Phonophoresis and topical drug delivery

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN012544 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Drug release kinetics from tablet matrices based upon ethylcellulose ether-derivatives: a comparison between different formulations

The present study involved the preparation of ibuprofen-containing controlled release tablets formulated from either the established granular product, Ethocel®Standard Premium, or the novel finely-milled product, Ethocel®Standard FP Premium. The tablets were prepared by either direct compression or wet granulation. The aim was to explore the influence of different parameters on the kinetics and mechanisms of ibuprofen release from the tablets. These parameters were; polymer particle size, polymer molecular weight, drug : polymer ratio, preparation methodology and partial replacement of lactose with the coexcipient-hydroxypropyl methylcellulose (HPMC). The derived drug release data were analyzed with reference to various established mathematical models while the f2-metric technique was used in order to determine profile equivalency. It was found that drug release was mostly modulated by several interactive factors apparently exhibiting crosstalk. Nevertheless, it was possible to identify some simple rules. Incorporation of Ethocel® FP polymers and application of the wet granulation technique facilitated greater efficiency in controlling ibuprofen release behavior from the matrices. Furthermore, drug release profiles could be modulated by partial substitution of the primary excipient with HPMC. Polymer concentrations and particle sizes, rather than viscosity grade, were found to be decisive factors in controlling drug release rates

A two-layer diffusive model for describing the variability of transdermal drug permeation

There is mounting evidence that the permeability coefficients (kp) that describe any given transdermal drug permeation process generally follow some form of positively skewed, non-symmetrical distribution rather than a simple normal distribution. Yet a suitable theoretical treatment of this area has not been undertaken to date. In this paper, we describe a two-layer model that can explain five drugs' kp variabilities as measured in two previously published papers. The model shows why rapidly permeating drugs would tend to exhibit more symmetrical kp distributions while progressively more slowly permeating drugs would tend to exhibit progressively more positively skewed kp distributions. Future research should take this effect into account when comparing the flux variabilities of hydrophilic and lipophilic drugs

Inter- and intra-individual variability in human skin barrier function : a large scale retrospective study

In vitro transepidermal tritiated water flux measurements are frequently used to evaluate skin barrier integrity for quality control purposes. However, research in this area to date has been largely based upon small-scale studies, each involving relatively few skin permeation measurements. In order to enhance our understanding in this area, we have conducted a much larger scale retrospective statistical analysis of tritiated water kp values. These values reflected the permeability of 2400 skin samples that were derived from 112 female volunteers over a 4 year period. It was found that the population of tritiated water kp values constituted a positively skewed, non-Normal distribution. Mean kp was 2.04 × 10−3 cm/h while the 95th percentile was 4.50 × 10−3 cm/h. Both values are higher than those reported in previous smaller studies. Hence, our study indicates that previously suggested upper limits for tritiated water flux are too low and that they be revised upwards to a value of 4.5 × 10−3 cm/h. Analysis was also performed on smaller data subsets allowing inter-individual and intra-individual comparisons. For intra-individual kp variability, site-related differences yielded a non-Normal, positively skewed pattern in most individuals. Inter-individual variability was Normally-distributed and showed scatter that was much smaller in magnitude

Evidence that drug flux across synthetic membranes is described by normally distributed permeability coefficients

Over recent decades, the use of in vitro diffusion cell studies to assess skin permeability has evolved into a major research tool, providing key insights into the relationships between skin, drug and formulation. Sometimes, such studies involve synthetic membranes as this approach can yield useful inferences with respect to drug-skin partitioning and diffusion phenomena. Yet despite the popularity of such studies, it is still not at all known whether typical solute transport across synthetic barriers results in a normal distribution of permeability coefficients or alternatively some type of skewed distribution. The present study aims to shed light on this issue. To this end, five compounds (testosterone, oestradiol, corticosterone, aldosterone and adenosine) exhibiting a broad range of octanol-water partition coefficient values were selected as test penetrants. The protocol involved taking multiple replicate measurements of each drug's passive steady state flux through poly(dimethylsiloxane) membrane. Each penetrant's resultant permeability coefficient database was subjected to a Kolmogorov-Smirnov (KS) test for normality. It was found that the permeability coefficients of all five drugs were distributed in a Gaussian-normal fashion. The theoretical significance and practical impact of these findings are discussed

Biomaterials

A biomaterial is essentially a material that is used and adapted for a medical application. Biomaterials can have a benign function, such as being used for a heart valve, or may be bioactive . Used for a more interactive purpose such as hydroxy-apatite coated hip implants (the Furlong Hip, by Joint Replacement Instrumentation Ltd, Sheffield is one such example - such implants are lasting upwards of twenty years). Biomaterials are also used every day in dental applications, surgery, and drug delivery (a construct with impregnated pharmaceutical products can be placed into the body, which permits the prolonged release of a drug over an extended period of time)

Factors influencing hydrocortisone permeation into human hair follicles: use of the skin sandwich system

The aim of the present study was to use the in vitro human skin sandwich system in order to quantify the influence of formulation variables on intrafollicular hydrocortisone permeation. The investigated variables were the pH and the viscosity of the topical formulation as well as the presence of chemical enhancers (carvone, menthone, oleic acid and sodium lauryl sulphate). Furthermore, skin sandwich hydration was also varied in order to determine if the method itself can be run using only partially hydrated skin tissues. It was determined that the follicular contribution to hydrocortisone flux decreased marginally with increasing alkalinity in the pH range 3-8.8. Intrafollicular penetration was markedly reduced when HPMC gels were used instead of an aqueous solution. Pretreating the skin with chemical enhancers also reduced the follicular contribution to flux, probably due to permeabilisation of the continuous stratum corneum. Furthermore, it was not possible to satisfactorily modify the skin sandwich method so that it could be deployed using less hydrated skin

Transdermal and buccal delivery of methylxanthines through human tissue in vitro

We examined the in vitro permeation of central nervous stimulants-caffeine, theophylline, and theobromine across human skin with the aid of six chemical enhancers. It was found that oleic acid was the most potent enhancer for all three methylxanthines. Further optimization studies with different solvents showed that caffeine transport could be enhanced to give flux values up to 585 μg/cm2.hr-1. Theobromine and theophylline delivery rates proved insufficient. An additional study involving a buccal tissue equivalent showed that this membrane was more permeable than skin for all model actives tested and would offer an alternate way of delivery

Enhanced iontophoretic delivery of buspirone hydrochloride across human skin using chemical enhancers

Buspirone hydrochloride (BH) is a structurally and pharmacologically unique anxiolytic that is used to treat a variety of different anxiety conditions. The marketed product is named BuSpar®. The in vitro iontophoretic delivery of BH through human skin was investigated in order to evaluate the feasibility of delivering a therapeutic dose of BH by this route. We also examined the influence of co-formulations of chemical enhancers (Azone®, oleic acid, menthone, cineole, and terpineol) on BH permeation, both without iontophoresis and with iontophoresis—to look for possible synergistic effects. By applying iontophoresis at 0.5 mA/cm2, it was possible to achieve a BH steady state flux of approximately 350 μg/cm2 h, which would be therapeutically effective if clinically duplicated. Importantly, 24 h of iontophoresis at 0.5 mA/cm2 did not affect skin morphology and after the current was switched off, the skin’s permeability to BH rapidly reverted to its pre-iontophoretic level. Without iontophoreis, BH transdermal flux was significantly enhanced by the application of 2.5% (v/v) concentrations of Azone®, oleic acid, or menthone but not cineole or terpineol. Furthermore, this paper identified a synergistic transport enhancement effect developing when very low current (0.025 mA/cm2) iontophoresis was applied in conjuction with Azone® treatment

The influence of drug partition coefficient on follicular penetration: in vitro human skin studies

The aim of this study was to employ the novel skin sandwich system in order to quantify the influence of the octanol-water partition coefficient on follicular drug absorption in human skin. To this end, seven different drugs - estradiol, corticosterone, hydrocortisone, aldosterone, cimetidine, deoxyadenosine and adenosine - exhibiting a wide range of log octanol-water partition coefficients (logK0/w) but relatively similar molecular weights were selected as candidate solutes. Application of the skin sandwich technique yielded an interesting relationship between % follicular contribution and logKo/w The follicular contribution to total flux was small (4 and 2%) for the two most lipophilic drugs but varied between 34 and 60% for the remaining drugs of intermediate and low logKo/w values. Lipophilicity seems to be an important modulator of drug absorption into follicular orifices only above a critical logKo/w threshold. Below this critical logKo/w value, lipophilicity does not apparently influence the follicular contribution in an obvious way and the process is probably governed by other molecular properties. Identification of these other active properties would require performing this kind of a study on a much larger set of candidate drugs