The effect of formulation excipients on the penetration and lateral diffusion of ibuprofen on and within the stratum corneum following topical application to humans.

Distribution profiles of topically applied drugs can be influenced by the presence of excipients. This study investigated the effect of common topical excipients on the simultaneous lateral diffusion and stratum corneum (SC) penetration of a model compound, ibuprofen (IBU) in humans. IBU solutions with and without propylene glycol (PG), polyethylene glycol 200 (PEG 200), and/or octisalate (OS) were dosed onto the forearm of participants. At various times, 10 "tape-strippings" were obtained with perforated concentric tapes and analyzed for IBU concentration and SC protein mass. Complimentary in vitro permeation studies assessed the effect of excipients on the percutaneous absorption of IBU across human skin. Following in vivo application, IBU displayed a greater tendency for lateral diffusion when applied with OS, whereas IBU resisted lateral diffusion when dosed with PG and PEG 200. After 24 h, 25.3 ± 8.0% and 55.5 ± 18.6% of IBU was recovered from the SC in vivo with and without excipients, respectively. There was a twofold-to threefold enhancement in IBU flux in vitro when applied with excipients. The lower IBU recovery from the SC when applied with excipients may be attributed to the permeation enhancement effects of these excipients. The ability of IBU to laterally diffuse appears to be dependent on formulation excipients.

The buccal mucosa as an alternative route for the systemic delivery of risperidone.

The purpose of this study was to investigate the potential of the buccal mucosa for the systemic delivery of risperidone (RISP), and to determine the impact of Azone® (AZ) on the transport of RISP via this route. The permeability of RISP through porcine buccal mucosa was assessed in modified Ussing chambers at various concentrations to determine the mechanisms involved in transport across the tissue. The effect of AZ was assessed by administering AZ 5% (w/w) to the tissue as a pretreatment or together with RISP in solution or in a mucoadhesive gel formulation. RISP permeated the buccal mucosa via a passive diffusion mechanism and pretreatment or coadministration of AZ 5% did not significantly modify the permeation of RISP. Application of a RISP mucoadhesive gel resulted in a steady state flux of 64.65 ± 8.0 µg/cm(2)/h, which when extrapolated to the in vivo setting, is predicted to result in RISP plasma concentrations of 11.2-56.1 µg/L for mucosal application areas between 2 and 10 cm(2). Given that these predicted concentrations are within the therapeutic range of RISP required in humans, delivery of RISP via the buccal mucosa has the potential to result in therapeutically relevant plasma concentrations for the treatment of schizophrenia.

A novel flow through diffusion cell for assessing drug transport across the buccal mucosa in vitro.

A novel flow through (FT) diffusion cell for assessing the permeability of compounds across the buccal mucosa was designed. Porcine buccal mucosa was mounted between two chambers with flow through capacity in both the donor and receptor chambers. The permeability of caffeine (CAF), triamcinolone acetonide (TAC), and estradiol (E(2)) was determined over 4 h and flux values were compared to those obtained using a modified Ussing chamber (MUC). No significant differences in the flux of each probe compound were observed using either the MUC or the novel FT cell. The design of the FT cell allowed for monitoring appearance of receptor solution within the donor chamber during the initial equilibration period, allowing for visual inspection of tissue integrity. These permeability studies demonstrate that this FT cell is a suitable alternative model for assessing drug permeability across the buccal mucosa, without the limitations associated with the static MUC. This novel model was then utilized to determine whether salmeterol xinafoate (SX) could permeate the buccal mucosa at concentrations expected in the oral cavity following inhalation. Concentration-dependent studies demonstrated that SX permeates the buccal mucosa via passive diffusion and that oral mucosal absorption may contribute significantly to the overall systemic exposure of inhaled SX.

Mechanisms of action of novel skin penetration enhancers: phospholipid versus skin lipid liposomes.

Employing thermal analysis, we investigated the mechanism of action of novel enhancers and probed phospholipid (PL) versus stratum corneum lipid (SCL) liposomes as model membranes. The enhancers included octyl salicylate (OS), padimate O (PADO) and 2-(1-nonyl)-1,3-dioxolane (ND). The negative controls were the empty liposomes. Positive controls employed dimethylsulfoxide (DMSO) and Azone (AZ). For PL liposomes, DMSO sharpened the transitions. AZ abolished the pre-transition, broadened the main transition and linearly reduced its transition temperature (T(m)). OS or PADO reduced T(m) and size of pre-transition, broadened the main transition and decreased its T(m) (non-linearly). ND abolished the pre-transition but increased T(m) of the main endotherm, suggesting retardation rather than enhancement. The results of SCL correlated with PL liposomes except for ND. In SCL liposomes, ND reduced T(m) and broadened the peaks indicating lipid disruption, which indicated its enhancing effects. In conclusion, OS, PADO and ND can enhance drugs by disrupting intercellular lipid domain but they differ from AZ in terms of the relationship between efficacy and concentration. Although PL liposomes are simple model membranes with sharp transitions which give detailed information about the effects of enhancers, they can provide misleading results. Simultaneous use of other models like SCL liposomes is recommended.

Enhancing the buccal mucosal uptake and retention of triamcinolone acetonide.

In this study, the buccal mucosal uptake and retention of triamcinolone acetonide (TAC) were assessed in the presence of the skin penetration enhancer, Azone (AZ). Porcine buccal mucosa was excised, mounted in modified Ussing chambers, and pretreated with ethanolic solutions of AZ. After 2 h, the rate of TAC disappearance from the donor chamber and TAC appearance in the receptor chamber was monitored, and the mucosal retention of TAC was determined at the completion of the experiment. The permeability and mucosal uptake of TAC was also determined using the TAC-containing proprietary product, Kenalog in Orabase (KO), in the presence and absence of AZ. Pretreatment of the buccal mucosa with AZ increased the TAC disappearance permeability coefficient from 4.78+/-0.31x10(-5) cm/s to 7.12+/-0.53x10(-5) cm/s. While the TAC appearance permeability coefficient was also enhanced 3.8-fold, a 4.4-fold increase in the tissue concentration of TAC was observed. Incorporation of AZ into KO did not result in an enhanced tissue concentration of TAC, however, when the tissue was pretreated with AZ, significantly higher amounts of TAC accumulated in the tissue. Pretreatment of the buccal mucosa with AZ results in increased tissue concentrations of TAC, which may be of clinical benefit in the treatment of oral mucosal inflammatory conditions.

Buccal penetration enhancers--how do they really work?

Certain agents that increase drug delivery through the skin, including surfactants, bile salts, and fatty acids, have been shown to exert a similar effect on the buccal mucosa. These agents enhance skin permeability by interacting with and disrupting the ordered intercellular lipid lamellae within the keratinized stratum corneum, and it has been assumed that a similar mechanism of action occurs in the nonkeratinized buccal mucosa. However, the chemical and structural nature of the lipids present within the intercellular regions of the buccal mucosa is quite different to that found within the stratum corneum, and so extrapolation of results between these two tissues may be misleading. To assume that the mechanism of action of buccal penetration enhancers is based on the disruption of intercellular lipids may be erroneous, and may result in the inappropriate prediction that certain skin penetration enhancers will similarly enhance drug delivery through the buccal mucosa. The data available in the literature suggest that agents that enhance buccal penetration exert their effect by a mechanism other than by disruption of intercellular lipids. Rather, buccal penetration enhancement appears to result from agents being able to (a) increase the partitioning of drugs into the buccal epithelium, (b) extract (and not disrupt) intercellular lipids, (c) interact with epithelial protein domains, and/or (d) increase the retention of drugs at the buccal mucosal surface. The purpose of this review is to identify the major differences in the structural and chemical nature of the permeability barriers between the buccal mucosa and skin, to clarify the mechanisms of action of buccal penetration enhancers, and to identify the limitations of certain models that are used to assess the effect of buccal penetration enhancers.

Synergistic enhancement of testosterone transdermal delivery.

In this study, the effects of occlusion, octisalate (OS), and propylene glycol (PG) on the in vitro skin permeability of testosterone (TES) have been investigated. TES (either alone or with OS 5% w/v) was applied as a finite dose to full-thickness neonatal porcine skin mounted in flow-through diffusion cells and the amount of TES appearing in the receptor solution (20% v/v ethanol) was determined over 24 h. The skin was occluded with a microscope glass cover slip and to determine the effect of PG, 400 microl of PG/water mixtures (of varying PG concentration) was applied. In addition, the effect of Solugel (a proprietary hydrogel containing PG 25% w/w) and Tegaderm (a semipermeable film dressing) on the permeation of TES was assessed. Occlusion had no effect on the permeation of TES, however, OS increased the flux of TES 2.9-fold. The concentration of PG which produced optimal TES flux was 20% v/v, and this concentration resulted in a 1.9-fold increase in TES permeation. By combining OS, PG, and occlusion, TES permeation was increased 8.7-fold, which was a synergistic enhancement. In addition, Solugel and Tegaderm, when applied to the skin, produced a similar enhancement in TES permeation to that produced by PG 25% w/w and occlusion.

Enhanced buccal mucosal retention and reduced buccal permeability of estradiol in the presence of padimate O and Azone: a mechanistic study.

In previous experiments, it was suggested that the reduction in estradiol (E2) buccal permeability after pretreatment with some skin penetration enhancers was attributed to enhanced membrane storage. To verify this, further in vitro permeability experiments were performed and the kinetics of E2 buccal mucosal uptake and permeability was assessed. Porcine buccal mucosa was pretreated with the skin penetration enhancers octisalate, padimate O (PO), or Azone (AZ) and placed in modified Ussing chambers. The disappearance of E2 from the donor chamber and appearance of E2 in the receptor chamber was then monitored over 4 h. The final concentration of E2 associated with the buccal mucosa and donor chamber walls in the presence of each enhancer was also determined. The rate of E2 disappearance from the donor chamber was 3.1-fold greater than the rate of E2 appearance in the receptor chamber, indicating significant membrane storage of E2. Pretreatment with PO and AZ significantly increased the rate of E2 disappearance and reduced the rate of E2 appearance in the receptor chamber. The corresponding enhancement in E2 tissue concentration after PO and AZ pretreatment was 1.7- and 3-fold, respectively. However, PO and AZ also increased the amount of E2 adsorbed to the walls of the donor chamber, which contributed to the reduction in E2 flux through the buccal mucosa.

The transdermal revolution.

Historically, developments in transdermal drug delivery have been incremental, focusing on overcoming problems associated with the barrier properties of the skin, reducing skin irritation rates and improving the aesthetics associated with passive patch systems. More-recent advances have concentrated on the development of non-passive systems to aid delivery of larger drug molecules, such as proteins and nucleotides, as the trend for discovering and designing biopharmaceuticals continues. Fundamentally, improvements in transdermal delivery will remain incremental until there is wider acceptance of this route of administration within the pharmaceutical industry. Only then will the transdermal revolution live up to its true potential.

Modification of buccal drug delivery following pretreatment with skin penetration enhancers.

The effect of the lipophilic skin penetration enhancers octisalate (OS), padimate O (PO), and Azone (AZ) on in vitro buccal permeability was assessed using caffeine (CAF), estradiol (E2), and triamcinolone acetonide (TAC) as model permeants. Buccal permeability was assessed in modified Ussing chambers, through both untreated porcine buccal mucosa and mucosa pretreated with an enhancer (5% w/v in 95% v/v ethanol) or ethanol alone. To ensure sink conditions were present, E2 permeability experiments were also performed with bovine serum albumin (BSA) 4% in the receptor solution. Mucosa-buffer partition studies were performed to determine the effect of enhancer pretreatment on the log mucosa-buffer partition coefficient (logK) of E2 and TAC. CAF permeability was only increased following pretreatment with ethanol 95%. E2 buccal transport was not altered following OS pretreatment, but was reduced by 26.3% with PO pretreatment and 67.6% with AZ pretreatment. Similar results were obtained with BSA 4% in the receptor solution. The logK of E2 was increased 1.4-fold and 2.2-fold in PO- and AZ-pretreated tissues, respectively, suggesting that the reduction in flux caused by PO and AZ may have been due to enhanced E2 tissue retention. The effect of OS and PO on TAC permeability was no different to that of ethanol. However, AZ enhanced TAC permeability 4.1-fold and this was accompanied by a 2.4-fold increase in the logK of TAC.

Assessment of the effects of sodium dodecyl sulfate on the buccal permeability of caffeine and estradiol.

The concentration-dependent effects of sodium dodecyl sulfate (SDS) on the in vitro permeability of the buccal mucosa were assessed using caffeine (CAF) and estradiol (E(2)) as model hydrophilic and lipophilic markers, respectively. The permeability of CAF and E(2) through porcine buccal mucosa was determined in modified Ussing chambers, with and without exposure to different concentrations of SDS (0.01, 0.05, 0.1, and 1% w/v in physiological buffer). Permeability experiments were complemented with light microscopic evaluation of untreated and SDS-treated tissues. Additionally, the critical micellar concentration of SDS in the physiological buffer and the effect of SDS pretreatment on drug solubility were determined. Pretreatment of buccal mucosa with SDS 0.01% had no effect on CAF or E(2) permeability. SDS 0.05, 0.1, and 1% significantly enhanced CAF flux by a factor of 1.57, 1.63, and 1.81, respectively, and caused significant removal of superficial cells, as observed with light microscopy. Interestingly, pretreatment with SDS 0.05% did not affect E(2) flux, whereas SDS at > or =0.1% significantly reduced E(2) permeability, possibly as a result of micellar solubilization. These results demonstrate that the effect of SDS on buccal permeability depends on both the concentration of SDS used and the physicochemical properties of the permeant.

The effect of various in vitro conditions on the permeability characteristics of the buccal mucosa.

The effect of various in vitro conditions on the permeability characteristics of the buccal mucosa was assessed using caffeine (CAF) and estradiol (E(2)) as model hydrophilic and lipophilic markers, respectively. The permeation of CAF and E(2) through porcine buccal mucosa was determined in modified Ussing chambers at 37 degrees C over 4 h. Comparative permeation studies were performed through full thickness and epithelial tissues, fresh and frozen tissues, and intact and intentionally damaged tissues. Tissue integrity was monitored by the absorption of the normally impermeable fluorescein isothiocyanate (FITC)-labeled dextran 20 kDa (FD20) and tissue viability was assessed using an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) biochemical assay and histological evaluation. Compared to full thickness buccal tissue, permeability through the buccal epithelium was 1.8-fold greater for CAF and 16.7-fold greater for E(2). Although the fluxes of the model compounds were no different in fresh and frozen buccal epithelium, histological evaluation demonstrated signs of cellular death in frozen tissue. FD20 permeated damaged tissue, and while this was associated with an increase in CAF transport, no significant change in E(2) transport was observed. The tissue appeared to remain viable for up to 12 h postmortem using the MTT viability assay, and this was supported by histological evaluation.