Dermal Delivery of Diclofenac Sodium-In Vitro and In Vivo Studies.

Previously, we reported the use of confocal Raman spectroscopy (CRS) as a novel non-invasive approach to determine drug disposition in the skin in vivo. Results obtained by CRS were found to correlate with data from the well-established in vitro permeation test (IVPT) model using human epidermis. However, these studies used simple vehicles comprising single solvents and binary or ternary solvent mixtures; to date, the utility of CRS for monitoring dermal absorption following application of complex marketed formulations has not been examined. In the present work, skin delivery of diclofenac sodium (DFNa) from two topical dermatological drug products, namely Diclac® Lipogel 10 mg/g and Primofenac® Emulsion gel 1%, was determined by IVPT and in vivo by both CRS and tape stripping (TS) methodologies under similar experimental conditions. The in vivo data were evaluated against the in vitro findings, and a direct comparison between CRS and TS was performed. Results from all methodologies showed that Diclac promoted significantly greater DFNa delivery to the skin (p < 0.05). The cumulative amounts of DFNa which permeated at 24 h in vitro for Diclac (86.5 ± 9.4 µg/cm2) were 3.6-fold greater than the corresponding amounts found for Primofenac (24.4 ± 2.7 µg/cm2). Additionally, total skin uptake of DFNa in vivo, estimated by the area under the depth profiles curves (AUC), or the signal intensity of the drug detected in the upper stratum corneum (SC) (4 µm) ranged from 3.5 to 3.6-fold greater for Diclac than for Primofenac. The shape of the distribution profiles and the depth of DFNa penetration to the SC estimated by CRS and TS were similar for the two methods. However, TS data indicated a 4.7-fold greater efficacy of Diclac relative to Primofenac, with corresponding total amounts of drug penetrated, 94.1 ± 22.6 µg and 20.2 ± 7.0 µg. The findings demonstrate that CRS is a methodology that is capable of distinguishing skin delivery of DFNa from different formulations. The results support the use of this approach for non-invasive evaluation of topical products in vivo. Future studies will examine additional formulations with more complex compositions and will use a wider range of drugs with different physicochemical properties. The non-invasive nature of CRS coupled with the ability to monitor drug permeation in real time offer significant advantages for testing and development of topical dermatological products.

Chemical Enhancer: A Simplistic Way to Modulate Barrier Function of the Stratum Corneum.

Human skin could be a prime target to deliver drugs into the human body as it is the largest organ of human body. However, the main challenge of delivering drug into the skin is the stratum corneum (SC), the outer layer of epidermis, which performs the main barrier function of the skin. Scientists have developed several techniques to overcome the barrier properties of the skin, which include other physical and chemical techniques. The most common and convenient technique is to use special formulation additives (chemical enhancers, CEs) which either drags the drug molecule along with it or make changes in the SC structure, thereby allowing the drug molecule to penetrate in to the SC. The main focus is to deliver drugs in the certain layers of the skin (for topical delivery) or ensuring proper percutaneous absorption (for transdermal delivery). However, skin drug delivery is still very challenging as different CEs act in different ways on the skin and they have different types of interaction with different drugs. Therefore, proper understanding on the mechanism of action of CE is mandatory. In this article, the effect of several CEs on skin has been reviewed based on the published articles. The main aim is to compile the recent knowledge on skin-CE interaction in order to design a topical and transdermal formulation efficiently. A properly designed formulation would help the drug either to deposit into the target layer or to cross the barrier membrane to reach the systemic circulation.

Topical delivery of anthramycin II. Influence of binary and ternary solvent systems.

Anthramycin (ANT) is a member of the pyrolobenzodiazepine family and is a potent cytotoxic agent. Previously, we reported the topical delivery of ANT from a range of solvents that may also act as skin penetration enhancers (SPEs). The skin penetration and uptake was monitored for simple solutions of ANT in propylene glycol (PG), dipropylene glycol (DiPG), Transcutol P (TC), isopropyl myristate (IPM), propylene glycol monocaprylate (PGMC) and propylene glycol monolaurate (PGML). The amounts of PG, DiPG and TC that were taken up by, and that penetrated the skin were also measured, with a clear dependence of ANT penetration on the rate and extent of PG and TC permeation. The present work investigates ANT skin delivery from a range of binary and ternary systems to determine any potential improvement in skin uptake compared with earlier results for the neat solvents. Following miscibility and stability studies a total of eight formulations were taken forward for evaluation in human skin in vitro. Binary systems of PG and water did not result in any skin permeation of ANT. Combining PG with either PGMC or PGML did promote skin penetration of ANT but no significant improvement was evident compared with PG alone. More complex ternary systems based on PG, DiPG, PGMC, PGML and water also did not show significant improvements on ANT permeation, compared with single solvents. Total skin penetration and retention of ANT ranged from 1 to 6% across all formulations studied. Where ANT was delivered to the receptor phase there were also high amounts of PG permeation with >50% and ~35% PG present for the binary systems and ternary vehicles, respectively. These findings along with our previous paper confirm PG as a suitable solvent / SPE for ANT either alone or in combination with PGML or PGMC. The results also underline the necessity for empirical testing to determine whether or not a vehicle is acting as a SPE for a specific active in a topical formulation.

Topical delivery of anthramycin I. Influence of neat solvents.

Anthramycin (ANT) was the first pyrrolobenzodiazepine (PBD) molecule to be isolated, and is a potent cytotoxic agent. Although the PBD family has been investigated for use in systemic chemotherapy, their application in the management of actinic keratoses (AK) or skin cancer has not been investigated to date. In the present work, anthramycin (ANT) was selected as a model PBD compound, and the skin penetration of the molecule was investigated using conventional Franz diffusion cells. Finite dose permeation studies of ANT were performed using propylene glycol (PG), 1,3-butanediol (BD), dipropylene glycol (DiPG), Transcutol P® (TC), propylene glycol monocaprylate (PGMC), propylene glycol monolaurate (PGML) and isopropyl myristate (IPM). The skin penetration of BD, DiPG, PG and TC was also measured. Penetration of ANT through human skin was evident for TC, PG and PGML with the active appearing to "track" the permeation of the vehicle in the case of TC and PG. Deposition of ANT in skin could be correlated with skin retention of the vehicle in the case of IPM, PGMC and PGML. These preliminary findings confirm the ability of ANT to penetrate human skin and, given the potency of the molecule, suggest that further investigation is justified. Additionally, the findings emphasise the critical importance of understanding the fate of the excipient for the rational design of topical formulations.

In vitro permeation and disposition of niacinamide in silicone and porcine skin of skin barrier-mimetic formulations.

Niacinamide (NIA) is an amide form of vitamin B3 which is used in cosmetic formulations to improve various skin conditions and it has also been shown to increase stratum corneum thickness following repeated application. In this study, three doses (5, 20 and 50µL per cm2) of two NIA containing oil-in-water skin barrier-mimetic formulations were evaluated in silicone membrane and porcine ear skin and compared with a commercial control formulation. Permeation studies were conducted over 24h in Franz cells and at the end of the experiment membranes were washed and niacinamide was extracted. For the three doses, retention or deposition of NIA was generally higher in porcine skin compared with silicone membrane, consistent with the hydrophilic nature of the active. Despite the control containing a higher amount of active, comparable amounts of NIA were deposited in skin for all formulations for all doses; total skin absorption values (permeation and retention) of NIA were also comparable across all formulations. For infinite (50µL) and finite (5µL) doses the absolute permeation of NIA from the control formulation was significantly higher in porcine skin compared with both test formulations. This likely reflects differences in formulation components and/or presence of skin penetration enhancers in the formulations. Higher permeation for the 50 and 20µL dose was also evident in porcine skin compared with silicone membrane but the opposite is the case for the finite dose. The findings point to the critical importance of dose and occlusion when evaluating topical formulations in vitro and also the likelihood of exaggerated effects of excipients on permeation at infinite and pseudo-finite dose applications.

Topical therapies for skin cancer and actinic keratosis.

The global incidence of skin cancer and actinic keratosis (AK) has increased dramatically in recent years. Although many tumours are treated with surgery or radiotherapy topical therapy has a place in the management of certain superficial skin neoplasms and AK. This review considers skin physiology, non-melanoma skin cancer (NMSC), the relationship between AK and skin cancer and drugs administered topically for these conditions. The dermal preparations for management of NMSC and AK are discussed in detail. Notably few studies have examined drug disposition in cancerous skin or in AK. Finally, recent novel approaches for targeting of drugs to skin neoplasms and AK are discussed.

Development and validation of a RP-HPLC method for simultaneous estimation of naproxen and ranitidinehydrochloride.

A simple, specific and accurate reverse phase liquid chromatographic method has been developed for the simultaneous determination of naproxen and ranitidine HCl. Both the drugs are official with British Pharmacopoeia 2007, but do not involve simultaneous determination of naproxen and ranitidine HCl. The separation was carried out using 4.6 × 250 mm Symmetry Shield TM RP 18 with a particle diameter of 5 µm and mobile phase containing 0.1M orthophosphoric acid: methanol (35:65, pH 3.1) in isocratic mode. The flow rate was 1.00 ml/min and effluent was monitored at 240 nm. The retention times (average) of ranitidine HCl and naproxen were 2.36 min and 12.39 min, respectively. The linearity for naproxen and ranitidine HCl was in the range of 5-35 µg/ml and 1.5-12 µg/ml, respectively. The potencies of naproxen and ranitidine HCl were found 99.40 % and 99.48 %, respectively. The proposed method was validated and successfully applied to the estimation of naproxen and ranitidine HCl in newly formulated combined tablet and in plasma.