Brian W. Barry

Novel mechanisms and devices to enable successful transdermal drug delivery

Optimisation of drug delivery through human skin is important in modern therapy. This review considers drug-vehicle interactions (drug or prodrug selection, chemical potential control, ion pairs, coacervates and eutectic systems) and the role of vesicles and particles (liposomes, transfersomes, ethosomes, niosomes). We can modify the stratum corneum by hydration and chemical enhancers, or bypass or remove this tissue via microneedles, ablation and follicular delivery. Electrically assisted methods (ultrasound, iontophoresis, electroporation, magnetophoresis, photomechanical waves) show considerable promise. Of particular interest is the synergy between chemical enhancers, ultrasound, iontophoresis and electroporation.

Mode of action of penetration enhancers in human skin

Abstract Skin penetration enhancers are molecules which reuersibly remove the barrier resistance of the stratum corneum. They allow drugs to penetrate more readily to the viable tissues and thus enter the systemic circulation. This paper presents a general theory for enhancer activity based on possible alterations at the molecular level of the stratum corneum. Within the intercellular route, accelerants may interact at the polar head groups of the lipids, within aqueous regions between lipid head groups, and between the hydrophobic tails of the bilayer. Within the corneocyte the keratin fibrils and their associated water provide the target. High concentrations of solvents may also alter partitioning phenomena. The theory has been applied specifically to water, Azone, dimethylsulfoxide, dimethylformamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, oleic acid, decylmethylsulfoxide, sodium lauryl sulfate and propylene glycol. The main techniques which supplied experimental support for the theory were permeation studies through human skin, the vasoconstrictor assay and differential scanning calorimetry; the results from DSC are mainly considered here.

Terpenes and the Lipid–Protein–Partitioning Theory of Skin Penetration Enhancement

A series of terpenes has been assessed as skin penetration enhancers towards the model polar penetrant 5-fluorouracil (5-FU). Cyclic terpenes were selected from the chemical classes of hydrocarbons (e.g., α-pinene), alcohols (e.g., α-terpineol), ketones (e.g., carvone), and oxides (e.g., 1,8-cineole, ascaridole). Permeation experiments were performed on excised human epidermal membranes and the terpenes varied in their activities; α-pinene only doubled the permeability coefficient of aqueous 5-FU, whereas 1,8-cineole caused a near 95-fold increase. Essential oils, e.g., chenopodium (70% ascaridole), were less effective than the corresponding isolated terpenes. 5-FU is less soluble in the terpenes than in water, and the terpenes did not exert their action by increasing partitioning of the drug into the membranes as illustrated by stratum corneum:water partitioning studies. The penetration enhancers increased drug diffusivity through the membranes, an effect which correlated empirically with the enhancer activities. The principal mode of action of these accelerants may be described by the lipid–protein–partitioning theory; the terpenes interacted with intercellular stratum corneum lipids to increase diffusivity, and the accelerant effects were not due to partitioning phenomena. Keratin interaction was assumed negligible.

Lipid-Protein-Partitioning theory of skin penetration enhancement

Abstract The Lipid-Protein-Partitioning theory of skin penetration enhancement suggests that accelerants usually act by one or more of three main mechanisms; they can alter the intercellular lipid or intracellular protein domains of the homy layer and they may also increase partitioning into the skin of a drug, a co-enhancer, water or any combination of these. This paper discusses these concepts, quoting examples of the three mechanisms as assessed by differential scanning calorimetry and permeation studies and relates such investigations to our ideas of the molecular architecture of the stratum coraeum.

Oestradiol skin delivery from ultradeformable liposomes: refinement of surfactant concentration.

The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and to evaluate Span 80 and Tween 80 as edge activators compared with sodium cholate. Vesicles containing phosphatidylcholine (PC) mixed with edge activators and oestradiol were prepared. Entrapment efficiency and vesicle size were determined. Interactions between activators and vesicles were investigated using differential scanning calorimetry. Transepidermal permeation of oestradiol from vesicles was studied compared to saturated aqueous control in vitro. The maximum flux (J(max)) and its time (T(max)) were calculated from the flux curves and skin deposition was assessed. The compositions of refined formulations were predicted, liposomes prepared, and tested against control. Entrapment efficiency depended on PC concentration with some contribution from sodium cholate and Tween 80. Vesicle sizes ranged from 124 to 135 nm. Edge activators interacted with lipid bilayers and disrupted packing. The refined edge activator concentrations in PC vesicles were 14.0, 13.3 and 15.5% w/w for sodium cholate, Span 80 and Tween 80, respectively; they increased J(max) by 18, 16 and 15-fold and skin deposition by 8, 7 and 8-fold compared with control. Ultradeformable vesicles thus improved skin delivery of oestradiol compared to control and Span 80 and Tween 80 were equivalent to sodium cholate as edge-activators.

Effects of freezing on human skin permeability

The percutaneous absorption of water was measured in‐vitro at 30 °C for pale caucasian abdominal skin which had been stored at −20 °C for up to 466 days and compared with fresh skin. Prolonged freezing of the skin did not affect the absorption of water which had a mean permeability coefficient of 1·71 ± 0·62 times 10−3 cm h−1 (180 diffusion experiments with 39 skin specimens). No significant difference was found between the absorption of water through human skin which was fresh or had been frozen. The mean permeability coefficient for skin which had not been frozen was 1·30 ± 0·55 times 10−3 cm h−1 for 6 skin specimens.

Oestradiol permeation through human skin and silastic membrane : effects of propylene glycol and supersaturation

One approach to transdermal permeation enhancement investigated in this paper is to increase the thermodynamic activity of a drug in the transdermal delivery system to supersaturation levels. Saturated solubilities of the model drug oestradiol (OE) in different concentrations of propylene glycol/water (PG/W) co-solvent systems were determined. Utilising the saturated solubility curve, a series of OE supersaturated solutions at different multiples of saturation in PG/W systems was prepared using a mixed co-solvents method. Antinucleating polymers including hydroxypropylmethylcelluose (HPMC), hydroxypropylcelluose (HPC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) and polyethylene glycols, 4000 and 8000 (PEG 4000 and PEG 8000), were used to stabilise the supersaturated solutions. All but the PEGs were able to retard the crystallisation of OE and polyvinylpyrrolidone (MW 40 000) was the most efficient. Mass transport characteristics of OE from saturated and supersaturated solutions through human skin and silastic membranes were then examined using an automated diffusion apparatus. OE flux was enhanced from saturated solutions with increased PG concentration. This increase was attributed to increased OE solubility in the membrane. Also, uptake of OE by human stratum corneum and silastic membrane from supersaturated solution was determined. The results were compared with those from saturated solutions having the same PG/W co-solvent compositions. Generally, both the uptake and flux of OE through both human skin and silastic membrane increased with increasing degree of saturation. Stratum corneum showed an 18.8 ± 4.88 times increase in uptake from a supersaturated solution of 18 times saturation. OE flux through human skin from a solution of 18 times saturation increased about 13-fold during the 12 h experiment when compared with the flux from saturated solution.

Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in‐vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: (1) solvents which enhanced permeation of polar and non‐polar compounds e.g. 2‐pyrrolidone, N‐methylpyrrolidone, N‐methylformamide and propylene glycol plus Azone; (2) enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and (3) accelerants which mainly modified the non‐polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.

Modes of action of terpene penetration enhancers in human skin; Differential scanning calorimetry, small-angle X-ray diffraction and enhancer uptake studies

The mechanisms through which the terpenes, d-limonene, 1–8-cineole and nerolidol, increase the permeability of human stratum corneum (s.c.) and the mechanisms underlying propylene glycol (PG)/terpene synergy were investigated using differential scanning calorimetry (DSC), small-angle X-ray diffraction (SAXD) and enhancer uptake studies. DSC experiments identified two major lipid transitions at 72° and 83°C. d-Limonene reduced the temperatures of both transitions by approx. 20°C without affecting their enthalpies (ΔH). 1–8-Cineole also reduced the temperatures of both transitions by approx. 20°C but also reduced ΔH for the first major lipid transition; ΔH for the second was unaffected. d-Limonene increased the combined entropy change (ΔS) associated with both lipid transitions by 11% whereas 1–8-cineole decreased ΔS by 32%. The decrease in ΔS produced by 1–8-cineole provides evidence that this enhancer is lipid disruptive at normal skin temperature. Nerolidol reduced the transition temperatures of both major lipid transitions by approx. 4°C and also decreased their cooperativity. Reduced bilayer cooperativity indicates that this enhancer also disrupts the intercellular lipids. Lack of a clear baseline prevented accurate measurement of ΔH and ΔS values following nerolidol treatment. SAXD experiments showed that d-limonene and 1–8-cineole act to reduce the intensity of lipid based reflections. Decreases in reflection intensities may be linked to a disruption of lipid packing within the bilayers and/or to a disturbance in the stacking of the bilayers. Treatment with nerolidol did not markedly reduce the intensities of the bilayer based reflections. Uptake studies revealed that large quantities of terpenes can be accommodated by the s.c. (mean uptake of d-limonene, 1–8-cineole and nerolidol was 8.90%, 26.2% and 39.6% w/w dry s.c.). The possibility that terpene enhancers pool in the s.c. is discussed. DSC and SAXD investigations provided fragmented evidence that PG/terpene synergy may produce enhanced lipid bilayer disruption. Enhancer uptake studies showed that PG does not significantly increase terpene delivery to the s.c. above that provided by application of neat terpenes.

Transdermal delivery from eutectic systems: enhanced permeation of a model drug, ibuprofen

The formation of eutectic systems between ibuprofen (ibu) and seven terpene skin penetration enhancers was studied and, by using the eutectic systems as donors, the effects of melting point depression of the delivery system on transdermal delivery were investigated. A range of ibu:terpene binary mixtures were melted together, cooled, and recrystallised. Composition/melting point phase diagrams were determined by DSC and FT-IR analysis was used to investigated the nature of the interaction. Permeation of ibu across human epidermal membrane from the eutectic system was measured and compared to the flux from a saturated aqueous solution across skin and skin pretreated with the terpenes. The eutectic, i.e. minimum, melting points of these systems ranged from 32 degrees C for ibu:thymol 40:60 (% w/w) to -13 degrees C for ibu:1,8-cineole 40:60 (% w/w) compared to 76 degrees C for ibu alone. FT-IR studies indicated that only the terpenes which formed hydrogen bonds with ibu produced eutectic systems. Each set of ibu:terpene eutectic systems produced a significant (t-test, p = 0.05) increase in flux compared to a saturated aqueous solution applied to untreated and to terpene pretreated skin. For example, ibu:thymol 40:60 (% w/w) produced a flux of 150 micrograms/cm2/h, 5.9 times the flux from a saturated aqueous solution with thymol pretreated skin and 12.7 times the flux from a saturated aqueous solution across non-pretreated skin. In conclusion, a hydrogen bonding interaction is the primary mechanism by which some terpenes form binary eutectic mixtures with ibu. The resultant melting point depression of the delivery system is correlated with a significant increase in transdermal permeation.