A territory-wide real-world efficacy and toxicity analysis of abiraterone acetate versus docetaxel in 574 Asian patients with metastatic hormone-sensitive prostate cancer.

INTRODUCTION: Abiraterone acetate (ABI) or docetaxel (DOC), in addition to androgen-deprivation therapy (ADT), are current treatment options for metastatic hormone-sensitive prostate cancer (mHSPC). No randomized head-to-head trial has compared these 2 mHSPC treatments, and real-world data regarding their outcomes in Asian patients are lacking. PATIENTS AND METHODS: The medical records of mHSPC patients who began upfront ABI or DOC treatment in addition to ADT at seven public oncology centers in Hong Kong between 2015 and 2021 were reviewed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) response, and toxicities. Kaplan-Meier and multivariate Cox regression analyses were performed. RESULTS: A total of 574 patients were included, of whom 419 received DOC and 155 received ABI. The median follow-up duration was 22.4 (DOC group: 23.8; ABI group: 17.3) months. The ABI group demonstrated significantly better PFS than the DOC group (not reached vs. 15.1 months: hazard ratio = 0.37; 95% confidence interval = 0.28-0.50; P < .001). No significant OS difference was observed (P = .58). Failure to achieve a ≥ 90% decline in PSA level at 3 months and failure to achieve an undetectable PSA nadir were each associated with unfavorable PFS and OS. Patients who received DOC had a higher rate of febrile neutropenia, whereas those who received ABI had higher rates of grade ≥ 3 hypokalemia and elevated alanine transaminase. Treatment discontinuation due to toxicities was more common in the DOC (3.6%) than the ABI (0.6%) group. CONCLUSION: In Asian mHSPC patients, upfront ABI + ADT was associated with better PFS than DOC + ADT, with no significant OS difference. PSA kinetics may help stratify the prognosis for treatment intensification. Toxicity profiles were different, with a higher rate of toxicity-related treatment discontinuation in the DOC group.

Liposomes and skin: from drug delivery to model membranes.

The early eighties saw the introduction of liposomes as skin drug delivery systems, initially promoted primarily for localised effects with minimal systemic delivery. Subsequently, a novel ultradeformable vesicular system (termed "Transfersomes" by the inventors) was reported for transdermal delivery with an efficiency similar to subcutaneous injection. Further research illustrated that the mechanisms of liposome action depended on the application regime and the vesicle composition and morphology. Ethical, health and supply problems with human skin have encouraged researchers to use skin models. Traditional models involved polymer membranes and animal tissue, but whilst of value for release studies, such models are not always good mimics for the complex human skin barrier, particularly with respect to the stratum corneal intercellular lipid domains. These lipids have a multiply bilayered organization, a composition and organization somewhat similar to liposomes. Consequently researchers have used vesicles as skin model membranes. Early work first employed phospholipid liposomes and tested their interactions with skin penetration enhancers, typically using thermal analysis and spectroscopic analyses. Another approach probed how incorporation of compounds into liposomes led to the loss of entrapped markers, analogous to "fluidization" of stratum corneum lipids on treatment with a penetration enhancer. Subsequently scientists employed liposomes formulated with skin lipids in these types of studies. Following a brief description of the nature of the skin barrier to transdermal drug delivery and the use of liposomes in drug delivery through skin, this article critically reviews the relevance of using different types of vesicles as a model for human skin in permeation enhancement studies, concentrating primarily on liposomes after briefly surveying older models. The validity of different types of liposome is considered and traditional skin models are compared to vesicular model membranes for their precision and accuracy as skin membrane mimics.

Study of protein conformational stability and integrity using calorimetry and FT-Raman spectroscopy correlated with enzymatic activity.

Maintaining protein conformational stability and integrity during formulation is critical for developing protein pharmaceuticals. Accordingly, high sensitivity differential scanning calorimetry (HSDSC) and Fourier transform (FT)-Raman spectroscopy were employed to assess conformational stabilities (thermal stability and folding reversibility) and structural integrities, respectively, for three model proteins: lysozyme, deoxyribonuclease I (DNase I) and lactate dehydrogenase (LDH) in lyophilised (as received) and spray-dried forms. Enzymatic assay after cooling of thermally denatured protein solutions from HSDSC determined if thermal transition reversibility was related to biological activity. HSDSC data showed that molecules from lyophilised lysozyme were able to refold better than the spray-dried form. This was confirmed by enzymatic assay. Moreover, enzymatic assay results revealed that lysozyme folding reversibility was related to the native structure of the protein that is essential for the biological activity. Thermal denaturation of DNase I and LDH samples in HSDSC was not reversible upon cooling of thermally denatured proteins (in contrast to lysozyme). Hence, it was decided to identify the effect of protein initial structures on its propensity to thermal denaturation via FT-Raman spectroscopy. In other words, proteins may denature with structural alterations due to stresses such as heat and the protein loses its enzymatic activity. Consequently, FT-Raman investigated the effects of spray drying and heating of solid DNase I and LDH samples, from differential scanning calorimetry, on protein conformational integrities. Lyophilised and spray-dried DNase I and LDH solid samples were heated to two temperatures, one before the apparent denaturation temperatures (Tm) and the other after the Tm. Samples heated below their Tm showed some alterations of the secondary structure and some enzymatic activity. HSDSC and FT-Raman spectroscopy are useful techniques to study protein conformations and their results correlate with those of enzymatic activity.

Drug interaction and location in liposomes: correlation with polar surface areas.

An important step in liposome characterization is to determine the location of a drug within the liposome. This work thus investigated the interaction of dipalmitoylphosphatidylcholine liposomes with drugs of varied water solubility, polar surface area (PSA) and partition coefficient using high sensitivity differential scanning calorimetry. Lipophilic estradiol (ES) interacted strongest with the acyl chains of the lipid membrane, followed by the somewhat polar 5-fluorouracil (5-FU). Strongly hydrophilic mannitol (MAN) showed no evidence of interaction but water soluble polymers inulin (IN) and an antisense oligonucleotide (OLG), which have very high PSAs, interacted with the lipid head groups. Accordingly, the drugs could be classified as: hydrophilic ones situated in the aqueous core and which may interact with the head groups; those located at the water-bilayer interface with some degree of penetration into the lipid bilayer; those lipophilic drugs constrained within the bilayer.

Interactions of surfactants (edge activators) and skin penetration enhancers with liposomes.

Incorporating edge activators (surfactants) into liposomes was shown previously to improve estradiol vesicular skin delivery; this phenomenon was concentration dependent with low or high concentrations being less effective. Replacing surfactants with limonene produced similar behaviour, but oleic acid effects were linear with concentration up to 16% (w/w), beyond which it was incompatible with the phospholipid. This present study thus employed high sensitivity differential scanning calorimetry to probe interactions of additives with dipalmitoylphosphatidylcholine (DPPC) membranes to explain such results. Cholesterol was included as an example of a membrane stabiliser that removed the DPPC pre-transition and produced vesicles with a higher transition temperature (T(m)). Surfactants also removed the lipid pre-transition but reduced T(m) and co-operativity of the main peak. At higher concentrations, surfactants also formed new species, possibly mixed micelles with a lower T(m). The formation of mixed micelles may explain reduced skin delivery from liposomes containing high concentrations of surfactants. Limonene did not remove the pre-transition but reduced T(m) and co-operativity of the main peak, apparently forming new species at high concentrations, again correlating with vesicular delivery of estradiol. Oleic acid obliterated the pre-transition. The T(m) and the co-operativity of the main peak were reduced with oleic acid concentrations up to 33.2mol%, above which there was no further change. At higher concentrations, phase separation was evident, confirming previous skin transport findings.

Penciclovir solubility in Eudragit films: a comparison of X-ray, thermal, microscopic and release rate techniques.

The solubility of penciclovir (C(10)N(5)O(3)H(17)) in a novel film formulation designed for the treatment of cold sores was determined using X-ray, thermal, microscopic and release rate techniques. Solubilities of 0.15-0.23, 0.44, 0.53 and 0.42% (w/w) resulted for each procedure. Linear calibration lines were achieved for experimentally and theoretically determined differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD) data. Intra- and inter-batch data precision values were determined; intra values were more precise. Microscopy was additionally useful for examining crystal shape, size distribution and homogeneity of drug distribution within the film. Whereas DSC also determined melting point, XRPD identified polymorphs and release data provided relevant kinetics.

Drug delivery routes in skin: a novel approach.

The role of hair follicles in transdermal delivery remains difficult to elucidate due partly to animal model complications. This paper explores a novel technique employing two human skin membranes to differentiate shunt route delivery from bulk transepidermal input. The method monitors penetration through epidermal membranes and compares this with delivery through a sandwich of stratum corneum and epidermis, with the corneum forming a top membrane. As orifices of shunts occupy only 0.1% of the area, there is negligible chance that shunts in the membranes will superimpose. The top layer blocks shunts available in the bottom layer. If shunts are important, delivery through sandwiches will be much reduced compared with that through epidermis, allowing for increased double membrane thickness. Experiments with penetrants under passive, iontophoretic and electroporation conditions illustrated the value of the method. A Monte Carlo simulation suggested that any failure of membrane adherence would not affect conclusions drawn.

Skin hydration and possible shunt route penetration in controlled estradiol delivery from ultradeformable and standard liposomes.

Human skin delivery of estradiol from ultradeformable and traditional liposomes was explored, comparing occlusive and open application, with the aim of examining the role of skin hydration. Partially hydrated epidermis was used for open hydration, but fully hydrated membranes were used for occluded studies. In addition, we developed a novel technique to investigate the role of shunt route penetration in skin delivery of liposomal estradiol. This compared delivery through epidermis with that through a stratum corneum (SC)/epidermis sandwich from the same skin with the additional SC forming the top layer of the sandwich. This design was based on the fact that orifices of shunts only occupy 0.1% of skin surface area and thus for SC/epidermis sandwiches there will be a negligible chance for shunts to superimpose. The top SC thus blocks most shunts available on the bottom membrane. If shunts play a major role then the delivery through sandwiches should be much reduced compared with that through epidermis, taking into consideration the expected reduction owing to increased membrane thickness. After open application, both ultradeformable and traditional liposomes improved estradiol skin delivery, with the ultradeformable liposomes being superior. Occlusion reduced the delivering efficiency of both vesicle types, supporting the theory that a hydration gradient provides the driving force. Shunt route penetration was found to play only a very minor role in liposomal delivery. In conclusion, full hydration of skin reduces estradiol delivery from liposomes and the shunt route is not the main pathway for this delivery.

Effect of melting point of chiral terpenes on human stratum corneum uptake.

The effect of melting point of chiral penetration enhancers on their stratum corneum uptake was investigated. The pure enantiomers of a chiral compound often possess different melting points, and therefore dissimilar solubilities, to the racemate because of variations in their crystal structure. Two terpenes, menthol and neomenthol, saturated in propylene glycol/water, were applied to stratum corneum. Racemic menthol melts at approximately 33 degrees C, some 9 degrees C lower than the pure enantiomers, whereas racemic neomenthol melts at 26 degrees C higher than the study temperature, considered as the theoretical melting point of its enantiomers, which are both liquids. Terpene solubility increased with the propylene glycol content of the vehicle. The lower melting forms of both penetration enhancers possessed the highest solubility in every vehicle. Maximum stratum corneum uptake was obtained from formulations containing the lower melting forms of each enhancer in 60% w/w propylene glycol systems (highest concentration used). Compared with menthol, the larger melting point difference between optical forms of neomenthol produced bigger differences in their uptake. Thus melting point depression of menthol and neomenthol, by selection of the appropriate optical form, increased the amount of terpene delivered to the stratum corneum, in agreement with theoretical predictions.

Is transdermal drug delivery research still important today?

When measured by the number of medicines consumed or prescriptions written, the topical and transdermal routes of drug delivery pale into insignificance compared with oral therapy. Industrial colleagues, therefore, occasionally adopt a somewhat utilitarian stance and question the value of academic research into skin treatment and drug permeation, with the rather parochial argument that it is of limited use to the UK pharmaceutical industry. To consider the validity of this somewhat dismissive approach, which in its extreme form essentially regards universities as servants of industry, we can consider the worldwide position with respect to commercial activity in dermatologicals and patches. We can then look at the intellectual challenges that make transdermal research so demanding (a prime role of universities is to seek out and tackle the difficult problems and, particularly, to pose such challenges to their PhD students). In skin research, it is essential that investigators apply fundamental physicochemical principles to an extremely variable and complex biological tissue. The work discussed here provides avenues for further research.

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.

Skin delivery of 5-fluorouracil from ultradeformable and standard liposomes in-vitro.

The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 microL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes, the non-rigid preparation was the best. However, stabilization of the liposome membrane with cholesterol abolished the benefit of this non-rigid preparation. It was concluded that ultradeformable vesicles are promising agents for skin delivery of drugs.

Mechanistic study into the enhanced transdermal permeation of a model beta-blocker, propranolol, by fatty acids: a melting point depression effect.

Transdermal permeation of propranolol through human skin in the presence of fatty acid (lauric, capric) penetration enhancers has been investigated. Thermal analysis showed that binary mixtures of propranolol with either fatty acid were not simple mechanical mixtures of the two components. Propranolol formed 1:1 molar addition compounds with both lauric and capric acids; the addition compound produced from propranolol and lauric acid (m.p. 79 degrees C) also developed eutectic systems with both propranolol (m.p. 54 degrees C) and lauric acid (m.p. 16 degrees C). Similarly, the addition compound made from propranolol and capric acid (m.p. 97 degrees C) formed eutectic systems with propranolol (m.p. 83 degrees C) and capric acid (m.p. 15 degrees C). Infrared analyses indicated that the addition compounds were fatty acid salts of the beta-blocker. The nature of the species permeating through human epidermal membranes from binary mixtures of propranolol with the fatty acids was investigated using a novel attenuated total reflectance Fourier transform infrared method. There was no clear difference in permeation rates of the fatty acids compared with the beta-blocker, suggesting that the permeating species was the intact addition compound. The influence of melting point depression of the beta-blocker fatty acid systems on transdermal permeation was predicted from a mathematical model; predicted and experimentally determined data correlated well thus providing an alternative explanation as to the mode of action of these permeation enhancers.

Skin delivery of oestradiol from lipid vesicles: importance of liposome structure.

The aim of this study was to investigate the importance of liposome structure in oestradiol skin delivery as a tool for understanding the delivery mechanism from lipid vesicles. Liposomes of phosphatidylcholine (PC) (1), PC, sodium cholate; 86:14 w/w (II), PC, Span 80; 86.7:13.3 w/w (III) and PC, oleic acid: 84:16 w/w (IV) with 1 mg/ml radiolabelled drug were prepared. Saturated radiolabelled oestradiol solutions containing the components of I-IV were separately prepared in 90% w/w propylene glycol in water. In addition, saturated solutions containing cholate, Span, oleic acid and ethanol at the same concentrations used in vesicles were formulated. Oestradiol permeation through human epidermis was studied. Formulations I-IV increased oestradiol flux by 8.6, 17, 17 and 13-fold when used as vesicles compared with control and by 2.9. 4.0, 4.7 and 6.9-fold when used in solution with drug. Testing individual components in solution, relative fluxes were 2.9, 0.87, 1.1, 2.9 and 1.1 for PC, cholate. Span, oleic acid and 7% ethanol, respectively. Accordingly, it is important to prepare phospholipids as vesicles for efficient oestradiol skin delivery even after inclusion of oleic acid. Penetration enhancement is not the main mechanism for improved flux. Liposome components in solution have additive effect with a possible synergism in some cases.

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.

Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies.

Deformable vesicles and traditional liposomes were compared as delivery systems for oestradiol to elucidate possible mechanisms of drug delivery through human skin. Accordingly, epidermal permeation of oestradiol from optimized deformable vesicles and traditional liposome formulations was studied under low dose non-occluded conditions. Five mechanisms were investigated. A free drug mechanism compared low-dose permeation through skin with drug release determined after separation of the free drug. Penetration enhancement was researched by studying skin pretreatment with empty vesicles. Improved drug uptake by skin was monitored by dipping stratum corneum into different formulations for 10 min and determining drug uptake. The possibility that intact vesicles permeate through the epidermis was tested by comparing permeation from 136-nm vesicles with that from >500-nm vesicles, assuming that penetration depends on vesicle size. The possibility that different entrapment efficiencies in alternative formulations could be responsible for the difference in delivery was also evaluated. Lipid vesicles improved the skin delivery of oestradiol compared with delivery from an aqueous control. Maximum flux (Jmax) was increased 14- to 17-fold by use of deformable vesicles and 8.2- to 9.8-fold by use of traditional liposomes. Deformable vesicles were thus superior to traditional liposomes. Drug release was negligible over the period during which skin flux was maximum. Pretreatment with empty vesicles resulted in an enhancement ratio of 4.3 for pure phosphatidylcholine (PC) vesicles but the enhancement ratio ranged from only 0.8 to 2.4 for other formulations. Vesicles increased drug uptake into the stratum corneum 23- to 29-fold. Relative flux values obtained from small and large vesicles were similar. No correlation was found between entrapment efficiency and skin delivery. The results showed no evidence of a free drug mechanism, but revealed a possible penetration-enhancing effect for pure PC vesicles, although this was not the only mechanism operating. The positive uptake suggested that lipid vesicles increased drug partitioning into the skin. The data provided no evidence for in-vitro liposome penetration through skin as distinct from vesicle penetration into the stratum corneum.

Enhancement by terpenes of 5-fluorouracil permeation through the stratum corneum: model solvent approach.

5-Fluorouracil permeates the stratum corneum through the intercellular pathway. 5-Fluorouracil is hydrophilic and, therefore, its partitioning from the aqueous region into the hydrocarbon interior of stratum corneum lipids is expected to be an important stage of its permeation and a target for some permeation enhancers. It has also been reported that complexation plays a role in the enhancement effect of some accelerants. These mechanisms have been investigated. For partitioning-permeation studies, isooctane was chosen as a model of the hydrocarbon interior of stratum corneum lipid bilayers and the effects of 26 different terpene enhancers on the solubility of 5-fluorouracil in isooctane were measured. Results were then compared with the effects of the same enhancers on the permeation of 5-fluorouracil through the epidermis in man. The stoichiometry of interaction of cineole and limonene with 5-fluorouracil were also studied to reveal possible complex formation. Solubility studies revealed good correlation between solubility and enhancement ratios for the majority of terpenes, indicating that one mechanism by which terpenes increase permeation of the stratum corneum by 5-fluorouracil is by improvement of partitioning. Stoichiometry studies showed that cineole can form 1:1 or higher complexes with 5-fluorouracil. With limonene, only a weak 1:1 complex was indicated. Data obtained using epidermis from man show that the enhancement effect of cineole toward 5-fluorouracil is much higher than that of limonene. These data reveal that terpenes might increase the permeation of 5-fluorouracil through the stratum corneum as a result of complex formation and a form of facilitated transport.

Interaction of salicylic acid with verrucae assessed by FT-Raman spectroscopy.

FT-Raman spectroscopy has been used to investigate treated verrucae (warts from the sole of the foot) with a local application of a salicylic acid paint. Differences in the molecular structure of the stratum corneum across the verruca sample were observed, and by comparison with normal and hyperkeratotic skin it was concluded that the tissue around the edges of the verrucae was typically hyperkeratotic skin. In the centre of the verruca, the molecular structure of the skin was altered showing evidence of the interaction with salicylic acid. Salicylic acid was not observed in its characteristic dimerised acid structure, but spectroscopic evidence suggested that fission of the intermolecular H-bonding essentially cleaved the dimer. Observed changes in the v(CCO) stretching mode of the carboxyl and hydroxyl groups indicate the inter H-bonds have broken. These spectral changes are believed to be more consistent with salicylic acid bonding within the human papillomavirus-containing verruca tissue rather than simple acid dissociation upon dissolution in water within the tissue. No evidence for the presence of the other paint components, lactic acid and flexible collodion, was found in the verrucae spectra. This Raman approach may help to elucidate the molecular basis for therapeutic agents interacting with diseased skin.

Transdermal permeation modulation by cyclodextrins: a mechanistic study.

The purpose of this study was to investigate permeation modulation by beta- and 2-hydroxypropyl-beta-cyclodextrins (beta-CD and HP-beta-CD, respectively) alone and complexed with penetration enhancers for the test drugs 5-fluorouracil and estradiol through human skin, and to probe the value of the CDs in a barrier cream against toluene exposure. Methods include phase solubility studies, permeation experiments, and thermal analysis of stratum corneum; inclusion complexes were characterized by Karl Fischer titrimetry, infrared spectroscopy, and thermal analysis. Results show that complexes of terpenes or toluene with beta-CD were insoluble, whereas those with HP-beta-CD were soluble. The CDs did not enhance flux of either the polar or lipophilic drugs through skin; estradiol permeation was reduced following membrane pretreatment with either CD. Complexation of the lipophilic terpenes with the CDs reduced enhancer efficacy. When formulated into a barrier ointment both CDs, but particularly beta-CD, retarded toluene permeation through the skin and delayed the onset of maximum flux. It is concluded that the CDs themselves are not penetration enhancers for 5-fluorouracil or estradiol in human skin, and that they may be usefully incorporated into a barrier formulation to reduce percutaneous absorption of toxic materials on occupational exposure.

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.