NSAIDS Dermal Delivery:A Review

Amrish Chandra

The dermal absorption of the various compounds can be predicted from physicochemical parameters obtainable from commercially available software and various mathematical models stated by various authors.

If this information is combined with knowledge of the potency of the NSAID, rational judgments can be made about the suitability of the drug for further development. This publication seeks to examine a number of representative NSAIDs with due potential for dermal delivery.

Nonsteroidal anti-inflammatory agents (NSAIDs) class of drugs which budded from the bark of willow in the mid-eighteenth century ¹ has now evolved as selective COX-2 inhibitors. There has been a rapid increase in the number of products that have been designed to deliver NSAIDs. These include simple creams, gels and more complex transdermal systems. A number of approaches have been continuously investigated so as to enhance dermal delivery by use of prodrugs ² , ultrasound ³ , inotophorosis ⁴ , microneeedles ⁵ but the most common and popular means is by the use of chemical penetration enhancers ⁶ .  The choice of the most appropriate drug depends on a number of factors which includes its potency, its ability to permeate the stratum corneum, its lack of local skin toxicity and stability towards metabolizing enzymes present on the skin surface.

The advent of COX-2 inhibitors, gave much relief to the patients battling the adverse effects of NSAIDs. NSAIDs have a number of side effects associated with them; especially the oral route has a lot many limitations. NSAIDs administered orally causes ulceration and stricture formation in esophagus, stomach and duodenum and may cause severe bleeding, perforation and obstruction ^7,8 , renal failure ^9,10 and congestive cardiac failure ^11,12,13 and cancer is also sometimes associated with their use ^{14, 15, 16} .

With the discovery of selective COX-2 inhibitors the side effects due to non selective cox inhibitors were overcome and therefore they became the drug of choice. Rofecoxib was marketed as the non-steroidal anti-inflammatory drug of choice because selective inhibition of enzyme made it highly effective but free from gastrointestinal toxicity. But then coxibs too were not devoid of adverse effects. Their withdrawal started in September 2004 with rofecoxib (Vioxx), a product of Merck after the adenomatous polyp prevention trial ¹⁷ showed an increase in major cardiovascular events in patients with a history of colorectal adenomas who were randomized to received Vioxx, compared with those on placebo group. The adverse effect was certainly not limited to rofecoxib and other coxibs like valdecoxib (Bextra, Pfizer) were also withdrawn. It was seen that valdecoxib taken after coronary artery bypass grafting was associated with an increased incidence of cardiovascular events ¹⁸ ; and the adenoma prevention trial with with celecoxib (Celebrex, Pfizer) ¹⁹ also reported an increased   risk of cardiovascular events though it was known to be less selective for COX 2 than rofecoxib or valdecoxib. ²⁰ A small increase in the risk of myocardial infarction was also observed for the highly selective lumiracoxib (Prexige, Novartis). ²¹

There has been thus a renewed interest in traditional NSAIDs; but the presence of oral adverse effects necessitates the need for investigating other routes of drug delivery. The dermal absorption of the various compounds can be predicted from physicochemical parameters obtainable from commercially available software and various mathematical models stated by various authors. If this information is combined with knowledge of the potency of the NSAID, rational judgments can be made about the suitability of the drug for further development. This publication seeks to examine a number of representative NSAIDs with due potential for dermal delivery.

Dermal Delivery Of Nsaids

In vitro studies and theoretical considerations indicate that NSAIDs could be effective when applied dermally. Formulation is crucial to good skin penetration.  For NSAIDs to be effective, they have to at least penetrate the skin. Only when the drug has entered the lower layers of the skin can it be absorbed by blood and transported to the site of action, or penetrate deeper into areas where inflammation occurs. This can be judged by in vivo and in vitro studies. Though results obtained from in vivo studies are most reliable they have their own limitations. In vitro  experiments are conducted in a manner similar to the permeation across skin. A device with two chambers is used; in between them is either an artificial membrane or a piece of skin human or animal. Drug is placed in the donor compartment i.e. on the dorsal surface of the skin. Samples are removed at defined intervals from the receptor chamber, and drug concentrations measured. Drug moves from donor to receptor compartment. It is important that sink conditions are always maintained in the receptor compartment. Depending upon the properties of drug, formulation ingredients and the barrier used, the drug diffuses across.

Table 1: Selected experimental results on NSAID permeation

Conclusion

It is evident from these and other studies various features of drug penetration:

1. Importance of the drug: Theoretical and experimental results suggest that a balance between lipid and aqueous solubility is needed to optimise penetration. Use of prodrug has led to enhancement of permeability ⁶¹ .

2. Importance of the formulations: Formulations can make a huge difference in drug permeation. Creams are generally less effective than gels or sprays, but newer formulations like microemulsions have greater potential. Reservoir type systems are effective in giving zero order release rate.

3. Use of physical enhancement (iontophorosis, ultrasound, microneedles) have greater potential for drug delivery and high molecular weight proteins like insulin can also be delivered via skin by their use ⁶² .

4. NSAID’s dermal use is has been questioned because they cost more than generic oral NSAIDs. But oral NSAIDs are associated with significant adverse events (gastrointestinal, heart failure, and renal failure). Topical NSAIDs have much lower plasma concentrations, and are not associated with higher rates of adverse events, or at any rate of gastrointestinal adverse events. Moreover they are easy to apply and easier for patient to comply.

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About Authors:

Chandra A

Rajiv Academy for Pharmacy, NH #2 Delhi-Mathura Bypass Road, Mathura U.P., India -286 001
e-mail:  amrish_chandra@yahoo.com.
Mobile :91-94128-95677

Dr.P.K.Sharma

M.Pharm, Ph.D, Principal, KIET School of Pharmacy, Ghaziabad-Meerut Road, Ghaziabad, U.P. India