Skin penetration and tissue permeation after topical administration of diclofenac

Figures & data

Table 1. Advantages of using topical NSAIDs in preference to oral NSAIDs in osteoarthritis.

•Administration directly at the site of pain

•Avoidance of first-pass metabolism

•Reduced systemic exposure, with a resultant lower risk of systemic adverse events (e.g. gastrointestinal, cardiovascular or renal complications)

•Ability to use in patients unable to tolerate oral NSAIDs

•Avoidance of drug–drug interactions

•Potential dose-sparing effect when used with oral NSAIDs

•Patient preference, with the potential for increased compliance

Abbreviations. NSAIDs; nonsteroidal anti-inflammatory drugs.

Figure 1. Penetration of topical diclofenac through the skin and permeation through the deeper layers to the inflamed joint.

Table 2. Overview of the factors affecting the ability of a topical drug to optimally penetrate skin and permeate through the underlying tissues.

Factor	Considerations	Topical diclofenac
Molecular size	•Small molecules (<500 g/mol^1) pass through stratum corneum more easily •Probably the main determinant of flux across skin^66	•Small molecular weight (296 g/mol)^67
Water solubility	•Must be water soluble^68, but also lipophilic enough to penetrate lipid matrix of stratum corneum^1^,^56	•Has both lipophilic and hydrophilic properties; can access all tissues^33^,^50^,^63
Acidity	•Inflamed tissues have acidic microenvironment •More acidic NSAIDs (lower pKa values) will be un-ionized and able to cross membrane barriers •Acidic NSAIDs will reach higher concentrations at cell membranes and in neutral intracellular spaces containing COX-2 enzymes than in the relatively acidic extracellular space of inflamed tissue^56^,^63	•Weak organic acid (pKa 3.9^69)
Vehicle used	•Solubility, molecular mass, depth of penetration, pharmacology and toxicology of its components need to be considered^70^,^71	•Diclofenac gel has higher flux than diclofenac solution or patch^72
Penetration enhancer	•Can greatly increase penetration through stratum corneum^42^,^47^,^73 •Should ideally be inactive with no adverse effects on skin	•Dimethylsulfoxide (DMSO) often used with diclofenac – but can cause skin irritation^73
Site and method of application	•Topical NSAIDs more likely to reach superficial joints (e.g. finger, knee) than deeper structures (e.g. hip joint)^15 •Prolonged rubbing increases flux through skin^74 •Occlusion hydrates the stratum corneum, often facilitates penetration through the skin and into the underlying tissues^75^,^76 •Repetitive administration can greatly increase bioavailability of drug^77	•Topical diclofenac indicated for finger or knee osteoarthritis •Recommended to use gentle massage upon application of diclofenac gel
Protein binding	•Concentration will be higher where albumin concentrations are higher •In an inflamed joint, the concentrations of albumin increase in synovial tissue and fluid	•Highly bound to plasma albumin (99.4%^69) •Diclofenac concentration five times higher in synovial fluid than plasma after one day, seven times higher at steady state after eight days^50

Abbreviations. COX, cyclooxygenase; NSAID, non-steroidal anti-inflammatory drug.

Table 3. Ratios of average plasma to tissue concentrations for topical versus oral diclofenac after administration over 3 days (data adapted from Brunner et al.^83,90).

	Skeletal muscle	Subcutaneous fat
Oral diclofenac tablets (150 mg/day)^90	0.006	0.006
Topical diclofenac 4% spray gel (144 mg/day)^90	0.51	0.74
Topical diclofenac diethylamine 1.0% gel (40 mg/day)^83	0.27	0.40
Topical diclofenac 1% ± menthol and eucalyptus oil (5 mg/day)^83	0.11	0.12

Table 4. Minimal effective therapeutic concentrations of diclofenac in target tissues, as reported in the literature.

Reference	Method used	Minimal therapeutic concentration for 50% PGE2 inhibition (IC50), ng/ml (mean ± SE)
Cordero et al., 2001^101	In vitro, human fibroblasts culture	8.9 ± 3.0
Kato et al., 2001^112	Bioassay, human peripheral monocytes (healthy volunteers)	7.7 ± 3.0
Riendeau et al., 2001^113	In vitro, human whole blood assays (healthy volunteers)	14.8 ± 3.0
Giuliano and Warner, 1999^29	In vitro, washed human platelets (healthy volunteers)	0.47
Warner et al., 1999^114	Human whole blood assay Human modified whole blood assay	11.2 5.9
Cryer and Feldman, 1998^115	Human whole blood assay (healthy volunteers)	2.96
Pairet et al., 1998^116	Human whole blood assay (healthy volunteers)	21.0

Abbreviations. COX, cyclooxygenase; IC₅₀, minimal concentration of an active substance that brings about a 50% reduction in the prostaglandin synthesis; PGE₂, prostaglandin E₂; SE, standard error of the mean.

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