Relative uptake of minoxidil into appendages and stratum corneum and permeation through human skin in vitro

We examined uptake of the model therapeutic agent, minoxidil, into appendages, stratum corneum (SC), and through human skin, under the influence of different vehicles. Quantitative estimation of therapeutic drug deposition into all three areas has not previously been reported. Finite doses of minoxidil (2%, w/v) in formulations containing varying amounts of ethanol, propylene glycol (PG), and water (60:20:20, 80:20:0, and 0:80:20 by volume, respectively) were used. Minoxidil in SC (by tape stripping), appendages (by cyanoacrylate casting), and receptor fluid was determined by liquid scintillation counting. At early times (30 min, 2 h), ethanol-containing formulations (60:20:20 and 80:20:0) caused significantly greater minoxidil retention in SC and appendages, compared to the formulation lacking ethanol (0:80:20). A significant increase in minoxidil receptor penetration occurred with the PG-rich 0:80:20 formulation after 12 h. We showed that deposition of minoxidil into appendages, SC, and skin penetration into receptor fluid were similar in magnitude. Transport by the appendageal route is likely to be a key determinant of hair growth promotion by minoxidil. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:712–718, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64562/1/21856_ftp.pd

Investigation of in vitro transdermal absorption of fentanyl from patches placed on skin samples obtained from various anatomic regions of dogs

Objective-To investigate in vitro transdermal absorption of fentanyl from patches through skin samples obtained from various anatomic regions of dogs. Sample Population-Skin samples from 5 Greyhounds. Procedure-Skin samples from the dogs' thoracic, neck, and groin regions were collected postmortem and frozen. After samples were thawed, circular sections were cut and placed in Franz-type diffusion cells in a water bath (32degreesC). A commercial fentanyl patch, attached to an acetate strip with a circular hole, was applied to each skin sample. Cellulose strips were used as control membranes. Samples of receptor fluid in the diffusion cells were collected at intervals for 48 hours, and fentanyl concentrations were analyzed by use of high-performance liquid chromatography. Results-Mean +/- SD release rate of fentanyl from the patch, defined by its absorption rate through the non-rate-limiting cellulose membrane, was linear during the first 8 hours (2.01 +/- 0.05 pg/cm(2) of cellulose membrane/h) and then decreased. Fentanyl passed through skin from the groin region at a faster rate and with a significantly shorter lag time, compared with findings in neck or thoracic skin samples. Conclusions and Clinical Relevance-In vitro, fentanyl from a patch was absorbed more quickly and to a greater extent through skin collected from the groin region of dogs, compared with skin samples from the thoracic and neck regions. Placement of fentanyl patches in the groin region of dogs may decrease the lag time to achieve analgesia perioperatively; however, in vivo studies are necessary to confirm these findings

Penetration of a topically applied nonsteroidal anti-inflammatory drug into local tissues and synovial fluid of dogs

Objective-To investigate penetration of a topically applied nonsteroidal anti-inflammatory drug (NSAID) into tissues and synovial fluid. Animals-5 Greyhounds. Procedure-Dogs were anesthetized and microdialysis probes placed in the dermis and gluteal muscle over each coxofemoral (hip) joint. Methylsalicylate (MeSA) was applied topically over the left hip joint. Dialysate and plasma (blood samples from the cephalic and femoral veins) were obtained during the subsequent 5 hours. Dogs were euthanatized, and tissue samples and synovial fluid were collected and analyzed for salicylic acid (SA) and MeSA by use of high-pressure liquid chromatography. Results-SA and MeSA concentrations increased rapidly (< 30 minutes after application) in dialysate obtained from treated dermis. Salicylic acid also appeared in plasma within 30 minutes and reached a plateau concentration after 2 hours, although combined drug concentrations (SA plus MeSA) in plasma obtained from femoral vein samples were twice those measured in plasma obtained from the cephalic vein (SA only). Treated muscle had a progressive decrease in NSAID concentration with increasing depth (SA and MeSA), but it was significantly higher than the concentration in untreated muscle. Substantial amounts of SA and MeSA were also measured in synovial fluid of treated joints. Conclusions and Clinical Relevance-Topically applied NSAIDs can penetrate deeply into tissues and synovial fluid. Local concentrations higher than circulating systemic concentrations are suggestive that direct diffusion and local blood redistribution are contributing to this effect. Systemic blood concentrations may be inadequate to describe regional kinetics of topically applied drugs

Percutaneous absorption of topically applied NSAIDS and other compounds: Role of solute properties, skin physiology and delivery systems

Topical NSAIDS and related solutes are often applied to the skin to target tissues directly below the application site. We have used both biopsy and microdialysis techniques to show that most solutes penetrate below dermal capillaries into the subcutaneous and deeper tissues of both rats and human subjects. The selectivity of local penetration is time related, the concentrations in underlying tissues at longer times often being defined by recirculation from the systemic blood supply. Increased depths of penetration may be achieved by the use of vasoactive agents. Iontophoretic and other delivery systems appear to increase the efficiency of drug delivery through the stratum corneum and do not appear to greatly facilitate penetration into tissues below the dermis. Vehicle polarity and solute properties such as size can be used to advantage in delivering NSAIDs to deeper tissues. The pharmacokinetics of NSAIDs in the dermis and other tissues appears to be related to the absorption of solutes through the stratum corneum, binding of the NSAIDs to dermal and other tissues and clearance of NSAIDs from these tissues through either diffusion into deeper tissues or removal by the systemic blood supply. The latter is dependent on the blood flow to the tissues and protein binding of the NSAIDs in the blood. Absorption of NSAIDs and other solutes through the stratum corneum is defined by their inherent hydrogen bonding ability, lipophilicity and size as well as the interactions between the solute, vehicle and skin. The literature contains a number of examples of pharmacological efficacy after topical application which can now be better explained in terms of our recently gained understanding of the pharmacokinetics of NSAIDs after topical application. A complicating aspect in this interpretation is the variation in efficacy between the various models used to date

Use of in vitro human skin membranes to model and predict the effect of changing blood flow on the flux and retention of topically applied solutes

The effect of dermal clearance on epidermal concentrations of topically applied drugs is poorly understood but fundamental to absorption kinetics and efficacy. Previously generated data quantifying changes in flux and epidermal retention of a series of alcohols and steroids was used to relate solute physicochemical properties to changes in flux under conditions of infinite vasoconstriction (full-thickness skin) and infinite vasodilatation (epidermal membranes) using stepwise regression. Flux through full-thickness skin decreased with increasing lipophilicity, up to 45-fold for alcohols and 4-fold for steroids. This change in flux was not uniformly predictable for the solutes, with alcohols showing a strong dependency on molecular weight (MW), indicative of stratum corneum diffusion limited penetration. Epidermal retention of lipophilic solutes was found to increase up to sixfold in full-thickness skin, with changes predictable from a combination of log P and MW (correlation 0.898, p < 0.001). This study shows that drug epidermal retention and penetration is significantly affected by dermal clearance, however aspects of these effects may be able be predicted from solute physicochemical properties, though extrapolation of the results of this study to other solute-membrane combinations remains to be proven. These findings have significant implications in understanding the effects of erythema and vasoconstriction on topical drug efficacy. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97: 3442-3450, 200

The effects of equine skin preparation on transdermal drug penetration in vitro

An increasing number of formulations are applied to equine skin, yet variable penetration can affect efficacy, or the incidence of adverse effects, or both. To investigate the effects of common methods of skin preparation on transdermal drug penetration in vitro, we clipped, harvested, and froze skin samples from 5 Thoroughbred geldings. Thawed samples were prepared as follows: control (no preparation); cleaned with aqueous chlorhexidine (Aq-C, 0.1% w/v); cleaned with alcoholic chlorhexidine (Al-C, 0.5% w/v); shaved (Sh); or tape-stripped (Ta) with the use of adhesive tape. The samples were then placed in diffusion cells, and 2 g of methylsalicylate (MeSa) gel (Dencorub) was applied to the stratum corneum side. The penetration of MeSa and its analyte, salicylate (Sa), through the skin samples was measured over 10 h. Compared with control skin, significantly more MeSa penetrated through skin prepared with Al-C or Sh (P < 0.01) or with Aq-C or Ta (P < 0.05), and significantly more Sa was recovered in the receptor phase from skin prepared with Aq-C, Al-C, or Sh (P < 0.05) or with Ta (P < 0.01). A significantly higher rate of penetration and shorter lag time were also noted for MeSa with all the prepared skin samples, compared with the control samples. The results show that clinical techniques routinely used to clean or prepare skin can significantly affect the rate and extent of penetration of a topically applied drug. This may result in greater systemic availability of active drug, which could lead to enhanced efficacy and, possibly, a higher incidence of adverse effects

Targeting the pilosebaceous gland

INTRODUCTION When one speaks of targeting of skin appendages using topically applied agents/products, one is referring to one or another (or both) of two skin structures-hair follicles (pilosebaceous units) and/or eccrine sweat glands. Very little information has been published concerning drug delivery to/through eccrine sweat glands, whereas follicular drug delivery has received a considerable amount of research attention in recent years. This review is mainly concerned with the body of literature covering targeted follicular drug delivery. Successful targeting, as the phrase is used here, simply means getting more drug molecules into the specified appendage of action than can be delivered with conventional dosage forms (delivery systems). At the same time, it implies restricting the amount of drug that reaches therapeutically uninvolved sites, most particularly, the systemic circulation. Targeted follicular delivery would be useful to stem hair loss or promote new hair growth. In principle, topically applied agents can reach the hair bulb by either transfollicular or transepidermal route, with the former involving drug diffusion through the upper reaches of the pilosebaceous gland and the latter involving secondary local/systemic distribution into hair follicles. In fact, both pathways occur simultaneously in most cases, but the relative contribution of each pathway to the overall delivery seemingly should vary substantially depending upon the physicochemical properties of the therapeutic agent, the nature of its formulation, the specific site of topical application, and the elapsed time after topical dosing

A novel way to investigate the effects of plasma exchange on antibiotic levels: Use of microdialysis

Plasma exchange (PE) is a treatment modality frequently used for many autoimmune diseases and may cause extracorporeal elimination of antibiotics. No data currently exist on antibiotic concentrations in extracellular fluid during PE. The aim of this study is to describe the effect of PE on the serum and subcutaneous tissue pharmacokinetics of piperacillin administered as a continuous infusion in a critically ill 17-year-old patient with Guillain–Barré syndrome and ventilator-associated pneumonia on Days 1 and 4 of antibiotic therapy. The effect of PE on piperacillin concentrations appears to be small. On Day 1, an estimated 7% of total piperacillin eliminated during PE was attributable to PE. On Day 4 this was estimated to be 11%. Using the in vivo sampling technique microdialysis, we have been able to show that a small redistribution of piperacillin from tissue to serum occurs in response to the reducing serum concentrations caused by PE. In critically ill patients, we believe that administration of a β-lactam antibiotic by continuous infusion should be considered to maintain serum and tissue concentrations of these time-dependent antibiotics

Relative uptake of minoxidil into appendages and stratum corneum and permeation through human skin in vitro

We examined uptake of the model therapeutic agent, minoxidil, into appendages, stratum corneum (SC), and through human skin, under the influence of different vehicles. Quantitative estimation of therapeutic drug deposition into all three areas has not previously been reported. Finite doses of minoxidil (2%, w/v) in formulations containing varying amounts of ethanol, propylene glycol (PG), and water (60:20:20, 80:20:0, and 0:80:20 by volume, respectively) were used. Minoxidil in SC (by tape stripping), appendages (by cyanoacrylate casting), and receptor fluid was determined by liquid scintillation counting. At early times (30 min, 2 h), ethanol-containing formulations (60:20:20 and 80:20:0) caused significantly greater minoxidil retention in SC and appendages, compared to the formulation lacking ethanol (0:80:20). A significant increase in minoxidil receptor penetration occurred with the PG-rich 0:80:20 formulation after 12 h. We showed that deposition of minoxidil into appendages, SC, and skin penetration into receptor fluid were similar in magnitude. Transport by the appendageal route is likely to be a key determinant of hair growth promotion by minoxidil.

Can increasing the viscosity of formulations be used to reduce the human skin penetration of the sunscreen oxybenzone?

The effect of adding thickening agents on the penetration of a sunscreen benzophenone-3 through epidermal and a high-density polyethylene membrane was studied using both very thick (infinite dose) and thin tin use) applications. Contradictory results were obtained. Thickening agents retard skin penetration, in a manner consistent with a diffusional resistance in the formulation, when applied as an infinite dose. In contrast, when applied as in thin (in use) doses, thickening agents promote penetration, most likely through greater stratum corneum diffusivity arising from an enhanced hydration by the thicker formulations. The two key implications from this work are (i) a recognition of the danger in the potential extrapolation of infinite dosing to in use situations, and (ii) to recognize that thicker formulations may sometimes enhance the penetration of other topical agents when applied in use