Dissolution and pharmacokinetics of a novel micronized aspirin formulation

Aspirin (acetylsalicylic acid, ASA) has been used as an analgesic, antipyretic and antiinflammatory drug for many years. A new 500 mg aspirin tablet formulation containing micronized active ingredient and an effervescent component has been developed for potential improvement in the onset of action for acute pain treatment. This paper describes the dissolution and the pharmacokinetics of the new formulation in comparison with regular aspirin tablets, aspirin granules and aspirin effervescent tablets. Micronized aspirin tablets dissolve significantly faster over a pH range from 1.2 to 6.8 compared to regular 500 mg aspirin tablets. Plasma concentration time curve comparison to regular 500 mg aspirin tablets showed a substantial improvement in the time to maximum plasma concentrations (T(max)) (ASA 17.5 min vs. 45 min) and an increase in maximum plasma concentration (C(max)) (ASA 13.8 μg/ml vs. 4.4 μg/ml) while the overall extent of exposure (AUC) remains almost unchanged. The data suggest a potential improvement for onset of action in treating acute pain with the new micronized aspirin formulation.     

Human skin penetration of cobalt nanoparticles through intact and damaged skin

Cobalt nanoparticles (CoNPs) are produced for several industrial and biomedical applications but there is a lack of data on human cutaneous absorption. Cobalt is also a skin sensitizer that can cause allergic contact dermatitis. Co applied as NPs, due to their small size and high surface, can penetrate into the skin in higher amount that bulk material. The aim of this study was to evaluate the absorption of Co applied as NPs in both intact and damaged skin. Experiments were performed using Franz cells and 1.0 mg cm^?2 of CoNPs was applied as donor phase for 24 h. Mean Co content of 8.5 ± 1.2 ng cm^?2 and 1.87 ± 0.86 μg cm^?2 were found in the receiving solutions of Franz cells when the CoNPs suspension was applied on intact skin and on damaged skin, respectively. Twenty-four hours Co flux permeation was 76 ± 49 ng cm^?2 h^?1 in damaged skin with a lag time of 2.8 ± 2.1 h. This study suggests that Co applied as NPs is able to penetrate the human skin in an in vitro diffusion cell system.     

Human skin penetration of gold nanoparticles through intact and damaged skin

Gold nanoparticles (AuNPs) are produced for many applications but there is a lack of available data on their skin absorption. Experiments were performed using the Franz diffusion cell method with intact and damaged human skin. A physiological solution was used as receiving phase and 0.5 mL (1st exp) and 1.5 mL (2nd exp) of a solution containing 100 mg L?1 of AuNPs (15 and 45 μg cm?2, respectively) was applied as donor phase to the outer surface of the skin for 24 h. Skin absorption was dose dependent. Mean gold content of 214.0 ± 43.7 ng cm?2 and 187.7 ± 50.2 ng cm?2 were found in the receiving solutions of cells where the AuNPs solution was applied in higher concentration on intact skin (8 Franz cells) and on damaged skin (8 Franz cells), respectively. Twenty-four hours gold flux permeation was 7.8 ± 2.0 ng cm?2 h?1 and 7.1 ± 2.5 ng cm?2 h?1 in intact and damaged skin, respectively, with a lag time less than 1 hour. Transmission Electron Microscope analysis on skin samples and chemical analysis using Inductively Coupled Plasma-Mass Spectrometry demonstrated the presence of AuNPs into epidermis and dermis. This study showed that AuNPs are able to penetrate the human skin in an in vitro diffusion cell system.     

Human skin penetration of silver nanoparticles through intact and damaged skin

There is a growing interest on nanoparticle safety for topical use. The benefits of nanoparticles have been shown in several scientific fields, but little is known about their potential to penetrate the skin. This study aims at evaluating in vitro skin penetration of silver nanoparticles. Experiments were performed using the Franz diffusion cell method with intact and damaged human skin. Physiological solution was used as receiving phase and 70 microg/cm2 of silver nanoparticles coated with polyvinylpirrolidone dispersed in synthetic sweat were applied as donor phase to the outer surface of the skin for 24h. The receptor fluid measurements were performed by electro thermal atomic absorption spectroscopy (ETAAS). Human skin penetration was also determined by using transmission electron microscope (TEM) to verify the location of silver nanoparticles in exposed membranes. Median silver concentrations of 0.46 ng cm(-2) (range 相似文献   

Human skin penetration of gold nanoparticles through intact and damaged skin

Abstract

Gold nanoparticles (AuNPs) are produced for many applications but there is a lack of available data on their skin absorption. Experiments were performed using the Franz diffusion cell method with intact and damaged human skin. A physiological solution was used as receiving phase and 0.5 mL (1st exp) and 1.5 mL (2nd exp) of a solution containing 100 mgL^-1 of AuNPs (15 and 45 μg cm^-2, respectively) was applied as donor phase to the outer surface of the skin for 24 h. Skin absorption was dose dependent. Mean gold content of 214.0 ± 43.7 ng cm^-2 and 187.7 ± 50.2 ng cm^-2 were found in the receiving solutions of cells where the AuNPs solution was applied in higher concentration on intact skin (8 Franz cells) and on damaged skin (8 Franz cells), respectively. Twenty-four hours gold flux permeation was 7.8 ± 2.0 ng cm^-2 h^-1 and 7.1 ± 2.5 ng cm^-2 h^-1 in intact and damaged skin, respectively, with a lag time less than 1 hour. Transmission Electron Microscope analysis on skin samples and chemical analysis using Inductively Coupled Plasma-Mass Spectrometry demonstrated the presence of AuNPs into epidermis and dermis. This study showed that AuNPs are able to penetrate the human skin in an in vitro diffusion cell system.     

Characterization of titanium dioxide and zinc oxide nanoparticles in sunscreen powder by comparing different measurement methods

Numerous consumer products, such as cosmetics, contain nanoparticles (NPs) of titanium dioxide (TiO₂) or zinc oxide (ZnO); however, this raises questions concerning the safety of such additives. Most of these products do not indicate whether the product includes NPs. In this study, we characterized metal oxide NPs according to size, shape, and composition as well as their aggregation/agglomeration characteristics. In order to comprehend quickly the characterization of metal oxide NPs, we employed single particle inductively coupled plasma (SP-ICPMS) to help quantify the size of metal oxide NPs; then, we use transmission electron microscopy (TEM) to corroborate the results. The crystal size and structure was measured by X-ray diffraction (XRD), there are two crystal phase of TiO₂ NPs in sunscreen powder showed in XRD. However, SP-ICPMS proved highly effective in determining the size of NPs, the results of which remarkably good agreement with the TEM measurements. Pre-treatment included a conventional copper grid (requiring sample dilution) to evaluate the size, shape and composition of primary particles or plastic embedding (without the need for sample dilution) to evaluate the aggregate/aggregation of native NOAAs. The proposed method is an effective and fast approach to the characterization of oxide NPs in cosmetic sunscreen powder. These findings outline an alternative approach to the analysis of NPs in powder-form matrix.     

Favourable dermal penetration of diclofenac after administration to the skin using a novel spray gel formulation

AIMS: The study was designed to evaluate the relative bioavailability of diclofenac in plasma, subcutaneous adipose and skeletal muscle tissue after repeated topical administration using MIKA Diclofenac Spray Gel (4%), a novel formulation, and after oral dosing using VOLTAREN 50 mg enteric coated tablets. METHODS: Diclofenac (48 mg) was administered topically three times daily for 3 days onto a defined area of the thigh of 12 healthy males. After a 14-day wash out period, subjects were orally treated with 50 mg diclofenac three times daily for 3 days. In vivo microdialysis in subcutaneous and muscle tissues was performed immediately after the final doses from both treatments on day 4, and 48 h later. Plasma samples were taken simultaneously. RESULTS: The relative bioavailability of diclofenac in subcutaneous adipose and skeletal muscle tissue was substantially higher after topical compared with oral dosing (324% and 209%, respectively) whereas relative plasma bioavailability was 50-fold lower. Plasma C(max) values were approximately 250-fold lower after topical compared with oral drug administration (i.e. median values = 4.89 ng mL(-1); 95% CI: 3.37-7.68 and 1240 ng mL(-1); 95% CI: 787-1389 ng mL(-1)). Both treatments were well tolerated. CONCLUSIONS: Owing to its favourable penetration characteristics and low systemic availability, MIKA Diclofenac Spray Gel 4% is a rational alternative to oral diclofenac formulations for the treatment of inflammatory soft tissue conditions.     

Facilitated skin penetration of lidocaine: combination of a short-term iontophoresis and microemulsion formulation

The objective of this study was to demonstrate the potential of the application of a short-term iontophoresis on the topical delivery of lidocaine hydrochloride from a microemulsion-based system. Five- and 10-min durations of anodal iontophoresis applied onto porcine skin were examined in combination with a microemulsion containing 2.5% lidocaine hydrochloride. A similar combination (10-min iontophoresis with microemulsion in the anodal electrode) was also examined in vivo in a rat model. It was shown in vitro that by combining microemulsion application with a 10-min iontophoresis of 1.13 mA/cm2 electric current density, a significantly increased flux was obtained compared with a combination of aqueous drug solution with the same iontophoresis protocol. In vivo studies revealed that 57.71 +/- 18.65 and 18.43 +/- 9.17 microg cm(-2) were reached in the epidermis and dermis, respectively, at t = 30 min of microemulsion application, when iontophoresis was applied for 10 min. In contrast, the application of aqueous solution-iontophoresis resulted in a relatively lower drug accumulation (21.44 +/- 10.42 and 5.30 +/- 2.25 microg cm(-2) in the epidermis and dermis, respectively, at t = 30) with more rapid clearance of the drug from the skin. Ten-minute application of a low-current electric field on a new topical microemulsion appears to make significant changes in skin permeability. The potential advantages of this procedure include significantly increased flux, accumulation of a large skin drug depot, short lag times, reduced irritation (compared to long-term iontophoresis), simplicity and ease of compliance.     

In vitro skin penetration of acetyl hexapeptide-8 from a cosmetic formulation

There is a concern that peptides in cosmetic creams marketed as anti-aging/anti-wrinkle may penetrate into the deep layers of the skin and potentially stimulate biological activity. Claims for one cosmetic peptide, acetyl hexapeptide-8 (Ac-EEMQRR-amide), suggest interference with neuromuscular signaling as its anti-wrinkle mechanism of action. Therefore, the skin penetration of commercially available Ac-EEMQRR-amide from a cosmetic formulation (oil-in-water (O/W) emulsion) was determined in hairless guinea pig (HGP) and human cadaver skin assembled into in vitro diffusion cells. An O/W emulsion containing 10% Ac-EEMQRR-amide was applied to skin at a dose of 2?mg/cm². After a 24-h exposure, the skin surface was washed to remove unabsorbed peptide. Skin disks were tape stripped to determine the amount of peptide in the stratum corneum. Removal of the stratum corneum layers was verified by confocal microscopy. The epidermis was heat separated from the dermis and each skin fraction was homogenized. Skin penetration of Ac-EEMQRR-amide was measured in skin layers by hydrophilic interaction liquid chromatography with tandem mass spectrometry using electrospray ionization (ESI) in the positive mode. Stable isotopically labeled hexapeptides were used as internal standards for the quantitation of native hexapeptides to correct for matrix effects associated with ESI. The results (percent of applied dose) showed that the majority of the Ac-EEMQRR-amide was washed from the surface of both HGP and human skin. Ac-EEMQRR-amide that penetrated skin remained mostly in the stratum corneum of HGP (0.54%) and human (0.22%) with the peptide levels decreasing as each layer was removed by tape stripping. Total Ac-EEMQRR-amide found in the epidermis of HGP and human skin was similar at 0.01%. No peptide was detected in the dermis or buffer collected underneath the skin for both human and HGP. There was no hexapeptide metabolite (H₂N-EEMQRR-amide) detected in any layers of HGP skin, human skin or buffer collected underneath the skin. This skin penetration data will be useful for evaluating the safety of cosmetic products containing small peptide cosmetic ingredients.     

Solid lipid nanoparticles: a possible vehicle for zinc oxide and octocrylene

An efficient sunscreen formulation shows good absorption in the relevant UV range. Efficacy also means that the UV absorber must be easily incorporated in any kind of formulation. In this study, a chemical absorber, octocrylene, and one of the most important physical blockers, zinc oxide, could be successfully incorporated into Solid Lipid Nanoparticle (SLN) systems which themselves have UV blocking potential similar to physical sunscreens, and remained stable for a period of 360 days while providing UVA and UVB protection. Crystalline structure related to the chemical nature of the solid lipid is a key factor to decide whether a sunscreening agent will be expelled or incorporated in the long-term and for a controlled optimization of active ingredient incorporation and loading, intensive characterization of the physical state of the lipid particles was highly essential. Thus, FT-IR, NMR, XRD and DSC analyses were performed and the results did not indicate stability problems. pH values of the SLN systems were found to be between 5.4-5.9 in all formulations which may be buffered by the skin. Transpore test results proved the UV blocking potential of the SLNs with not any active ingredient and the synergistic effects by the incorporation of molecular sunscreens. Therefore, concentration of molecular sunscreens in the formulations was decreased to 0.6%. UVA and UVB screening potentials of octocrylene and zinc oxide formulations were compared in the 290-400 nm wavelength region. Zinc oxide loaded SLN suspensions were found to be more effective in the UVA region while octocrylene loaded ones performed better in the UVB region.     

氧化锌纳米粒的制备与表征（英文）

本研究采用溶胶-凝胶法制备氧化锌纳米粒(ZnO NPs),并对其粒径、形貌、晶型、光学特性和pH敏感性等理化性质进行表征,在PC-3M和4T1两株细胞系上对ZnO NPs的体外抗肿瘤药效进行评价。实验结果表明,ZnO NPs为粒径均匀的球形纳米颗粒,具有优良的光学性能及pH敏感性能,对PC-3M和4T1两株细胞系有明显的抗肿瘤细胞药效。上述结果表明, ZnO NPs可作为载体载带活性物质以产生抗肿瘤诊断和治疗作用。     

Human skin penetration of selected model mycotoxins

Dermal exposure data for mycotoxins are very scarce and fragmentary, despite their widespread skin contact and hazard toxicity. In this study, the transdermal kinetics of aflatoxin B1 (AFB1), ochratoxin A (OTA), fumonisin B1 (FB1), citrinin (CIT), zearalenone (ZEA) and T-2 toxin (T-2) were quantitatively evaluated, using human skin in an in vitro Franz diffusion cell set-up. All mycotoxins penetrated through the skin, except for FB1, which showed concentrations in the receptor fluid below the LoD, resulting in a K(p)<3.24×10(-6)cm/h. OTA showed the highest permeation (K(p)=8.20×10(-4)cm/h), followed by CIT (K(p)=4.67×10(-4)cm/h). AFB1 and ZEA showed lower permeability rates (K(p)=2.11 and 2.33×10(-4)cm/h, respectively). T-2 was found to have the lowest permeability (K(p)=6.07×10(-5)cm/h). From literature-based mycotoxin-concentrations, dermal contact surface, exposure time and apparent K(p)'s obtained in this study, the daily dermal exposure (DDE) in two industrial and one residential scenario was estimated. Dermal exposure to the DNA-reactive genotoxic carcinogenic AFB1 can lead to a health risk for agricultural workers which are exposed to a mycotoxin contaminated solution in a worst case situation. For all the other investigated mycotoxins, no significant health risk is calculated after dermal contact in neither agricultural nor residential environments.     

The toxicology of ion-shedding zinc oxide nanoparticles

Zinc oxide nanoparticles (ZnO NPs) are nanomaterials that are widely used in many fields. ZnO NPs are ion-shedding particles, and zinc ions produce important and potent effects that differ from those of other metal or metal oxide NPs. Several studies have reported the toxicological effects of ZnO NPs administered via several different routes, including orally, dermally, by pulmonary absorption, intraperitoneally, and intravenously. Some potential routes for human exposure have produced various toxic effects in animal models. Moreover, several in vitro studies using a range of cell lines have reported the mechanisms underlying ZnO NP toxicity. Zinc ions play a very important role in ZnO NP toxicity, although the effects of the particulate form cannot be excluded. A crucial determinant of toxicity is the solubility of ZnO NPs, which is influenced by various factors, including the pH of the environment in tissues, cells, and organelles. In addition to the inflammatory responses and oxidative stress known to be induced by ZnO NPs, these NPs also exhibit some positive anti-inflammatory, anti-diabetic, and pro-coagulant effects at sub-toxic doses; these effects are probably induced by zinc ions, which are an essential element in cell homeostasis. It is highly likely that there are additional distinct mechanisms at sub-toxic doses and concentrations, which may be concealed or altered by the toxic effects observed at higher levels of ZnO NPs. Furthermore, many signaling pathway molecules associated with necrosis and apoptosis can be activated, leading to cell death. This review presents the status of ZnO NP toxicology and highlights areas requiring further investigation.     

Microemulsion: a novel transdermal delivery system to facilitate skin penetration of indomethacin

In this study, we aimed to develop thermodynamically stable microemulsion formulations of indomethacin with lower surfactant and cosurfactant contents, to improve drug permeability. Formulations were based on the oil/water microemulsion region of pseudo-ternary phase diagrams. The characteristic parameters (viscosity, diameter, and polydispersity) of the microemulsion formulations were then determined. In vitro permeation studies were performed using Franz diffusion cells. Permeation through mouse skin and skin retention of indomethacin microemulsions and ointment were tested. The cumulative amount of permeated indomethacin and its skin retention were significantly higher in microemulsion formulations compared with ointment. Drug flux and skin retention improved with decreasing droplet diameter of the microemulsions. On the basis of these results, we suggest some possible mechanisms for the enhanced transdermal permeation of drugs in microemulsions, including high drug-loading capacity, permeation enhancement by surfactants and cosurfactants, and smaller droplet diameter. In conclusion, microemulsions represent a novel transdermal delivery vehicle for increasing the solubility and permeability of indomethacin.     

Formulation and characterization of tobramycin-chitosan nanoparticles coated with zinc oxide nanoparticles

Herein we describe the preparation, characterization and the antibacterial effect of Tobramycin-chitosan nanoparticles (TOB-CS NPs) coated with zinc oxide nanoparticles (ZnO NPs). Four formulations of TOB-CS NPs (A-D) were prepared to study the effect of experimental variables on the NPs behavior. Two formulations of ZnO NPs were prepared using the solvothermal and the precipitation methods (ZnO₁ and ZnO₂), and then characterized. TOB-CS NPs (Formula d) was coated with the ZnO₁. Moreover, the antibacterial activity of TOB-CS NPs, ZnO NPs and the coated nanoparticles against S. aureus and E. coli was examined. Changing the variables in preparing TOB-CS NPs resulting in variabilities in sizes (297.6–1116.3 nm), charges (+8.29–+39.00 mV), entrapment (51.95–90.60%). Further, TOB release was sustained over four days. ZnO NPs have sizes of 47.44 and 394.4 nm and charges of ?62.3 and 89.4 mV when prepared by solvothermal and precipitation technique, respectively. Coated TOB-CS NPs had a size of 342 nm, a charge of +4.39 and released 100 µg/ mL of the drug after four days. The antimicrobial activity of TOB-CS NPs was lower than free TOB against S. aureus and E. coli. The coated NPs showed higher antimicrobial effect in comparison to formula D and ZnO₁. In conclusion, coating TOB-CS NPs with ZnO NPs exhibited a great antibacterial effect that may be sustained for days.     

Phosphate-enhanced cytotoxicity of zinc oxide nanoparticles and agglomerates

Zinc oxide (ZnO) nanoparticles (NPs) have been found to readily react with phosphate ions to form zinc phosphate (Zn₃(PO₄)₂) crystallites. Because phosphates are ubiquitous in physiological fluids as well as waste water streams, it is important to examine the potential effects that the formation of Zn₃(PO₄)₂ crystallites may have on cell viability. Thus, the cytotoxic response of NIH/3T3 fibroblast cells was assessed following 24 h of exposure to ZnO NPs suspended in media with and without the standard phosphate salt supplement. Both particle dosage and size have been shown to impact the cytotoxic effects of ZnO NPs, so doses ranging from 5 to 50 μg/mL were examined and agglomerate size effects were investigated by using the bioinert amphiphilic polymer polyvinylpyrrolidone (PVP) to generate water-soluble ZnO ranging from individually dispersed 4 nm NPs up to micron-sized agglomerates. Cell metabolic activity measures indicated that the presence of phosphate in the suspension media can led to significantly reduced cell viability at all agglomerate sizes and at lower ZnO dosages. In addition, a reduction in cell viability was observed when agglomerate size was decreased, but only in the phosphate-containing media. These metabolic activity results were reflected in separate measures of cell death via the lactate dehydrogenase assay. Our results suggest that, while higher doses of water-soluble ZnO NPs are cytotoxic, the presence of phosphates in the surrounding fluid can lead to significantly elevated levels of cell death at lower ZnO NP doses. Moreover, the extent of this death can potentially be modulated or offset by tuning the agglomerate size. These findings underscore the importance of understanding how nanoscale materials can interact with the components of surrounding fluids so that potential adverse effects of such interactions can be controlled.     

Mechanisms of action of novel skin penetration enhancers: phospholipid versus skin lipid liposomes

Employing thermal analysis, we investigated the mechanism of action of novel enhancers and probed phospholipid (PL) versus stratum corneum lipid (SCL) liposomes as model membranes. The enhancers included octyl salicylate (OS), padimate O (PADO) and 2-(1-nonyl)-1,3-dioxolane (ND). The negative controls were the empty liposomes. Positive controls employed dimethylsulfoxide (DMSO) and Azone (AZ). For PL liposomes, DMSO sharpened the transitions. AZ abolished the pre-transition, broadened the main transition and linearly reduced its transition temperature (T(m)). OS or PADO reduced T(m) and size of pre-transition, broadened the main transition and decreased its T(m) (non-linearly). ND abolished the pre-transition but increased T(m) of the main endotherm, suggesting retardation rather than enhancement. The results of SCL correlated with PL liposomes except for ND. In SCL liposomes, ND reduced T(m) and broadened the peaks indicating lipid disruption, which indicated its enhancing effects. In conclusion, OS, PADO and ND can enhance drugs by disrupting intercellular lipid domain but they differ from AZ in terms of the relationship between efficacy and concentration. Although PL liposomes are simple model membranes with sharp transitions which give detailed information about the effects of enhancers, they can provide misleading results. Simultaneous use of other models like SCL liposomes is recommended.     

Anionic clays for sunscreen agent safe use: photoprotection, photostability and prevention of their skin penetration.

The use of sunscreen preparations is recently growing and their efficacy and safety must be taken into account since they are applied on the skin frequently and for many hours. Exposition to sunlight, in fact, can cause sunscreen photodegradation and determine their decrease in UV protection often with the occurrence of allergic and/or toxic degradation products. A high photostability is hence very important for their effectiveness and safety. The aim of this work is to obtain new sunscreen formulations stabilized by intercalating PABA, within the lamellar structures of two kinds of hydrotalcite. PABA was chosen as model sunscreen because of its high photoinstability and photosensitizing properties that nowadays bar its utilization. Both intercalated products showed an increased protection range and, in one case, an improved sunscreen photostability. Sunscreen release from creams containing intercalated or free PABA was evaluated as well. The very low or negligible sunscreen release, obtained from the intercalated product loaded formulations, resulted in a lack of a close contact between skin and filter with the consequence that cutaneous reactions and allergy problems are eliminated. The use of these materials resulted in a good strategic technological approach in order to increase efficacy and safety of solar products.     

纳米氧化锌抗菌性能及机制的研究进展

纳米氧化锌因具有优良的抗菌性能,已成为目前抗菌材料研究的新热点。本文对现有相关研究成果进行了总结、归纳和分析,详细介绍了纳米氧化锌的强抗菌性能,并介绍了粒径大小、浓度、与细菌作用时间、细菌的类型及外界条件等因素对其抗菌性能的影响,深入探讨了纳米氧化锌的抗菌机制,主要包括锌离子的释放、与细菌表面的相互作用、活性氧及光催化机制,进一步对纳米氧化锌在今后研究中的抗菌机制和安全性研究及其应用范围等方面进行了综述。