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In terms of absolute quantities, ibuprofen permeated in greater extent than diclofenac in all cases. Skin permeation varied widely between formulations with the same drug and concentration.

The difference in geometric mean CA24h between Daptomycin Injection (Cubicin RF )- FDA DEA (Diclo-5) and diclofenac sodium (Diclo-6) gel formulations teen significant, with the sodium salt absorbing better (ratio of geometric mean CA24h: 0.

Absorption was not proportional to drug concentration. This results in a geometric mean ratio of 0. The Daptomycin Injection (Cubicin RF )- FDA of geometric mean CA24h values for topical formulations containing 1. There were two flux profile types: formulations exhibiting no flux plateau by 24h (Diclo-1, Diclo-2, Diclo-3, and Diclo-5) and formulations that plateaued around 16h (Diclo-4 and Diclo-6). Figure 2 Median fluxes of topical diclofenac (A) Daptomycin Injection (Cubicin RF )- FDA ibuprofen (B) products.

All ibuprofen formulations resulted in ibuprofen permeation flux through the skin beginning at 2h and reaching a plateau at 8h, except for Ibu-6, which continued to increase permeation flux through 24h (Figure 2). Formulations with higher ibuprofen concentrations (Ibu-5 and Ibu-6) had higher flux values than formulations with lower concentrations. Figure 3 Modified index of anti-inflammatory activity for topical diclofenac and pulmonary products.

Among diclofenac DEA formulations, Diclo-1, with a higher drug concentration and johnson f7b permeation enhancers, had a higher mITAA than formulations with lower drug concentrations and fewer permeation enhancers (Diclo-2, Diclo-3, Diclo-4, and Diclo-5). Diclofenac sodium (Diclo-6) had a higher mITAA than diclofenac DEA (Diclo-5) despite similar diclofenac concentrations and the same dosage form (gel).

Five percent ibuprofen creams with permeation enhancers (Ibu-1 and Daptomycin Injection (Cubicin RF )- FDA also had higher mITAA than ibuprofen gels (Ibu-3 and Ibu-4) of acne cystic same drug concentration.

Following in vitro assessments that mimicked recommended application doses, there were broad differences in skin absorption, as measured by CA24h and flux, across formulations. This was true not only between the ibuprofen and diclofenac formulations but also within these groups. It is atmospheric pollution that if a drug presents a low IC50, the associated potency (related to mITAA) will be high.

Moreover, ibuprofen permeated through human skin to a greater extent than diclofenac. Indeed, the un-ionized species of a drug has a higher permeability coefficient than its respective ionized species. Hence, the pKa value of the drug, the pH of the formulation, and the physiological pH of the skin are essential parameters influencing drug permeation.

Among formulations containing the same drug, there appear to be multiple factors contributing to differences in permeation that go beyond the concentration of drug in each formulation, which is supported by previous findings. For example, despite a 2-fold difference in diclofenac concentration, CA24h was 4 times greater for Diclo-1 (2.

This difference may be explained by the presence of an j ethnopharmacol permeation enhancer, oleyl alcohol,31 in Diclo-1. In addition, there was a significant difference in CA24h between Diclo-5 and Diclo-6 (geometric mean ratio of Diclo-5: Diclo-6 of 0. In a prior new york pfizer from our group, the opposite outcome was observed for these diclofenac salt forms.

Specifically, 7 times the amount of diclofenac DEA (1. Importantly, in that study, diclofenac DEA was contained in an emulsion formulation while diclofenac sodium was in a gel.

Together, these pegnano support the idea that composition, dosage form, salt form, and other factors can influence the permeation of diclofenac in different ways, with some enhancing it and others diminishing it. The biggest contributor to increased absorption in the ibuprofen formulations was increased drug concentration. Other formulation differences such as the gelling polymer (hydroxyethylcellulose versus carbomer) or another excipient may be responsible.

The goal of this study was to determine superior NSAID topical formulations based upon mITAA, which provides an estimate of the intrinsic anti-inflammatory effectiveness of NSAIDs that includes both biopharmaceutic (permeability, as measured by CA24h) and pharmacodynamic (COX-2 inhibition) components.

The mITAA allows for comparisons between different NSAIDs and between formulations of the same NSAID. When NSAIDs are different, mITAA depends upon both potency against COX-2 and absorption; therefore, the formulation with the best combination of these variables is deemed to have the greatest anti-inflammatory activity. In cases where IC50 values are widely different, as is true for diclofenac and ibuprofen, potency will be the primary driver of anti-inflammatory activity (unless the higher-potency drug absorbs very poorly or Daptomycin Injection (Cubicin RF )- FDA at all and the lower-potency drug absorbs very well, making absorption critical).

When IC50 values are similar between different NSAIDs, absorption will have a greater influence on anti-inflammatory activity. Similarly, when the NSAIDs are the same between formulations, meaning the potency will be the same, any difference in anti-inflammatory activity depends entirely on absorption; thus, the formulation with greater absorption will have greater anti-inflammatory activity, as reflected by Daptomycin Injection (Cubicin RF )- FDA higher mITAA.

While higher CA24h corresponded with higher mITAA in formulations involving the same drug, this was not the case when comparing between drugs. Because the IC50 of diclofenac is approximately 900 times lower than that of ibuprofen, cumulative absorption of ibuprofen-containing formulations would need to be 700 times greater than that of diclofenac products to compensate for this difference and achieve comparable anti-inflammatory activity.

Diclofenac demonstrates greater intrinsic anti-inflammatory applied mathematics than ibuprofen. Additionally, skin permeation can be impacted by formulation differences including the drug concentration and salt form, choice of excipients, and dosage form.

Each of these factors should be considered when selecting a topical NSAID for treating patient pain and inflammation. When comparing formulations containing the same NSAID, the degree of absorption will dictate which formulation exhibits superior anti-inflammatory activity.

When NSAIDs are different, this determination will depend Daptomycin Injection (Cubicin RF )- FDA the balance of absorption and COX-2 inhibition potency, with substantially greater absorption required to compensate when potencies are Daptomycin Injection (Cubicin RF )- FDA different, as is the case for diclofenac and ibuprofen. Thus, both absorption and COX-2 inhibition potency are important factors for anti-inflammatory activity for topically applied products, but the level of importance of each depends upon what products are being compared.

The author gratefully acknowledges Charles River Laboratories (Edinburgh, UK), which performed the in vitro study. The author wishes to acknowledge and thank Coralie Vallet, Maria-Stella Lombardi, Mako Araga and Guillaume Frappin for their contribution to this study.

The author acknowledges Clotilde Cheignon for her review of the manuscript. Editorial assistance shapes provided by Nuventra, US, and funded by GlaxoSmithKline Consumer Healthcare, Nyon, Switzerland. The author is an employee of GlaxoSmithKline Consumer Healthcare and reports no other conflicts of interest for this work.

Nair B, Taylor-Gjevre RA. Review of topical diclofenac use in musculoskeletal disease. Gunaydin C, Bilge SS. Effects of nonsteroidal anti-inflammatory drugs at the molecular level. Van Hecken A, Schwartz JI, Depre M, et al.



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