Flux Of Hydrocortisone Research Articles

Galactosyl Pentadecene Reversibly Enhances Transdermal and Topical Drug Delivery.

To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. Initial evaluation identified 1-(α-D-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer - it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60μM. Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action.

Permeability and lipid organization of a novel psoriasis stratum corneum substitute

Lipids in the uppermost layer of the skin, the stratum corneum (SC), play an important role in the skin barrier properties. The main lipid classes are ceramides, cholesterol and free fatty acids. In previous studies a stratum corneum substitute (SCS) was developed, solely prepared from the SC lipids. The SCS mimics the lipid barrier properties of SC very closely. The present study aimed to design a psoriasis SCS (PS-SCS) mimicking several aspects of the lipid composition in SC from psoriasis patients. This PS-SCS showed a different lipid organization than SCS. The main differences were a reduced presence of an orthorhombic packing and an increased level of crystalline cholesterol. These changes resulted in lower flux of hydrocortisone across PS-SCS than across SCS and SC, which was most likely attributed to the higher level of phase separated crystalline cholesterol in PS-SCS. As propylene glycol (PG) is often used in dermatological formulations, in subsequent studies the interaction of PG with SC and SCS membranes was also investigated. These studies revealed that PG increased the permeability of hydrocortisone, mainly by selectively extracting cholesterol from SCS membranes and SC. This may play an important role in the penetration enhancing effect of PG.

The effects of skin disease on the penetration kinetics of hydrocortisone through canine skinin vitro

This study investigated the effects of allergic skin disease on the penetration kinetics of hydrocortisone through canine skin in vitro. Full-thickness lesional and nonlesional (normal) skin was removed from the dorsal lumbosacral and dorsocaudal thoracic regions, respectively, of five canine cadavers. The dogs were suspected of having flea allergy dermatitis based on their distribution and types of skin lesions. Nonlesional skin was confirmed to be histologically normal, and the histopathology of the lesional skin was consistent with allergic dermatitis. Excised skin was clipped, mounted in Franz-type diffusion cells, and the transdermal penetration of a saturated, radiolabelled hydrocortisone solution was measured over 30 h. When the penetration data for all five dogs were pooled, a restricted (or residual) maximal likelihood mixed model predicted that the permeability coefficient and pseudosteady-state flux of hydrocortisone was more than twice as great (95% confidence interval 1.55-2.71 times as great; P < 0.0001) through lesional compared with nonlesional skin. There was no significant difference in the lag time for hydrocortisone penetration through lesional compared with nonlesional skin of the dogs. This study has confirmed that the transdermal penetration of hydrocortisone may be altered, typically increased twofold, but could be as high as 10-fold, through lesional compared with nonlesional skin of dogs with suspected flea allergy dermatitis. This is likely to be affected by variables such as disease severity, concurrent infections and interindividual differences in skin characteristics.

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.

Development of octanol membranes for drug screening

Most drugs permeate biological membranes via passive diffusion and it is generally assumed that the main barrier is the lipophilic structure of the membranes. However, it has been observed that an unstirred water layer adjacent to the membrane surface can in some cases be just as effective barrier as the lipophilic membrane itself. Hydrophilic cyclodextrins can enhance drug delivery through biological membranes by increasing the availability of dissolved drug molecules immediate to the membrane surface, i.e., by increasing drug delivery through the unstirred water layer. We have developed an artificial octanol membrane that is cheap and simple to prepare. The novel membrane consists of a hydrated semi-permeable cellophane membrane with a molecular weight cut off (MWCO) of 12,000–14,000 that mimics the unstirred water layer and a lipophilic membrane of pure n-octanol in a nitrocellulose matrix. The membrane was used to investigate the effects of 2-hydroxypropyl-β-cyclodextrin (HPβCD) on the flux of hydrocortisone through the membrane. In aqueous HPβCD saturated with hydrocortisone the drug concentration gradient, over the unstirred water layer, increased with increasing HPβCD concentration which resulted in enhanced drug delivery through the membrane. When excess HPβCD was present in the donor phase the octanol/water partition coefficient decreased with increasing HPβCD concentration that lead to decreased drug delivery through the membrane.

Effects of vehicle and region of application on absorption of hydrocortisone through canine skin

To determine the effects of various vehicles on the penetration and retention of hydrocortisone applied to canine skin. 20 canine skin samples obtained from the thorax, neck, and groin regions of 5 Greyhounds. Skin was harvested from dogs after euthanasia and stored at -20 degrees C until required. The skin was then defrosted and placed into diffusion cells, which were maintained at approximately 32 degrees C by a water bath. Saturated solutions of hydrocortisone that contained trace amounts of radiolabelled [14C]-hydrocortisone in each vehicle (ie, PBS solution [PBSS] alone, 50% ethanol [EtOH] in PBSS [wt/wt], and 50% propylene glycol in PBSS [wt/wt]) were applied to the outer (stratum corneum) surface of each skin sample, and aliquots of receptor fluid were collected for 24 hours and analyzed for hydrocortisone. The maximum flux of hydrocortisone was significantly higher for all sites when dissolved in a vehicle containing 50% EtOH, compared with PBSS alone or 50% propylene glycol, with differences more prominent in skin from the neck region. In contrast, higher residues of hydrocortisone were found remaining within the skin when PBSS alone was used as a vehicle, particularly in skin from the thorax and neck. Penetration of topically applied hydrocortisone is enhanced when EtOH is used in vehicle formulation. Significant regional differences (ie, among the thorax, neck, and groin areas) are also found in the transdermal penetration and skin retention of hydrocortisone. Variability in clinical response to hydrocortisone can be expected in relation to formulation design and site of application.

Absorption rate limit considerations for oral phosphate prodrugs.

To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs. Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats. Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 microM fosphenytoin, respectively. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 microM. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension. Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.

The Effects of Cyclodextrins on Hydrocortisone Permeability Through Semi-permeable Membranes

Determinations of drug fluxes through semi-permeable cellophanemembranes are used to evaluate cyclodextrin complexes and cyclodextrin containingdrug formulations. In the present study we investigated how the cyclodextrin concentration,the membrane thickness and the molecular weight cut off (MWCO) of the membraneinfluence drug fluxes. The cyclodextrin used was 2-hydroxypropyl-β-cyclodextrin(HP-β-CD) and the sample drug was hydrocortisone. The MWCO ofthe membranes ranged from 500 to 14,000 and the HP-β-CD concentrationranged from 0 to 25% (w/v). The hydrocortisone flux from saturated solutions through the MWCO 500 membrane was unaffected by the cyclodextrin concentration. When MWCO of the membrane was greater than the molecular weight of the complex the flux fromsolutions saturated with hydrocortisone increased with increasing HP-β-CD concentration.This increase showed negative deviation from linearity. When the flux was correctedfor the viscosity increase with increasing HP-β-CD concentration then the fluxpattern could be described on the basis of Fick's first law and Stokes–Einsteinequation. However the flux did not correlate with the viscosity when it was increasedby adding polymer to the saturated drug solutions. It was shown that the observed fluxpattern was consistent with self-association of cyclodextrin complexes in the aqueousdonor phase.

Cyclodextrins and drug permeability through semi-permeable cellophane membranes

Determinations of drug fluxes through semi-permeable cellophane membranes are used to evaluate cyclodextrin complexes and cyclodextrin containing drug formulations. In the present study we investigated how the cyclodextrin concentration, the membrane thickness and the molecular weight cut off (MWCO) of the membrane influence drug fluxes. The cyclodextrin used was 2-hydroxypropyl-β-cyclodextrin (HPβCD) and the sample drug was hydrocortisone. The MWCO of the membranes ranged from 500 to 14,000 and the HPβCD concentration ranged from 0 to 25% (w/v). The hydrocortisone flux from saturated solutions through the MWCO 500 membrane was unaffected by the cyclodextrin concentration. When MWCO of the membrane was greater than the molecular weight of the complex the flux from solutions saturated with hydrocortisone increased with increasing HPβCD concentration. This increase showed negative deviation from linearity. When the flux was corrected for the viscosity increase with increasing HPβCD concentration then the flux pattern could be described on the basis of Fick's first law and Stokes–Einstein equation. However, the flux did not correlate with the viscosity when it was increased by adding polymer to the saturated drug solutions. It was shown that the observed flux pattern was consistent with self-association of cyclodextrin complexes in the aqueous donor phase.

Fish Skin as a Model Membrane to Study Transmembrane Drug Delivery with Cyclodextrins

The possibility of using fish skin as model membrane tostudy drug permeation and penetration enhancement by cyclodextrins was investigated.The permeability of the skin from four species of fish, Anarhichas lupus (catfish),Pleuronectes platessa (Plaice), Hippoglossus hippoglossus (Halibut)and Anarhichas minor (Spotted catfish), was compared in a Franz diffusion cell set-up using 1% hydrocortisone aqueous solution as a donor phase. The drug fluxthrough fish skin was more than 100 times faster than the flux through hairless mouse skin and more than 10 000 times faster than through snake skin. Catfishskin was most easily accessible and was therefore used for further study. The octanol-water partition coefficient did not affect the transmembrane flux of small molecules whereas the aqueous diffusion coefficient could be correlated with the flux.The hydrocortisone flux of from aqueous hydroxypropyl-β-cyclodextrin solutions, which were saturated with the drug, increased with increasing cyclodextrinconcentration. From these and other observations it was concluded that small moleculesare transported through fish skin in aqueous channels. The properties of thesechannels resemble the properties of the aqueous diffusion layer present in human andanimal skin and other types of biological membranes. Previous studies have shown thatcyclodextrins will enhance drug delivery by increasing aqueous diffusion rate. Catfish skin can therefore be a good model membrane to study penetration enhancementby cyclodextrins.

Probing the effect of vehicles on topical delivery: understanding the basic relationship between solvent and solute penetration using silicone membranes.

In the present study we examined the relationship between solvent uptake into a model membrane (silicone) with the physical properties of the solvents (e.g., solubility parameter, melting point, molecular weight) and its potential predictability. We then assessed the subsequent topical penetration and retention kinetics of hydrocortisone from various solvents to define whether modifications to either solute diffusivity or partitioning were dominant in increasing permeability through solvent-modified membranes. Membrane sorption of solvents was determined from weight differences following immersion in individual solvents, corrected for differences in density. Permeability and retention kinetics of 3H-hydrocortisone, applied as saturated solutions in the various solvents, were determined over 48 h in horizontal Franz-type glass diffusion cells. Solvent sorption into the membrane could be related to differences in solubility parameters, MW and hydrogen bonding (r2=0.76). The actual and predicted volume of solvent sorbed into the membrane was also found to be linearly related to Log hydrocortisone flux, with changes in both diffusivity and partitioning of hydrocortisone observed for the different solvent vehicles. A simple structure-based predictive model can be applied to the sorption of solvents into silicone membranes. Changes in solute diffusivity and partitioning appeared to contribute to the increased hydrocortisone flux observed with the various solvent vehicles. The application of this predictive model to the more complex skin membrane remains to be determined.

Dissolution of hydrocortisone in human and simulated intestinal fluids.

To compare solubility and dissolution rate of hydrocortisone in aspirated human intestinal fluids (HIFs) with simulated intestinal fluids (SIFs) and buffer. Solubility and flux from a rotating disk of hydrocortisone were measured. The bile salt content, pH and osmotic pressure were determined in HIFs. In fasted state the solubility of hydrocortisone was higher in HIFs than in the buffer and SIFs. The flux of hydrocortisone in HIFs was similar to the flux in the buffer but lower than the flux in SIFs at fasted state. Addition of intestinal surfactants in SIFs increased solubility and flux at both fasted and fed state. The increase in solubility was caused by micelle formation in SIFs. The increase in flux may partly be explained by increased solubility. The bile salt content of the HIFs did not correlate with the solubility or the flux but pH in the HIFs seems to have some effect on the components of the HIFs resulting in increased solubility. It is possible to perform comparable dissolution tests in HIFs and SIFs. The lack of correlation between the results in HIFs and the bile salt content may be explained by the relatively low lipophilicity of the model drug.

Effect of transdermal iontophoresis codelivery of hydrocortisone on metoclopramide pharmacokinetics and skin‐induced reactions in human subjects

The effects of transdermal iontophoresis (IP) codelivery of hydrocortisone (HC) on metoclopramide hydrochloride (MCP) pharmacokinetics and on skin‐induced reactions were evaluated in a randomized, crossover clinical study. MCP, an antiemetic, low molecular weight, cationic drug intended for systemic delivery, was delivered from the anode of IP systems at a constant current of 100 μA/cm2. HC, a neutral endogenous antiinflammatory agent, was codelivered from the same electrode, primarily by electroosmotic processes. Each subject (n = 7) wore two identical IP systems (MCP alone or MCP plus HC), each supplying 500 μA, one on each upper arm for 4 h. One week later, each subject repeated the procedure with the alternate type of MCP system. HC did not change the pharmacokinetics of MCP: There were no statistically significant differences in MCP plasma concentrations, half‐life, area under the curve (AUC), or rate of absorption between the two treatment groups. However, HC significantly decreased erythema and edema scores produced by the IP of MCP. In both groups, a steady‐state MCP flux of about 100 μg/(cm2 × h) was achieved after only 1 h of transport, and input rate dropped dramatically immediately after removal of the system. In vitro, HC flux through human epidermis from an MCP plus HC formulation was 2.8 ± 1.1 μg/(cm2 × h) after 4 h transport at 100 μ A/cm2, suggesting negligible systemic exposure to hydrocortisone. These data indicate that MCP input rate and its clearance from the skin are unaltered by HC and that the codelivery of HC by IP is an effective strategy for inhibition of local reactions resulting from the transdermal delivery of drugs.

The effect of polyvinylpyrrolidone on cyclodextrin complexation of hydrocortisone and its diffusion through hairless mouse skin

The effect of nine different cyclodextrin derivatives on the aqueous solubility of hydrocortisone was investigated. Three of these derivatives were selected for further investigation. The effect of methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin and maltosyl-ß-cyclodextrin on the flux of hydrocortisone, from an aqueous suspension or solution, through hairless mouse skin was investigated in vitro. When the hydrocortisone concentration was kept constant and the cyclodextrin concentration was gradually increased, the flux through the skin was increased up to a point when all the hydrocortisone molecules were in solution, then the flux decreased with increasing cyclodextrin concentration. Polyvinylpyrrolidone (PVP) increased the complexation of hydrocortisone which increased solubility of the drug in the aqueous cyclodextrin solutions. Also, the flux of hydrocortisone through hairless mouse skin was increased by addition of small amount of PVP to the cyclodextrin vehicle. The flux of hydrocortisone could be increased even further by addition of oleic acid to the aqueous cyclodextrin PVP vehicle systems.

The effect of polyvinylpyrrolidone and hydroxypropyl methylcellulose on HPβCD complexation of hydrocortisone and its permeability through hairless mouse skin

The effect of 2-hydroxypropyl-β-cyclodextrin (HPβCD), polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) on the flux of hydrocortisone from an aqueous solution through hairless mouse skin was investigated in vitro. When the drug concentration was kept constant and the HPβCD concentration was gradually increased, the flux through the skin was increased until all the drug had dissolved; after that the flux decreased with increasing HPβCD concentration. PVP and HPMC increased the hydrocortisone-HPβCD complexation resulting in increased solubilization of the drug. Also, the transdermal delivery of hydrocortisone could be increased by addition of a small amount of PVP or HPMC to an HPβCD-containing vehicle.

Effect of Formulation Factors on Penetration of Hydrocortisone through Mouse Skin

The effect of formulation factors on the steady-state flux of hydrocortisone through mouse skin was evaluated. The flux of hydrocortisone from solutions containing propylene glycol as a cosolvent varied inversely with the propylene glycol concentration. Solutions containing 2-propanol gave flux values higher than those obtained from propylene glycol solutions and independent of the 2-propanol concentration. Addition of polysorbate 80 to 2-propanol–water solutions produced an increase in flux at low surfactant concentrations that reached an apparent limiting value at higher concentrations. The penetration flux was the same from solutions and gels. The role of vehicle–skin interactions in penetration is emphasized.