From decoding the perception of tightness to a clinical proof of soothing effects derived from natural ingredients in a moisturizer.

OBJECTIVE: To decode the feeling of skin tightness after application of a cosmetic product and how to soothe this discomfort. To pursue this aim, we considered the ingredient's effect on stratum corneum (SC) biomechanics to differentiate between consumers prone to tightness from those that are not and correlate these effects with mechanoreceptor activation. METHODS: In vivo clinical trials were used to assess the tightness perception dichotomy between groups of Caucasian women; in vitro experiments were used to measure the mechanical stresses induced in the SC after cleanser and moisturizer application; and in silico simulations were used to illustrate how the measured mechanical stresses in the SC result in the development of strains at the depth of cutaneous mechanoreceptors, triggering tightness perceptual responses. RESULTS: Before any cream application, women prone to tightness tend to have a more rigid SC than their less sensitive counterparts, however cleanser application increases SC stiffness in all women. Surprisingly, no correlation was found between tightness perception and hydration measurements by the Corneometer or barrier function, as evaluated by transepidermal water loss. Self-declared tightness and dryness scores were strongly associated with a self-described sensitive skin. After application of the optimized moisturizing formula, Osmoskin® containing natural waxes with good filming properties, consumers report a strong decrease in tightness and dryness perception. These results match with laboratory experiments where the cleanser was shown to increase SC drying stresses by 34%, while subsequent application of Osmoskin® decreased stresses by 48%. Finite element modelling, using experimental results as input, elucidates the differences in perception between the two groups of women. It makes clear that Osmoskin® changes the mechanical status of the SC, producing strains in underlying epidermis that activates multiple cutaneous mechano-receptors at a level correlated with the self-perceived comfort. CONCLUSION: Integration of the in vivo, in vitro and in silico approaches provides a novel framework for fully understanding how skin tightness sensations form and propagate, and how these sensations can be alleviated through the design of an optimized moisturizer.

OBJECTIF: Décoder l'impression de tiraillement de la peau après l'application d'un produit cosmétique et la manière d'apaiser cette sensation désagréable. Pour poursuivre cet objectif, nous avons pris en compte l'effet de l'ingrédient sur la biomécanique de la couche cornée afin de différencier les consommatrices sujettes à un tiraillement de celles qui ne le sont pas et de corréler ces effets avec l'activation des mécanorécepteurs. MÉTHODES: Des essais cliniques in vivo ont été utilisés pour évaluer la dichotomie de perception de tiraillement entre des groupes de femmes de race caucasienne; des expériences in vitro ont été utilisées pour mesurer les contraintes mécaniques induites dans la couche cornée après application d'un produit nettoyant et d'un produit hydratant; et des simulations in silico ont servi à illustrer comment les contraintes mécaniques mesurées dans la couche cornée entraînent le développement de souches à la profondeur des mécanorécepteurs cutanés, qui déclenchent les réponses perceptives de tiraillement. RÉSULTATS: Avant toute application de crème, les femmes sujettes au tiraillement tendent à avoir une couche cornée plus rigide que leurs homologues moins sensibles, mais l'application d'un produit nettoyant augmente la raideur de la couche cornée chez toutes les femmes. Étonnamment, aucune corrélation n'a été observée entre la perception de tiraillement et les mesures d'hydratation réalisées par le cornéomètre ou la fonction barrière, évaluée par la perte d'eau transépidermique. Les scores de tiraillement et de sécheresse auto-déclarés étaient fortement corrélés à une peau décrite par les sujets elles-mêmes comme sensible. Après application de la formule hydratante optimisée, Osmoskin®, qui contient des cires naturelles ayant de bonnes propriétés de dépôt de film, les consommateurs rapportent une forte diminution de la sensation de tiraillement et de sécheresse. Ces résultats concordent avec les expériences en laboratoire où le produit nettoyant s'est avéré augmenter les contraintes de séchage de la couche cornée de 34 %, tandis que l'application ultérieure d'Osmoskin® a réduit les contraintes de 48 %. La modélisation à éléments finis, en utilisant les résultats expérimentaux comme données, élucide les différences de perception entre les deux groupes de femmes. Il est clair qu'Osmoskin® modifie l'état mécanique de la couche cornée, et produit des souches dans l'épiderme sous-jacent qui activent plusieurs mécano-récepteurs cutanés à un niveau corrélé au confort perçu par la patiente. CONCLUSION: La combinaison des approches in vivo, in vitro et in silico fournit un nouveau cadre pour comprendre pleinement comment les sensations de tiraillement de la peau se forment et se propagent, et comment elles peuvent être soulagées en mettant au point une crème hydratante optimisée.

Quality by design tools reducing the gap from bench to bedside for nanomedicine.

Pharmaceutical nanotechnology research is focused on smart nano-vehicles, which can deliver active pharmaceutical ingredients to enhance their efficacy through any route of administration and in the most varied therapeutical application. The design and development of new nanopharmaceuticals can be very laborious. In recent years, the application of mathematics, statistics and computational tools is emerging as a convenient strategy for this purpose. The application of Quality by Design (QbD) tools has been introduced to guarantee quality for pharmaceutical products and improve translational research from the laboratory bench into applicable therapeutics. In this review, a collection of basic-concept, historical overview and application of QbD in nanomedicine are discussed. A specific focus has been put on Response Surface Methodology and Artificial Neural Network approaches in general terms and their application in the development of nanomedicine to monitor the process parameters obtaining optimized system ensuring its quality profile.

Blockade of α1 subtype GABAA receptors attenuates the development of tolerance to the antinociceptive effects of midazolam in rats.

Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABAA receptor subtype mediation of the tolerance to midazolam-induced antinociception in rats. Midazolam (3.2 mg/kg) significantly reduced the locomotion in rats which was prevented by the selective α1-preferring GABAA receptor antagonist ß-carboline-3-carboxylate-t-butyl ester (ßCCt) (3.2 mg/kg). Midazolam increased the paw withdrawal threshold as tested by the von Frey filament assay in the complete Freund's adjuvant-induced inflammatory pain model in rats, and this effect was not altered by ßCCt or another α1-preferring GABAA receptor antagonist 3-propoxy-ß-carboline hydrochloride (3PBC). Repeated treatment with midazolam in combination with vehicle, ßCCt or 3PBC (twice daily) for 7 days led to a progressive increase of the ED50 values in the midazolam- and vehicle-treated rats, but not in other rats, suggesting the development of tolerance to midazolam but not to the combination of midazolam with α1-preferring GABAA receptor antagonists. These results suggest the essential role of the α1-subtype of GABAA receptors in mediating the development of tolerance to midazolam-induced antinociceptive effects and raise the possibility of increasing therapeutic profiles of benzodiazepines by selectively blocking specific α-subtypes of GABAA receptors.

Biosurfactants as a Novel Additive in Pharmaceutical Formulations: Current Trends and Future Implications.

BACKGROUND: Surfactants are an important category of additives that are used widely in most of the formulations as solubilizers, stabilizers, and emulsifiers. Current drug delivery systems comprise of numerous synthetic surfactants (such as Cremophor EL, polysorbate 80, Transcutol-P), which are associated with several side effects though used in many formulations. Therefore, to attenuate the problems associated with conventional surfactants, a new generation of surface-active agents is obtained from the metabolites of fungi, yeast, and bacteria, which are termed as biosurfactants. OBJECTIVES: In this article, we critically analyze the different types of biosurfactants, their origin along with their chemical and physical properties, advantages, drawbacks, regulatory status, and detailed pharmaceutical applications. METHODS: 243 papers were reviewed and included in this review. RESULTS: Briefly, Biosurfactants are classified as glycolipids, rhamnolipids, sophorolipids, trehalolipids, surfactin, lipopeptides & lipoproteins, lichenysin, fatty acids, phospholipids, and polymeric biosurfactants. These are amphiphilic biomolecules with lipophilic and hydrophilic ends and are used as drug delivery vehicles (foaming, solubilizer, detergent, and emulsifier) in the pharmaceutical industry. Despite additives, they have some biological activity as well (anti-cancer, anti-viral, anti-microbial, P-gp inhibition, etc.). These biomolecules possess better safety profiles and are biocompatible, biodegradable, and specific at different temperatures. CONCLUSION: Biosurfactants exhibit good biomedicine and additive properties that can be used in developing novel drug delivery systems. However, more research should be driven due to the lack of comprehensive toxicity testing and high production cost which limits their use.

Enhanced Follicular Delivery of Finasteride to Human Scalp Skin Using Heat and Chemical Penetration Enhancers.

PURPOSE: The aim of this work was to evaluate whether improved topical delivery of finasteride, focussed to the hair follicles of human scalp skin could be achieved with application of short durations of heat and use of specific chemical penetration enhancers. METHODS: Franz cell experiments with human scalp skin were performed with a range of chemical penetration enhancers at 32°C and 45°C to simulate normal and heated conditions. Selected chemical penetration enhancers were taken forward for finite dose Franz cell studies which examined the effect of heat produced by a prototype external heating system that supplied either 20 or 30 min of additional heat over both a 24 h and a 1 h time period. RESULTS: Short durations of externally applied heat significantly increased finasteride penetration into human scalp skin after 24 h. Analysis of drug distribution in the skin after 1 h and 24 h indicated that both heat and chemical penetration enhancer selection influenced drug delivery to the hair follicles. CONCLUSION: The use of short durations of heat in combination with specific chemical penetration enhancers was able to increase the delivery of finasteride to human scalp skin and provide focussed drug delivery to the hair follicles.

Encapsulation of curcumin into layered double hydroxides improve their anticancer and antiparasitic activity.

OBJECTIVES: Curcumin (CUR) has well-known activity against cancer cells and parasites; however, its applications are limited since this is an unstable molecule, which may suffer degradation by light and temperature, also, the low water solubility reduce its bioavailability. Layered double hydroxides (LDH) are well-known materials owing to the excellent anion exchange capacity, good biocompatibility and low toxicity. METHODS: Layered double hydroxides nanoparticles prepared with zinc and magnesium cations were used as a vehicle for CUR in Caco-2, Giardia lamblia and Entamoeba histolytica cultures. The physicochemical properties of Mg-LDH-CUR and Zn-LDH-CUR were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FTIR) and X-ray powder diffraction (XRD). Additionally, the load efficiency, release profiles and photostability of CUR were quantified by high-performance liquid chromatography (HPLC) and UV-Vis spectrometry. Then, Mg-LDH-CUR and Zn-LDH-CUR were tested on Caco-2, G. lamblia and E. histolytica cultures. KEY FINDINGS: The experiments demonstrated that Zn-LDH-CUR protects better against photodegradation by UV light, while Mg-LDH-CUR showed increased toxicity against Caco-2 cell, G. lamblia and E. histolytica, in comparison with free CUR. CONCLUSIONS: Layered double hydroxides are good vehicles to improve stability, resistance to degradation of CUR, also they are useful to improve solubility, provide a controlled release and improve the cytotoxic activity. Additionally, it was shown that the composition of the M+2 cation of LDH affects its properties and structure and that this directly influences its biological activity. The findings are important to select the composition of the encapsulation vehicle for a specific activity.

The effect of vehicle on skin absorption of Mg2+ and Ca2+ from thermal spring water.

OBJECTIVE: Thermal spring waters (TSW) are commonly used as active ingredients in cosmetics. Their biological activities directly depend on the ionic composition of the spring. However, in order to exhibit beneficial properties, the minerals need to reach viable skin layers. The present study addresses the incorporation of marketed TSW in model cosmetic formulations and the impact of the formulation on skin absorption of magnesium and calcium ions that are known to improve skin barrier function. METHODS: Marketed TSW was introduced into five formulations. Liposomes were prepared using saturated or unsaturated phospholipids mixed with cholesterol by the thin layer evaporation technique. Emulsions water-in-oil (W/O), oil-in-water (O/W) or double: water-in-oil-in-water (W/O/W) were prepared by high-shear mixing. Skin absorption of Mg2+ and Ca2+ from those formulations was studied in vitro using static Franz diffusion cells under infinite dose condition and under occlusion of the apparatus. RESULTS: Mg2+ and Ca2+ penetrate skin samples from TSW. Encapsulating TSW into double emulsion (TSW/O/W) increased skin absorption of both cations of interest and kept the Ca2+ /Mg2+ ratio equal to that of TSW in each skin layer. The dermal absorption of Mg2+ from the double emulsion departs from both single emulsions. Application of liposome suspension improved the skin absorption of Ca2+ while keeping constant that of Mg2+ , leading to unbalanced Ca2+ /Mg2+ ratio inside skin. CONCLUSION: The beneficial effects of TSW are not only due to their action on the skin surface. Their active components, especially Ca2+ and Mg2+ cations, reach viable skin layers in a formulation-dependent manner. The distribution of ions inside skin depends on the type of formulation.

OBJECTIFS: Les eaux thermales sont couramment utilisées comme substances actives dans les formulations cosmétiques. Leurs activités biologiques dépendent directement de leur composition en ions. L'action des ions s'exerce à différents niveaux dans la peau, mais bien souvent dans les couches profondes, au-delà du stratum corneum, qu'ils doivent donc atteindre. L'objectif de cet article est d'étudier l'absorption des ions magnésium et calcium, reconnus pour leur effet bénéfique sur la fonction barrière de la peau, depuis différentes formes galéniques formulées avec une eau thermale. METHODES: Une eau thermale commerciale a été utilisée comme phase aqueuse dans 5 formulations différentes : des liposomes formulés avec des phospholipides saturés et insaturés et du cholestérol ; des émulsions de différents sens, eau thermale/huile (TSW/O) et huile/eau thermale (O/TSW) ; une émulsion multiple eau thermale/huile/eau (TSW/O/W). L'absorption cutanée du calcium et du magnésium a été étudiée depuis ces différentes formulations, en utilisant la méthode des cellules de Franz, en dose infinie, et en fermant les cellules pour prévenir toute évaporation. RESULTATS: Les ions magnésium et calcium pénètrent dans la peau depuis l'eau thermale, utilisée comme contrôle. L'encapsulation de l'eau thermale dans les gouttelettes internes de l'émulsion double (TSW/O/W) permet de promouvoir la pénétration des deux ions d'intérêt dans chaque couche de la peau tout en respectant le rapport Ca2+ /Mg2+ obtenu avec l'eau thermale, contrairement aux émulsions simples. Les liposomes augmentent la pénétration cutanée des ions calcium, tandis que celle des ions magnésium reste constante, ce qui conduit à des rapports Ca2+ /Mg2+ élevés dans la peau. CONCLUSION: Les effets thérapeutiques des eaux thermales ne sont pas seulement dus à une action de surface. Les ions comme le calcium et le magnésium pénètrent dans la peau et exercent une action en profondeur qui dépend de la formulation dans laquelle ils sont formulés. En effet, leur distribution ions dépend de la formulation qui les contient.

Formulation evaluation of ketoconazole microemulsion-loaded hydrogel with nigella oil as a penetration enhancer.

BACKGROUND: Onychomycosis is an opportunistic fungal infection often infecting people with compromised immune system. Currently available treatment interventions such as physical, surgical, and chemical-based approaches are successful in treating the condition, however, are painful and nonpatient complaint. Moreover, dermal creams with antifungal agents do not penetrate nail plate as required; hence, there is a necessity of developing a novel formulation with enhanced penetration. AIMS: The aim of the present research work was to develop ketoconazole microemulsion-loaded hydrogel formulation containing nigella oil as permeation enhancer for the treatment of onychomycosis. METHODS: Screening of oils, surfactants, and cosurfactants were done based on solubility studies followed by the construction of pseudo-ternary phase diagrams with 2% ketoconazole. The microemulsion was characterized for globule size, zeta potential, viscosity, and thermodynamic stability. Ex-vivo studies were carried out using Franz diffusion cells using porcine skin membrane. The antifungal activity of microemulsion-loaded hydrogel was evaluated using cup plate method using Candida albicans and Aspergillus niger. RESULTS: The optimized microemulsion had a composition of 54.97% Capryol:Nigella (2:1), 36.07% Transcutol:Propylene glycol (2:1), and 7.13% water and was later incorporated into polymeric gel base. The microemulsion-loaded hydrogel exhibited a 10 hours sustained release profile as compared to the marketed cream and an enhanced activity against marketed ketoconazole cream and compared with marketed ketoconazole formulation. CONCLUSION: The thermodynamic stability, sustained drug release with greater permeation, and enhanced activity due to the presence of nigella oil in microemulsion-loaded hydrogel warrant its application as an excellent vehicle for treating fungal infections.

Permeation Mechanism of Caffeine and Naproxen through in vitro Human Epidermis: Effect of Vehicles and Penetration Enhancers.

BACKGROUND/AIMS: The mechanisms by which permeation enhancers increase human skin permeation of caffeine and naproxen were assessed in vitro. METHODS: Active compound solubility in the vehicles and in the stratum corneum (SC), active compound flux across epidermal membranes and uptake of active and vehicle components into the SC were measured. The effect of vehicle pH on the permeation of caffeine and naproxen was also determined. RESULTS: Oleic acid and eucalyptol significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous controls. Naproxen permeation was increased from vehicles with pH presenting more ionized naproxen. Caffeine maximum flux enhancement was associated with an increase in caffeine SC solubility and skin diffusivity, whereas for naproxen a penetration enhancer/vehicle-induced increase in solubility in the SC correlated with an increase in maximum flux. SC solubility was related to experimentally determined active uptake, which was in turn predicted by vehicle uptake and active compound solubility in the vehicle. CONCLUSION: A permeation enhancer-induced alteration in diffusivity, rather than effects on SC solubility, was the main driving force behind increases in permeation flux of the hydrophilic molecule caffeine. For the more the lipophilic molecule naproxen, increased SC solubility drove the increases in permeation flux.

The Clinical Relevance and Therapeutic Benefit of Established Active Ingredients Incorporated into Advanced Foam Vehicles: Vehicle Characteristics Can Influence and Improve Patient Outcomes

Topical delivery of therapeutic agents for skin diseases is a major advantage in dermatology. However, the efficacy and tolerability of topically applied therapies is dependent on several characteristics, including percutaneous penetration and permeation of active ingredient and lack of side effects, especially local tolerability reactions. Importantly, the ultimate performance of a topical product includes collectively the effects of the active ingredient and the impact that specific additives have on vehicle characteristics, such as penetration, permeation, epidermal barrier properties, relative irritancy, allergenicity potential, and patient acceptance/preference of the vehicle formulation used. Foam vehicles have evolved over time with the emergence of a menu of alcohol-based and aqueous-based variations that provide various advantages depending on clinical circumstances and the disease being treated. Aqueous-based foams have gained widespread acceptance and preference, especially due to favorable skin tolerability and the cosmetic elegance of the products. In this manuscript, data are presented supporting the efficacy, tolerability, and safety, of specific aqueous-based foam vehicles for calcipotriene used to treat plaque psoriasis, and for tazarotene used to treat acne vulgaris. Discussions include both vehicle-based properties that are relevant to clinical practice, and outcomes from the large-scale pivotal clinical trials that review efficacy and safety results and patient reported outcomes. The latter also discusses several practical subject assessments about use of the foam vehicle. J Drugs Dermatol. 2019;18(2 Suppl):s100-107.

Overcoming Poor Tabletability of Bulky Absorption Enhancers by Spray Drying Technology.

Absorption enhancers are often a major component of solid oral peptide formulations as compared to the active pharmaceutical ingredient and excipients. This commonly results in poor tabletability that is hard to mitigate in direct compaction by addition of small amounts of excipients. To improve the tabletability of bulky absorption enhancers, the model absorption enhancers, sodium cholate and deoxycholic acid, were co-spray-dried with hydroxypropyl methylcellulose E5, where the percentage of absorption enhancers was not lower than 90% (w/w). The physicochemical properties of the resulting powders were assessed by laser diffraction, scanning electron microscopy, X-ray powder diffraction, thermogravimetric analysis, and differential scanning calorimetry. The powders were compressed into tablets, and the tabletability was evaluated. Co-spray drying with 10% of hydroxypropyl methylcellulose significantly improved the tabletability of the both absorption enhancers. Moreover, it was demonstrated that small particle size and amorphous state rather than high moisture content contributed to the improved tabletability of the spray-dried powders. The study suggests that spray drying technology can be promising to overcome the poor tabletability of oral peptide formulation consisting of large amounts of absorption enhancers.

The Role of Surface Active Agents in Ophthalmic Drug Delivery: A Comprehensive Review.

With the significant advances made in nanotechnology, research efforts focused on developing novel drug delivery platforms that can overcome the multitude of challenges encountered in ophthalmic drug delivery. Surface active agents (SAAs) have been extensively used for the formulation of many of the dosage forms targeting ocular tissues. Novel ophthalmic carriers utilizing SAAs were broadly classified into particulate, vesicular, and controlled release drug delivery systems. Depending on their physicochemical properties, SAAs can perform a variety of roles ranging from wetting agents, emulsifiers, stabilizers, charge inducers, solubilizers, antimicrobial agents, corneal permeation enhancers, and gelling agents. Nevertheless, their use is limited by their potential toxicity and possible interactions with other formulation ingredients. This review provides a comprehensive analysis of the different functional roles of SAAs in novel ophthalmic drug delivery platforms, their mechanism of action, and limitations that need to be considered during formulation to maximize their potential benefit. Understanding the mechanisms by which they perform their different roles and the possible interactions between SAAs and other formulation ingredients can help orientate the choice of formulators toward the SAA most suitable for the intended ocular application at a concentration that is both safe and effective.

Reconstituted Discoidal High-Density Lipoproteins: Bioinspired Nanodiscs with Many Unexpected Applications.

PURPOSE OF REVIEW: Summarize the initial discovery of discoidal high-density lipoprotein (HDL) in human plasma and review more recent innovations that span the use of reconstituted nanodisc HDL for membrane protein characterization to its use as a drug carrier and a novel therapeutic agent for cardiovascular disease. RECENT FINDINGS: Using a wide variety of biophysical techniques, the structure and composition of endogenous discoidal HDL have now largely been solved. This has led to the development of new methods for the in vitro reconstitution of nanodisc HDL, which have proven to have a wide variety of biomedical applications. Nanodisc HDL has been used as a platform for mimicking the plasma membrane for the reconstitution and investigation of the structures of several plasma membrane proteins, such as cytochrome P450s and ABC transporters. Nanodisc HDL has also been designed as drug carriers to transport amphipathic, as well as hydrophobic small molecules, and has potential therapeutic applications for several diseases. Finally, nanodisc HDL itself like native discoidal HDL can mediate cholesterol efflux from cells and are currently being tested in late-stage clinical trials for cardiovascular disease. The discovery of the characterization of native discoidal HDL has inspired a new field of synthetic nanodisc HDL, which has offered a growing number of unanticipated biomedical applications.

Influences of the vehicle in the spreading and release of betamethasone.

AIM: We compared the performances of two different commercial products both based on betamethasone and an antibiotic but using different pharmaceutical vehicles: a polymer and lipid-enriched cream and a conventional oil-in-water emulsion. METHODOLOGY: Evaluation was conducted on a reconstructed human epidermis model. Moreover, skin barrier properties and cutaneous hydration of the two vehicles were evaluated on 20 human healthy volunteers. RESULTS: Overall, the polymer and lipid-enriched formulation works as a film-forming product that retains the therapeutic agent for a long time, ensuring its penetration and absorption through the skin, and promoting skin hydration. CONCLUSION: The above characteristics are useful in the clinical setting, especially in the context of eczematous diseases with a strong xerotic component.

Postnatal steroids in extreme preterm infants: Intra-tracheal instillation using surfactant as a vehicle.

Chronic Lung Disease (CLD) is a common respiratory morbidity in survivors following extreme preterm birth, and is associated with adverse neurodevelopment in the long term. Besides demographics, multiple risk factors are implicated in the pathogenesis of CLD. However, early lung inflammation appears to be the common pathway that leads to the pathological and clinical changes observed in CLD. Postnatal use of systemic steroids has been successful in reducing the incidence of CLD but resulted in unacceptable adverse neurodevelopmental outcomes. The efficacy of inhaled steroids is not yet established. We review the evidence of tracheal instillation of steroids using surfactant as a lipid vehicle, including published data on drug distribution, in vitro physical studies, and clinical trials in animals and human infants.

Calcium hydroxide associated with a new vehicle: Psidium cattleianum leaf extracts. Tissue response evaluation.

The aim of this study was to evaluate edemogenic activity and subcutaneous inflammatory reaction induced by Psidium cattleianum leaf extracts associated with Ca(OH)2. Thirty male Wistar rats, split equally into three groups [aqueous extract + Ca(OH)2; ethanolic extract + Ca(OH)2; and propylene glycol + Ca(OH)2], were assessed every 3 h or 6 h (five animals in each period). Under general anesthesia, 0.2 mL of 1% Evans blue per 100 g of body weight was injected into the penile vein and each combination to be evaluated was subcutaneously injected into the dorsal region 30 min thereafter. Edemogenic activity was analyzed by spectrophotometry (λ=630 nm). For inflammatory reaction analysis, 50 rats received four polyethylene tubes (three experimental groups) and an empty tube (control group). The assessments were made at 7, 15, 30, 60, and 90 days, followed by hematoxylin-eosin staining and by the assignment of scores for evaluation of tissue response intensity. Ethanolic extract + Ca(OH)2 yielded the largest edemogenic activity at 3 h. Intergroup differences at 6 h were not significant. The histological analysis showed progressive repair over time (p<0.05) and aqueous and ethanolic extracts produced similar responses to those of the control and Ca(OH)2 + propylene glycol groups. Psidium cattleianum leaf extracts used as Ca(OH)2 vehicles evoked similar tissue response when compared to Ca(OH)2 associated with propylene glycol.

Cutaneous Penetration-Enhancing Effect of Menthol: Calcium Involvement.

Menthol is a naturally occurring terpene used as a penetration enhancer in topical and transdermal formulations. Literature shows a growing interest in menthol's interactions with the transient receptor potential melastatin 8. A decrease in extracellular Ca2+ due to the activation of the transient receptor potential melastatin 8 receptor produces inhibition of E-cadherin expression that is responsible for cell-cell adhesion. Because calcium is present in the entire epidermis, the purpose of this study is to evaluate whether the aforementioned properties of menthol are also related to its penetration-enhancing effects. We formulated 16 gels: (i) drug-alone (diphenhydramine or lidocaine), (ii) drug with menthol, (iii) drug, menthol, and calcium channel blocker (CCB; verapamil or diltiazem), and (iv) drug and CCB. In vitro studies showed no effect of the CCB on the release of the drugs either with or without menthol. In vivo experiments were performed for each drug/menthol/CCB combination gel by applying 4 formulations on a shaved rabbit's dorsum on the same day. Dermis concentration profiles were assessed with microdialysis. The gels containing menthol showed higher penetration of drugs than those without whereas the addition of the CCB consistently inhibited the penetration-enhancing effects of menthol. In summary, these findings strongly support the involvement of calcium in the penetration-enhancing effect of menthol.

A clinical evaluation of the pharmacokinetics and pharmacodynamics of intravenous alfaxalone in cyclodextrin in male and female rats following a loading dose and constant rate infusion.

OBJECTIVE: To characterise, as a clinical study, the pharmacokinetics and pharmacodynamics and describe the hypnotic effect of the neurosteroid alfaxalone (3α-hydroxy-5 α-pregnane-11, 20-dione) formulated with 2-hydroxypropyl-ß-cyclodextrin in male and female rats. STUDY DESIGN: Prospective, experimental laboratory study. ANIMALS: A total of 12 (six male and six female) adult, aged-matched Sprague Dawley rats. METHODS: Surgery and instrumentation was performed under isoflurane anaesthesia in an oxygen/nitrous oxide mixture (1:2) and local anaesthetic infiltration. All animals received a loading dose (1.67 mg kg-1 minute-1) for 2.5 minutes followed by a constant rate infusion (0.75 mg kg-1 minute-1) for 120 minutes of alfaxalone. Isoflurane and nitrous oxide was discontinued 2.5 minutes after the alfaxalone infusion started. Cardiorespiratory variables (heart rate, respiratory rate, arterial blood pressure and end tidal carbon dioxide tension) and clinical signs of anaesthetic depth were evaluated throughout anaesthesia. Carotid artery blood samples were collected at strategic time points for blood gas analysis, haematology, biochemistry, and plasma concentrations of alfaxalone. Plasma samples were assayed using liquid chromatography-mass spectrometry. RESULTS: There were significant differences between the sexes for plasma clearance (p=0.0008), half-life (p=0.0268) and mean residence time (p=0.027). Mean arterial blood pressure was significantly higher in the male rats (p=0.0255). CONCLUSIONS AND CLINICAL RELEVANCE: This study confirms that alfaxalone solubilised in 2-hydroxypropyl-ß-cyclodextrin provides excellent total intravenous anaesthesia in rats. Sex-based differences in pharmacokinetics and pharmacodynamics were demonstrated and must be considered when designing biomedical research models using alfaxalone.

Formulation and Optimization of Multiparticulate Drug Delivery System Approach for High Drug Loading.

The aim of the present work was to develop and optimize multiparticulate formulation viz. pellets of naproxen by employing QbD and risk assessment approach. Mixture design with extreme vertices was applied to the formulation with high loading of drug (about 90%) and extrusion-spheronization as a process for manufacturing pellets. Independent variables chosen were level of microcrystalline cellulose (MCC)-X 1, polyvinylpyrrolidone K-90 (PVP K-90)-X 2, croscarmellose sodium (CCS)-X 3, and polacrilin potassium (PP)-X 4. Dependent variables considered were disintegration time (DT)-Y 1, sphericity-Y 2, and percent drug release-Y 3. The formulation was optimized based on the batches generated by MiniTab 17 software. The batch with maximum composite desirability (0.98) proved to be optimum. From the evaluation of design batches, it was observed that, even in low variation, the excipients affect the pelletization property of the blend and also the final drug release. In conclusion, pellets with high drug loading can be effectively manufactured and optimized systematically using QbD approach.

Vehicle effects on human stratum corneum absorption and skin penetration.

This study evaluated the effects of three vehicles-ethanol (EtOH), isopropyl alcohol (IPA), and isopropyl myristate (IPM)-on stratum corneum (SC) absorption and diffusion of the [14C]-model compounds benzoic acid and butenafine hydrochloride to better understand the transport pathways of chemicals passing through and resident in SC. Following application of topical formulations to human dermatomed skin for 30 min, penetration flux was observed for 24 h post dosing, using an in vitro flow-through skin diffusion system. Skin absorption and penetration was compared to the chemical-SC (intact, delipidized, or SC lipid film) binding levels. A significant vehicle effect was observed for chemical skin penetration and SC absorption. IPA resulted in the greatest levels of intact SC/SC lipid absorption, skin penetration, and total skin absorption/penetration of benzoic acid, followed by IPM and EtOH, respectively. For intact SC absorption and total skin absorption/penetration of butenafine, the vehicle that demonstrated the highest level of sorption/penetration was EtOH, followed by IPA and IPM, respectively. The percent doses of butenafine that were absorbed in SC lipid film and penetrated through skin in 24 h were greatest for IPA, followed by EtOH and IPM, respectively. The vehicle effect was consistent between intact SC absorption and total chemical skin absorption and penetration, as well as SC lipid absorption and chemical penetration through skin, suggesting intercellular transport as a main pathway of skin penetration for model chemicals. These results suggest the potential to predict vehicle effects on skin permeability with simple SC absorption assays. As decontamination was applied 30 min after chemical exposure, significant vehicle effects on chemical SC partitioning and percutaneous penetration also suggest that skin decontamination efficiency is vehicle dependent, and an effective decontamination method should act on chemical solutes in the lipid domain.