

Spreadability is a term communicated to indicate the degree of region to which the gel promptly spreads on application to skin. The helpful productivity of a definition additionally relies upon its spreading esteem. A unique mechanical assembly has been intended to think about the spreadability of definitions. Spreadability is imparted with respect to time in seconds taken by two slides to slip off from plan, set between, under the use of a particular weight. Lesser the time taken for the detachment of the two slides is having better spreadability.

 

Method:

Two glass slides of 6×2cm each were selected. The Spreadability is imparted with respect to time in seconds taken by two slides to slip off from plan, set between, under the use of a particular weight. Lesser the time taken for the filmy layer. The weight was expelled and the overabundance of the plan holding fast to the slides was rejected off. The lower slide was fixed on the leading group of the mechanical assembly and the upper slide was fixing to a string to which 80gm burden could be connected with the assistance of a basic pulley. The time taken for the upper slide to venture to every part of the separation of 6cm and separate far from lower slide under the heading of the weight was noted. The trial was rehashed and the normal of three such conclusions was determined for each formulation19.

 

S = mL/T

 

Where,

S is the spreadability of gel formulations, ‘m’ is the weight (g) tied to upper slide (80gm)

L is the length of glass slide (6cm) and T is the time in seconds.

 

Extrudability:

The extrudability test was carried out by using Pfizer hardness tester. A 15gm of gel was filled in aluminium tube. Plunger was changed in accordance with hold the cylinder legitimately. The weight of 1kg/cm2 was connected for 30 sec. The amount of gel expelled was gauged. The system was rehashed at three equidistance spots of the cylinder. Test was completed in.

 

Skin irritation test:

The hair on the dorsal side of Wister albino rabbits was removed by clipping 1 day before this portion of the experiment. The rabbits were divided into 4 groups. Group I served as the control, group II received transdermal gel N3, group III received transdermal gel N10, and group IV received an 0.8% v/v aqueous solution of formalin as a standard irritant. A new gel, or new formalin solution, was applied daily for 7 days. Finally, the application sites were graded according to visual scoring scale. The skin bothering test was performed on white rabbit, by applying 1gm gel definition on 9cm2 territories; immersed sedate arrangement (1ml) absorbed 9cm2 cotton fleece. A fluid arrangement of 1ml, containing 0.8% formalin absorbed 9cm2 cotton fleece (standard aggravation) was put in the back of the rabbit. The cotton fleece was verified immovably in the back of the rabbit. The cotton fleece was verified solidly in the spot with glue mortar. The animal was observed for 7 days for any sign of edema and erythema20.

 

Drug Release study:

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 utilized as a disintegration media. The temperature of the cell was kept up at 37ºC by flowing water coat. This entire gathering was kept on an attractive stirrer and the arrangement was mixed ceaselessly utilizing an attractive globule. Test (5ml) was pulled back at appropriate time interims and supplanted with equivalent measures of crisp disintegration media. Samples were analyzed spectrophotometrically at 273 nm and the cumulative % drug release was calculated21.

 

RESULTS AND DISCUSSION:

Formulation and development of emulgel formulation:

Naproxen emulgel were formulated in order to bypass the side effects associated with oral therapy and concentrate the drug at required site for prolong period. Emulgel were formulated by using carbopol 940 and HPMC K100 in concentrations of 0.5 and 2.5% w/w respectively to provide the adequate consistency and elegancy also it is free from the toxicological effects on skin. Arachis oil containing Span 20 acts as oil phase and water containing Tween 20 constitutes aqueous phase. Along with the oil as well as water phases, propylene glycol also included in the formulation to enhance solubility and permeability of the drug. Methyl and propyl paraben are well known preservatives used to avoid the microbial growth.

 

Physical appearance:

The physical appearance of different definitions was dictated by visual investigation under highly contrasting foundation and all plans (F1-F10) were observed to be white gooey velvety arrangements with a smooth and homogenous appearance. All formulations are having acceptable consistency. And there was no phase separation in all the formulations.

 

Determination of pH:

The pH of the selected formulations were determined by digital pH meter and the pH values of all prepared formulation ranged from 6.81±0.12 to 6.95±0.02, Which are considered acceptable to avoid the risk of irritation upon application to the skin.

 

Homogeneity:

Homogeneity of all the formulated gels was determined by visual inspection and all the selected formulations were found to be homogenous without any aggregates or lumps.

 

Drug content estimation:

The % drug content values were determined all the values were found to be in the range of standard value of 98.5-100.5%.

 

Measurement of viscosity:

It was observed that, as the oil, surfactant, co surfactant concentration varies the viscosity of the formulation also varies. This affects the Extrudability of the gel from the container. Viscosity values of all formulations (F1-F10) were found to be comparable with the viscosity of marketed formulation. The observed viscosity of all formulations (F1-F10) 3018.5±0.07 to 2996.3±0.07

 

Determination of spreadability:

Spread ability of the formulated gels was determined and all the selected gels were found to be easily spreadable and thus shows good patient compliance and good absorption from skin. The observed spread ability values were27.31±0.09 to 27.25±0.34.

 

Extrudability of emulgel:

The extrudability test was carried out by using Pfizer hardness tester. All the selected formulations (F1-F10) were found to be easily extrudable from the container. Easier the gel extrudes out, better the patient compliance.

 

 

Skin irritation test:

The selected gel formulations were found to show no redness of skin and no skin irritation. The formulation was found to be safe when topically applied.

 

Drug Release study:

In vitro release studies:

In vitro drug release study of different emulgel formulations were carried out through dialysis sac is tabulated (Table 2 and 3) and plotted (Fig 1 and 2). The release of the drug from all emulgel formulation can be observed and the emulgel formulation can be ranked in the following descending order: F4 > F9 > F5 > F2 > F10 > F1 > F7> F8 > F3 >F6, Where the amounts of the drug released after 5 hours were 99.68±0.54, 92.65±0.61, 85.32±0.45, 80.47±0.46, 79.94±0.65, 78.34±0.24, 76.35±0.62, 75.35±0.67, 71.24±0.24, and 69.65±0.59respectively. The higher drug release was observed with formulations F4 and F9. This finding may be due to presence of liquid paraffin in its optimum level and the emulsifying agent in its high level respectively, which lead to an increase in the solubility of the Naproxen, which, in turn, facilitates penetration of the release medium into the emulgel and diffusion of drug from the emulgel. The presence of liquid paraffin leads to retardation of naproxen release from its emulgel formulation.

 

Table 2: In-vitro drug release of Naproxen from Carbopol emulgels (F1 – F5)

Time

(Hours)

                   Cumulative percent of drug release

F1

F2

F3

F4

F5

0

0

0

0

0

0

1

5.03

6.30

6.35

9.63

7.12

2

10.91

11.18

12.54

21.24

13.35

4

14.43

15.33

19.74

31.25

24.65

6

20.82

26.34

28.48

41.56

31.38

8

26.56

30.91

33.12

52.76

39.64

12

44.91

46.58

49.64

63.25

56.34

24

76.42

78.18

82.21

96.32

87.62

 

Figure 1:  In-vitro drug release of Naproxen from Carbopol emulgel (F1 – F5)

 

Figure 2:   In-vitro drug release of Naproxen from HPMC emulgel (F6 – F10)

 

Table 3: In-vitro drug release of Naproxen from HPMC emulgel (F6 – F10)

Time

(Hours)

Cumulative percent of drug release

F6

F7

F8

F9

F10

0

0

0

0

0

0

1

6.03

6.13

6.30

8.56

7.12

2

10.01

10.17

11.25

18.73

12.61

4

15.31

16.34

17.32

28.65

20.48

6

22.64

24.28

27.24

35.68

28.12

8

29.61

30.91

32.65

43.27

33.35

12

42.06

44.37

47.64

61.63

53.39

24

74.51

76.51

79.31

93.54

85.14

 

Accelerated stability studies:

Significant changes were not noticed. The formulation F4 was observed to be steady after presentation to quickened temperature and mugginess conditions for a time of 3 months. No noteworthy changes were seen in physical assessment parameters and in-vitro medicates discharge information.

 

CONCLUSION:

In the coming years, topical medication conveyance will be utilized broadly to bestow better patient consistence. Since emulgel is useful in upgrading spreadability, thickness and expulsion, this novel medication conveyance become popular. Similarly in the investigation, topical emulgel of Naproxen were detailed and exposed to physicochemical examinations for example rheological studies, spreading coefficient studies and appearance, in vitro release studies and ex vivo release studies through rat skin. In vitro release of the tests formulations were performed to determine drug release from emulgel and rate and duration of drug release. From the in vitro studies the maximum drug release was observed with formulations F4 and F9 of 96.32%, 93.54% in 24 hours respectively. So Naproxen emulgel formulation F4 can be used as an anti-inflammatory analgesic agent for topical drug delivery.

 

CONFLICT OF INTEREST:

All the authors Rohini Reddy, Shanthi Priya, Ganesh Akula, Suddagoni Santhosh, Albert Jaswanth express no conflicts of interest.

 

REFERENCES:

1.     Lehman, MD: Microscopy of normal and abnormal skin 1964 US Army chemical research and development laboratories, Special Publication2: 56 10,

2.     Vesicles and Skin: From surface to systemic effects (Gamal M. El Maghraby, Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt, and others) pp.99-120

3.     Tortora, G.J. and Derrickson, B. Principles of Anatomy and Physiology, 2006;11th ed. Wiley, Hoboken, NJ, USA.

4.     Shaw JE, Urquhart J. Transdermal drug administration - A nuisance becomes an opportunity. BMJ 1981; 283: 875-6.

5.     Webster RC, Maibach HI. Cutaneous pharmacokinetics: 10 steps to percutaneous absorption. Drug Metabolism Rev 1983; 14: 169-205.

6.     Pathan DN, Shaikh NH, Thube RT, Bhise KS and Polshettiwar SA, Formulation and Evaluation of Floating Drug Delivery System of Cefpodoxime Proxetil, Research J. Pharm. and Tech. 2 (4): Oct.-Dec. 2009, 82-815.

7.     Eswaraiah S, Swetha K, Lohita M, P.Jaya Preethi, B.Priyanka, Kiran Kumar Reddy, Emulgel: Review on Novel Approach to Topical Drug Delivery, Asian J. Pharm. Res. 2014; Vol. 4: Issue 1, 04-11.

8.     Inayat Bashir Pathan, Mallikarjun Shetty C, Chemical penetration enhancers for transdermal drug delivery systems, Tropical journal of Pharmaceutical Research, 8(2): April 2009; pp. 173-179.

9.     K. Moser, K. Kriwet, A. Naik, Y.N.Kalia, R.H. Guy, “Passive skin penetration enhancement and its quantification in vitro”, Eur. J. Pharm. Bio pharmaceutics, Vol. 52, 103-112, 2001.

10.  Surber C, et al. Optimization of topical therapy: partitioning of drugs into stratum corneum. Pharma Research. 1990; 7:1320-24.

11.  Shah VP, Behl CR, Flynn GL, Higuchi WI, Schaefer H. Principles and criteria in the development and optimization of topical therapeutic products. Pharma Research. 1992; 9:1107-12.

12.  Pratiksha V. Shrikhande, Formulation and Evaluation of Polyherbal Topical Anti-Inflammatory Emulgel, Research J. Pharm. and Tech. 6(1): January 2013, 118-122.

13.  Govil, S.K., In; Tyle, P., Eds., Drug Delivery: Fundamentals and application, Marcel Dekker, Inc., New York, 1998, 385-406.

14.  Chein Y.W. Transdermal drug delivery and delivery system. In, Novel drug delivery system, Vol. 50, Marcel Dekker, Inc., New york, 1992 pp.301-381.

15.  Sushil Raut, Vaibhav Uplanchiwar, Santosh Bhadoria, Avinash Gahane, Sunil Kumar Jain, Shrishail Patil, Comparative Evaluation of Zidovudine Loaded Hydrogels and Emulgels, Research J. Pharm. and Tech. 5 (1): Jan. 2012, 41-45.

16.  Wiechers J. Use of chemical penetration enhancers in transdermal drug delivery-possibilities and difficulties. ActaPharma. 1992 : 4: 123.

17.  Jain NK. Advances in controlled and novel drug delivery, 1st Ed., CBS publishers and distributors, New Delhi, 2001; 108-110.

18.  Wiechers J. Use of chemical penetration enhancers in transdermal drug delivery-possibilities and difficulties. Acta pharm. 1992; 4: 123

19.  Barrie C. Finnin, Timothy M. Morgan. Transdermal penetration enhancers: Applications, limitations, and potential. Journal of Pharmaceutical Sciences, 1998, Volume 88, Issue 10: 955–958

20.  A.M. Lowman, N.A. Peppas, Solute transport analysis in pH-responsive, complexing hydrogels of poly (methacrylic acid-ethyleneglycol), J. Biomaterial. Science and, Polymers Ed. 10 1999: 9991009.

21.  C.S. Brazel, N.A. Peppas, Modeling of drug release from sellable polymers, Eur. J. Pharm. Biopharm. 49 2000: 4758.

 

 

 

 

Received on 07.01.2020            Modified on 15.05.2020

Accepted on 25.08.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(4):1961-1965.

DOI: 10.52711/0974-360X.2021.00347