Comparison of Skin Permeation and Putative Anti-Inflammatory Activity of Commercially Available Topical Products Containing Ibuprofen and Diclofenac.

PURPOSE: The therapeutic effect of topical nonsteroidal anti-inflammatory drugs (NSAIDs) depends on the drug's ability to penetrate and permeate the skin and subsequently inhibit cyclo-oxygenase (COX) isoforms responsible for pain and inflammation. Most commercially available topical NSAID formulations are clinically effective, but direct comparisons of anti-inflammatory activity including both skin absorption and inhibitory potency are lacking. This study examined the skin absorption of representative commercially available topical diclofenac- and ibuprofen-based formulations along with published potency values to determine formulations with superior anti-inflammatory activity. MATERIALS AND METHODS: Cumulative absorption and flux profiles of 12 commercially available topical NSAIDs (6 diclofenac-based and 6 ibuprofen-based) were evaluated in vitro using human skin in static Franz diffusion cells. Each formulation was applied as a single dose. In vitro permeation parameters and published COX-2 inhibition values were used to calculate a modified index of topical anti-inflammatory activity (mITAA). RESULTS: All diclofenac and ibuprofen formulations permeated human skin in vitro. The rate and degree of absorption differed between diclofenac and ibuprofen formulations and between formulations of the same drug. NSAID concentration within a product was not solely responsible for the permeation flux or degree of absorption. Ibuprofen formulations permeated the skin more rapidly and to a greater degree than diclofenac, but calculated mITAAs were higher for diclofenac. CONCLUSION: Diclofenac exhibited superior anti-inflammatory activity as measured by the index. Differences beyond drug concentration, including excipients, drug salt form, and dosage form, contribute to differences in absorption and thus in anti-inflammatory activity. Both absorption and COX-2 inhibition potency are important for anti-inflammatory activity, but their priority depends upon the products being compared-with the same NSAID, absorption determines superiority; with different NSAIDs, superiority is determined by the balance between absorption and COX-2 potency. These findings should be considered when selecting a topical NSAID for treating patient pain and inflammation.

Importance of the formulation in the skin delivery of topical diclofenac: not all topical diclofenac formulations are the same.

Purpose: The current study aimed to compare 2 topical diclofenac products (diclofenac diethylamine [DEA] 1.16% emulsion and diclofenac sodium [Na] 5% gel). The quantitative evaluation of skin permeability and the qualitative evaluation of their physical characteristics were performed. Methods: The skin permeability of diclofenac DEA 1.16% emulsion and diclofenac Na 5% gel was compared in vitro using Franz diffusion cells following a single, fixed, 10 mg/cm2 dose of product applied to a 0.64 cm2 area of the stratum corneum surface of ex vivo human skin samples. The physical characteristics of the 2 formulations were assessed by rheological measurement and microscopy observation. Results: Diclofenac DEA 1.16% emulsion exhibited a statistically significant higher permeation through human skin at 24 hrs than diclofenac Na 5% gel (554 vs 361 ng/cm2, respectively; ratio of adjusted geometric means, 1.54 [95% CI, 1.14-2.07]). When expressed as a percentage of the applied dose of diclofenac that permeated through human skin, a 7-fold difference was observed between the diclofenac DEA 1.16% emulsion (0.54%) and the diclofenac Na 5% gel (0.077%). Qualitative composition and physical characterization showed differences between the formulations that may explain some of the permeation data observed. Based on rheological assessments, diclofenac Na 5% gel had a higher viscosity (24.82 Pa.s) than diclofenac DEA 1.16% emulsion (10.29 Pa.s). Conclusion: A topical diclofenac product with a higher concentration of the active ingredient does not necessarily lead to greater absorption relative to a product with lower concentration of the active ingredient but different characteristics. These observations highlight the importance of considering parameters beyond drug concentration, such as composition, which may influence the solubility of the drug and permeation of topical nonsteroidal anti-inflammatory drugs.

Effect of particle size on the biodistribution of nano- and microparticles following intra-articular injection in mice.

Intra-articular (IA) injection of extended drug release forms based on biodegradable microparticles holds promise for the treatment of joint diseases. However, the fate of microparticles following intra-articular injection is controversial and has not been thoroughly investigated. The aim of this work was therefore to evaluate the biodistribution of fluorescent poly(lactic acid) particles of different sizes after IA injection in arthritic or healthy mice. Regardless of the inflammatory status of the joint, 300 nm-nanoparticles leaked from the joint. Due to inflammation and related increase of vascular permeability, 3 µm-microparticles that were retained in the non-inflamed synovial membrane leaked from the inflamed joint. Complete retention of 10 µm-microparticles was observed independently of the joint inflammatory status. Embedding particles in a hyaluronic acid gel prolonged the retention of the formulations only in inflamed joints. Depending on particle's size, formulations were preferentially eliminated by blood vessels or lymphatic pathways. Poly(lactic acid) particles of 3 µm were biocompatible and retained in knee joints at least for 6 weeks. This work highlights the need to deliver hyaluronic acid-embedded particles of at least 3 µm to guarantee their retention in inflamed joints. These results will contribute to the rational design of long-lasting formulations to treat acute and chronic joint diseases.

Intra-articular bioactivity of a p38 MAPK inhibitor and development of an extended-release system.

In the treatment of arthritic diseases, oral or systemic administration of anti-inflammatory substances, such as p38 MAPK inhibitors, is hampered by numerous side effects. To overcome them, formulations of rapid and extended drug delivery systems were studied in intra-articular administration. For the first time, VX-745, a highly selective p38 MAPK inhibitor, demonstrated in vivo bioactivity, similar to dexamethasone activity, following intra-articular administration in an antigen-induced arthritic (AIA) mouse model. The in vitro bioactivity of VX-745 was also shown on synoviocytes, reducing the IL-6 concentration. Process and formulation parameters (i.e., polymer concentration, aqueous/organic phase ratio, emulsification speed and process, and evaporation pressure) and particle characterisation (i.e., drug loading, size of particle, and surface aspect) were extensively examined to produce optimised formulations. Indeed, a burst release provides a rapid saturation of intracellular p38 MAPK to relieve patients from pain and inflammation. Then, drug diffusion would be sufficient to maintain an effective dose over 2-3 months. This study confirms the effectiveness of encapsulated p38 MAPK inhibitors in extended drug delivery systems and seems to be a promising strategy for intra-articular treatment.