Research Articles
Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt

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Abstract

In this study, matrix‐type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran® gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran® gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2076–2089, 2002

Section snippets

INTRODUCTION

Diclofenac is a well‐established nonsteroidal anti‐inflammatory agent, widely used in musculoskeletal disorders, arthritis, toothache, dysmenorrhea, etc., for symptomatic relief of pain and inflammation.1 Diethylammonium salt of diclofenac (diclofenac diethylamine) is reportedly used for topical applications.2 The drug undergoes substantial hepatic first‐pass metabolism and thus only about 50% of the administered dose reaches systemic circulation.3,4 This originates the need of an alternative

Materials

EC (ethoxy content 47.5–49%, viscosity 14 cps in 5% w/w solution in 80:20 toluene/ethanol at 25°C) was purchased from BDH Chemicals Ltd., Poole, England. PVP (K value: 26–35) and Polyvinylalcohol (PVA) were purchased from HiMedia Laboratories Pvt. Ltd, Mumbai, India and S.D. Fine‐Chem. Ltd. Boisar, India, respectively. di‐n‐Butylphthalate was purchased from Central Drug House (P) Ltd., Mumbai, India.

A gift sample of diclofenac diethylamine was received from Kothari Laboratories, Saugor, India.

Solubility Study

An attempt was made at this point to learn whether the media phosphate buffer, pH 7.4, was able to maintain sink conditions in dissolution as well as in permeation studies. E1%1cm was 317.512 [where mean absorbance was 0.0335 (n = 3), drug concentration was 2.637 mg/mL phosphate buffer pH 7.4, volume taken was 10 mL, dilution used was 1:2500] obtained from the solubility studies. Thus, phosphate buffer was chosen as the dissolution and permeation media because sufficient amount of drug

DISCUSSION

Diclofenac diethylamine is a well‐established nonsteroidal antiinflammatory drug, which undergoes substantial hepatic first‐pass metabolism, and thus only about 50% of the administered drug reaches the circulation.1,2 Therefore, there is a need to search for an alternative route of administration, which may bypass the hepatic first‐pass metabolism. The transdermal patch delivery system may be an attractive choice of an alternative route of administration of this drug because the drug also

Acknowledgements

We are indebted to UGC for financial support for conducting this work and to Kothari Laboratories, Sagour, India, for providing the drug as a free gift sample.

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