Adapalene Microemulsion for Transfollicular Drug Delivery

The aim of this study was to develop a microemulsion formulation of adapalene for transfollicular delivery. A pseudoternary phase diagram was developed for microemulsion consisting of oleic acid as oil phase, tween 20 as surfactant, Transcutol® as cosurfactant, and deionized water. Differential tape stripping and confocal laser scanning microscopy were performed to determine the penetration of microemulsion through hair follicles. Transmission electron microscopy, dynamic light scattering, polarizing light microscopy, and differential scanning calorimetry were performed to characterize the microstructures of microemulsion. The pH and viscosity of the microemulsions were also determined. Permeation studies were carried out in vitro on porcine ear skin over a period of 24 h using Franz diffusion cells. The drug penetration in the hair follicles increased from 0.109 ± 0.03 to 0.292 ± 0.094 μg, as the microstructure of microemulsion shifted from oil-in-water to bi-continuous, with increase in water content of microemulsion. Confocal laser scanning microscopy images suggested that hair follicles provided the path for transfollicular permeation of adapalene microemulsion. These results suggest that microemulsion penetrated through hair follicles and are promising for transfollicular drug delivery. © 2013 Wiley Periodicals, Inc. and the American Pharmacists AssociationJ Pharm Sci 102:2622–2631, 2013     

Hexyl Aminolaevulinate Is a More Effective Topical Photosensitiser Precursor than Methyl Aminolaevulinate and 5-Aminolaevulinic Acids When Applied in Equimolar Doses

Aminolaevulinic acid (ALA) is known to poorly penetrate into thick lesions, such as nodular basal cell carcinomas. Short chain ALA esters, possessing increased lipophilicity relative to their hydrophilic parent, have previously been shown to be highly efficient at inducing protoporphyrin IX (PplX) production in cell culture, at equimolar concentrations. In contrast, in vitro skin permeation and in vivo animal studies, which up to now have compared prodrugs on a % w/w basis, have failed to demonstrate such benefits. For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into an o/w cream preparation. In vitro penetration studies into excised porcine skin revealed that increased levels of h-ALA, compared to ALA and m-ALA were found in the upper skin layers, at all drug loadings studied. Topical application of the formulations to nude murine skin in vivo, revealed that creams containing h-ALA induced significantly higher levels of peak PplX fluorescence (F_max = 289.0) at low concentrations compared to m-ALA (F_max = 159.2) and ALA (F_max = 191.9). Importantly, this study indicates that when compared on an equimolar basis, h-ALA has improved skin penetration, leading to enhanced PpIX production compared to the parent drug and m-ALA. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3486–3498, 2010     

Noninvasive delivery of siRNA and plasmid DNA into skin by fractional ablation: Erbium:YAG laser versus CO2 laser

The present study was conducted to evaluate the impacts of fractional erbium (Er):YAG and CO₂ lasers on skin permeation of small interfering (si)RNA and plasmid (p)DNA vectors. In vitro skin delivery was determined with a Franz diffusion cell. In vivo absorption was investigated by observing fluorescence and confocal microscopic imaging. Fractional laser-mediated ablation of the skin resulted in significant enhancement of dextran and siRNA penetration. Respective fluxes of dextran (10 kDa) and siRNA, which had similar molecular size, with Er:YAG laser irradiation at 5 J/cm² were 56- and 11-fold superior to that of intact skin. The respective permeation extents of dextran and siRNA by the CO₂ laser at 4 mJ/400 spots were 42- and 12-fold greater than that of untreated skin. Fluorescence and confocal images showed increased fluorescence intensities and penetration depths of siRNA and pDNA delivery. According to an examination of the follicular permeant amount and fluorescence microscopy, hair follicles were important deposition areas for fractional laser-assisted delivery, with the Er:YAG modality revealing higher follicular siRNA selectivity than the CO₂ modality. This is the first report of siRNA and pDNA penetrating the skin with a sufficient amount and depth with the assistance of fractional lasers.     

Formulation,optimization and evaluation of transferosomal gel for transdermal insulin delivery

The present study deals with the development of transferosomal gel containing insulin by reverse phase evaporation method for painless insulin delivery for use in the treatment of insulin dependent diabetes mellitus. The effect of independent process variables like ratio of lipids (soya lecithin:cholesterol), ratio of lipids and surfactants, and ratio of surfactants (Tween 80:sodium deoxycholate) on the in vitro permeation flux (μg/cm²/h) of formulated transferosomal gels containing insulin through porcine ear skin was optimized using 2³ factorial design. The optimal permeation flux was achieved as 13.50 ± 0.22 μg/cm²/h with drug entrapment efficiency of 56.55 ± 0.37% and average vesicle diameter range, 625–815 nm. The in vitro insulin permeation through porcine ear skin from these transferosomal gel followed zero-order kinetics (R² = 0.9232–0.9989) over a period of 24 h with case-II transport mechanism. The in vitro skin permeation of insulin from optimized transferosomal gel by iontophoretic influence (with 0.5 mA/cm² current supply) also provided further enhancement of permeation flux to 17.60 ± 0.03 μg/cm²/h. The in vivo study of optimized transferosomal gel in alloxan-induced diabetic rat has demonstrated prolonged hypoglycemic effect in diabetic rats over 24 h after transdermal administration.     

Enhanced Skin Permeation of Naltrexone by Pulsed Electromagnetic Fields in Human Skin In Vitro

The aim of the present study was to evaluate the skin permeation of naltrexone (NTX) under the influence of a pulsed electromagnetic field (PEMF). The permeation of NTX across human epidermis and a silicone membrane in vitro was monitored during and after application of the PEMF and compared to passive application. Enhancement ratios of NTX human epidermis permeation by PEMF over passive diffusion, calculated based on the AUC of cumulative NTX permeation to the receptor compartment verses time for 0–4 h, 4–8 h, and over the entire experiment (0–8 h) were 6.52, 5.25, and 5.66, respectively. Observation of the curve indicated an initial enhancement of NTX permeation compared to passive delivery whilst the PEMF was active (0–4 h). This was followed by a secondary phase after termination of PEMF energy (4–8 h) in which there was a steady increase in NTX permeation. No significant enhancement of NTX penetration across silicone membrane occurred with PEMF application in comparison to passively applied NTX. In a preliminary experiment PEMF enhanced the penetration of 10 nm gold nanoparticles through the stratum corneum as visualized by multiphoton microscopy. This suggests that the channels through which the nanoparticles move must be larger than the 10 nm diameter of these rigid particles.     

In Vitro,Ex Vivo,and In Vivo Evaluation of the Effect of Saturated Fat Acid Chain Length on the Transdermal Behavior of Ibuprofen-Loaded Microemulsions

In this study, the effect of the saturated fatty acid (FA) chain length in the oil phase on the behavior of Ibuprofen (IBU)-loaded transdermal microemulsion (ME) was evaluated in vitro, ex vivo, and in vivo. Three oils classified as long (LFA), medium (MFA), and short (SFA) chain length oils, Cremophor RH40 (surfactant) and Transcutol P (cosurfactant) were selected after experimental optimization. The physicochemical properties of ME were characterized, including IBU solubility in excipients, pseudo-ternary phase diagram construction, particle size, zeta potential, viscosity, and stability. Permeation flux and residual amount of IBU ex vivo using Franz cell system occurred in the following order: MFA-based ME > LFA-based ME > SFA-based ME, which correlated well with the results of confocal scanning laser microscopy study and the in vivo retention study. The results of in vitro cytotoxicity study and skin irritation tests measured by differential scanning calorimetry were ranked in the following order: LFA-based ME > MFA-based ME > SFA-based ME. Moreover, MFA-based ME has the highest analgesic activity among all the treatment groups. MFA was found to be an optimal oil phase with appropriate FA chain length for IBU-loaded transdermal ME, which exhibited excellent physicochemical properties, low toxicity, and good permeability profile. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1680-1691, 2014     

Cyclobutane pyrimidine dimers are photosensitised by carprofen plus UVA in human HaCaT cells

Every year in the UK about 75,000 cases of non-melanoma skin cancer (NMSC) are registered, and about 9500 people are diagnosed with cutaneous melanoma (CM). The main risk factor for these cancers is exposure to sunlight. The effects of light on skin are wavelength dependent, with wavelengths in the UVB waveband (280–315 nm) being the most carcinogenic. UVB is directly absorbed by DNA, producing dimeric pyrimidine photoproducts including cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimodone photoproducts (6-4PP). However UVA (315–400 nm) can also produce CPD, induce skin tumours in mice, and has been shown to be mutagenic in cell culture. Although the precise role of UVA in human skin cancer remains to be elucidated, it comprises the major portion of solar UV radiation, transmits through window glass and can be delivered in high doses from tanning lamps. Non-steroidal anti-inflammatory drugs (NSAIDs), in particular the 2-aryl propionic acid derivatives, are a well-documented group of photosensitising chemicals producing clinical phototoxic and photoallergic reactions. We have used carprofen, a model compound from this group to see if it could amplify the effects of UVA and contribute to the formation of CPD by UVA. Preliminary work has shown that carprofen combined with low doses of UVA (λ_max: 365 nm; 5 J/cm²) can produce both strand breaks (SB) and CPD in human skin or blood cells. CPD were detected indirectly by both an immunofluorescence method and as T4 endonuclease V sensitive sites in the comet assay. These findings show that compounds other than fluoroquinolones and psoralen derivatives may contribute to CPD formation in skin cells in combination with UVA.     

In vivo sustained dermal delivery and pharmacokinetics of interferon alpha in biphasic vesicles after topical application

Biphasic vesicles, a novel nanostructured lipid-based delivery system show potential for topical application of interferon alpha (IFN α) for the treatment of human papillomavirus (HPV) infections (anogenital warts). Dermal delivery of IFN α encapsulated in biphasic vesicles (BPV-IFN α), applied topically to the skin, was characterized in a guinea pig model.BPV-IFN α (1 g, 2 MIU/g) was topically applied either as a single or multiple treatments on the skin of guinea pigs. As a comparison with currently used regimens, IFN α solution was administered intravenously or intradermally. Skin and serum samples were collected over 96 h, IFN α levels were determined by an antiviral assay, and half-life (t_1/2) and elimination (k) rates were calculated.Topical BPV-IFN α treatment resulted in maximum skin levels (about 100,000 U/100 cm²) of IFN α within 6 h and maintained for 72–96 h. Clearance from the skin after intradermal injections was initially fast (t_1/2 0.62 h, k 1.1179 h⁻¹), followed by a slower steady decrease after 6 h. After intravenous and intradermal administration, IFN α was rapidly cleared from the serum, t_1/2 0.75 h, k 0.9271 h⁻¹ and t_1/2 1.28 h, k 0.5421 h⁻¹, respectively, whereas after topical application, IFN α levels remained below 100 U/mL. Topical application of BPV- IFN α resulted in sustained delivery of biologically active IFN α locally into skin with minimal systemic exposure.     

Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats

Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control – receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats.     

Permeability Enhancement for Transdermal Delivery of Large Molecule Using Low-Frequency Sonophoresis Combined with Microneedles

Transdermal drug delivery is limited by the high resistance of skin towards diffusion of high-molecular-weight drugs. This is mainly because of the fact that the outer layer of the skin, that is the stratum corneum, can prevent diffusion of molecules whose molecular weight is greater than 500 Da. Sonophoresis can be used to enhance the permeability of the skin. However, in the delivery of large molecules, ultrasound alone cannot provide sufficient permeability enhancement. In addressing this issue, we propose optimised ultrasound combined with microneedles to further increase the permeation rates. In this paper, we use porcine ear skin to simulate human skin and treat the skin samples with both ultrasound and microneedles. Further, bovine serum albumin (BSA) is used as a model of larger molecular weight molecule. Our results show that the permeability of BSA is increased to 1 μm/s with the combination of 1.5 mm microneedles patch and 15-W ultrasound output which is about 10 times higher than the permeability obtained in passive diffusion. Diffusion with only microneedles or ultrasound pre-treatment is also tested. The maximum permeability from microneedles and ultrasound treatment reached 0.43 and 0.4 μm/s, respectively. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3614–3622, 2013     

Folate-mediated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting drug delivery

A novel targeting drug delivery system (TDDS) has been developed. Such a TDDS was prepared by W₁/O/W₂ solvent extraction/evaporation method, adopting poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] as the drug carrier, folic acid (FA) as the targeting ligand, and doxorubicin (DOX) as the model anticancer drug. The average size, drug loading capacity and encapsulation efficiency of the prepared DOX-loaded, folate-mediated P(HB-HO) nanoparticles (DOX/FA–PEG–P(HB-HO) NPs) were found to be around 240 nm, 29.6% and 83.5%. The in vitro release profile displayed that nearly 50% DOX was released in the first 5 days. The intracellular uptake tests of the nanoparticles (NPs) in vitro showed that the DOX/FA–PEG–P(HB-HO) NPs were more efficiently taken up by HeLa cells compared to non-folate-mediated P(HB-HO) NPs. In addition, DOX/FA–PEG–P(HB-HO) NPs (IC₅₀ = 0.87 μM) showed greater cytotoxicity to HeLa cells than other treated groups. In vivo anti-tumor activity of the DOX/FA–PEG–P(HB-HO) NPs showed a much better therapeutic efficacy in inhibiting tumor growth, and the final mean tumor volume was 178.91 ± 17.43 mm³, significantly smaller than normal saline control group (542.58 ± 45.19 mm³). All these results have illustrated that our techniques for the preparing of DOX/FA–PEG–P(HB-HO) NPs developed in present work are feasible and these NPs are effective in selective delivery of anticancer drug to the folate receptor-overexpressed cancer cells. The new TDDS may be a competent candidate in application in targeting treatment of cancers.     

Antidermatitic Perspective of Hydrocortisone as Chitosan Nanocarriers: An Ex Vivo and In Vivo Assessment Using an NC/Nga Mouse Model

The aim of this study to administer hydrocortisone (HC) percutaneously in the form of polymeric nanoparticles (NPs) to alleviate its transcutaneous absorption, and to derive additional wound-healing benefits of chitosan. HC-loaded NPs had varied particle sizes, zeta potentials, and entrapment efficiencies, when drug-to-polymer mass ratios increased from 1:1 to 1:8. Ex vivo permeation analysis showed that the nanoparticulate formulation of HC significantly reduced corresponding flux [~24 μg/(cm² h)] and permeation coefficient (~4.8 × 10^? 3 cm/h) of HC across the full thickness NC/Nga mouse skin. The nanoparticulate formulation also exhibited a higher epidermal (1610 ± 42 μg/g of skin) and dermal (910 ± 46 μg/g of skin) accumulation of HC than those associated with control groups. An in vivo assessment using an NC/Nga mouse model further revealed that mice treated with the nanoparticulate system efficiently controlled transepidermal water loss [15 ± 2 g/(m² h)], erythema intensity (232 ± 12), dermatitis index (mild), and thickness of skin (456 ± 27 μm). Taken together, histopathological examination predicted that the nanoparticulate system showed a proficient anti-inflammatory and antifibrotic activity against atopic dermatitic (AD) lesions. Our results strongly suggest that HC-loaded NPs have promising potential for topical/transdermal delivery of glucocorticoids in the treatment of AD. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1063–1075, 2013     

Intake of high-fat diet stimulates the risk of ultraviolet radiation-induced skin tumors and malignant progression of papillomas to carcinoma in SKH-1 hairless mice

Previously, we showed that administration of a high-fat diet (HF-diet) to C57BL/6 mice exacerbates their response to short-term UVB radiation-induced inflammation in the skin. To explore the effects of an HF-diet on UVB-induced tumorigenesis, we have used the SKH-1 hairless mouse model in which the mice are exposed to UVB radiation (180 mJ/cm²) three times a week for 24 weeks. The development of UVB-induced skin tumors was rapid and the tumor multiplicity and tumor size were significantly higher (P < 0.01–0.005) in the mice fed an HF-diet than the mice fed a control-diet (C-diet). Moreover, the malignant progression of UVB-induced papillomas to carcinomas was higher in HF-diet-fed mice. On analysis of tumors and tumor-uninvolved skin samples from the tumor-bearing mice, we found that administration of an HF-diet significantly enhanced the levels of UVB-induced expression of cyclooxygenase-2 (COX-2), prostaglandin E₂ (P < 0.01), and PGE₂ receptors, and activation of NF-κB in the UVB-exposed skin as well as in tumors. In addition the HF-diet enhanced the expression of proinflammatory cytokines, including tumor necrosis factor-α (P < 0.01), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.05) in the UVB-exposed skin as well as in tumors. Western blot analysis revealed that HF-diet enhanced the levels of epidermal cell proliferation, phosphatidylinositol 3-kinase and phosphorylation of Akt at Ser⁴⁷³ in UVB-exposed skin and skin tumors. Collectively, these data demonstrate that the regular consumption of an HF-diet increases the risk of photocarcinogenesis in mice and that this is associated with enhanced expression of inflammatory mediators in the UVB-exposed skin and tumors.     

Iontophoretic transport kinetics of ketorolac in vitro and in vivo: Demonstrating local enhanced topical drug delivery to muscle

The objective of the study was to investigate the iontophoretic delivery kinetics of ketorolac (KT), a highly potent NSAID and peripherally-acting analgesic that is currently indicated to treat moderate to severe acute pain. It was envisaged that, depending on the amounts delivered, transdermal iontophoretic administration might have two distinct therapeutic applications: (i) more effective and faster local therapy with shorter onset times (e.g. to treat trauma-related pain/inflammation in muscle) or (ii) a non-parenteral, gastrointestinal tract sparing approach for systemic pain relief. The first part of the study investigated the effect of experimental conditions on KT iontophoresis using porcine and human skin in vitro. These results demonstrated that KT electrotransport was linearly dependent on current density – from 0.1875 to 0.5 mA/cm² – (r² > 0.99) and drug concentration – from 5 to 20 mg/ml (r² > 0.99). Iontophoretic permeation of KT from a 2% hydroxymethyl cellulose gel was comparable to that from an aqueous solution with equivalent drug loading (584.59 ± 114.67 and 462.05 ± 66.56 μg/cm², respectively). Cumulative permeation (462.05 ± 66.56 and 416.28 ± 95.71 μg/cm²) and steady state flux (106.72 ± 11.70 and 94.28 ± 15.47 μg/cm² h), across porcine and human skin, were statistically equivalent confirming the validity of the model. Based on the results in vitro, it was decided to focus on topical rather than systemic applications of KT iontophoresis in vivo. Subsequent experiments, in male Wistar rats, investigated the local enhancement of KT delivery to muscle by iontophoresis. Drug biodistribution was assessed in skin, in the biceps femoris muscle beneath the site of iontophoresis (‘treated muscle’; TM), in the contralateral muscle (‘non-treated muscle’; NTM) and in plasma (P). Passive topical delivery and oral administration served as negative and positive controls, respectively. Iontophoretic administration for 30 min was superior to passive topical delivery for 1 h and resulted in statistically significant increases in KT levels in the skin (91.04 ± 15.48 vs. 20.16 ± 8.58 μg/cm²), in the biceps femoris at the treatment site (TM; 6.74 ± 3.80 vs. <LOQ), in the contralateral site (NTM; 1.26 ± 0.54 vs. <LOQ) and in plasma (P; 8.58 ± 2.37 μg/ml vs. <LOD). In addition to increasing bioavailability, iontophoretic administration of KT showed clear selectivity for local delivery to the biceps femoris at the treatment site – the TM:NTM ratio was 5.26 ± 1.45, and the TM:P and NTM:P ratios were 0.75 ± 0.32 and 0.14 ± 0.04, respectively. Furthermore, the post-iontophoretic concentration of KT in the ‘treated’ biceps femoris muscle and the muscle:plasma ratio were also superior to those following oral administration of a 4 mg/kg dose (6.74 ± 3.80 vs. 0.62 ± 0.14 μg/g and 0.75 ± 0.32 vs. 0.14 ± 0.03, respectively). In conclusion, the results demonstrate that iontophoresis of ketorolac enables local enhanced topical delivery to subjacent muscle; this may have clinical application in the treatment of localised inflammation and pain.     

Enhanced Oral Absorption of Paclitaxel in N-Deoxycholic Acid-N,O-Hydroxyethyl Chitosan Micellar System

The overall goal of this study was to develop a micellar system of paclitaxel (PTX) to enhance its oral absorption. An amphiphilic chitosan derivative, N-deoxycholic acid-N, O-hydroxyethyl chitosan (DHC), was synthesized and characterized by FTIR, 1H NMR, elemental analysis, and X-ray diffraction (XRD) techniques. The degree of substitution (DS) of hydroxyethyl group and deoxycholic acid group ranged from 89.5–114.5% and 1.11-8.17%, respectively. The critical micelle concentration (CMC) values of DHC decreased from 0.26 to 0.16 mg/mL as the DS of deoxycholic acid group increased. PTX was successfully loaded in DHC micelles with a high drug loading (31.68 ± 0.14%) and entrapment efficiency (77.57 ± 0.51%). The particle size of PTX-loaded DHC micelles ranged from 203.35 ± 2.19 to 236.70 ± 3.40 nm as the DS of deoxycholic acid group increased. After orally administration of PTX-loaded DHC micelles, the bioavailability was threefold compared with that of an orally dosed Taxol®. The single-pass intestinal perfusion studies (SPIP) showed that the intestinal absorption of micelles was via endocytosis involving a saturable process and a p-glycoprotein (P-gp)-inde-pendent way. All these indicated that the DHC micelles might be a promising tool for oral delivery of poorly water-soluble drugs. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4543–4553, 2010     

Endo-symbiont mediated synthesis of gold nanobactericides and their activity against human pathogenic bacteria

Synthesis of gold nanobactericides (AuNBs) were achieved by treating 1 mM chloroaurate with cell free supernatant of Aneurinibacillus migulanus. Formation of AuNBs was initially was monitored with change in colour to ruby red. Further confirmation was assessed with UV–visible spectra with maximum absorption occurring at 510 nm. Transmission electron microscopy (TEM) analysis revealed the polydispersity of AuNBs with size distribution ranging from 10 to 60 nm with an average size of 30 nm. Crystalline nature was studied using X-ray diffraction which exhibited characteristic peaks indexed to Bragg's reflection at 2θ angle which confers (111), (200), (220), and (311) planes suggesting AuNBs were face-centred cubic. Fourier transform infrared spectroscopy (FTIR) analysis revealed absorption peaks occurring at 3341 cm⁻¹, 1635 cm⁻¹ and 670 cm⁻¹ which corresponds to functional groups attributing to synthesis. The antibacterial efficacy of AuNBs was tested against selective human pathogenic bacteria and activity was measured as zone of inhibition by using disc and well diffusion. Bactericidal activity was interpreted with standard antibiotics gentamicin and kanamycin. Micro broth dilution assay expressed the minimal concentration of AuNBs to inhibit the growth of test pathogens. Highest activity was observed against Pseudomonas aeruginosa (MTCC 7903) with 21.00 ± 0.57 mm compared to other pathogens. The possible mode of action of AuNBs on DNA was carried out with in vitro assay as preliminary test against pathogenic DNA isolated from P. aeruginosa. Further studies will be interesting enough to reveal the exact interactive mechanism of AuNBs with DNA. Overall study contributes towards biogenic synthesis of AuNBs as one of the alternative in combating drug resistant pathogens.     

Size-dependent biodistribution of carbon nanohorns in vivo

Carbon nanotubules, such as nanotubes and nanohorns, are potentially useful as drug delivery or hyperthermia agents for cancer therapy. However, the biokinetics of variously sized nanocarbons are important for their medical application and risk assessment. To examine the time course of the biodistribution of carbon nanohorns (CNHs) in mice, CNH aggregates of 100 nm (L-CNHs) or CNHs of 30–50 nm (S-CNHs) were dispersed with lipid polyethylene glycol and administered to mice through tail vein injection. Histological observation revealed that S-CNHs accumulated more slowly than did L-CNHs in the liver and spleen. The accumulation of L- and S-CNHs in spleen reached saturation within 1 and 48 h, respectively, and the accumulation in liver reached saturation within 48 h and > 7 days, respectively. CNHs did not accumulate appreciably in the lung, skin, or kidney. Histologic, hematologic, and immunologic (IL-6, TNF-α, and IFN-γ) tests did not reveal obvious toxicologic lesions at any time point.From the Clinical EditorIn this study the biodistribution and accumulation characteristics of small and large carbon nanohorns were characterized in mice. Data demonstrate slower accumulation of small carbon nanohorns in liver and spleen, no accumulation in skin, lung, or kidney, and no obvious hematologic or immunologic toxicity.     

Effects of Oxygen-Containing Terpenes as Skin Permeation Enhancers on the Lipoidal Pathways of Human Epidermal Membrane

The present study investigated the effects of oxygen-containing terpenes as skin permeation enhancers on the lipoidal pathways of human epidermal membrane (HEM). The enhancement (E_HEM) effects of menthol, thymol, carvacrol, menthone, and cineole on the transport of a probe permeant, corticosterone, across HEM were determined. It was found that the enhancer potencies of menthol, thymol, carvacrol, and menthone were essentially the same and higher than that of cineole based on their aqueous concentration in the diffusion cell chamber at E_HEM = 4. Thymol and carvacrol also had the same E_HEM = 10 concentration further supporting that they had the same enhancer potency based on the aqueous concentration. The uptake amounts of terpene into the HEM stratum corneum (SC) intercellular lipid under the same conditions indicate that the intrinsic potencies of the studied terpenes are the same based on their concentration in the SC and similar to those of n-alkanol and n-alkylphenyl alcohol. Moreover, they are all better enhancers compared to branched-chain alkanol. The approximately same uptake enhancement of β-estradiol induced by the studied terpenes and alcohols at E_HEM conditions into the SC intercellular lipids suggests that the mechanism of enhancement action for the terpenes and those of alcohols are essentially the same. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3617–3632, 2009     

In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration

Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.), that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(ɛ-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245 ± 10 nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n = 6/group) received a single-dose of saline solution (1.2 ml/kg) or LNC (7.2 × 10¹² LNC/kg), or repeated-doses of two controls, saline solution or Tween 80 (0.9 ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4 × 10¹² LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80–treated group (p < 0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p < 0.05) were found. Genotoxicity was evaluated through the comet assay, and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch-based devices for enhancing the delivery of drugs.