Assessment of the lateral diffusion and penetration of topically applied drugs in humans using a novel concentric tape stripping design.

PURPOSE: To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique. METHOD: Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin. RESULTS: CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3 mins ranged between 83.0 and 92.9 % and decreased to between 64.5 and 66.9 % at 3 h. IBU recovery further decreased to 47.7 ± 5.6 % at 6 h, correlating with greater in vitro penetration relative to CAF and HC. CONCLUSION: Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.

Predicting skin penetration of actives from complex cosmetic formulations: an evaluation of inter formulation and inter active effects during formulation optimization for transdermal delivery.

Twenty products, containing a radiolabelled form of each active in typical cosmetic formulations, were made and applied to female human epidermal membranes mounted in Franz diffusion cells for 48 h under 'in use' conditions. The products consisted of combinations of five formulations (a hydro-alcoholic gel, an oil in water emulsion, a water in oil emulsion, a microemulsion and an oil) with four model drug actives (testosterone, hydrocortisone, 5-fluorouracil and ketoconazole). Steady-state flux appeared to be reached by 8 h and maintained for all products, other than for the microemulsions, consistent with the actives being present in the residual formulation on the skin at saturation. The recovery for each active at the end of the 48-h study (from a series of stratum corneum tape strips, the remaining skin, cumulative amount penetrating into the receptor solution, product washed from the skin and on the donor chamber cap) ranged from 86.5% to 100.6%. The rank order of the fluxes for the actives from the hydro-alcoholic gel is consistent with the known active molecular size and polarity determinants for maximum epidermal flux. Actives with similar steady-state (maximum) fluxes from a range of formulations had retention in the stratum corneum and similar transport rate constants through the stratum corneum. The microemulsion formulation significantly enhanced both the stratum corneum steady-state flux and transport rate constant for 5-fluorouracil, hydrocortisone and testosterone. The penetration flux of each active could be related to its size and polarity and appeared maximal when the actives in the different cosmetic formulations applied to the skin under 'in use' conditions were likely to remain in the residual product on the skin as a saturated solution after solvent evaporation. Enhanced penetration fluxes can be achieved by formulation selection and an appropriate choice/mix of emollients/adjuvants. The principles described here provide a framework for understanding the delivery of cosmetic ingredients from various formulations.

The history of a transdermal product: From innovation to generic.

The development, registration and successful launch of a novel, innovative transdermal pharmaceutical product requires an idea, structured planning and a highly skilled, specialist team. It is not often that the opportunity arises to document this activity. This paper demonstrates the multidisciplinary effort required to take such a product (Axiron®, a transdermal testosterone product) from innovation to market and also describes its ultimate fate after the generic drug industry took an interest in its commercial success. Although many understand various aspects of this drug development process this understanding is often, by necessity, limited to the specialities of each of the individuals involved. It is hoped that this paper will provide an interesting overview of the entire process from beginning (innovation) to end (genericization).

Navigating transdermal diffusion with multiphoton fluorescence lifetime imaging.

We demonstrate the potential of fluorescence lifetime imaging by time-correlated single-photon counting as a method for monitoring the transdermal diffusion pathway and diffusion rate of pharmaceuticals in human skin. The current application relies on observing subtle changes in the fluorescence lifetime of the intrinsic fluorophores present in the intracellular region between corneocytes of the stratum corneum. We have comprehensively characterized the measured fluorescence lifetimes from intracorneocyte junctions in three skin section types (dermatomed skin, epidermal membranes and stratum corneum) revealing statistically significant differences of the short lifetime component between each of the types, which we attribute to the sample preparation and imaging method. We show using epidermal membrane sections that application of a drug/solvent formulation consisting of ethinyl estradiol and spectroscopic grade ethanol to the surface gives rise to a slight but statistically significant shortening of the fluorescence lifetime of the long-lived emitting species present in the sample, from approximately 2.8 ns to 2.5 ns. The method may be useful for future studies where the kinetics and pathways of a variety of applied formulations could be investigated.

Application of microemulsions in dermal and transdermal drug delivery.

Microemulsions are thermodynamically stable colloidal dispersions of water and oil stabilized by a surfactant and, in many cases, also a cosurfactant. In the pharmaceutical field, microemulsions have been used as drug carriers for percutaneous, ocular, oral and parenteral administration. This review discusses some of the applications of microemulsions specifically for topical and transdermal applications. Microemulsion nomenclature and composition, with particular emphasis on choice of surfactant and cosurfactant, is discussed. Methods used to characterize microemulsions are reviewed. Microemulsion formulations for dermal and transdermal delivery of pharmaceutical agents with particular emphasis on anti-inflammatory and anaesthetic agents are critically evaluated. Finally, the issues which warrant further investigation by researchers in order to realize the full potential of the technology are discussed.

Comparison of the transdermal delivery of estradiol from two gel formulations.

OBJECTIVE: Conventional oral oestrogen replacement therapy can relieve postmenopausal symptoms but is associated with undesirable side-effects which can be minimised by avoiding the fluctuating hormonal blood levels resulting from oral therapy and eliminating hepatic first-pass metabolism by the use of the transdermal route. The two commercially available transdermal gel formulations differ in composition and application recommendations. Sandrena Gel contains 0.1% (w/w) and Oestrogel 0.06% (w/w) estradiol and recommended dosages are 0.5-1.5 g over 200-400 cm2 (Sandrena Gel) and 2.5 g gel over 720 cm2 (Oestrogel). In transdermal therapy the formulation composition may have a significant effect on drug delivery and we have therefore compared the permeation of estradiol from these formulations across human skin in vitro. METHODS: The in vitro percutaneous penetration of estradiol from the formulations through epidermal membranes prepared from excised female human thing skin was assessed over a 24 h period using static type Franz diffusion cells. RESULTS: Permeation of the active was similar from each formulation representing (at 24 h) 18.2 +/- 3.5% of the applied dose from Sandrena Gel and 17.4 +/- 4.8% of the applied dose from Oestrogel. These percentages equate to cumulative skin permeations of 0.65 +/- 0.15 microgram/cm2 and 0.45 +/- 0.15 microgram/cm2 respectively. CONCLUSION: The results suggest that the two formulations are bioequivalent at the recommended dose levels.

Percutaneous penetration of octyl salicylate from representative sunscreen formulations through human skin in vitro.

The human skin penetration of [14C]octyl salicylate from two representative sunscreen vehicles was determined in vitro. 3H-sucrose was incorporated into all formulations and provided a marker for membrane integrity. When applied as a finite dose in an oil-in-water emulsion vehicle containing 5% (w/w) octyl salicylate, the average total absorption of 14C over 48 hr was 0.65+/-0.16% of the applied dose (representing a total amount permeated of 1.58+/-0.36 microg/cm2). When applied as an infinite dose in the oil-in-water emulsion vehicle the average total absorption of 14C over 48 hr was 0.47+/-0.22% of the applied dose (representing a total amount permeated of 27.54+/-13.91 microg/cm2). When applied as a finite dose in a representative hydroalcoholic formulation containing 5% (w/w) octyl salicylate, the average total absorption of 14C over 48 hr was 0.59+/-0.09% of the applied dose (representing a total amount permeated of 1.58+/-0.25 microg/cm2). When applied as an infinite dose in the hydroalcoholic formulation the average total absorption of 14C over 48 hr was 0.23+/-0.05% of the applied dose (representing a total amount permeated of 11.28+/-2.55 microg/cm2). The penetration of [14C]salicylic acid [applied at a concentration of 2.7% (w/w), in the oil-in-water emulsion] was also determined. When applied as a finite dose the average total absorption of 14C over 48 hr was 1.14+/-0.23% of the applied dose (representing a total amount permeated of 1.65+/-0.39 microg/cm2). These results suggest that the in vitro human skin permeation of octyl salicylate is relatively low. The amounts of octyl salicylate and salicylic acid permeated when applied in similar vehicles were remarkably similar over 48 hr (1.58 microg/cm2 and 1.65 microg/cm2, respectively). This suggests the possibility that the 14C label appearing in the receptor fluid may, in both cases, represent salicylic acid. If this is the case, then it is possible that the amount of octyl salicylate permeating through the skin is much less than that suggested by the data obtained here. This supposition is, however, entirely speculative and has yet to be confirmed experimentally.

Percutaneous penetration of N-nitroso-N-methyldodecylamine through human skin in vitro: application from cosmetic vehicles.

The human skin penetration of N-nitroso-N-methyldodecylamine (NDOMA) from isopropyl myristate (IPM) and two vehicles representative of cosmetic/personal care formulations was determined in vitro. When applied as an infinite dose in IPM (1 microgram/microliter) the average total absorption over 48 hr was 0.10 +/- 0.01% of the applied dose (all data are expressed as means +/- SE). When applied as a finite dose in a representative oil-in-water emulsion formulation the average total absorption over 48 hr was 4.66 +/- 0.76% of the applied dose. When applied as a finite dose in a representative shampoo formulation for 10 min, followed by rinsing (to represent in-use exposure conditions), the average total absorption over 48 hr was 0.75 +/- 0.17% of the applied dose. Approximately 72% of the NDOMA in the applied shampoo formulation was removed by rinsing. The overall data indicated that NDOMA could penetrate the skin but that penetration was low. The rate and extent of absorption, however, could be affected by differences in the vehicle of application, time of exposure and whether the formulation is (and the conditions are designed to mimic) a rinse-off or leave-on product.

Experience with ITI osseointegrated implants at five centres in the UK.

Experience with the two-part ITI titanium implant system at five centres in the UK is reported. A total of 461 implants were inserted in 176 patients, who received 189 prostheses. Criteria for the assessment of success following implantation are listed. Results over a 3-year period showed a success rate of 94% when implants were used for mandibular overdentures and crown and bridge prosthetics. A lower success rate in the edentulous maxilla was recorded.

Influence of penetration enhancer on drug permeation from volatile formulations.

Previously we have reported the influence of supersaturation on the permeation of fentanyl across model membranes and skin. The findings indicated that the vehicle and, specifically its residence time in skin, influence the ability of the formulation to enhance membrane drug permeation. The aim of the present study was to probe the role of vehicle components on (trans)dermal drug delivery in more detail. To this end, three commonly used chemical penetration enhancers were selected for investigation namely, propylene glycol (PG), octyl salicylate (OSAL) and isopropyl myristate (IPM). A further objective was to clarify the mechanism of action of OSAL. Model spray formulations were prepared consisting of 10% (v/v) of individual enhancers in ethanol. Saturated and supersaturated systems were evaluated for their ability to promote fentanyl transport across human skin in vitro. Mass balance studies and determination of the extent of uptake of enhancers by skin were also conducted. The results indicated that increasing the degree of drug saturation (DS) does not promote drug permeation for formulations in PG but increasing drug DS did promote drug permeation for IPM and some OSAL systems. This probably reflects faster depletion of PG compared with IPM and OSAL. Non-linear modelling of the permeation data indicated that PG and IPM act to promote drug solubility in the membrane whereas OSAL appears to act as a skin penetration enhancer by increasing drug diffusivity in the skin.

Formulation issues associated with transdermal fentanyl delivery.

Supersaturation has previously been studied as a mechanism to enhance membrane transport of fentanyl from propylene glycol:water formulations (PG:H(2)O) across silicone. In this study these supersaturated fentanyl formulations were evaluated in human skin. A number of polymers were also screened for their ability to stabilise the supersaturated formulations and permeation was evaluated for both infinite and finite doses. For infinite dose studies, permeation in skin increased linearly with increasing degree of drug saturation (DS) for formulations containing 0.5, 1, 2 DS of fentanyl and a 3 DS formulation stabilised with 1% (w/v) hydroxypropylcellulose (HPC). An excellent correlation was obtained for flux values in silicone compared with flux values in skin, for infinite dose studies for formulations containing 0.5, 1, 2 DS of fentanyl and the 3 DS formulation stabilised HPC. The concentration of the fentanyl in the stratum corneum also increased in proportion to the DS. However the same trend was not observed for finite dose studies. This is because the depletion of the solvent carrier promotes drug crystallisation with consequent implications for membrane transport. Tape-stripping experiments indicated that supersaturation of the drug is maintained in the outer layers of the stratum corneum. The ideal vehicle must, therefore, maintain the drug in solution on and in the skin in a sustained manner for effective transdermal delivery.

Enhanced permeation of fentanyl from supersaturated solutions in a model membrane.

The aim of the present study was to investigate the permeation of fentanyl from supersaturated formulations when applied to silicone membrane. Silicone was chosen in order to separate the effects of supersaturation from other possible influences of volatile formulation components on biological membranes. Supersaturated formulations containing either propylene glycol/water (PG/H(2)O) or propylene glycol/ethanol (PG/Et) were prepared containing varying degrees of saturation (DS) of fentanyl. Permeation of finite and infinite doses of the PG/H(2)O formulations, and finite doses of the PG/Et formulations was investigated using Franz-type diffusion cells. For the PG/H(2)O formulations a good correlation between the flux and the DS of the formulation up to 5 DS for infinite dose studies (r(2)=0.99), and up to 7 DS for finite dose studies (r(2)=0.98), was evident. Similarly, for the PG/Et formulations there is a good correlation between the mean flux and the theoretical DS of the formulation (r(2)=0.95). Except for the 2 DS formulations, no significant differences were seen in the mean flux between PG/H(2)O and PG/Et finite dose studies. The larger fluxes observed for infinite doses of the PG/H(2)O formulations versus finite doses reflect changes in the effective area of diffusion over the time of the experiment for the latter set of experiments. The permeation enhancement observed for PG/Et formulations confirms that enhanced drug thermodynamic activity was induced by ethanol evaporation.

Oxybutynin permeation in skin: the influence of drug and solvent activity.

The influence of degree of saturation (DS) of oxybutynin on permeation from octyl salicylate (OSAL) or propylene glycol (PG) vehicles was investigated, in vitro, in human skin. The permeation of OSAL and PG was also evaluated and the quantity of drug and solvent in the skin at the end of the diffusion study was measured. For OSAL the permeation of oxybutynin increased linearly with DS of drug for both 25 and 50% OSAL formulations. However, no differences were seen in oxybutynin permeation for formulations with the same DS but with different OSAL amounts, although the drug permeation was always slightly higher for 50% OSAL formulations. There was a decrease in the amount of OSAL extracted from skin with drug concentration (up to 5 DS). There was also a good correlation between the DS calculated from the amount of oxybutynin and OSAL extracted from the skin, and the actual DS of the formulation. In contrast oxybutynin DS did not affect PG permeation and there were no significant differences in oxybutynin permeation for the formulations with different DS. The lack of permeation enhancement for PG formulations appears to be related to PG depletion from the skin. The findings emphasise the importance of maintaining the drug in solution in order to achieve effective permeation from dermal and transdermal formulations.