Abstract  The slow, non-mediated transmembrane movement of the lipid probes lysophosphatidylcholine, NBD-phosphatidylcholine and NBD-phosphatidylserine in human erythrocytes becomes highly enhanced in the presence of 1-alkanols (C2-C8) and 1,2-alkane diols (C4-C8). Above a threshold concentration characteristic for each alcohol, flip rates increase exponentially with the alcohol concentration. The equieffective concentrations of the alcohols decrease about 3-fold per methylene added. All 1-alkanols studied are equieffective at comparable calculated membrane concentrations. This is also observed or the 1,2-alkane diols, albeit at a 5-fold lower membrane concentration. At low alcohol concentrations, flip enhancement is reversible to a major extent upon removal of the alcohol. In contrast, a residual irreversible flip acceleration is observed following removal of the alcohol after a treatment at higher concentrations. The threshold concentrations to produce irreversible flip acceleration by 1-alkanols and 1,2-alkane diols are 1.5- and 3-fold higher than those for flip acceleration in the presence of the corresponding alcohols. A causal role in reversible flip-acceleration of a global increase of membrane fluidity or membrane polarity seems to be unlikely. Alcohols may act by increasing the probability of formation of transient structural defects in the hydrophobic barrier that already occur in the native membrane. Membrane defects responsible for irreversible flip-acceleration may result from alterations of membrane skeletal proteins by alcohols.

Abstract  Aliphatic, linear dicarboxylic acids and branched dicarboxylic acids are the subject of this article. These dibasic acids are referred to by their trivial names, IUPAC system or by adding the suffix “dicarboxylic acid“ to the name of the hydrocarbon skeleton. For example a 10‐carbon atom dibasic acid is designated sebacic acid, decanoic or 1,8‐octane‐dicarboxylic acid. Physical and chemical properties of the most common dibasic acids are discussed. Manufacture and uses for glutaric acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, dodecanoic acid, brassylic acid and C‐19, C‐20, and C‐22 dicarboxylic acids are given. These diacids are intermediates for the manufacture of diesters, polyesters, and polyamides. These derivatives have many applications ,eg, as plasticizing agents, lubricants, heat‐transfer fuids, inks and coatings, insecticides. Azaleic acid is used in acne preparations. Toxicities and environmental concerns are also discussed.

Abstract  To study the potential for delayed Type IV dermal sensitivity of a new preservative system containing 1,2-hexanediol and caprylyl glycol, 200-subject repeat insult patch tests were performed with a 15% mixture of 1,2-hexanediol and caprylyl glycol (equal parts of the 2 ingredients) in carbomer gel and a cosmetic formulation at an actual use concentration. No delayed Type IV hypersensitivity reactions were observed.

Abstract  Background: Traditional preservation systems currently used in cosmetic and skin care products are safe and effective. New ingredients with similar efficacy are continually being introduced to fulfill this function. Objective: To study the potential for delayed type IV allergic hypersensitivity and irritation of a new preservative system containing 1,2-hexanediol and caprylyl glycol. Methods: A 200-subject repeat insult patch test (RIPT) was performed. A 15% mixture of 1,2-hexanediol and caprylyl glycol (equal parts of the two ingredients) in carbomer gel was placed under a series of 9 continuous occlusive induction patches, each 48 hours in duration. Three induction patches were applied each week, for a total of 3 weeks. Following a 10-day rest period during which no patches were applied, a single challenge application using the same mixture was applied and left on for 48 hours and read at 48 and 72 hours postapplication. A cosmetic formulation containing this same preservation system at an actual use concentration was tested by the same RIPT protocol. Results: Two hundred and twelve subjects completed the study. One hundred and sixty-eight were female and 44 were male ranging in age from 18 to 70 years. No reactions were seen during the induction or challenge phases. An additional 212 subjects were enrolled in a separate RIPT that evaluated the cosmetic formulation containing the same preservation system. No delayed type IV allergic hypersensitivity or irritation reactions were observed. Conclusion: A new preservative system utilizing 1,2-hexanediol and caprylyl glycol did not induce delayed type IV allergic hypersensitivity or irritation in human subjects.

Abstract  Parabens are used as antimicrobial preservatives in consumer products. Exposure to methylparaben (MP) has been associated with adverse health outcomes, therefore, an alternative compound, 1,2-hexanediol (1,2-H), has been applied for cosmetics. In the present study, the phototoxicity of MP and 1,2-H, as well as the toxic effect caused by chronic exposure, were investigated using Daphnia magna. The 48 h acute toxicity tests with D. magna were conducted under indoor or ultraviolet (UV) light irradiation conditions, i.e., exposure to 4 h/d sunlight. Changes in the transcription of genes related to oxidative stress were determined in D. magna juveniles, to investigate the underlying mechanism of phototoxicity. The 21 d chronic toxicity tests of MP and 1,2-H were performed under indoor light irradiation. Exposure to MP under environmental level of UV light was more detrimental to D. magna. Transcripts of catalase and glutathione-S-transferase genes in D. magna was significantly increased by co-exposure to MP and UV light. After 21 d of chronic exposure to MP and 1,2-H, the reproduction no-observed effect concentrations for D. magna were 1 and >10 mg/L, respectively. The present study showed that exposure to UV could magnify the toxicity of MP on daphnids. Although acute and chronic toxicities of 1,2-H were generally lower than those of MP, its effects on other aquatic organisms should not be ignored. Further studies are needed to identify other mechanisms of MP phototoxicity.

Abstract  Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.

Abstract  The objective of the present study is to investigate the effect of hydrocarbon chain length in 1,2-alkanediols on percutaneous absorption of metronidazole (MTZ). Twelve formulations (1,2-propanediol, 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol in 4% concentration, 1,2-hexanediol, and 1,2-heptanediol in 1% concentration, in the absence and presence of 1,4-cyclohexanediol, respectively) were studied in an in vitro hairless mouse skin model using Franz diffusion cell. Based on the flux values and retardation ratios (RR), a penetration retardation effect on percutaneous absorption of MTZ was observed for the formulations containing 1,2-diols having six- to seven-carbon chain in the presence of 1,4-cyclohexanediol (1,2-hexanediol with chain length of six hydrocarbons, RRs are 0.69 and 0.76 in the concentration of 4% and 1%, respectively; 1,2-heptanediol with chain length of seven hydrocarbons, RR is 0.78 in the concentration of 1%). On the other hand, no retardation effect was observed in formulations containing short alkyl chains (RRs of 1,2-propanediol, 1,2-butanediol, and 1,2-pentanediol are 0.99, 1.61, and 0.96, respectively). Instead, a penetration enhancement effect was observed for 1,2-diols having four and five carbons. In other words, effect of 1,2-alkanediols on percutaneous absorption of MTZ can be systematically modulated by simply varying number of -CH2 groups in the hydrocarbon chain-from being a penetration enhancer to retardant. These observations shed light on mechanism of the penetration enhancement and retardation effect and provide insight into rational design of penetration enhancers and retardants. Furthermore, the combination of 1,2-alkanediols and 1,4-cyclohexanediol could become a general vehicle for controlled release of pharmaceutical and cosmetic active ingredients.

Abstract  The purpose of this study was to develop tretinoin-loaded phospholipid vesicles, namely conventional liposomes, hexosomes, glycerosomes and ethosomes, and to investigate their efficacy on croton oil induced rosacea. Vesicles were prepared with soy phospholipid, sodium deoxycholate and tretinoin; 1,2-hexanediol, glycerol and ethanol were added to obtain hexosomes, glycerosomes and ethosomes, respectively. The prepared formulations were characterized in terms of size distribution, morphology, zeta potential and entrapment efficiency. All vesicles were spherical in shape with a mean diameter ranging between 60 and 132 nm and a fairly narrow distribution (0.23-0.29), negative zeta potential values (from -19 to -29 mV) and entrapment efficiency between 32 and 63%. Furthermore, vesicles were evaluated for an in vitro model of dermal delivery, and their mode of action was studied by performing confocal laser scanning microscopy (CLSM) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) analyses. In addition, in vivo skin penetration was also investigated. The results of in vitro and in vivo studies showed that vesicular formulations, especially hexosomes, promoted the drug deposition into the skin stratums and reduced the permeation into the blood. Finally, administration of vesicular tretinoin on croton oil-induced skin resulted in marked attenuation of oedema and inflammatory cells, especially using hexosomes. The proposed approach based on tretinoin vesicular formulations may be of value in the treatment of rosacea.

Abstract  The present study was aimed at the encapsulation of ketoconazole (KCZ) in the novel modified nanovesicles for dermal targeting delivery. To this purpose, innovative modified vesicles were prepared with soy phospholipid and aqueous solutions containing different concentrations of two targeting modifiers, 1,2-hexanediol and 1,4-cyclohexanediol. Conventional liposomes, with soy phospholipid and cholesterol, were used as control. The prepared formulations were characterized in terms of entrapment efficiency, size distribution, morphology, and stability. Dermal KCZ targeting delivery from modified vesicles was investigated in vitro and in vivo through newborn pig and rat skin, respectively. All vesicles showed a mean size ranging from 58 to 147 nm with fairly narrow size distribution and drug entrapment efficiency between 20 and 75 %. Results of in vitro and in vivo studies indicated that modified vesicles provided an improved KCZ targeting delivery into skin layers. Images of the confocal laser scanning microscopy analyses supported the conclusion that modified vesicles could enhance the drug deposition into the skin strata and reduce the drug permeation into the blood, due to a synergic effect of phospholipid and modifiers. Finally, histological evaluation showed that KCZ-loaded modified vesicles caused no irritation to the skin. The results obtained encouraged the use of the KCZ-loaded modified vesicles as the formulation for the potential topical treatment of fungal infections.

Abstract  n-Alkanol inhibition of N-methyl-D-aspartate (NMDA) receptors exhibits a "cutoff" effect: alcohols with up to eight to nine carbon atoms inhibit the receptor, whereas larger alcohols do not. This phenomenon was originally proposed to result from size exclusion; i.e., alcohols above the cutoff are too large to bind to an amphiphilic site on the receptor. In the present study, 1,Omega-diols with 3 to 14 carbon atoms inhibited NMDA-activated current in Chinese hamster ovary and human embryonic kidney 293 cells transiently expressing NR1 and NR2B NMDA receptor subunits. Results of fluctuation analysis experiments were consistent with a similar mechanism of inhibition of NMDA-activated current by alcohols and diols. The average change in apparent energy of binding of the diols caused by addition of a methylene group was 2.1 kJ/mol, which is consistent with an important role of hydrophobic interactions. Because 1,Omega-diols with 9 to 14 carbons inhibited NMDA-activated current, despite having molecular volumes exceeding that at the cutoff point for 1-alkanols, a size exclusion mechanism seems inadequate to explain the cutoff effect. A disparity in hydrophobicity values at the cutoff for alcohols and diols, however, revealed that hydrophobicity could also not entirely explain the cutoff phenomenon. From these results, it seems that the cutoff effect on NMDA receptors results primarily from the inability of long-chain alcohols to achieve adequate concentrations at their site of action due to low aqueous solubility, although other factors may also contribute to the effect.

Abstract  The objective of this study was to investigate the percutaneous absorption of metronidazole (MTZ) in the topical formulations containing a combination of 1,4-cyclohexanediol and 1,2-hexanediol. Six formulations were studied in an in vitro hairless mouse skin model using Franz Diffusion Cell. MTZ was applied at infinite doses (50mg and 100mg of the formulations, which correspond to 375 and 750 μg of MTZ, respectively). Based on the flux values and retardation ratio (RR), a synergistic retardation effect on percutaneous absorption of MTZ was observed for the formulations containing a combination of 1,4-cyclohexanediol and 1,2-hexanediol (RRs are 0.40 for 375 μg dose and 0.69 for 750 μg dose, respectively). Interestingly, retention of MTZ in epidermis and dermis layer showed no significant differences (p>0.05) between the formulations containing the retardant combination and control formulations. In other words, the retardant combination in the formulation decreases MTZ fluxes while maintaining similar level of retention in epidermis and dermis layer when compared to the control formulations. These observations provide insight in formulating superior topical formulations with minimized potential systematic toxicity while maintaining therapeutic efficiency. A mechanistic explanation of the observed synergistic effect is proposed.

Abstract  Several studies have reported that 1,2-alkanediols show increasing anti-microbial activity as their alkane chain length increases. However, there are no reports on the influence of alkane chain length on the skin irritation potential of 1,2-alkanediols. To investigate the influence of alkane chain length on the skin irritation potential of 1,2-alkanediols. The objective and subjective (sensory) skin irritation potentials of five 1,2-alkanediols - 1,2-butanediol, 1,2-pentanediol, 1,2-hexanediol, 1,2-octanediol and 1,2-decanediol - were evaluated. We also estimated percutaneous absorption by measuring in vitro skin penetration using a Franz diffusion cell system. Like anti-microbial activity, sensory irritation potential increased as alkane chain length increased, most likely due to increasing membrane interference and/or intrinsic toxicity of 1,2-alkanediols. 1,2-Hexanediol showed the lowest objective skin irritation potential, which increased when the alkane chain length decreased or increased. Furthermore, percutaneous absorption negatively correlated with the alkane chain length of 1,2-alkanediols. These results show that a lower skin absorption potential is not indicative of a low skin irritation potential. Our results suggest that the factors and processes involved in skin irritation potential are complex and that skin irritation potential is influenced by intrinsic toxicity and the potential for penetration or integration in the lipid bilayer.