Comparison of the physicochemical properties of the N-(2-hydroxyethyl) pyrrolidine, diethylamine and sodium salt forms of diclofenac.

Non steroidal anti-inflammatory agents (NSAIDs) such as diclofenac have very low aqueous solubilities and consequently salt formation may be used to enhance solubility and dissolution rate. In this study, we examined the physicochemical properties of three diclofenac salts, diclofenac sodium (DNa), diclofenac N-(2-hydroxyethyl)pyrrolidine (DHEP) and diclofenac diethylamine (DDEA), and their different solid state forms to determine the influence of salt form on solubility, dissolution rate and membrane transport. The equilibrium solubility of DDEA at 25 degrees C was determined as 33 mM, lower than the solubilities of DHEP (273 mM) and DNa (66 mM) previously reported (Ledwidge and Corrigan, 1998). In addition to the dihydrate form of DHEP previously characterised, monohydrate forms of DHEP and DDEA were identified. Intrinsic dissolution rate studies were used to determine the solubility ratios of the hydrated and anhydrous forms. The monohydrate form of DHEP was found to be 1.8 times less soluble than the anhydrate, whereas DDEA anhydrate was approximately 1.7 times as soluble as the monohydrate form. On investigation of the pH-solubility profile (25 degrees C) of DDEA, appreciable supersaturation (76 mM) relative to the theoretical profile, was detected at the pH(max). This contrasts with values of >800 and 67 mM for DHEP and DNa, respectively. The transport of salt solutions through a porous membrane (Visking) was investigated. A linear relationship between concentration (mM) and rate of transport (mmol/h) was established for DNa and DHEP solutions. The mass transfer coefficient determined for DHEP was lower than that for the other two salts. Nevertheless, the maximum transport rate obtained for DHEP is almost six times higher than that obtained for DDEA.     

Diclofenac salts. I. Fractal and thermal analysis of sodium and potassium diclofenac salts.

Sodium and potassium diclofenac salts form hydrates when crystallized from water; the sodium salt contains four crystallization water molecules, while the potassium salt precipitates as a dihydrate. Crystallization from organic solvents occurs with a change of the crystal habit. The fractal dimension of the particle surface of both salts obtained from water is low and is in agreement with the formation of smooth and regular surfaces during crystallization. The fractal dimension for dissolution is relatively high and comparable for hydrate and anhydrate forms of both salts, and the result was interpreted as being due to the surfactant behavior of diclofenac anions. Thermograms of both salts show a couple of endotherms in the range 30-100 degrees C, which disappear when the salts have been previously heated at 100 degrees C, but slowly reappear when the anhydrate forms are stored in a humid environment. Both salts present a complex exotherm of decomposition at 284 and 314 degrees C, respectively. The results are briefly discussed with regard to the formulations of the anti-inflammatory agent diclofenac.     

The study of drug permeation through natural membranes

In this study, natural membranes such as the outer membrane of Prunus persica (peach) and Lycopersicon esculentum (tomato), the inner layer of the egg of Gallus domesticus (hen) and the middle membrane of the Allium cepa (onion) were used as controlling barriers for permeation of some model drugs with different MW and lipophilicities. Drug permeation studies were done by using modified Franz diffusion cell. The permeation of drugs through these natural membranes was compared to permeation of them through human skin and synthetic cellophane membrane. Results showed that the rate and amount of diclofenac permeated through onion membrane was not significantly different from that with tomato (p>0.17), egg (p>0.29) and human skin (p>0.93). Permeation of diclofenac through tomato skin and cellophane was not significantly different (p>0.35). Permeation of diclofenac through all studied membranes except for human skin that follows the Fickian kinetic followed non-Fickian mechanism and their permeabilities were not significantly different from each other (p>0.05). Permeation of metronidazole through onion membrane and tomato skin were not significantly different from human skin (p>0.053 and 0.38, respectively). All membranes were significantly different from each other (p<0.0001) for permeation of erythromycin as a relatively large molecular weight and lipohilic molecule through human skin and other studied membranes. Permeation of diclofenac through human skin and metronidazole through egg and tomato skin followed Fick's first law. Diffusion of diclofenac through onion, tomato, egg, cellophane, and peach; metronidazole through onion, peach, cellophane, and human skin, and erythromycin through all studied membranes followed non-Fickian mechanism for diffusion. Statistical analysis showed the most similarity between onion and human skin for diclofenac, tomato and human skin for metronidazole, onion and cellophane for erythromycin.     

Transdermal iontophoretic delivery of diclofenac sodium from various polymer formulations: in vitro and in vivo studies

The objective of this study was to evaluate the in vitro and in vivo transdermal iontophoresis of various diclofenac sodium polymer formulations. The excised rat skin, human skin as well as cellulose membrane were used to examine the in vitro drug permeation whereas the microdialysis technique was used to monitor the drug concentration in vivo. Polymer solutions based on polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) binary system showed higher drug permeability than that of single polymer vehicle. The effect of formulations on drug permeation through cellulose membrane was quite different from those through rat skin and human skin, which can be explained by the different permeation pathways between them. It appeared to be a membrane-controlled mechanism but not the vehicle matrix-controlled mechanism for diclofenac hydrogels when using skin as the diffusion barrier. The recovery of diclofenac sodium in the in vivo microdialysis was approximately 80-90%, indicating this technique can be used in the intradermal drug monitoring. For all the polymer formulations tested, there was a good relationship between the in vitro and in vivo drug permeation. A synergistic effect on drug permeation was observed when transdermal iontophoresis combined with the pretreatment of cardamom oil as a permeation enhancer.     

Diclofenac solubility: independent determination of the intrinsic solubility of three crystal forms

The solubility in water of diclofenac ({2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid), a potent nonsteroidal anti-inflammatory drug, has been investigated. The various solid forms have been characterized by thermogravimetric analysis, differential scanning calorimetry, and X-ray diffraction. The commercially available form of diclofenac is the anhydrous sodium salt. This was recrystallized from ethanol and precipitated as a hydrate containing four diclofenac anions, four sodium cations, and nineteen water molecules per unit cell. This crystal structure is similar to but different from an earlier report of the structure. Crystals of the acid form of diclofenac were anhydrous and corresponded to an earlier crystal structure. Separate solubility measurements on all three of these solid forms of diclofenac gave consistent results for the intrinsic solubility. The aqueous solubility values reported in the literature for diclofenac are spread over a large range, with a factor of 100 separating the largest and the smallest. Our value is at the smaller end of this range. It is the only one supported by three independent procedures and rigorous characterization of the solid forms. The experimental conditions were precisely controlled.     

Influence of electrical and chemical factors on transdermal iontophoretic delivery of three diclofenac salts

The aim of this present study was to investigate the in vitro transdermal iontophoretic delivery of three diclofenac salts--diclofenac sodium (DFS), diclofenac potassium (DFP), and diclofenac diethylammonium (DFD). A series of physicochemical and electrical variables which might affect iontophoretic permeation of diclofenac salts was studied. Application of 0.3 mA/cm2 current density significantly increased the transdermal flux of diclofenac salts as compared to passive transport. The iontophoretic enhancement increased in the order of DFS>DFP>DFD. The permeability coefficient of diclofenac salts all decreased with increasing donor concentration during iontophoresis. The addition of buffer ions and salt ions such as NaCl, KCl, and C4H12ClN reduced the permeation of diclofenac salts due to competition. However, this effect was lesser for DFD than for DFS and DFP. Comparing the various application modes of iontophoresis, the discontinuous on/off mode showed lower but more constant flux than the continuous mode.     

Preparation and characterisation of a range of diclofenac salts

Physicochemical properties of diclofenac salts prepared using eight different counterions and including five novel salts, obtained with the bases 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methylpropanol, tert-butylamine, benzylamine and deanol, were compared. Four of the bases used to prepare these salts were related in their chemical structure, differing only in the number of hydroxy groups. Characterisation techniques included X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, thermomicroscopy, Karl Fischer titration, FT-IR spectroscopy and elemental analysis. In the case of salts prepared from 2-amino-2-methylpropanol and benzylamine, two polymorphic forms of each salt were identified. For the 2-amino-2-methyl-1,3-propanediol salt, a pseudopolymorphic form was identified. The aqueous solubilities of the salts studied ranged from 3.95 mM (tris(hydroxymethyl)aminomethane salt) to 446 mM (deanol salt), corresponding to a 113-fold difference in solubility. The solubility of diclofenac deanol was higher than the solubilities for diclofenac salts reported earlier. Correlation was found between the inverse of the salt melting point and the logarithm of salt solubility. A log-log relationship was observed between salt solubility and hydrogen ion concentration in the salt solution. Relationships between the properties of the salt-forming agents and those of the resulting diclofenac salts were explored. Reasonable correlation was found between the free base melting point and the salt melting point.     

Ion-pairs of ibuprofen: increased membrane diffusion

The purpose of the present study was to determine the influence of pH and ion-pairing on the permeation of ibuprofen across polydimethylsiloxane (PDMS) membrane. The solubility of ibuprofen sodium was determined at a range of pH values. Saturated solutions were then used to determine the influence of pH on diffusion across PDMS as a model membrane. The apparent partition coefficient of ibuprofen sodium between n-octanol and phosphate buffer at various pH values was also investigated. Organic salts of ibuprofen using ethylamine, diethylamine, triethylamine and ethylene diamine as counter-ions were synthesized and the influence of these counter-ions on the permeation of ibuprofen was studied. The presence of ion-pairing was confirmed using 1H NMR and 13C NMR. Diffusion studies at different pH values (4.0, 5.0, 6.0, 7.0 and 8.0) indicated that ibuprofen sodium flux increased significantly with increasing pH from 4.0 to 7.0. Above pH 7.0 a decrease in diffusion was observed. The permeability coefficient increased with an increase in the amount of unionized acid. The apparent partition coefficient was directly related to the steady-state flux. The steady-state flux of ibuprofen increased up to 16-fold using different counter-ions. The highest flux was measured from ibuprofen triethylamine. The flux of ibuprofen salts across a lipophilic membrane can be increased by formation of ion-pairs. The extent of enhancement is associated with the lipophilicity, extent of ion-pairing and reduction in charge over the drug molecule.     

The effect of terpene concentrations on the skin penetration of diclofenac sodium

Terpenes and sesquiterpenes have been suggested as promising non-toxic, non-irritating transdermal penetration enhancers. This investigation aimed to study the effect of terpene concentration on the transdermal absorption of diclofenac sodium from ethanol:glycerin:phosphate buffer solution (60:10:30). Therefore, enhancing effects of various terpenes (menthone, limonenoxide, carvone, nerolidol and farnsol) with different concentrations (0.25, 0.5, 1, 1.5 and 2.5%, v/v) on the permeation of diclofenac sodium were evaluated using Franz diffusion cells fitted with rat skin. Furthermore, solubility of diclofenac sodium in the vehicle in presence of different concentrations of terpenes was determined. The results showed that despite the negligible effect of terpenes on the drug solubility, there was a profound skin penetration enhancement effect, although the terpene enhancers varied in their ability to enhance the flux of diclofenac sodium. The results showed that at the highest concentration of terpene (2.5%, v/v) the rank order of enhancement effect for diclofenac sodium was nerolidol>farnesol>carvone>methone>limonenoxide, whereas at the low concentration of 0.25% the rank order was farnesol>carvone>nerolidol>menthone>limonenoxide. No direct relationship existed between terpene concentration and the permeation rate. The most outstanding penetration enhancer was nerolidol, providing an almost 198-fold increase in permeability coefficient of diclofenac sodium, followed by farnesol with a 78-fold increase.     

Passive and iontophoretic delivery of three diclofenac salts across various skin types

The in vitro permeation of three diclofenac salts--diclofenac sodium (DFS), diclofenac potassium (DFP) and diclofenac diethylammonium (DFD)-across skin by both passive and iontophoretic transport were investigated. Various skin types were used as the barriers to elucidate the mechanism controlling transdermal delivery of diclofenac salts. The importance of the intercellular (paracellular) route for both DFS and DFP in passive permeation was elucidated. The transfollicular route constitutes an important permeation pathway for DFS but not for DFP. The route and mechanism for transdermal iontophoresis of DFD across the skin was somewhat different to that of the other salts. Hair follicles may be a more important pathway for DFD than for DFS and DFP under iontophoresis, while the intercellular lipid pathway showed the opposite result. Combination of iontophoresis and a penetration enhancer, cardamom oil, did not show a synergistic effect on diclofenac salt permeation. The results of this investigation suggest that the transdermal mechanism and the route of diclofenac salt uptake via passive and iontophoretic transport can be affected by their counterions.     

Effect of a basic organic excipient on the dissolution of diclofenac salts

Dissolution of diclofenac from compressed discs containing mixtures of a diclofenac salt and a basic excipient, in various w/w ratios, was examined. Two diclofenac salts, diclofenac deanol (DDNL) and diclofenac tert-butylamine, and the basic excipient 2-amino-2-methyl-1,3-propanediol (AMPD) were examined. Inclusion of the soluble basic excipient at high loadings enhanced the dissolution rate of diclofenac tert-butylamine fivefold; however, it retarded dissolution of the DDNL salt 40-fold in the weight fraction range 40-80% AMPD, despite the fact that AMPD is more than four times more soluble than DDNL. These findings were attributed to the solubilities of salts formed between diclofenac and the basic excipient used. The "salt conversion model" was developed to predict dissolution from mixtures of a salt of an ionizable drug and an ionizable excipient capable of forming a salt with the drug. Deviations from the model at high weight fractions of base and, in the case of the systems containing the more soluble drug, at low weight fractions of base were attributed to carrier-controlled dissolution. The present work illustrates that the solubility of potential salts, which may form between the drug and ionizable excipients present has an important influence on the dissolution of the drug from such compressed mixtures.     

Influence of membrane-solvent-solute interactions on solute permeation in skin

The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. Previously, we have studied the effect of different vehicles on the permeation of caffeine, benzoic acid (BA) and salicylic acid (SA) through silicone membranes. The present paper investigates diffusion of the selected permeants from different saturated solutions through human epidermis.

The permeation of caffeine was strongly affected by the vehicle chosen and the maximum enhancement observed for the permeation of caffeine was 288-fold. A maximum of 12-fold enhancement in the flux was observed for the permeation of SA and a maximum of 10-fold enhancement was observed for the permeation of BA. The diffusion profiles obtained for SA in the different solvents were very similar when compared with those obtained for BA but the permeation rates were higher for BA than for SA. This similarity results from the similar chemical structure and lipophilicity.     

氟非尼酮凝胶的研制及其体外透皮转运

采用HPLC法测定了25℃、100 r/min条件下平衡48 h时氟非尼酮在水性溶剂和非水溶剂中的溶解度。结果表明,氟非尼酮在水及其他水性溶剂中微溶,溶解度约为2.5 mg/ml,溶剂的pH值对溶解度影响小;氟非尼酮易溶于乙醇,可溶于聚乙二醇400、1,2-丙二醇和异丙醇,微溶于甘油。摇瓶法测得氟非尼酮的油水分配系数(logP)值为1.182,略有亲脂性。以乳猪皮肤为模型,采用改良的Franz扩散池法评价不同载药量(0.5%和1%)凝胶及溶液的经皮渗透特性。结果表明,2种载药量的氟非尼酮凝胶的经皮渗透行为均符合零级模型,1%凝胶的24 h单位面积累积渗透量(Q24h)和单位面积皮肤滞留量(Qskin)均比0.5%凝胶增加约1倍;同时,0.5%溶液的Q24h和Qskin结果介于2种载药量凝胶之间。     

The modified extended Hansen method to determine partial solubility parameters of drugs containing a single hydrogen bonding group and their sodium derivatives: benzoic acid/Na and ibuprofen/Na

Sodium salts are often used in drug formulation but their partial solubility parameters are not available. Sodium alters the physical properties of the drug and the knowledge of these parameters would help to predict adhesion properties that cannot be estimated using the solubility parameters of the parent acid. This work tests the applicability of the modified extended Hansen method to determine partial solubility parameters of sodium salts of acidic drugs containing a single hydrogen bonding group (ibuprofen, sodium ibuprofen, benzoic acid and sodium benzoate). The method uses a regression analysis of the logarithm of the experimental mole fraction solubility of the drug against the partial solubility parameters of the solvents, using models with three and four parameters. The solubility of the drugs was determined in a set of solvents representative of several chemical classes, ranging from low to high solubility parameter values. The best results were obtained with the four parameter model for the acidic drugs and with the three parameter model for the sodium derivatives. The four parameter model includes both a Lewis-acid and a Lewis-base term. Since the Lewis acid properties of the sodium derivatives are blocked by sodium, the three parameter model is recommended for these kind of compounds. Comparison of the parameters obtained shows that sodium greatly changes the polar parameters whereas the dispersion parameter is not much affected. Consequently the total solubility parameters of the salts are larger than for the parent acids in good agreement with the larger hydrophilicity expected from the introduction of sodium. The results indicate that the modified extended Hansen method can be applied to determine the partial solubility parameters of acidic drugs and their sodium salts.     

The effect of beta-cyclodextrins on the permeation of diclofenac from supersaturated solutions

Supersaturation is a very useful method of enhancing the permeation of drugs across membranes such as skin, because unlike other methods, it does not interfere with the ultrastructure of the stratum corneum. Many drugs are able to form inclusion complexes with beta-cyclodextrins (beta-CDs) and this study investigates the anti-nucleating effects of these compounds on supersaturated solutions of diclofenac. The ability of various betaCDs to form inclusion complexes with diclofenac was assessed by measuring their saturated solubilities. Solutions containing hydroxypropyl beta-cyclodextrin (HPbeta-CD, with a molar substitution of 0.9) produced a 7.5-fold increase in the solubility of diclofenac, which suggested that a strong complex was formed between the two compounds. This association was characterized using differential scanning calorimetry. Permeation across silicone membranes of these saturated solutions of diclofenac in the presence of the different betaCDs produced similar flux values suggesting that the overall activity was also similar. The effect of different molar ratios of HPbeta-CD and diclofenac, and the anti-nucleating effect of HPbeta-CD (both on its own and in combination with a known anti-nucleant, hydroxypropylmethyl cellulose (HPMC)) on the diffusion of diclofenac across silicone membranes was investigated. HPbeta-CD appears to have a stabilizing effect on supersaturated solutions of diclofenac as a co-ingredient with HPMC.     

Influence of the formulation on the in vitro transdermal penetration of sodium diclofenac. Evaluation of the topical and systemic anti-inflammatory activity in the rat

A study on the transdermal permeation through human skin was performed with a series of 6 semisolid formulations (A-F) containing 1% sodium diclofenac (CAS 15307-79-6) (w/w). A commercially available drug preparation was tested as a reference. Based on permeation characteristics, a study on the topical and systemic anti-inflammatory activities of three formulations (A, F and the reference formulation) was conducted using the model of erythema induced by UV radiation in hairless rats. This is expected, together with the index of topical anti-inflammatory activity to allow the selection of the most suitable formulation for dermal application. The following representative parameters were measured in the permeation study: amount of diclofenac permeated at 24 h, flow, lag time and amount of drug retained in skin at 24 h. Of the formulations tested, diclofenac formulated in the reference formulation showed the highest values of amount of diclofenac permeated at 24 h, amount of drug retained in skin at 24 and flow. As regards the skin inflammation test, no significant differences (p < 0.05) are seen between the topical and systemic anti-inflammatory activities of the three formulations tested. However, in absolute value, formulation F shows a lower systemic activity, which would prevent potential side effects of diclofenac. Since the topical anti-inflammatory index obtained for this formulation was > 1, it is concluded that a good therapeutic performance could be obtained in the treatment of local inflammation with diclofenac by using formulation F.     

Prediction of the in-vitro human skin permeability of nicorandil from animal data

A method for estimating the in-vitro permeability of human skin to drugs, based on in-vitro permeation studies using animal skins, has been developed. The skins from hairless rats, guinea-pigs, dogs and pigs were used, with nicorandil and deionized water as model drug and solvent in a drug-donor compartment. Diffusion coefficients through the skin barrier, D, and partition coefficients from the drug-donor compartment to skin, K, of the drug, in each species, were calculated by curve-fitting the in-vitro permeation data to a diffusion equation describing the drug permeation through a homogeneous membrane, using a non-linear least squares method. Each barrier thickness, L, was measured microscopically from microtomed skin sections. A positive relationship was found between the skin permeability, Kp, and K value among the four species, but species differences in the D and L values were small in spite of the Kp values being different among the four species. A positive correlation was also observed between the calculated and experimental K values among the four species, and hence it was suggested that the main factor for the species difference in the skin permeability of nicorandil would be the difference in partitioning of the drug from vehicle to stratum corneum. As a result, it has become feasible to predict and estimate skin permeability of nicorandil in humans by substituting each parameter, extrapolated from the animal skin permeation data and partition experiments, in the diffusion equation.     

Influence of membrane-solvent-solute interactions on solute permeation in model membranes

The interaction of the components of topical formulations with the skin is an important consideration for effective drug delivery and efficacy. The relative importance of solubility parameters and other solvent properties on membrane diffusion processes has not been fully elucidated in the literature. In this paper, the effect of different vehicles on the permeation of caffeine, salicylic acid and benzoic acid through silicone membranes was evaluated. Polydimethylsiloxane membranes were used as model membranes for comparing the release characteristics of saturated solutions of model permeants because of their homogeneity and uniformity. Log P (octanol-water partition coefficient) and solubility parameter values were calculated for the compounds under study. In vitro diffusion studies indicated that the permeation profiles of all solutes showed a similar pattern. The permeation rates of benzoic acid and salicylic acid through silicone membrane from saturated solutions were higher than those for caffeine reflecting the more lipophilic nature of these compounds in comparison with caffeine. Solvent uptake studies confirmed that the vehicles that were highly sorbed by the membrane altered its properties and hence the flux. Vehicles that were not sorbed by the membrane showed similar steady-state fluxes for the model drugs. This suggests that the diffusion process is mainly influenced by the interactions between the vehicles and the membrane. Solubility parameter alone cannot explain the interactions between the membrane and the vehicles in all cases. Rather, it is likely that membrane flux reflects a combination of different solvent and solute characteristics, such as size, shape and charge distribution.     

Ex vivo permeability experiments in excised rat intestinal tissue and in vitro solubility measurements in aspirated human intestinal fluids support age-dependent oral drug absorption

The possible influence of advanced age on intestinal drug absorption was investigated by determining the effects of aging on (i) solubility of model drugs in human intestinal fluids (HIF) obtained from two age groups (18–25 years; 62–72 years); and (ii) transepithelial permeation of model drugs across intestinal tissue excised from young, adult and old rats. Average equilibrium solubility values for 10 poorly soluble compounds in HIF aspirated from both age groups showed high interindividual variability, but did not reveal significant differences. Characterization of the HIF from both age groups demonstrated comparable pH profiles, while concentrations of individual bile salts showed pronounced variability between individuals, however without statistical differences between age groups. Transepithelial permeation of the transcellular probe metoprolol was significantly increased in old rats (38 weeks) compared to the younger age groups, while the modulatory role of P-glycoprotein in transepithelial talinolol transport was observed in adult and old rats but not in young rats. In conclusion, age-dependent permeability of intestinal tissue (rather than age-dependent luminal drug solubility) may contribute to altered intestinal drug absorption in older patients compared to young adults.     

Dissolution/Permeation of Albendazole in the Presence of Cyclodextrin and Bile Salts: A Mechanistic In Vitro Study into Factors Governing Oral Bioavailability

We aimed to understand the impact of the interplay between bile salts and cyclodextrins on the dissolution-permeation of poorly soluble drug compounds with a moderate-strong binding constant to cyclodextrin. Phase diagrams were prepared on the chosen model compound albendazole in phosphate buffer, fasted state simulated intestinal fluid (FaSSIF), and a modified fed state simulated intestinal fluid (FeSSIF_mod) with (2-hydroxypropyl)-beta-cyclodextrin (HP-β-CD) concentrations of up to 10 % (m/m). Then we investigated the dissolution/permeation interplay of albendazole dissolved/suspended in the different media through a biomimetic barrier on a 96-well in vitro model. The apparent solubility of albendazole was enhanced by HP-β-CD and FaSSIF/FeSSIF_mod separately. However, when albendazole was dissolved in HP-β-CD and biomimetic media together, the solubility was significantly lower than the predicted additive solubility from the solubilizing effects. It is postulated that this is due to the sodium taurocholate from the biomimetic media displacing albendazole from the hydrophobic cavity of HP-β-CD. In the permeation experiments, the highest permeation was observed at cyclodextrin concentrations able to solubilize close to the total dose of albendazole without a major surplus of solubilization capacity. Furthermore, an over-proportional permeation enhancement was observed when both, cyclodextrin and biomimetic media were present. These results indicate that the interplay between bile salts and cyclodextrins can enhance the free (molecularly dissolved) fraction of drug in solution to a greater extent than could be obtained with one of the solubilizing components alone. In conclusion, at carefully selected cyclodextrin-concentrations in combination with biomimetic media, obviously, a transient supersaturation is induced, which is made responsible for the observed major permeation enhancement.