Heather A. E. Benson

Influence of Ultrasound on the Percutaneous Absorption of Nicotinate Esters

The influence of ultrasound on the percutaneous absorption of three nicotinate esters was investigated in 10 healthy volunteers in a double-blind placebo controlled crossover clinical trial. Using a specially designed experimental protocol, the effect of continuous output ultrasound (at frequency 3.0 MHz and intensity 1.0 W/cm2 for 5 min) on the percutaneous absorption of methyl, ethyl, and hexyl nicotinates, from gel bases, was investigated. A placebo control, involving massage with each of the gels, without ultrasound for 5 min, was also incorporated. The pharmacodynamic parameter of vasodilation caused by the nicotinates was used to monitor the percutaneous absorption of the drugs. Laser Doppler velocimetry, a noninvasive optical technique, was used to measure vasodilation of the cutaneous vessels within the treatment site. Ultrasound treatment led to enhanced vasodilator response to the nicotinates, therefore indicating an enhancement of their percutaneous absorption. These agents may prove to be useful compounds in examination of the mechanism of action of phonophoresis.

High-performance liquid chromatographic assay for common sunscreening agents in cosmetic products, bovine serum albumin solution and human plasma

This paper reports the development of a reversed-phase high-performance liquid chromatographic assay for quantifying five of the most common sunscreen agents, namely 2-ethylhexyl-p-dimethyl aminobenzoate (Escalol 507), 2-ethylhexyl-p-methoxycinnamate (Parsol MCX); 4-tert.-butyl-4-methoxydibenzoylmethane (Parsol 1789), 2-hydroxy-4-methoxybenzophenone-3 (oxybenzone) and 2-ethylhexyl-salicylate (octylsalicylate). The assay permits analysis of the sunscreen agents in formulations and in biological fluids, including bovine serum albumin (BSA) solution, a common additive to in vitro skin diffusion cell receptor fluids, as well as human plasma. Separation was achieved using an ODS C154 column with a methanol-water (88:12) mobile phase. The analytes were detected by ultraviolet light absorption at a wavelength of 315 nm. The assay was linear with minimum detectable limits, calculated as greater than 3-times the baseline noise level: for oxybenzone and Escalol 507, 0.05 microgram/ml; for Parsol 1789 and Parsol MCX, 0.1 microgram/ml; for octylsalicylate, 1 microgram/ml. Recoveries from both plasma and 2% BSA were within the range 89-107%. The inter- and intra-day coefficients of variation for the five agents were not more than 4% at the upper end of the linear range and not more than 10% at the lower end. Preliminary stability studies of the sunscreen agents in a commercial product and in two diffusion cell receptor fluids were also conducted.

Phonophoresis of lignocaine and prilocaine from Emla cream

The influence of ultrasound on the percutaneous absorption of lignocaine and prilocaine from Emla cream was investigated in 11 healthy volunteer subjects in a double-blind placebo controlled cross-over clinical trial. Using a specially designed experimental protocol, the effect of both 1:1 pulsed output ultrasound (1.5 MHz and 3.0 MHz at intensity 1.0 W · cm−2 for 5 min) and continuous output ultrasound at a range of frequencies (0.75 MHz; 1.5 MHz and 3.0 MHz, each at intensity 1.5 W · cm−2 for 5 min) were investigated. A placebo control, involving massage without ultrasound for 5 min, was incorporated into each protocol. The pharmacodynamic parameter of loss of sensation caused by lignocaine and prilocaine, was used to monitor the percutaneous absorption of the drugs. A modified skin prick test, which involved pressing the blunt end of a paper clip onto the treatment site, was used. This prevented enhanced drug penetration due to trauma caused by hypodermic needles used in the standard skin prick method. Ultrasound treatment led to an increased rate of absorption of lignocaine and/or prilocaine as determined by onset of anaesthesia; however, this increase was not statistically significant (P > 0.05; analysis of variance). Ultrasound increased the extent of absorption of lignocaine and/or prilocaine, as determined by duration of anaesthesia, to a statistically significant degree (P < 0.05; analysis of variance).

Ion-pair formation as a strategy to enhance topical delivery of salicylic acid

An in‐vitro study was carried out to determine the possibility of improving the efficiency of transdermal delivery of salicylate through human epidermis by ion‐pair formers (alkylamines and quaternary ammonium ions). Further, the relationship between the physico‐chemical properties of the counter‐ions and salicylate flux was examined.

Effect of Ion Pairing with Alkylamines on the In‐vitro Dermal Penetration and Local Tissue Disposition of Salicylates

Hydrophilic ionic drugs can be rendered lipophilic by ion‐pair formation with hydrophobic counter‐ions. This study examines the value of forming ion pairs between anionic salicylate and a series of amines as model cationic counter‐ions to facilitate topical delivery and skin penetration. The in‐vitro translocation of salicylate ions from a non‐aqueous vehicle through human epidermis was estimated in the presence or absence of amines. The distribution into, and accumulation of the salicylate ion in various tissues following topical application to anaesthetised rats were also investigated.

Transmission of Ultrasound Energy Through Topical Pharmaceutical Products

Summary The transmission of ultrasound energy through a wide range of topical products was investigated. Great variation existed, and relatively few products were considered to have transmission characteristics suitable for phonophoresis (ie movement of drugs through intact skin into soft tissue by ultrasonic perturbation). The need exists for the formulation of drugs, with which phonophoresis may offer advantage, into topical products with good ultrasound energy transmission characteristics. Gels appear to be the most appropriate formulation type.

Self Promotion of Deep Tissue Penetration and Distribution of Methylsalicylate After Topical Application

AbstractPurpose. To determine how changes in cutaneous blood flow induced in-vivo by methylsalicylate (MeSA), compared to non-rubefacient trie-thanolamine salicylate (TSA), affected topical salicylate absorption and distribution, and to assess formulation therapeutic potential by comparing tissue concentrations to published antiinflammatory concentrations.nMethods. Flux of salicylate from MeS A and TSA formulations applied to full-thickness rat skin was determined using in vitro diffusion cells. Anaesthetised rats were then used to quantify salicylate concentrations in plasma and tissues underlying the application site for the two formulations over a 6h period. In vitro and in vivo absorption profiles were then compared and the effect of MeSA on cutaneous blood flow assessed.nResults. In vitro flux of salicylate from the MeSA formulation was 40% higher, though after correcting for differences in formulation concentrations the ratio of permeability coefficients was reversed. Contrary to the in vitro predictions, in vivo tissue and plasma concentrations of salicylate in rats rose rapidly in the first 1 hr and were more than the predicted 1.4-fold higher for MeSA. This effect was mirrored by the increase in blood flow induced by MeSA in human cutaneous vessels and that reported in the literature. Potential therapeutic levels were not seen below superficial muscle layers.nConclusions. Direct tissue penetration of salicylate occurs below application sites from both MeSA and TSA formulations. Tissue concentrations of MeSA were higher than predicted due to its rapid distribution in the blood.

In vitro human epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 from a range of solvents.

AbstractPurpose. To study epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 (BP) from a range of single solvent vehicles and evaluate solvent effects on permeability parameters.nMethods. The solubility of BP was measured in a number of solvents. Penetration of BP across human epidermis and high density polyethylene (HDPE) membranes was studied from 50% saturated solutions in each solvent.nResults. Maximal BP fluxes from the solvents across the two membranes varied widely. Highest fluxes were observed from 90% ethanol (EtOH) for epidermis and from isopropyl myristate (IPM) and C12−15 benzoate alcohols (C12−15 BA) for HDPE membrane. Both the flux and estimated permeability coefficient and skin-vehicle partitioning of BP appeared to be related to the vehicle solubility parameter (δv). The major effects of solvents on BP flux appear to be via changes in BP diffusivity through the membranes.nConclusions. Minimal penetration of sunscreens such as BP is best achieved by choosing vehicles with a δv substantially different to the solubility parameter of the membrane.

PHONOPHORESIS OF METHYL NICOTINATE - A PRELIMINARY-STUDY TO ELUCIDATE THE MECHANISM OF ACTION

The skin penetration enhancement effect of ultrasound (phonophoresis) on methyl nicotinate was investigated in 10 healthy volunteers in a double-blind, placebo-controlled, crossover clinical trial. Each treatment consisted of the application of ultrasound massage (3.0 MHz, 1.0 W/cm2 continuous output) or placebo massage (0 MHz) for 5 min to the forearms of the volunteers, followed by a standardized application of methyl nicotinate at intervals of 15 sec, 1 min, and 2 min postmassage. Percutaneous absorption of methyl nicotinate was monitored using laser Doppler velocimetry. Ultrasound treatment applied prior to methyl nicotinate led to enhanced percutaneous absorption of the drug, for example, ultrasound treatment data versus control data at 2 min showed significant increases (P < 0.05; analysis of variance) in the peak blood flow (125.8 ± 12.0 vs 75.3 ± 10.4% flux) and in the area under the curve for blood flow (2630.3 ± 387.5 vs 1567.6 ± 183.5% flux · min). The results of this study suggest that ultrasound affects the skin structure to provide skin penetration enhancement. This finding is consistent with the proposed hypothesis that phonophoresis acts by disordering the structured lipids in the stratum corneum.

Percutaneous Absorption of Salicylates from Some Commercially Available Topical Products Containing Methyl Salicylate or Salicylate Salts in Rats

Studies to determine the extent of local tissue penetration of topically applied, commercially available salicylate esters and salts were conducted in male Wistar rats.