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Topical NSAIDs: penetrating the skin

 

Clinical bottom line

In vitro studies and theoretical considerations indicate that NSAIDs could be effective when applied topically. Formulation is crucial to good skin penetration. Diclofenac, ketorolac, and ketoprofen are good candidates on theoretical grounds.

Background

For topical 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 there inflammation occurs.

There are two ways of answering this question. In volunteers of patients we can measure drug levels in the blood or underlying tissues. Another method is to use experimental systems to investigate how different drugs pass through skin.

Experimental design

These latter experiments tend to be conducted in a similar manner. A device with two chambers is used, in which the chambers are separated by either an artificial membrane or a piece of human skin removed at operation. Typically only the epidermis is used.

Drug can either be placed on the outer surface of the skin, or kept in solution in high concentration in one chamber, and samples removed at intervals from the other chamber, and drug concentrations measured. Drug should move from high to low concentration. The more difficult the barrier is to penetrate, the slower the diffusion, and the easier it is to penetrate, the faster the diffusion.

Diffusion depends on several factors, and these will include the skin or membrane itself, the drug, and any other materials that are used either to increase or decrease diffusion.

Experimental results

Selected experimental results are shown in Table 1. Reading these and other studies demonstrates various features of drug penetration:

Table 1: Selected experimental results on NSAID penetration of skin

Reference
Design
Results
Hadgraft et al. Skin Pharmacol Appl Skin Physiol 2003 16: 137-142 Human skin samples used as permeation barrier to ibuprofen preparations, and permeation of ibuprofen measured over 48 hours at 37 C Mean absorption was between 4% and 25%, linearly over 48 hours. Ibuspray, Ibugel and Ibumousse best.
Escribano et al. Europ J Pharm Sci 2003 19: 203-210 Human skin samples used as permeation barrier to diclofenac preparations, and permeation of diclofenac measured over 24 hours at 32 C Permeated amount varied depending on formulation, with some formulations much better than others
Sloan & Wasdo. Med Res Rev 2003 23: 763-793 Review and theoretical approach to transdermal drug delivery Indicates that balance between lipid and aqueous solubility is needed to optimise permeation, and that use of prodrug esters of NSAIDs could enhance dermal penetration
Paolino et al. Int J Pharm 2002 244: 21-31 Human skin samples used as permeation barrier to ketoprofen preparations, and permeation of ketoprofen measured over 24 hours Microemulsions showed enhanced permeation of ketoprofen compared with creams. Microemulsions were better than gels, which were better than creams
Montastier et al. Med du Sport 1994 68: 40-42 Diffusion across an artificial membrane Ketoprofen had much better penetration, with 22% released compared with 11% diclofenac, 4% niflumic acid, 1% piroxicam

 

Theoretical considerations

For a topical NSAID to be effective, it has not only to reach inflamed tissue, but also be there in sufficient concentration to produce a relevant anti-inflammatory activity. The ratio of these two factors has been called an index of topical anti-inflammatory activity [2].

Theoretical considerations indicate that four drugs are particularly good candidates, diclofenac, ketorolac, ketoprofen and indomethacin might be good candidates, while piroxicam and tenoxicam would not (ibuprofen was not tested). It is interesting to compare this theoretical approach to results from use of topical NSAIDs for strains and sprains, where indirect comparison suggests that ketoprofen and ibuprofen has the best activity, while piroxicam and indomethacin had the worst.

Comment

In vitro studies and theoretical considerations indicate that NSAIDs could be effective when applied topically. Formulation is crucial to good skin penetration.

References


  1. KB Sloan. S Wasdo. Designing for topical delivery: prodrugs can make the difference. Medicinal Research Reviews 2003 23: 763-793.
  2. JA Cordero et al. In vitro based index of topical anti-inflammatory activity to compare a series of NSAIDs. European Journal of Pharmaceutics and Biopharmaceuticals 2001 51: 135-142.