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  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  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  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  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  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  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.

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  The purpose of the present study was to determinate the significance of ion pairing on the topical permeation of retinoic acid (R.A) using microemulsions as delivery vehicles. Phenylalanine methyl ester, phenylalanine ethylester, histidine methyl ester, tryptophan methyl ester and valine methyl ester were used as counter ions. Results of diffusion studies through polydimethylsiloxane membrane (PDMS) indicate that retinoic acid permeation from ethanol-pH 6.4 buffer mixture significantly increased in the presence of counter ions. A linear relationship was found between apparent partition coefficients and permeation coefficients. The highest values were with valine methyl ester and phenylalanine ethyl ester. In order to develop alternative formulations for topical administration of R.A, microemulsions were evaluated as delivery vehicles. Oil-in-water (O/W) and water-in-oil (W/O) microemulsion formulations were prepared using water, isopropyl myristate, lecithin, caprylyl-capryl glucoside and ethanol or 1,2 hexanediol. Experiments with PDMS membranes showed decreasing permeabilities of R.A from microemulsions in the presence of counter ions. This was related to the increased lipophilicity and different vehicle membrane affinity of the ion pairs The ability of the systems to deliver R.A through the skin was evaluated in vitro using pig-skin. R.A permeabilities were much lower with microemulsions than with solution, while a large increase in R.A skin deposition was observed only from O/W microemulsions in the presence of counter ions. The depth of skin accumulation was below 100 mum after 24 h application. The results suggest that O/W microemulsions containing a counter ion can be used to optimise drug targeting without a concomitant increase in systemic absorption. (C) 2002 Elsevier Science B.V. All rights reserved.

Abstract  In a previous study, a synergistic retardation effect of 1,4-cyclohexanediol and 1,2-hexanediol on percutaneous absorption and penetration of metronidazole (MTZ) was discovered. A complex formation between 1,4-cyclohexanediol and 1,2-hexanediol was proposed to be responsible for the observed effect. The objective of this study was to investigate the necessity of hydroxyl group and the ring structure in 1,4-cyclohexanediol on percutaneous absorption and penetration of MTZ. Eleven formulations were studied in an in vitro porcine skin model using glass vertical Frans Diffusion Cell. 1,4-Cyclohexanediol was changed into 1,4-cyclohexanedicarboxylic acid, trans (and cis)-1,2-cyclohexanediol and 1,6-hexanediol, respectively, to study if H-bonding or ring structure would influence the retardation effect. MTZ was applied at infinite dose (100 mg), which corresponded to 750 μg of MTZ. Based on modifier ratios (MR) calculated by the flux values, the retardation effect on percutaneous absorption and penetration of MTZ was found in the formulations containing 1,4-cyclohexanedicarboxylic acid or cis-1,2-cyclohexanediol (MR values were 0.47 for which only contains 1,4-cyclohexanedicarboxylic acid, 0.74 for the formulation containing both 1,4-cyclohexanedicarboxylic acid and 1,2-hexanediol, and 0.90 for the formulation containing cis-1,2-cyclohexanediol and 1,2-hexanediol, respectively). The results showed that the hydroxyl group and structure of 1,4-cyclohexanediol played a significant role in retardation effects and provided valuable insight on the mechanisms of retardation effect through structure-activity relationships.

Abstract  OBJECTIVE: This study was to investigate the topical skin targeting effects and mechanism of combination penetration modifiers of 1,2-hexanediol (or 1,2-heptanediol) and 1,4-cyclohexanediol on transdermal absorption of metronidazole (MTZ) in different skin models.

METHODS: Six formulations were applied to pig abdominal skin and pig ear skin models, respectively, and the results were compared with the previous data on hairless mouse skin worked out by our laboratory. Four parameters (flux, Tlag, Q24 and targeting ratio) were used to evaluate permeability and targeting effect in skin.

RESULTS: The combined penetration modifiers played a general role on decreasing permeability without reducing skin retention. The most significant skin permeability decrement to MTZ was pig abdominal skin (permeability decrement was ∼20% for hairless mouse skin, 60% for pig abdominal skin and 40% for pig ear skin, respectively) while the strongest skin targeting effect appeared in hairless mouse skin (targeting ratios were 1.79 for hairless mouse skin, 1.24 for pig abdominal skin and 1.05 for pig ear skin, respectively) under the role of penetration modifiers.

CONCLUSIONS: Thickness of stratum corneum (SC) was the major factor impact on skin targeting effect. Selection criteria of skin models also have been discussed in this study.