Evaluation iontophoretic delivery of a cationic ketoprofen prodrug for treating nociceptive symptoms in monosodium iodoacetate induced osteoarthritic rat model.

Topical nonsteroidal anti-inflammatory drugs have been used in treatment of osteoarthritis but their efficacy is marginal. One major reason is because of limited drug direct penetration to affected joint and muscle tissues from the topical application. The main purpose of this study was to evaluate a new topical treatment through enhancing the direct drug penetration to local muscle and joint tissues for improving topical treatment of osteoarthritis. A cationic prodrug, ketoprofen choline chloride (KCC) was synthesized for iontophoretic topical delivery. Anodal iontophoretic delivery of KCC and cathodal iontophoretic delivery of ketoprofen to the knee of live hairless rats were evaluated and the drug concentrations in the joint and muscle tissues over the time were determined. In addition, a knee osteoarthritis rat model was induced with intra-articular injection of monosodium iodoacetate solution. Anodal iontophoretic delivery of KCC, cathodal iontophoretic delivery of ketoprofen, or anodal iontophoretic delivery of sodium chloride were applied to the affected knee joint of each rat group, respectively. Knee joint pain was evaluated through a hind paw weight bearing study and knee joint inflammation was evaluated through measuring of the knee diameter. Iontophoretic delivery of KCC showed much higher drug concentration in the knee joint and muscle tissues, compared to iontophoretic delivery of ketoprofen. Treatment of rat knee joint with anodal iontophoresis of KCC also showed significant pain relief and knee inflammation reduction comparing to the control group, while treatment results from cathodal iontophoresis of ketoprofen were mostly not significantly different from the control group.

Improving the direct penetration into tissues underneath the skin with iontophoresis delivery of a ketoprofen cationic prodrug.

Current topical nonsteroidal anti-inflammatory drugs (NSAIDs) showed marginal efficacy in treatment of musculoskeletal disorders due to their fast clearance by skin blood flow and thus little direct penetration into the underlying muscle and joint tissues. Using ketoprofen (Kt) as a model NSAID and converting it to a cationic ester prodrug ketoprofen choline chloride (KCC), this study was to investigate the iontophoresis delivery of the prodrug KCC for improving the drug retention in the skin and the direct penetration into underlying tissues. From in vitro flux study, anodal iontophoresis of KCC showed 5 times higher flux than cathodal iontophoresis of Kt across human epidermis skin, and also 1.5 times higher across full thickness rat skin. From in situ dual agar gel model rat study, anodal iontophoresis of KCC showed 35 times more drug penetrating across the live skin into underlying agar gel and 22 times more drug retained in the skin than those from cathodal iontophoresis of Kt. Co-iontophoresis of a vasoconstrictor phenylephrine with KCC did not show better result than the iontophoresis of KCC alone. Overall, iontophoresis delivery of the cationic prodrug KCC showed great potential for direct penetration into local tissues underneath the skin.

Role of pressure-sensitive adhesives in transdermal drug delivery systems.

Transdermal drug delivery systems (TDDS) are employed for the delivery of drugs across skin into the systemic circulation. Pressure-sensitive adhesive (PSA) is one of the most critical components used in a TDDS. The primary function of PSA is to help in adhesion of patch to skin, but more importantly it acts as a matrix for the drug and other excipients. Hence, apart from adhesion of the patch, PSA also affects other critical quality attributes of the TDDS such as drug delivery, flux through skin and physical and chemical stability of the finished product. This review article provides a summary of the adhesives used in various types of TDDS. In particular, this review will cover the design types of TDDS, categories of PSAs and their evaluation and regulatory aspects.

Evaluation of diclofenac prodrugs for enhancing transdermal delivery.

UNLABELLED: Abstract Objective: The purpose of this study was to evaluate the approach of using diclofenac acid (DA) prodrugs for enhancing transdermal delivery. METHODS: Methanol diclofenac ester (MD), ethylene glycol diclofenac ester (ED), glycerol diclofenac ester (GD) and 1,3-propylene glycol diclofenac ester (PD) were synthesized and evaluated for their physicochemical properties such as solubilities, octanol/water partition coefficients, stratum corneum/water partition coefficients, hydrolysis rates and bioconversion rates. In vitro fluxes across human epidermal membrane (HEM) in the Franz diffusion cell were determined on DA-, MD-, ED-, GD- and PD-saturated aqueous solutions. RESULTS: The formation of GD and ED led to the prodrugs with higher aqueous solubilities and lower partition coefficients than those of the parent drug. Prodrugs with improved aqueous solubility showed better fluxes across HEM in aqueous solution than that of the parent drug, with GD showing the highest aqueous solubility and also the highest flux. There is a linear relationship between the aqueous solubility and flux for DA, ED and PD, but GD and MD deviated from the linear line. CONCLUSION: Diclofenac prodrugs with improved hydrophilicity than the parent drug could be utilized for enhancing transdermal diclofenac delivery.

Enhancing DNA delivery into the skin with a motorized microneedle device.

The purpose of this study was to evaluate a motorized microneedle device in delivery of DNA into skin for gene expression. A plasmid DNA encoding both luciferase (Luc) and enhanced green fluorescent protein (EGFP) was delivered into rat skin by puncturing the skin with the microneedle device. Puncturing rat skin with a pre-applied DNA solution on the skin showed much higher luciferase gene expression than that with the procedure of puncturing the skin first then applied the DNA solution. The microneedle puncturing method was more efficient than intradermal injection method in generating high gene expression in the skin. There was no significant difference in the skin gene expression when rat skin was punctured with the microneedle device of different microneedle lengths (0.25 mm, 0.5mm or 0.75 mm). On the other hand, there was a significant difference in the skin gene expression between the short (10s) and the long puncturing durations (30 or 60s), with longer puncturing duration showed higher gene expression. Puncturing the skin with longer needles (0.75 mm) caused some skin damage, while puncturing the skin with shorter microneedle length (0.25 mm) caused only minimal skin damage. The EGFP gene expression was observed predominately in the epidermis layer of the skin from the puncturing method in delivery of DNA into the skin. In summary, the motorized microneedle device could have great potential in skin gene delivery.