OBJECTIVE Systematic reviews previously reported in the literature document that topical nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in relieving pain in acute and chronic painful musculoskeletal disorders including osteoarthritis, tendonitis, and muscle strains. Because several topical NSAIDs are available, with important differences among the formulations, there is a need to address and summarize the evidence of their effectiveness and safety. DESIGN We searched Medline and Cochrane CENTRAL databases for clinical trials and systematic reviews of topical NSAIDs in musculoskeletal pain, using the following keywords:"NSAID,"nonsteroidal,"antiinflammatory,"topical,"cream,"gel,"solution,"lotion,"patch,"plaster,"musculoskeletal,"tendonitis,"strain,"sprain,"trauma," and word roots "pain" and "arthritis." CONCLUSIONS Topical NSAIDs may vary significantly in their absorption kinetics and pharmacodynamic effects, based on NSAID molecule and the formulation chosen. Some topical NSAID formulations have been shown to be more effective than placebo in multiple studies, or to have comparable efficacy and a better safety profile than oral NSAIDs for single joint osteoarthritis and acute muscle injuries. In acute and chronic low back pain, widespread musculoskeletal pain, and in peripheral neuropathic pain syndromes, the current evidence does not support the use of topical NSAIDs.

The present study concerns the percutaneous absorption of naproxen (NPX), as model anti-inflammatory drug, included in liposome formulations constituted of different lipids: stratum corneum lipids (SCL) and phosphatidylcholine/cholesterol (PC/CHOL). Liposome dispersions were produced using two different methods: reverse-phase evaporation (REV) and thin layer evaporation (TLE). Morphology and dimensions of the disperse phase were characterized by cryo-transmission electron microscopy (cryo-TEM) and photon correlation spectroscopy, respectively. X-ray diffraction was employed to determine the structural organization of the vesicles. In vitro diffusion was studied by Franz cell on liposome dispersions viscosized by carbomer. Tape stripping was performed to investigate in vivo the performance of differently composed liposomes as NPX delivery system. Cryo-TEM showed spherical vesicles and bigger irregular elongated nanoparticles for TLE SCL liposomes. REV resulted in spherical and elongated multilamellar vesicles. Also X-ray diffraction evidenced L alpha or L beta multilamellar vesicles for PC/CHOL and SCL liposome respectively. The in vitro study showed a lower NPX flux for SCL with respect to PC/CHOL liposome. Tape stripping corroborate the in vitro findings regarding SCL, suggesting that liposomes create a drug reservoir mixing with SC lipids, whilst PC/CHOL liposome promoted NPX permeation through the skin. Liposome lipid composition seems to affect NPX permeation through the skin.

Transdermal drug delivery is an attractive alternative to conventional techniques for administration of systemic therapeutics. One challenge in designing transdermal drug delivery systems is to overcome the natural transport barrier of the skin. Chemicals offer tremendous potential in overcoming the skin barrier to enhance transport of drug molecules. Individual chemicals are however limited in their efficacy in disrupting the skin barrier at low concentrations and usually cause skin irritation at high concentrations. Multicomponent mixtures of chemicals, however, have been shown to provide high skin permeabilization potency as compared to individual chemicals without necessarily causing irritation. Here we review systems employing synergistic mixtures of chemicals that offer superior skin permeation enhancement. These synergistic systems include solvent mixtures, microemulsions, eutectic mixtures, complex self-assembled vesicles and inclusion complexes. Methods for design and discovery of such synergistic systems are also discussed.

Human skin is a remarkably efficient barrier designed to keep our insides in and the outside out. The modulation of this efficient barrier's properties, including its permeability to chemicals, drugs and biologically active agents is the prime target for various dermal, transdermal, drug, antigen and gene delivery approaches. Therefore, several methods have been attempted to enhance the permeation rate of biologically active agents, temporarily and locally. One of the approaches is the application of drug-laden vesicular formulations. This review presents various mechanisms involved in increasing drug transport across the skin via different vesicular approaches, such as liposomes, elastic vesicles and ethosomes, along with compiling the research work conducted in this field.

The present mini-review explores the current methods used for the delivery of antiseptics and topical antimicrobials. Relevance of hand scrub with antiseptic liquid soap (e.g. chlorhexidine, PVP-iodine, triclosan) and alcohol-based hand rub is discussed and compared in terms of bactericidal activity, skin tolerance, and medical staff observance. New strategies for antibacterial delivery focus on the challenge of colloidal drug carrier such as liposomes, micro- and nanoparticles enabling sustained bactericidal effect and effective bacterial targeting.

PURPOSE: The present study concerns the production and characterization of monooleine (MO) dispersions as drug delivery systems for indomethacin, taken as model anti-inflammatory drug. METHODS: Dispersions were produced by emulsification and homogenization of MO and poloxamer in water. Morphology and dimensional distribution of the disperse phase have been characterized by cryo-transmission electron microscopy and photon correlation spectroscopy, respectively. X-ray diffraction has been performed to determine the structural organization of the disperse phase. Sedimentation field flow fractionation (SdFFF) has been performed to investigate drug distribution in the dispersion. An in vitro diffusion study was conducted by Franz cell associated to stratum corneum epidermis membrane on cubosome dispersions viscosized by carbomer. In vivo studies based on skin reflectance spectrophotometry and tape stripping were performed to better investigate the performance of cubosome as indomethacin delivery system. RESULTS: Microscopy studies showed the coexistence of vesicles and cubosomes. X-ray diffraction revealed the presence of a bicontinuous cubic phase of spatial symmetry Im3m (Q(229)). SdFFF demonstrated that no free drug was present in the dispersion. Indomethacin incorporated in viscosized MO dispersions exhibited a lower flux with respect to the analogous formulation containing the free drug in the aqueous phase and to the control formulation based on carbomer gel. Reflectance spectroscopy demonstrated that indomethacin incorporated into MO dispersions can be released in a prolonged fashion. Tape-stripping experiments corroborated this finding. CONCLUSIONS: MO dispersions can be proposed as nanoparticulate systems able to control the percutaneous absorption of indomethacin.

We have investigated the influence of charge and lipid concentration on the in-vivo percutaneous absorption of a model compound, methyl nicotinate (MN), from liposomal vesicles. MN-loaded liposomes were produced by the reverse-phase evaporation method (REV) using different concentrations of phosphatidyl choline (PC), in association with surfactants such as dioctadecyl dimethyl ammonium bromide (DDAB18) and dicetyl phosphate (DCP), which impart a positive or negative charge to the systems, respectively. The liposomal suspensions were then processed to hydrogels and used to study in-vivo the MN permeation profile. MN was chosen as the model compound since it was capable of causing cutaneous erythema, the intensity and duration of which was proportional to the amount entering the living epidermis over time. The extent of the erythema was monitored by reflectance spectrophotometry, a non-invasive technique. In-vivo findings showed an interesting MN delayed release, which was proportional to the amount of phospholipids in each liposomal formulation. Furthermore, it could be noted that the erythematous effect was more prolonged when MN was delivered from neutral or negatively-charged liposomal forms.

The aim of this study was the evaluation, in vitro and in vivo, of indomethacin (IND) release through the skin from nanostructured lipid carriers (NLC). NLC were prepared by ultrasonication, and were characterized in order to determine drug content, and particle size; finally the NLC were processed to hydrogels (A and B). The IND release pattern from NLC hydrogels was evaluated in vitro, to determine its percutaneous absorption through excised human skin (stratum corneum and epidermis, SCE), and in vivo. To evaluate the in vivo IND release, two methods were employed:(1) the IND topical anti-inflammatory activity was determined at different time-points after its cutaneous application; in this case, the UVB-induced erythema on healthy human volunteers, chosen as inflammatory model, was monitored by reflectance visible spectrophotometry;(2) the extent of IND absorption into human skin was performed by the tape-stripping technique. The in vitro percutaneous absorption studies showed lower fluxes of IND through SCE membranes from NLC hydrogels (A and B) in comparison to an aqueous dispersion (C) and a hydro-alcoholic gel (D) both containing free IND. The findings from the former in vivo method showed that the anti-inflammatory effect, following IND topical application, was more prolonged with IND-loaded NLC gel formulation (A) if compared to formulation C and D. The results from tape stripping technique confirmed the trend obtained by the former in vivo method and indicated that IND topical bioavailability in the stratum corneum varied substantially depending upon the formulations (A-D).

Three oily extracts, obtained by acetone extraction from the entrails of different varieties of Mediterranean fishes, such as mackerel (Scomber scombrus), sardine (Sardina pilchardus) and horse mackerel (Trachurus mediterraneus), were characterized to determine their unsaturated fatty acid content. In an in-vitro model, their inhibitory effect was then evaluated against protein aggregation and their protective efficacy against heat-induced albumin denaturation assessed. The fish oil extracts tested in this study presented a significant amount of unsaturated fatty acids; in particular the extract obtained from the entrails of horse mackerel proved to have higher concentrations of DHA (docosahexaenoic acid) and oleic acid compared with the other two oils. The in-vitro study revealed an interesting protective effect of the oil extracts (particularly the horse mackerel extract) against heat-induced denaturation of albumin.

The antiallergic properties of two lyophilized extracts obtained from Capparis spinosa L. flowering buds (capers) by methanol extraction, carried out at room temperature (CAP-C) or with heating at 60 degrees C (CAP-H), were investigated. The protective effects of CAP-H and CAP-C, orally administered (14.28 mg[sol ]kg), were evaluated against Oleaceae antigen challenge-induced and histamine-induced bronchospasm in anaesthetized guinea-pigs. Furthermore, the histamine skin prick test was performed on humans, applying a gel formulation containing 2% CAP-C (the only extract able to protect against histamine-induced bronchospasm) on the skin for 1 h before histamine application and monitoring the erythema by reflectance spectrophotometry. The CAP-H showed a good protective effect against the bronchospasm induced by antigen challenge in sensitized guinea-pigs; conversely, a significant decrease in the responsiveness to histamine was seen only in CAP-C pretreated animals. Finally, the CAP-C gel formulation possessed a marked inhibitory effect (46.07%) against histamine-induced skin erythema. These two caper extracts displayed marked antiallergic effectiveness; however, the protective effect of CAP-H was very likely due to an indirect mechanism (for example, inhibition of mediator release from mast cells or production of arachidonic acid metabolites); conversely, CAP-C is endowed with direct antihistaminic properties. The different mechanisms of action of CAP-H and CAP-C may be related to a difference in the extraction procedure and, thus, in their qualitative[sol ]quantitative chemical profile.

Several pathological conditions have all been associated with a higher release of atmospheric pollutants. There is growing evidence that oxidative stress may represent one of the agents involved in the initiation and/or progression of many of these pathologies. The aim of the present study was to evaluate the effects of short-term dietary supplementation with a standardised red orange extract (ROC) on a group of traffic police officers exposed to traffic exhaust pollution and cigarette smoking, by measuring some noninvasive biomarkers of oxidative stress. At the beginning of the study, all the groups showed similar serum lipid hydroperoxide levels, but traffic officers showed lower serum concentrations of thiol (SH) groups; furthermore, the frequency of spontaneous sister chromatide exchanges (SCEs) in peripheral lymphocytes was increased by smoking (but not by pollution exposure alone) at a higher degree in subjects exposed to traffic pollution. After 1 month of ROC administration, serum lipid hydroperoxide levels decreased only in all non-smoking subjects; furthermore, SH group levels measured in traffic officers appeared restored to normal values observed in the respective controls. Finally, the increase in SCE frequency induced by smoking was reduced by treatment with ROC especially in traffic officers. Our study suggests that ROC supplementation could be useful to minimise the detrimental effects caused by exposure to air pollution and smoking.

The present article reports the antimicrobial efficacy of four monoterpenes (thymol, carvacrol, p-cymene, and gamma-terpinene) against the Gram-positive bacterium Staphylococcus aureus and the Gram-negative bacterium Escherichia coli. For a better understanding of their mechanism of action, the damage caused by these four monoterpenes on biomembranes was evaluated by monitoring the release, following exposure to the compounds under study, of the water-soluble fluorescent marker carboxyfluorescein (CF) from large unilamellar vesicles (LUVs) with different lipidic composition (phosphatidylcholine, PC, phosphatidylcholine/phosphatidylserine, PC/PS, 9:1; phosphatidylcholine/stearylamine, PC/SA, 9:1). Furthermore, the interaction of these terpenes with dimyristoylphosphatidylcholine multilamellar vesicles as model membranes was monitored by means of differential scanning calorimetry (DSC) technique. Finally, the results were related also with the relative lipophilicity and water solubility of the compounds examined. We observed that thymol is considerably more toxic against S. aureus than the other three terpenes, while carvacrol and p-cymene are the most inhibitory against E. coli. Thymol and carvacrol, but not gamma-terpinene and p-cymene, caused a concentration-dependent CF leakage from all kinds of LUVs employed; in particular, thymol was more effective on PC and PC/SA LUVS than on PC/PS vesicles, while carvacrol challenge evoked a CF leakage from PC/PS LUVs similar to that induced from PC/SA LUVs, and lower than that measured with PC vesicles. Concerning DSC experiments, these four terpenes caused a decrease in Tm and (especially carvacrol and p-cymene) DeltaH values, very likely acting as substitutional impurities. Taken together, our findings lead us to speculate that the antimicrobial effect of thymol, carvacrol, p-cymene, and gamma-terpinene may result, partially at least, from a gross perturbation of the lipidic fraction of the plasmic membrane of the microorganism. In addition to being related to the physicochemical characteristics of the compounds (such as lipophilicity and water solubility), this effect seems to be dependent on the lipidic composition and net surface charge of the microbic membranes. Furthermore, the compounds might cross the cell membranes, thus penetrating into the interior of the cell and interacting with intracellular sites critical for antibacterial activity.

In the present paper, we report the antimicrobial efficacy of three monoterpenes [linalyl acetate,(+)menthol, and thymol] against the gram-positive bacterium Staphylococcus aureus and the gram-negative bacterium Escherichia coli. For a better understanding of their mechanisms of action, the capability of these three monoterpenes to damage biomembranes was evaluated by monitoring the release, following exposure to the compounds under study, of the water-soluble fluorescent marker carboxyfluorescein from unilamellar vesicles with different lipidic compositions (phosphatidylcholine, phosphatidylcholine/phosphatidylserine [9:1], phosphatidylcholine/stearylamine [9:1], and phosphatidylglycerol/cardiolipin [9:1]). Furthermore, the interaction of the terpenes tested with dimyristoylphosphatidylcholine multilamellar vesicles as model membranes was monitored by means of differential scanning calorimetry. Finally, the results were related to the relative lipophilicity and water solubility of the compounds examined. Taken together, our findings lead us to speculate that the antimicrobial effect of (+)menthol, thymol, and linalyl acetate may result, at least partially, from a perturbation of the lipid fraction of microorganism plasma membrane, resulting in alterations of membrane permeability and in leakage of intracellular materials. Besides being related to physicochemical characteristics of the drugs (such as lipophilicity and water solubility), this effect seems to be dependent on lipid composition and net surface charge of microbial membranes. Furthermore, the drugs might cross the cell membranes, penetrating into the interior of the cell and interacting with intracellular sites critical for antibacterial activity.

Six ketoprofen (CAS 22071-15-4) alkylazacycloalkan-2-one ester derivatives (I-VI) were synthesized and evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities after oral administration. Furthermore these derivatives were assayed to determine in vitro their stability in pH 7.4 phosphate buffer and in simulated gastric fluid (pH 2.0 buffer) and their susceptibility to enzymatic cleavage in rat plasma. All the prodrugs showed a good stability both in pH 7.4 phosphate buffer and in pH 2.0 buffer, and they were readily hydrolyzed by rat plasma. Esters I-VI showed an anti-inflammatory activity, determined as the percent of inhibition of carrageenan-induced edema, similar to that of ketoprofen, although at higher doses. They were significantly less irritating to the gastric mucosa than the parent drug. In the mouse acetic acid induced writhing assay, the prodrugs exhibited, following acute administration, a good analgesic activity.

The aim of the present study was to evaluate the in vitro antioxidant and in vivo photoprotective activities of an ethanolic extract of Culcitium reflexum H.B.K. leaves (ECR extract). The antioxidant activity of the extract was assessed by means of three different in vitro tests:(1) bleaching of the stable 1,1-diphenyl-2-picrylhydrazyl radical;(2) peroxidation, induced by the water-soluble radical initiator 2,2'-azobis(2-amidinopropane)hydrochloride, on mixed dipalmitoylphosphatidylcholine/linoleic acid unilamellar vesicles;(3) UV radiation-induced peroxidation in phosphatidylcholine multilamellar vesicles. In all in vitro tests used the ECR extract showed a significant antioxidant effect. Furthermore, a gel formulation containing this extract proved, when topically applied, to afford a significant in vivo protection against UV-B-induced skin erythema in healthy human volunteers. Then, by chromatographic fractionation and spectroscopic methods, we identified some cinnamic acid derivatives and the major flavonoid constituents of the ECR extract, viz. the flavonols rutin, quercetin-3-O-beta-D-galactopyranoside-4'-O-beta-D-glucopyranoside, quercetin-3-O-beta-D-glucopyranoside, isorhamnetin-3-O-beta-D-galactopyranoside, quercetin and kaempferol.

BACKGROUND Gelatin tannate is a mixture of tannic acid and gelatin. Tannic acid has astringent properties, due to its capacity to form protein-macromolecular complexes, as well as antibacterial and antioxidant properties. However, little is known about its anti-inflammatory properties. PURPOSE To evaluate the anti-inflammatory activity of gelatin tannate by quantifying the suppression of key molecules produced during inflammatory events in lipopolysaccharide (LPS)-stimulated human intestinal cells. METHODS Intercellular adhesion molecule-1 (ICAM-1) expression was determined by Western blot analysis; interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α) concentrations were measured by enzyme-linked immunosorbent assays in Caco-2 cells 24 hours after treatment with LPS (1 μg/mL) in presence of different concentrations of gelatin tannate. RESULTS ICAM-1 is induced on a wide variety of cells by inflammatory stimuli such as LPS. Our results have shown gelatin tannate as a potent inhibitor of ICAM-1 expression in LPS-stimulated Caco-2 cells. IL-8 and TNF-α are important inflammatory mediators, recruiting neutrophils and T-lymphocytes. Together with LPS, adding gelatin tannate at different concentrations induced a dose-dependent inhibition of IL-8 and TNF-α released by Caco-2 cells. CONCLUSION These results suggest that gelatin tannate exerts anti-inflammatory effects by inhibiting the specific cytokines and adhesion molecules involved in several inflammatory disorders.

The natural p300-specific histone acetyltransferase (HAT) inhibitor, curcumin (CUR), has been widely investigated for its potential therapeutic effect as an anticancer and anti-inflammatory agent. Notwithstanding this interesting pharmacological profile, CUR shows some drawbacks, such as poor absorption and a very fast metabolism and elimination, that limit its clinical use. Aim of the present study was to formulate CUR loaded nanostructured lipid carriers (NLC-CUR) in order to improve the bioavailability and stability of this compound after systemic administration with increased effects in the central nervous system (CNS). NLC-CUR were prepared and characterized on their physicochemical properties by PCS and DSC analyses. Thus, NLC-CUR were systemically injected and the effects in the CNS were compared with a CUR control formulation containing 0.05% DMSO (DMSO-CUR). Our results demonstrate that CUR is able to decrease histone acetylation in the CNS when included in NLCs. Western blot analysis shows that intraperitoneal injection of NLC-CUR (100mg/kg) in mice induces a marked hypoacetylation of histone 4 (H4) at lysine 12 (K12) in the spinal cord compared with control group. Notably, DMSO-CUR (100mg/kg) did not change the H4K12 acetylation level in the CNS. Our study suggests a novel approach to ameliorate the pharmacokinetics of CUR that allows a better permeation in the CNS.

INTRODUCTION: Lipid nanoparticles are innovative carrier systems developed as an alternative to traditional vehicles such as emulsions, liposomes and polymeric nanoparticles. Solid lipid nanoparticles (SLN) and the newest nanostructured lipid carriers (NLC) show important advantages for dermal application of cosmetics and pharmaceuticals. AREA COVERED: This article focuses on the main features of lipid nanoparticles, in terms of their preparation and recent advancements. A detailed review of the literature is presented, introducing the importance of these systems in the topical delivery of drugs and active substances. EXPERT OPINION: Lipid nanoparticles are able to enhance drug penetration into the skin, allowing increased targeting to the epidermis and consequently increasing treatment efficiency and reducing the systemic absorption of drugs and cosmetic actives. The complete biodegradation of lipid nanoparticles and their biocompatible chemical nature have secured them the title of 'nanosafe carriers.' SLN and NLC represent a new technological era, which has been taken over by the cosmetic and pharmaceutical industry, which will open new channels for effective topical delivery of substances.

There is today a very great deal of interest among members of the global natural products community in investigating new plant constituents. Recent studies demonstrate that liquorice extracts are useful in the treatment of dermatitis, eczema, and psoriasis, with an efficacy comparable to that of corticosteroids. In this work, niosomes made up of surfactants (Tween 85 and Span 20) and cholesterol at various concentrations were prepared to investigate the potential application of niosomes for the delivery of ammonium glycyrrhizinate (AG), useful for the treatment of various inflammatory based diseases. Vesicle were characterized evaluating dimensions, ζ potential, anisotropy, drug entrapment efficiency, stability, citotoxicity evaluation and skin tolerability. Release profiles of ammonium glycyrrhizinate/niosomes were evaluated in vitro using cellulose membranes. The best formulation was used to evaluate the in vitro/in vivo efficacy of the ammonium glycyrrhizinate/niosomes in murine and human models of inflammation The AG-loaded non-ionic surfactant vesicles showed no toxicity, good skin tolerability and were able to improve the drug anti-inflammatory activity in mice. Furthermore, an improvement of the anti-inflammatory activity of the niosome delivered drug was observed on chemically induced skin erythema in humans.

The d-vitamin analogue calcipotriol is commonly used for topical treatment of psoriasis, but skin penetration is required for calcipotriol to reach its pharmacological target: the keratinocytes in the lower epidermis. Liposomes can enhance the delivery of drugs into the skin, but a major challenge for the development of dosage forms containing liposomes is to maintain the colloidal stability in the formulation. The purpose of this study was to investigate the effect of stabilising liposomes with the lipopolymer poly(ethylene glycol)-distearoylphosphoethanolamine (PEG-DSPE) on the physicochemical properties of the liposomes and the ability to deliver membrane-intercalated calcipotriol into the skin. Inclusion of 0.5, l and 5mol% PEG-DSPE in the membrane enhanced the colloidal stability of the liposomes without compromising the delivery of calcipotriol from the vehicle into excised pig skin. Calcipotriol-loaded liposomes with 1mol% PEG-DSPE did even provide for a significantly increased deposition of calcipotriol into the stratum corneum. The size of the liposomes affected the penetration of calcipotriol into the stratum corneum since small unilamellar vesicles enhanced calcipotriol penetration as compared to large multilamellar vesicles, indicating that the liposomes to some extent migrate as intact vesicles into the stratum corneum. However, calcipotriol penetrated the skin better than the lipid component of the liposomes, suggesting that at least a fraction of the drug is released from the liposomes during skin migration. In conclusion, PEGylation is therefore a promising approach for stabilising calcipotriol-containing liposomal dispersions without compromising their favourable skin accumulation properties.

Local intravaginal drug therapy is preferred for treatment of ascending genital infections during pregnancy. In the present study, an in situ forming biodegradable hydrogel for sustained release of amoxicillin in the cervicovaginal region is described. A generation 4 poly(amidoamine)[G4-(NH(2))(64)] dendrimer with peripheral thiopyridyl terminations is cross-linked with 8-arm polyethylene glycol (PEG) bearing thiol terminations. The hydrogels were formulated and tested in vivo in a pregnant guinea pig model for volume, retention times, biodegradation, tolerability and transport across fetal membrane. The physicochemical characterization of the hydrogels was carried out using differential calorimetry, SEM, and confocal imaging. The hydrogels offer antibacterial activity arising from sustained release of amoxicillin from gels. The in vivo studies in guinea pig showed that 100-200 μL of gel sufficiently covered the cervicovaginal region with a residence time of at least 72 h and gel was primarily retained in the maternal tissues without crossing the fetal membranes into the fetus. The dendrimer gels were stable up to 72 h, and the in vivo biodegradation of gel occurred after 72 h; this correlated well with the in vitro degradation pattern. The pH of the vagina was not altered upon application of the gel, and none of the animals aborted up to 72 h after application of gel. The histological evaluation of the cervical tissues showed absence of edema in the epithelial cell layer, no sloughing of the epithelial or superficial mucous layer, and absence of necrosis and infiltration of inflammatory cells in the submucosal layers, confirming that tissues were tolerant to the gel. The immunohistofluorescence images showed the localization of the gel components on the superficial mucified epithelial layer. The cross-linking density and swelling of hydrogels was impacted by the polymer content, and the 10% hydrogels exhibited the highest cross-link density. The in vitro drug release studies carried out using Franz diffusion cells showed that amoxicillin release from 6 and 10% gels was sustained for 240 h as compared to 3% gels. As the polymer concentration increased to 10%, the release pattern from gels approached diffusion controlled mechanism with diffusional exponent n = 0.49. In conclusion, the biodegradable in situ forming hydrogels of the present study offer a therapeutic option to provide sustained localized delivery of amoxicillin intracervically to the pregnant woman for the treatment of ascending genital infections.

A gallate derivative with three propargyl groups was coupled to palmitoyl oleoyl phosphoethanolamine (POPE). The resulting anionic lipid was formulated with common lipids such as palmitoyl oleoyl phosphatidyl choline (POPC) to form large unilamellar vesicles (LUVs). Polymerization of the LUVs was accomplished by the Cu(I)-catalyzed click reaction between the propargyl groups and the azide groups in the cross-linker. When the cross-linker contained a disulfide or ketal group, the resulting polymerized liposomes depolymerized and released entrapped contents upon the addition of a reducing thiol or under weakly acidic conditions. The click reaction allowed simultaneous multivalent surface functionalization during cross-linking, making these cleavable polymerized liposomes (CPLs) potentially very useful in the delivery and controlled release of pharmaceutical agents.

Objectives This study aimed to investigate the distribution and release profile in the skin of a lipophilic model molecule, octylmethoxycinnamate (OMC), loaded in poly(epsilon-caprolactone) nanocapsules (NC) by the Franz cell method. Methods Nanocapsules were formulated in a hydroxyethylcellulose gel and compared to the same gel containing 5% of free OMC as control. A new extraction method was used to discriminate the OMC still entrapped in the NC from free OMC released in the skin strata. The OMC extraction from the skin was performed using acetonitrile, which broke the NC, or isopropyl myristate, which kept the NC intact. Key findings When isopropylmyristate was used to determine the OMC released from NC, the results showed that more than 80% of the OMC was released from the NC at the skin surface after 6 h, whereas only 30% was released in the stratum corneum and epidermis. Conclusions It is suggested that the mechanism of release is different at the surface and in viable skin, probably due to the different local environments surrounding the NC. The small amount of OMC that reached the dermis was no longer encapsulated, suggesting that the NC did not reach the dermis. The viable epidermis seemed to be the limiting barrier against NC diffusion into the skin.

It has been shown that mixtures of palmitic acid (PA) and cholesterol (Chol) or cholesterol sulfate (Schol) can form fluid bilayers. These bilayers could be extruded using standard extrusion techniques to obtain nonphospholipid large unilamellar vesicles (LUVs). These LUVs displayed a very limited passive permeability, associated with their high sterol content (typically 70 mol %). In addition, they showed a pH-dependent behavior dictated by the electrostatic interfacial interactions, which are drastically modulated by the protonation state of PA. Interestingly, the LUVs prepared with cholesterol were stable at high pH and the release of the content could be triggered by a pH decrease (i.e., the protonation of PA). In contrast, the LUVs including Schol were stable at low pH and a pH increase (leading to the deprotonation of PA) would induce the release. In the present study, we demonstrate that the pH triggering the release in these two systems can be dictated in a predictable manner by selecting a fatty acid with an appropriate pK(a). The pK(a) of the fatty acids was modulated by the presence of an electro-withdrawing group (hydroxyl or fluoro) in the alpha position of the carboxylic function. The fatty acid protonation state is shown to be a critical factor for the modulation of the liposome permeability. The described systems display a remarkable versatility regarding the pH-sensitivity because the nature of the sterol controls the overall pH stability of the LUVs while the fatty acid pK(a) fine-tunes the pH-induced release. Therefore, it is possible to rationally design LUVs with controlled release at a specific pH; this original aspect is beneficial to the use of LUVs for encapsulation, vectorization, and controlled release of active agents.

Fatty acids have been widely used as adjuvant, vehicles in drug delivery viz penetration enhancers in topical delivery and in polymeric micelles to provide sustained release. However, the present investigation aims at exploring the potential of fatty acid vesicles for the topical delivery of fluconazole. Vesicles were prepared by film hydration method using oleic acid as a fatty acid principal component. Developed vesicles were characterized for size, size distribution, shape, in vitro release, pH dependent and storage stability, skin irritation study, and ex-vivo skin permeation. Penetration behavior of vesicles was further evaluated and elucidated using confocal microscopic study. Optical microscopy and TEM studies confirmed vesicular dispersion of fatty acid. The vesicles possessed higher entrapment efficiency (44.11%) with optimum vesicle size and homogeneity in regard to size distribution (PDI = 0.234 +/- 0.016) at 7:3 oleic acid-to-fluconazole ratio. In vitro drug release study suggested sustained release of drug from the vesicles. The release pattern followed Higuchian kinetics. The vesicles were fairly stable at refrigerated conditions. Ex-vivo skin permeation and confocal microscopic studies suggested that oleic acid vesicles penetrate the stratum corneum and retain the drug accumulated in the epidermal part of the skin. On the basis of sustained release behavior and skin retention it can be inferred that oleic acid vesicles can serve as a potential carrier for the topical localized delivery of bioactives.

Nitric oxide (NO) is a gaseous molecule that has specific functions dictated by its localization and its kinetics of release. As NO-donors have a range of potential uses in the skin, much attention has been paid to the development of topical NO delivery systems. The aim of this work was to study the release rate and the skin penetration of the NO-donor cis-[Ru(NO(2))(bpy)(2)(4-pic)](+) from different gel formulations and their potential as topical NO delivery systems under light stimuli. Among the formulations developed, the anionic gel retarded the nitro-ruthenium complex diffusion and also obstructed NO release after light irradiation. On the other hand, NO release before light irradiation was observed when the complex was dispersed in the cationic chitosan gel, possibly due to oxi-redox reactions between the amino groups of the polymer and the drug molecule. Finally, the non-ionic gel released the NO after light irradiation to the same extent as a drug aqueous solution at the same pH. The drug dispersed in this gel also penetrated into the stratum corneum skin layer, and the nitro-ruthenium complex present in the skin was able to release the NO after light stimuli, suggesting the potential use of this formulation as a topical NO delivery system.

Nano-emulsions are innovative colloidal systems characterized by high kinetic stability, low viscosity, and optical transparency, which make them very attractive in many dermatological applications. Furthermore their small size seems to favor the topical administration of actives which scarcely cross the skin. In the light of these interesting features, the present study was aimed to the evaluation, in vitro and in vivo, of glycyrrhetic acid (GA) release through the skin from the nanoemulsion system. GA-loaded nanoemulsion (GA(N)) was prepared by phase inversion temperature (PIT) method, and was characterized in order to determine mean droplet size and its stability during a well-defined storage period. Further Cryo-TEM studies were performed to obtain information regarding nanoemulsion structure. The GA release pattern from nanoemulsion was evaluated in vitro, to determine its percutaneous absorption through excised human skin (stratum corneum and epidermis, SCE), and in vivo evaluating GA topical anti-inflammatory activity on healthy human volunteers by the UVB-induced erythema model. Nanoemulsions prepared by PIT method showed a mean droplet diameter of 210 nm that drastically changed during a storage of 5 weeks at room temperature. In vitro and in vivo evidence showed that the nanoemulsion system significantly increased the transdermal permeability of GA in comparison to a control O/W emulsion (GA(O/W)) containing the same amount of active compound.

The successful application of liposomes in topical ophthalmic drug delivery requires knowledge of vesicle stabilization in the presence of tear fluid. The release of procaine hydrochloride (PCH) from large unilamellar liposomes in the presence of simulated tear fluid was studied in vitro as a function of bilayer lipid content and tear protein composition. Reverse-phase evaporation vesicles were prepared from egg phosphatidylcholine, stearylamine or dicetyl phosphate, and cholesterol. The relationship between lipid composition and encapsulation efficiency, vesicle size, drug leakage upon storage at 4 degrees C, and the release of PCH-loaded liposomes was studied. The encapsulation efficiency was found to be dependent upon the lipid composition used in the liposome preparation. In particular, phosphatidylcholine vesicles containing cholesterol and/or charged lipids had a lower entrapment efficiency than liposomes prepared with phosphatidylcholine alone. However, the drug release rate was reduced significantly by inclusion of cholesterol and/or charged lipids in the liposomes. The release kinetics of the entrapped agent seemed to be a biphasic process and the drug-release in both simulated tear fluid (STF) and pH 7.4 phosphate buffered saline (PBS) solutions followed pseudo first-order kinetics in the early stage of the release profile. The drug-release appeared to be diffusion and/or partition controlled. Drug release from liposomes into STF, pH 7.4 PBS, and five different modified tear formulations was also evaluated. While serum-induced leakage is attributed to high-density lipoprotein-mediated destabilization, it was determined that lactoferrin might be the protein component in tear fluid that has the primary influence on the liposome-entrapped drug release rate. Five local anesthetics, benoxinate, proparacaine, procaine, tetracaine, and benzocaine were entrapped in liposomal vesicles by a reverse-phase evaporation (REV) technique. The release of these structurally similar topical anesthetics entrapped in positively charged liposomes (egg phosphatidylcholine, stearylamine, and cholesterol in a 7:2:1 molar ratio) was evaluated in a simulated tear fluid and pH 7.4 phosphate buffered saline solution. The liposomes appeared to be useful carriers for these drugs to retard their in vitro release in tear fluid and perhaps sustain or control their release in the eye for better therapeutic efficacy. An analysis of the release data demonstrated that for this series of drugs, drug partition coefficient has the largest effect on release rate, with molecular weight exhibiting a smaller effect. Release rate was found to decrease with increased lipophilicity or increased molecular weight.