The effect of prolonged exposure on sodium dodecyl sulfate penetration into human skin.

The purpose of this study was to examine the effect of prolonged surfactant exposure on mechanisms of anionic surfactant penetration into human skin. A radiolabeled probe (14-carbon sodium dodecyl sulfate (14C-SDS)) was used to trace the penetration of a model anionic surfactant, sodium dodecyl sulfate (SDS), into excised human skin and into an inert membrane composite in vitro. SDS dose varied from 0.03 to 15 mg/cm2, mimicking the exposure of a rinse-off cleanser on skin. Two surfactant exposure lengths were tested, 2 min and 5 h. SDS penetration into excised human skin was constant from 50 to 600 mM for skin samples exposed to SDS for 2 min. For skin samples exposed to SDS for 5 h, SDS penetration into skin increased log-linearly with increasing SDS concentration. SDS penetration into the inert membrane composite was constant from 50 to 600 mM SDS regardless of length of surfactant exposure. Penetration of the radiolabeled probe into skin and into the inert membrane correlated well with the monomeric concentration of the radiolabeled probe in the applied surfactant solution. These results support that monomer concentration is the driving force for initial SDS penetration into upper layers of the stratum corneum over a wide range of concentrations. With prolonged exposure, SDS penetrates the skin in a dose-dependent manner due to surfactant-induced damage to the skin.

Improving Oral Bioavailability of Luteolin Nanocrystals by Surface Modification of Sodium Dodecyl Sulfate.

Luteolin suffers from drawbacks like low solubility and bioavailability, thus hindering its application in the clinic. In this study, we employed sodium dodecyl sulfate (SDS), an efficient tight junction opening agent, to modify the surface of luteolin nanocrystals, aiming to enhance the bioavailability of luteolin (LUT) and luteolin nanocrystals (LNC). The particle sizes of SDS-modified luteolin nanocrystals (SLNC) were slightly larger than that of LNC, and the zeta potential of LNC and SLNC was -25.0 ± 0.7 mV and -43.5 ± 0.4 mV, respectively. Both LNC and SLNC exhibited enhanced saturation solubility and high stability in the liquid state. In the cellular study, we found that SDS has cytotoxicity on caco-2 cells and could open the tight junction of the caco-2 monolayer, which could lead to an enhanced transport of luteolin across the intestinal membrane. The bioavailability of luteolin was enhanced for 1.90-fold by luteolin nanocrystals, and after modification with SDS, the bioavailability was enhanced to 3.48-fold. Our experiments demonstrated that SDS could efficiently open the tight junction and enhance the bioavailability of luteolin thereafter, revealing the construction of SDS-modified nanocrystals is a good strategy for enhancing the oral bioavailability of poorly soluble drugs like luteolin.

A new and efficient carboxymethyl-hexanoyl chitosan/dodecyl sulfate nanocarrier for a pyrazoline with antileukemic activity.

We describe herein a chitosan nanocarrier for drug delivery applications obtained through the self-assembly of carboxymethyl-hexanoyl chitosan and dodecyl sulfate (CHC-SDS). Nanocapsules with spherical morphology were obtained in phosphate buffer at pH 7.4. These CHC-SDS nanocapsules showed no toxicity toward Jurkat cells (acute lymphoblastic leukemia) and were used to encapsulate a new pyrazoline (H3TM04) with antileukemia activity. The samples were characterized by dynamic light scattering (DLS) and Laser Doppler Micro-Electrophoresis. The encapsulation efficiency was higher than 96% (293.6 µg mL-1) and the H3TM04-loaded nanocapsules (CHC-SDS-H) had a negative surface charge (-29.8 ±â€¯0.7 mV) and hydrodynamic radius of around 84 nm. For the first time, CHC-SDS-H were formed and the antitumoral cancer activity was proved. The in vitro assays showed the controlled release of H3TM04 from the CHC-SDS-H nanocapsules in phosphate buffer pH 7.4. The H3TM04 release data were described by the power law model, indicating that H3TM04 delivery occurred via an erosion mechanism. The cytotoxicity assays with Jurkat and K-562 cells (acute myeloid leukemia) demonstrated that the CHC-SDS-H nanocapsule decreases the half maximal inhibitory concentration (IC50). The study showed that CHC-SDS nanocapsules represent a promising nanocarrier for pyrazoline derivates that could be applied in leukemia therapy.

Exploration of supersaturable lacidipine ternary amorphous solid dispersion for enhanced dissolution and in vivo absorption.

Amorphous solid dispersion stands out among different formulation strategies for the improvement of dissolution rate and bioavailability via generating supersaturated drug solution, which provides a higher solubility than the crystalline counterpart, leading to a promoted intestinal absorption. Soluplus (SOL), termed as the fourth generation of solid dispersion carrier, presented a preferable effect on supersaturation maintaining and bioavailability enhancement for poorly water soluble drugs. However, some binary drug/SOL systems still suffer from insufficient dissolution and unsatisfied in vivo absorption. Thus, taking Lacidipine (LCDP) as a model drug, the aim of this study was to explore a ternary amorphous solid dispersion consisted of SOL and a surfactant to further increasing the dissolution rate and in vivo absorption. First of all, various surfactants were screened via equilibrium solubility enhancement and sodium dodecyl sulfate (SDS) was selected as the most effective candidate. Thereafter, the influence of SOL/SDS and drug/carrier weight ratio on the supersaturation maintaining was investigated. The supersaturated drug solutions were spray dried and the in vitro release, pharmacokinetic behavior as well as physical stability were investigated. It was found that although combination use of SOL and SDS did not present remarkable advantage in supersaturation maintenance in liquid state, 6-7 times higher dissolution rate under non-sink condition was noticed at SOL/SDS ratio 3:1 after spray drying, for LCDP/SOL/SDS based formulation compared to that of the binary LCDP/SOL system, which was maintained even after 92.5% humidity and 60 °C accelerated stability test. Moreover, compared to the LCDP/SOL formulation, approximately 3.3 and 3.7-fold increase in C max and AUC0-∞ was achieved with LCDP/SOL/SDS based formulation. In conclusion, the presented SDS could not only be regarded as solubility enhancer but also dissolution or bioavailability promoter, highlighting its potential application in ternary supersaturable amorphous solid dispersion for further increasing the dissolution and in vivo absorption of poorly water soluble drugs.

Understanding the Role of Sodium Lauryl Sulfate on the Biorelevant Solubility of a Combination of Poorly Water-Soluble Drugs Using High Throughput Experimentation and Mechanistic Absorption Modeling.

This study investigates the influence of surfactant sodium lauryl sulfate (SLS) on the solubility of poorly-water soluble drug substances, model Compound X and Compound Y, used in a fixed dose combination oral solid dosage form. To determine the impact of SLS concentration on the solubility of compounds X and Y, we experimentally determined the critical micelle concentration (CMC) of SLS in water, simulated gastric fluid (SGF), and fed state simulated intestinal fluid (FeSSIF) in the presence of Compound X and Compound Y using UV/Visible spectrophotometry at 25°C. The aggregation of SLS was characterized by calculating the standard Gibbs free energy of micellization in all the media investigated.  To enhance the understanding of SLS aggregation, high throughput experiments and in-vivo mechanistic modelling were used to determine the effect of increasing levels of SLS on the solubility of compounds X and Y as both single agent and combination products to be formulated into a suitable oral solid dosage form. Micellar formation of SLS is a spontaneous process as shown by the negative values of the standard free energy of micellization. The CMC of SLS in the various media investigated in the presence of compounds X and Y decreases in the following order: water> FeSSIF> SGF. However, the aggregation of SLS in the various media is overall more spontaneous in the following order: SGF>FeSSIF>water. Using high throughput experimentation and in-vivo mechanistic modelling, it was determined that a combination oral solid product of compounds X and Y will have optimum solubility and in-vivo absorption if 2 mg of SLS was used in the oral solid dosage form.  The results obtained from this study will help broaden the understanding of the micellization process involving SLS and poorly-water soluble drugs used in combination oral solid dosage forms.

Mechanisms of anionic surfactant penetration into human skin: Investigating monomer, micelle and submicellar aggregate penetration theories.

OBJECTIVE: Once penetrated into the stratum corneum, anionic surfactants bind to and denature stratum corneum proteins as well as intercalate into and extract intercellular lipids. With repeated exposures, this leads to skin dryness and irritation, compromising barrier function and skin health. The mechanisms of anionic surfactant penetration into the skin, however, are still widely debated. The objective of this study was to evaluate current theories of surfactant penetration into human skin. METHODS: A test set comprising 15 anionic surfactant systems and one non-ionic surfactant, all having either dodecyl or lauryl alkyl chains, was tested for surfactant penetration into split-thickness human cadaver skin in vitro using radiolabelled sodium dodecyl sulphate (14 C-SDS). Select physical properties of these formulations thought to be associated with skin penetration including critical micelle concentration, micelle diameter, filtrate concentration and zeta potential were also measured. RESULTS: 14 C-SDS penetration into human cadaver skin from surfactant systems in vitro was found to correlate well with CMC (R2  = 0.34, P < 0.05), filtrate concentration (R2  = 0.36, P < 0.05) and zeta potential (R2  = 0.76, P < 0.001), but poorly with micelle diameter (R2  = 0.12). Furthermore, the latter measure correlated inversely with penetration compared to what would be expected based on the micelle penetration theory. CONCLUSION: Neither monomer nor micelle penetration theories are sufficient to explain anionic surfactant penetration into human skin. Submicellar (or premicellar) aggregate penetration theory is difficult to defend at relevant surfactant concentrations. We propose a new hypothesis for this mechanism in which short-term penetration is based on monomer concentration and longer term penetration is based on surfactant-induced damage to the skin barrier.

OBJECTIF: Une fois pénétrés dans la couche cornée, les tensioactifs anioniques se lient aux protéines de la couche cornée, le dénaturent, s'intercalent dans les lipides intercellulaires et les extraient. Avec des expositions répétées, ceci entraîne un assèchement et une irritation de la peau, compromettant ainsi la fonction de barrière et la santé de la peau. Les mécanismes de pénétration du tensioactif anionique dans la peau restent toutefois largement débattus. L'objectif de cette étude est d'évaluer les théories actuelles de la pénétration de surfactant dans la peau humaine. MÉTHODES: Un ensemble de contrôle comprenant 15 systèmes de tensioactifs anioniques et un tensioactif non ionique, tous possédant des chaînes dodécyles ou lauryle alkyles, a été testé vis-à-vis de la pénétration du tensioactif dans la peau d'un cadavre humain partiellement épaisse in vitro en utilisant du sulfate de sodium dodécyl radiomarqué (14 C-SDS). Certaines propriétés physiques de ces formulations supposées être associées à la pénétration dans la peau, notamment la concentration critique micellaires, le diamètre des micelles, la concentration de filtrat, et le potentiel zêta, ont également été mesurées. RÉSULTATS: La pénétration du 14 C-SDS dans la peau de cadavre humain provenant de systèmes de tensioactifs in vitro était bien corrélée avec la CMC (R2  = 0,34, P < 0,05), la concentration de filtrat (R2  = 0,36, P < 0,05) et le potentiel zêta (R2  = 0,76, P < 0,001), mais faiblement avec un diamètre de micelle (R2  = 0,12). De plus, cette dernière mesure était inversement corrélée à la pénétration par rapport à ce que l'on pouvait attendre de la théorie de la pénétration des micelles. CONCLUSION: Ni les théories de pénétration de monomères ni de micelles ne sont suffisantes pour expliquer la pénétration de tensioactif anionique dans la peau humaine. La théorie de la pénétration des agrégats submicellaires (ou prémicellaires) est difficile à défendre aux concentrations pertinentes de surfactant. Nous proposons une nouvelle hypothèse pour ce mécanisme dans laquelle la pénétration à court terme est basée sur la concentration en monomères et la pénétration à plus long terme est basée sur les dommages à la barrière cutanée induits par les tensioactifs.

Double controlled release of highly insoluble cilostazol using surfactant-driven pH dependent and pH-independent polymeric blends and in vivo bioavailability in beagle dogs.

Commercially available cilostazol (CIL) tablet releases drug immediately and is given twice a day as an antiplatelet and vasodilatory agent. However, clinical usefulness of immediate release (IR) preparation is limited due to its extremely poor water solubility and the difficulty in sustaining the blood concentration, resulting in unwanted side effects such as headaches, pyknocardia and heavy-headed symptoms. To achieve once a day dosage form with enhanced solubility and controlled release, double controlled release CIL matrix tablets (DCRT) were designed by modulating a sol-gel process of binary polymeric blends of a pH-independent hydroxylpropylmethylcellulose (HPMC) and a pH-dependent polymer (carbomer) assisted with anionic surfactant (sodium lauryl sulfate, SLS). The release profiles of the DCRT were varied according to the ratio of the two polymers. This DCRT enhanced dissolution rate of CIL in a controlled manner due to the sol-gel and erosion process of HPMC, and SLS-driven modulation of charged carbomer via neutralization and micellar interaction. The near-infrared (NIR) chemical imaging and gravimetric behaviors of DCRT clearly showed dynamic modulation of CIL during the swelling and hydration process. Furthermore, the plasma concentration of CIL in DCRT was highly improved and sustained in beagle dogs in a controlled manner.

Effect of the Interaction Between an Ionic Surfactant and Polymer on the Dissolution of a Poorly Soluble Drug.

Surfactants are commonly incorporated in conventional and enabled formulations to enhance the rate and extent of dissolution of drugs exhibiting poor aqueous solubility. Generally the interactions between the drug and excipients are systematically evaluated, however, limited attention is paid towards understanding the effect of interaction between functional excipients and its impact on the performance of the product. In the current study, the effect of potential interaction between a nonionic polymer binder, povidone, and anionic surfactant docusate sodium on the rate and extent of dissolution of a drug exhibiting poor aqueous solubility was evaluated by varying the proportions of the binder and the surfactant in the formulation. Potential complexation or aggregation between the excipients was investigated by fluorescence spectroscopy and zeta potential measurements of the aqueous solutions of docusate sodium, povidone, and sodium lauryl sulfate (SLS). The rate and extent of drug release was found to decrease with an increase in the proportion of docusate sodium and povidone in the formulations. Difference in magnitude of surface charge (zeta potential) of docusate sodium in presence of povidone indicated potential surfactant-polymer aggregation during dissolution which was corroborated by CAC/CMC values derived from fluorescence spectroscopic measurements. The decrease in the rate of drug release was attributed to an increase in the viscosity of the microenvironment of dissolving particles due to the interaction of docusate sodium and povidone in the aqueous media during dissolution. These findings highlight the importance of systematic evaluation of the interaction of ionic surfactants with the polymeric components within the formulation to ensure the appropriate selection of the type of surfactant as well as its proportion in the formulation.

Penetration monitoring of drugs and additives by ATR-FTIR spectroscopy/tape stripping and confocal Raman spectroscopy - A comparative study.

Vibrational spectroscopy is a useful tool for analysis of skin properties and to confirm the penetration of drugs and other formulation compounds into the skin. In particular, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and confocal Raman spectroscopy (CRS) have been optimised for skin analysis. Despite an impressive amount of data on these techniques, a comparative methodological assessment for skin penetration monitoring of model substances is still amiss. Thus, in vitro skin penetration studies were conducted in parallel using the same porcine material and four model substances, namely sodium laureth sulfate (SLES), sodium dodecyl sulfate (SDS), sulfathiazole sodium (STZ) and dimethyl sulfoxide (DMSO). ATR-FTIR spectroscopy in combination with tape stripping and CRS were employed to evaluate the skin penetration of the applied substances. In addition, the skin hydration status or change in skin hydration after application was investigated. The results show that both methods provide valuable information on the skin penetration potential of applied substances. The penetration profiles determined by CRS or ATR-FTIR/tape stripping were comparable for all substances; a slow decrease in relative substance concentration was visible from the skin surface inwards within the stratum corneum (SC). In general, deeper penetration into the SC was observed with CRS, which may be related to the depth resolution of the employed device. However, when related to the respective total SC thickness of each experiment, the penetration depths determined by parallel CRS and ATR-FTIR analysis were in good agreement for all model substances. The observed order of the penetration depth was DMSO > SDS > SLES > STZ with both techniques. A decrease of the relative concentration to 10% of the maximum value was found approximately between 34 and 89% of total SC thickness. Summarising these findings, advantages and drawbacks of the two techniques for in vitro skin penetration studies are discussed.

Trypsin decorated self-emulsifying drug delivery systems (SEDDS): Key to enhanced mucus permeation.

It was the aim of this study to prepare trypsin decorated mucus permeating self-emulsifying drug delivery systems (SEDDS). Lipophilicity of enzyme was increased by hydrophobic ion pairing (HIP) with the anionic surfactants sodium dodecyl sulfate (SDS), sodium taurocholate (ST) and sodium deoxycholate (SDO) to facilitate its incorporation in SEDDS. Blank SEDDS and trypsin decorated SEDDS were characterized regarding droplet size, polydispersity index (PI), zeta potential and proteolytic activity using Nα-benzoyl-l-arginine ethyl ester (BAEE) assay. Log DSEDDS/release medium of each complex was determined to assess its affinity towards SEDDS oily droplet upon emulsification. Ability of trypsin decorated SEDDS to enhance mucus permeation was studied on mucus gel from porcine small intestine for the period of 4 h at 37 °C. Degree of enzyme precipitation via HIP was 94.5%, 85.7% and 48.2% for SDS, ST and SDO complex, respectively. SEDDS composed of 50% (w/w) cremophor EL, 20% (w/w) captex 300, and 30% (w/w) propylene glycol with a complex payload of 1% (w/w) exhibited a droplet size in the range of 29.92 ±â€¯0.09 nm to 39.15 ±â€¯0.37 nm, a polydispersity index of 0.116-0.265 and zeta potential in the range of -2.36 mv to -4.25 mv. The enzymatic activity of trypsin complexed with SDO, SDS and ST in SEDDS was 51.9%, 44.8%, and 40.7% respectively, of the corresponding activity of free trypsin. Log D values of trypsin, SDS, ST and SDO complex were -2.73, 1.97, 1.89 and 1.68, respectively, suggesting higher lipophilicity of trypsin complexes as compare to free trypsin and ability to reside on SEDDS droplets. Enzyme decorated SEDDS improved mucus permeation 1.6- to 2.6-fold in comparison to blank SEDDS. Results demonstrated that decorating SEDDS with trypsin can be a promising technique to improve their mucus permeating properties.

Bottom-Up and Top-Down Approaches to Explore Sodium Dodecyl Sulfate and Soluplus on the Crystallization Inhibition and Dissolution of Felodipine Extrudates.

The objectives of this study were to explore sodium dodecyl sulfate (SDS) and Soluplus on the crystallization inhibition and dissolution of felodipine (FLDP) extrudates by bottom-up and top-down approaches. FLDP extrudates with Soluplus and SDS were prepared by hot melt extrusion, and characterized by polarized light microscopy, differential scanning calorimetry, and fourier transform infrared spectroscopy. Results indicated that Soluplus inhibited FLDP crystallization, and the whole amorphous solid dispersions (ASDs) were binary FLDP-Soluplus (1:3) and ternary FLDP-Soluplus-SDS (1:2:0.15∼0.3 and 1:3:0.2∼0.4) extrudates. Internal SDS (5%-10%) decreased glass transition temperatures of FLDP-Soluplus-SDS ternary ASDs without presenting molecular interactions with FLDP or Soluplus. The enhanced dissolution rate of binary or ternary Soluplus-rich ASDs in the nonsink condition of 0.05% SDS was achieved. Bottom-up approach indicated that Soluplus was a much stronger crystal inhibitor to the supersaturated FLDP in solutions than SDS. Top-down approach demonstrated that SDS enhanced the dissolution of Soluplus-rich ASDs via wettability and complexation with Soluplus to accelerate the medium uptake and erosion kinetics of extrudates, but induced FLDP recrystallization and resulted in incomplete dissolution of FLDP-rich extrudates. In conclusion, top-down approach is a promising strategy to explore the mechanisms of ASDs' dissolution, and small amount of SDS enhances the dissolution rate of polymer-rich ASDs in the nonsink condition.

The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.

Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

Oral insulin delivery, the challenge to increase insulin bioavailability: Influence of surface charge in nanoparticle system.

Oral administration of insulin increases patient comfort and could improve glycemic control thanks to the hepatic first passage. However, challenges remain. The current approach uses poly (d, lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), an effective drug carrier system with a long acting profile. However, this system presents a bioavailability of less than 20% for insulin encapsulation. In this context, physico-chemical parameters like surface charge could play a critical role in NP uptake by the intestinal barrier. Therefore, we developed a simple method to modulate NP surface charge to test its impact on uptake in vitro and finally on NP efficiency in vivo. Various NPs were prepared in the presence (+) or absence (-) of polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), and/or coated with chitosan chloride. In vitro internalization was tested using epithelial culture of Caco-2 or using a co-culture (Caco-2/RevHT29MTX) by flow cytometry. NPs were then administered by oral route using a pharmaceutical complex vector (100 or 250 UI/kg) in a diabetic rat model. SDS-NPs (-42 ±â€¯2 mV) were more negatively charged than -PVA-NPs (-22 ±â€¯1 mV) and chitosan-coated NPs were highly positively charged (56 ±â€¯2 mV) compared to +PVA particles (-2 ±â€¯1 mV), which were uncharged. In the Caco-2 model, NP internalization was significantly improved by using negatively charged NPs (SDS NPs) compared to using classical NPs (+PVA NPs) and chitosan-coated NPs. Finally, the efficacy of insulin SDS-NPs was demonstrated in vivo (100 or 250 UI insulin/kg) with a reduction of blood glucose levels in diabetic rats. Formulation of negatively charged NPs represents a promising approach to improve NP uptake and insulin bioavailability for oral delivery.

Contact Angle Measurements: an Alternative Approach Towards Understanding the Mechanism of Increased Drug Dissolution from Ethylcellulose Tablets Containing Surfactant and Exploring the Relationship Between Their Contact Angles and Dissolution Behaviors.

The addition of surfactant in tablet was a well-defined approach to improve drug dissolution rate. While the selected surfactant played a vital role in improving the wettability of tablet by medium, it was equally important to improve the dissolution rate by permeation effect due to production of pores or the reduced inter-particle adhesion. Furthermore, understanding the mechanism of dissolution rate increased was significant. In this work, contact angle measurement was taken up as an alternative approach for understanding the dissolution rate enhancement for tablet containing surfactant. Ethylcellulose, as a substrate, was used to prepare tablet. Four surfactants, sodium dodecyl sulfate (SDS), sodium dodecylbenzenesulfonate (SDBS), dodecyltrimethylammonium bromide (DTAB), and sodium lauryl sulfonate (SLS), were used. Berberine hydrochloride, metformin hydrochloride, and rutin were selected as model drugs. The contact angle of tablet in the absence and presence of surfactant was measured to explore the mechanism. The dissolution test was investigated to verify the mechanism and to establish a correlation with the contact angle. The result showed that the mechanism was the penetration effect rather than the wetting effect. The dissolution increased with a reduction in the contact angle. DTAB was found to obtain the highest level of dissolution enhancement and the lowest contact angle, while SDS, SDBS, and SLS were found to be the less effective in both dissolution enhancement and contact angle decrease. Therefore, contact angle was a good indicator for dissolution behavior besides exploring the mechanism of increased dissolution, which shows great potential in formula screening.

Comparative study on stabilizing ability of food protein, non-ionic surfactant and anionic surfactant on BCS type II drug carvedilol loaded nanosuspension: Physicochemical and pharmacokinetic investigation.

Carvedilol (CAR) in its pure state has low aqueous solubility and extremely poor bioavailability which largely limit its clinical application. The aim of the study is to improve the dissolution rate and the bioavailability of CAR via preparing nanosuspensions with different stabilizers. Antisolvent precipitation-ultrasonication technique was used here. Attempts have been made to use food protein- Whey protein isolate (WPI) as a stabilizer in CAR loaded nanosuspension and also to compare its stabilizing potential with conventional nanosuspension stabilizers such as non-ionic linear copolymer-poloxamer 188 (PLX188) and anionic surfactant-sodium dodecyl sulfate (SDS). Optimized nanosuspensions showed narrow size distribution with particle size ranging from 275 to 640nm. Amorphous state of CAR nanocrystals which also improved the solubility by 16-, 25-, 55-fold accordingly was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). From scanning electron microscopy (SEM), flaky shape of PLX188 and SDS nanosuspensions could be revealed but WPI nanosuspension was sphere-shaped. Up to 70% dissolution of loaded drug was observed within 15min in phosphate buffer (pH6.8). A pharmacokinetic study in rats indicated that both Cmax and AUC0-36 values of nanosuspensions were estimated to be 2-fold higher than those of reference, suggesting a significant increase in CAR bioavailability.

Self-assembly of Gd3+/SDS/HEPES complex and curcumin entrapment for enhanced stability, fluorescence image in cellular system.

At present, strategies to disperse hydrophobic molecules in water without altering their chemical structures include conventional surfactant-based micellar and vesicular systems, encapsulation into water dispersible polymeric nanoparticles, and loading onto the surface of various metal nanoparticles. Here, we report a simple and low cost platform to incorporate hydrophobic molecules into a stable water dispersible nanostructure that can significantly increase the stability of the encapsulated materials. The platform is based on the incorporation of hydrophobic molecules into the self-assembled complex of gadolinium ion (Gd3+), sodium dodecyl sulfate (SDS), and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) called GdSH. After being incorporated, the two model hydrophobic dyes, curcumin and curcumin borondifluoride show approximately 50% and 30% improved stability, respectively. Investigation of the self-assembled 10-14 multilayered 60nm spheres with inter-layer distances of 4.25nm indicates coordination of SDS and HEPES with Gd3+. Incorporation of the hydrophobic molecules into the multilayered spheres results in reduction of the interlayer distance of the multilayer spheres to 4.17nm, suggesting enhanced packing of the hydrophobic chain of SDS and HEPES around the Gd3+. The incorporation of the two curcuminoids into the self-assembled complex also causes an increase in fluorescence quantum yield of the two dyes, thus suggesting spatial confinement of the packed dye molecules. The better cellular uptake of the nanoparticles is responsible for the expected enhancement in fluorescence image of the encapsulated materials.

Sustained release of simvastatin from hollow carbonated hydroxyapatite microspheres prepared by aspartic acid and sodium dodecyl sulfate.

Hollow carbonated hydroxyapatite (HCHAp) microspheres as simvastatin (SV) sustained-release vehicles were fabricated through a novel and simple one-step biomimetic strategy. Firstly, hollow CaCO3 microspheres were precipitated through the reaction of CaCl2 with Na2CO3 in the presence of aspartic acid and sodium dodecyl sulfate. Then, the as-prepared hollow CaCO3 microspheres were transformed into HCHAp microspheres with a controlled anion-exchange method. The HCHAp microspheres were 3-5µm with a shell thickness of 0.5-1µm and were constructed of short needle nanoparticles. The HCHAp microspheres were then loaded with SV, exhibiting excellent drug-loading capacity and sustained release properties. These results present a new material synthesis strategy for HCHAp microspheres and suggest that the as-prepared HCHAp microspheres are promising for applications in drug delivery.

Non-occlusive topical exposure of human skin in vitro as model for cytotoxicity testing of irritant compounds.

Testing of irritant compounds has traditionally been performed on animals and human volunteers. Animal testing should always be restricted and for skin irritancy mice and rabbits hold poor predictive value for irritant potential in humans. Irritant testing on human volunteers is restricted by the duration subjects can be exposed, and by the subjectivity of interpreting the visual signs of skin irritation. We propose an irritant testing system using viable human full thickness skin with the loss of cell viability in the exposed skin area as end point measurement. Skin was exposed to sodium dodecyl sulfate (SDS) at 20% concentration by non-occluded topical exposure to establish a positive control response and subsequent test compounds were statistically compared with the 20% SDS response. Cell viability and metabolism were measured with 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The model presents correlation between increased concentration of SDS and decreased viability of cells in the exposed skin area (R(2) = 0.76). We propose the model to be used for cytotoxicity testing of irritant compounds. With fully intact barrier function, the model comprises all cells present in the skin with quantifiable end point measurement.

Anti-irritant and anti-inflammatory effects of glycerol and xylitol in sodium lauryl sulphate-induced acute irritation.

BACKGROUND: Glycerol is known to possess anti-irritant and hydrating properties and previous studies suggested that xylitol may also have similar effects. OBJECTIVE: Our aim was to study whether different concentrations of these polyols restore skin barrier function and soothe inflammation in sodium lauryl sulphate (SLS)-induced acute irritation. METHODS: The experiments were performed on male SKH-1 hairless mice. The skin of the dorsal region was exposed to SLS (5%) for 3 h alone or together with 5% or 10% of glycerol respectively. Further two groups received xylitol solutions (8.26% and 16.52% respectively) using the same osmolarities, which were equivalent to those of the glycerol treatments. The control group was treated with purified water. Transepidermal water loss (TEWL) and skin hydration were determined. Microcirculatory parameters of inflammation were observed by means of intravital videomicroscopy (IVM). Furthermore, accumulation of neutrophil granulocytes and lymphocytes, the expression of inflammatory cytokines and SLS penetration were assessed, as well. RESULTS: Treatment with the 10% of glycerol and both concentrations of xylitol inhibited the SLS-induced elevation of TEWL and moderated the irritant-induced increase in dermal blood flow and in the number of leucocyte-endothelial interactions. All concentrations of the applied polyols improved hydration and prevented the accumulation of lymphocytes near the treatment site. At the mRNA level, neither glycerol nor xylitol influenced the expression of interleukin-1 alpha. However, expression of interleukin-1 beta was significantly decreased by the 10% glycerol treatment, while expression of tumour necrosis factor-alpha decreased upon the same treatment, as well as in response to xylitol. Higher polyol treatments decreased the SLS penetration to the deeper layers of the stratum corneum. CONCLUSION: Both of the analysed polyols exert considerable anti-irritant and anti-inflammatory properties, but the effective concentration of xylitol is lower than that of glycerol.

Artificial membranes as models in penetration investigations.

BACKGROUND/AIMS: In vitro methods used in the research of transepidermal transport of active substances generally rely on the penetration rate of test compounds through standard membranes. Models typically used in penetration experiments are specially prepared human or animal skin samples or synthetic membranes. The objective of this study was to establish if the test results for an artificial liposome membrane can be extrapolated to determine the actual bioavailability of active substances. METHODS: Tests were conducted in a side-by-side diffusion cell. As model membranes, a liquid-crystal lipid membrane (LM), phospholipid membrane (PM) and pig skin sample were used. The test compounds were eight synthetic dyes used in hair colouring products. RESULTS/CONCLUSION: Research findings reveal that membranes composed of lipids, identical to those present in the epidermis and forming analogical liquid-crystal structures provide a close approximation of the actual bioavailability of active substances (correlation between the results obtained for pig skin and LM was significant: R = 0.95 and R = 0.93 in the presence of a 1% Sodium dodecyl sulphate in donor system). Unlike biological membranes, intercellular cement does not contain phospholipids. The observed correlation between penetration coefficients through the PM and pig skin was not significant (R = 0.82). The experiments confirm that the PM constitutes a less credible model for the studies of transepidermal transport in real life conditions.