Publication Ref No.

: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

EFFECT OF PENETRATION ENHANCER ON IN VITRO RELEASE OF DICLOFENAC SODIUM GEL FORMULATION Hitesh Jain*1, Bhavin Shah1, Dhara Shah1, Mansi Khirwadkar1, Krishna Prajapati1, T. Y. Pasha2
1

Hitesh Jain

Sigma Institute of Pharmacy, Baroda. Gujarat, India Pioneer Pharmacy College, Baroda, Gujarat, India E-mail: hitesh_hitachi@rediffmail.com

ABSTRACT Transdermal drug therapy has been one of the major research fields in the area of drug therapy for last few decades. However inspite of its large therapeutic potential market success has been limited. It provides the several advantages over the oral drug delivery. The skin is very effective as a selective penetration barrier. Percutaneous absorption involves the passage of the drug molecule from the skin surface into the stratum corneum under the influence of a concentration gradient and its subsequent diffusion through the stratum corneum and underlying epidermis, through the dermis, and into the blood circulation. The skin behaves as a passive barrier to the penetrant molecule. The stratum corneum provides the greatest resistance to penetration, and it is the rate limiting step in percutaneous absorption studies have been carried out to find safe and suitable permeation enhancers to promote the percutaneous absorption of a number of drugs. Penetration enhancers represent a popular method of increasing drug flux through the skin for local or systemic activity. Here the influence of different concentrations of oleic acid (1% and 3%) in gel formulations on percutaneous penetration of diclofenac sodium was investigated using Franz-type diffusion cells and egg membrane. The results of permeation studies showed that oleic acid enhance the percutaneous penetration and 3 % oleic acid was found to be more effective as a penetration enhancer. Key Words: Diclofenac sodium, Skin, Transdermal, Permeation enhancer.
3].

INTRODUCTION Diclofenac Sodium is a potent member of the nonsteroidal anti inflammatory drugs (NSAIDs), widely used because of its strong analgesic, antipyretic and anti inflammatory effects [1-

Because of disadvantages of oral diclofenac, topical diclofenac has been investigated very early on and now several successful formulations are available in the market [4] The skin is an ever-changing organ that contains

International Journal of Pharma Research and Development Online

www.ijprd.com
18

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

many specialized cells and structures as shown in figure 1. Mainly skin composed of three layers such as epidermis, dermis, and subcutaneous tissue. The major barrier for the transport of drugs through the skin is the stratum corneum, with most transport occurring through the intercellular region. Another potential advantage of this type of drug delivery is the optimization of drug concentration at the desirable sites, reducing the chances of side effects [5]. Therapeutic efficacy of any topical formulation depends on its ability to deliver drugs to their sites of action from the skin surface for either local or systemic purposes [6-7]. The clinical efficacy of such drugs is being impeded by their low aqueous solubility resulting in poor penetration and absorption mainly when they are designed for transdermal administration. Skin is a remarkably efficient barrier, designed to keep our insides in and the outsides out. One long-standing approach to increase the range of drugs that can be effectively delivered via this route has been to use penetration enhancers [8, 9]. Therefore, in recent years, numerous studies have been conducted in the area of penetration enhancement [10, 11]. The permeation of drug through skin can be enhanced by both chemical penetration enhancement and physical methods. Penetration enhancers are the substances that facilitate the absorption of penetrant through the skin by temporarily diminishing the impermeability of the skin. Ideally, these materials should be pharmacologically inert, nontoxic, nonirritating, nonallergenic and compatible with the drug and excipients, odorless, tasteless, colorless, and inexpensive and have good solvent properties. The enhancer should not lead to the loss of body fluids, electrolytes, and other endogenous materials, and skin should immediately regain its barrier properties on its removal [12]. It is generally assumed that the nature of penetration enhancer strongly influences the rate and extent of drug release. Release may

be improved by selecting the appropriate penetration enhancer. The best penetration enhancer for topical use has been described as the one which contributes a reversible decrease in the stratum corneum resistance [7]. Penetration enhancers such as hydrogenated soybean phospholipids [13], ethanol, alcohols with long carbon chains (C8 to C14), n-octanol and cyclic monoterpenes [14, 15], nonionic surfactants, propylene glycol and isopropyl myristate [16] have been used in many studies to increase the percutaneous absorption of drugs. An improved diclofenac formulation with a high degree of skin permeation could be useful in the treatment of not only locally inflamed skin tissues, but also inflammatory and painful states of supporting structures of the body bones, ligaments, joints, tendons and muscles [17, 18]. RATIONALE Stratum corneum is the principal barrier for cutaneous penetration allowing slow absorption for the majority of drugs. The objective of the present investigation was to deliver the Diclofenac sodium as a gel. The present work aims to evaluate that in vitro release of drug improved by the different concentration of oleic acid as a penetration enhancer MATERIALS AND METHODS Diclofenac sodium was obtained as the gift sample from Alembic Pharma, Baroda, Gujarat, India. All other chemicals were used of analytical grade. IDENTIFICATION OF DRUG [19] Identification of drug was carried out by thin layer chromatography. Mobile phase was used Methanol: 0.1 % aqueous CTAB (N-cetyl-N, N, N trimethylammonium Bromide): glacial acetic acid in the ratio of 4:5:1 and stationary phase was Silica gel G. The drug was dissolved in methanol and was spotted on stationary phase and the Rf value was calculated.

International Journal of Pharma Research and Development Online

www.ijprd.com
19

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

DRUG EXCEPIENT INTERACTION STUDY Two solutions one of drug and the other of enhancer were prepared in methanol and two spots were spotted on the stationary phase- one of drug alone and the other was the mixture of the two solutions. FORMULATION OF GEL The composition of the Diclofenac sodium gels (1%) used in this study is shown in Table 1. The gels prepared with two different concentration of oleic acid as a penetration enhancer (1 %-F2, 3%-F3 and without any enhancer as a control (F1) by geometric trituration. IN-VITRO RELEASE STUDIES The Franz diffusion cell as shown in figure 2 was used to determine the amount of the drug diffused from different formulations. Approximately 1 g of medicated formulation was then packed into each of three cell donor chambers, ensuring that there were no air bubbles between the formulation and donor surface of the egg membrane [20]. The receptor phase was filled with phosphate buffer pH 6.8 and continuously stirred with a small magnetic bar at a speed of 100 rpm during the experiments to ensure homogeneity and maintained at 370.5 0C. The samples were withdrawn at various time intervals and analyzed spectrophotometrically at 276 nm. Cumulative percentage drug released were calculated and plotted against time. RESULTS Identification of drug The Rf value of diclofenac sodium was found to be 0.30. The reported Rf value of drug is 0.27. Drug excepient interaction study Rf value of drug when the drug was spotted alone and when was spotted with the enhancer was found to remain same. So it can be

concluded that there is no presence interaction between the drug and carrier.

of

In vitro release studies The comparison of in vitro drug release profile of diclofenac sodium prepared without penetration enhancer (F1), with 1 % oleic acid (F2) and with 3 % oleic acid (F3) are shown in figure 3, 4 and 5. DISCUSSION AND CONCLUSION Diclofenac sodium was incorporated with gel Formulation F1 contained 1% Diclofenac sodium in gel base, F2contained 1% Diclofenac sodium with 1% oleic acid in gel base and F3 contained 1% Diclofenac sodium with 3% oleic acid in gel base as penetration enhancer. Different release profiles of Diclofenac sodium were observed. The control formulation showed the less drug release as compared to enhancer. The highest drug release obtained with 3% oleic acid formulation. The oleic acid can be used as an ideal penetration enhancer. There was no evidence of phase separation development of disagreeable odour, change in colour and consistency of the all three products.

REFERENCES: 1. Skoutakis VA, Carter CA, Mickle TR, Smith VH, Arkin CR, Alissandratos J, Petty DE, Review of diclofenac and evaluation of its place in therapy as a nonsteroidal anti-inflammatory agent, Drug Intell. Clin. Pharm., 22, 1988, 85059. 2. Mitchell JA, Warner TD, Cyclooxigenase2: pharmacology, physiology,

International Journal of Pharma Research and Development Online

www.ijprd.com
20

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

biochemistry and relevance to NSAID therapy, Br. J. Pharmacol, 128, 1999, 1121-32. 3. Todd PA, Sorkin EM, Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs, 35, 1988, 244-85. 4. Banning M, Topical diclofenac: clinical effectiveness and current uses in osteoarthritis of knee and soft tissue injuries, Expert. Opin. Pharmacotherapy. 9, 2008, 2921-2929 5. Sawynok J, Topical and peripherally acting anagescics, J Pharm Pharmacol, 55, 2003, 1-20. 6. Saqueira JA, Optimization of the skin availability of topical products, Cosmet Toilet, 105, 1990, 114-121. 7. Pithayanukul P, Chansri N, Sugibayashi K, The enhancing effects of common pharmaceutical solvents on the in vitro skin permeation of estradiol , Thai J Pharm Sci, 26, 2002, 109-119. 8. Williams AC, Barry BW, Penetration enhancers, Advanced Drug Delivery Reviews, 56, 2004, 603-618. 9. Nagwhirunpat T, Opanasopit P, Panomsuk S, Rojanarata T, Kumprakrob U, Skin permeation enhancement of ketoprofen supersaturated solution with antinucleant polymers, Thai J Pharm Sci, 29(1-2), 2005, 11-19. 10. Barry BW, Novel mechanisms and devices to enable successful transdermal drug delivery, Eur J Pharm Sci, 14, 2001,101-114. 11. Moser K, Kriwet K, Naik A, Kalia YN, Guy RH, Passive skin penetration enhancement and its quantification in vitro, Eur J Pharm Biopharm, 52, 2001, 103-112. 12. Sinha VR, Maninder PK, Drug Development and Industrial Pharmacy, 26(11), 2000, 11311140.

13. Nishihata T, Kamada A, Sakai K, Percutaneous absorption of diclofenac in rats and humans: aqueous gel formulation, Int J Pharm, 46, 1988, 1-7. 14. Huang FC, Sokolaski TD, Sheu MT, The influence of cosolvents on the in-vitro percutaneous penetration of diclofenac sodium from a gel system, J Pharm Pharmacol, 46, 1994, 636-642. 15. Iwasa A, Irimoto K, Kasai S, Okuyama H, Nagai H, Effect of nonionic surfactants on percutaneous absorption of diclofenac sodium. Yakuzaigaku, 51, 1991, 16-21. 16. Santoyo S, Arellano A, Ygartua P, Martin C, Penetration enhancer effects on the in vitro percutaneous absorption of piroxicam through rat skin, Int J Pharm, 117, 1995, 219-224. 17. Arellano A, Santoyo S, Martin C, Ygartua P, Enhancing effect of terpens on the in vitro percutaneous absorption of diclofenac sodium , Int J Pharm, 130, 1996, 141-45. 18. Escribano E, Calpena AC, Queralt J, Obach R, Domenech J. Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula, Eur. J. Pharm. Sci., 19, 2003, 203-210. 19. Shinde VM, Tendolkar N, Desai BS, Simultaneous Determination of Paracetamol and Diclofenac Sodium in Pharmaceutical Preparations by Quantitative TLC, J. Planar Chromtogr. , 7, 1994, 50-53. 20. Ansari M, Kazemipour M, Aklamli M, The study of drug permeation through natural membranes, Int J Pharm., 327(1-2), 2006, 6-11.

International Journal of Pharma Research and Development Online

www.ijprd.com
21

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

FIGURES & TABLES:

Fig. 1: Cross section of skin

Fig. 2: Franz diffusion cell

International Journal of Pharma Research and Development Online

www.ijprd.com
22

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

Fig. 3: In vitro release of F1 formulation

Fig. 4: In vitro release of F2 formulation

International Journal of Pharma Research and Development Online

www.ijprd.com
23

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

Fig. 3: In vitro release of F3 formulation

Fig. 5: Comparison of in vitro release of different formulations

International Journal of Pharma Research and Development Online

www.ijprd.com
24

Publication Ref No.: IJPRD/2011/PUB/ARTI/VOV-2/ISSUE-11/JAN/003

ISSN 0974 9446

Ingredients Diclofenac sodium Carbopol 940 Oleic acid Triethanolamine Methyl P-hydroxy benzoate glycerin Purified water

F1 1% 1% 0.5 % 0.04% 10 % q.s. 87 %

F2 1% 1% 1% 0.5 % 0.04% 10 % q.s. 87 %

F3 1% 1% 3% 0.5 % 0.04% 10 % q.s. 87 %

Table: 1 Composition of diclofenac sodium gel

End

International Journal of Pharma Research and Development Online

www.ijprd.com
25