Hexyl Nicotinate Research Articles

Circadian dosing time dependency in the forearm skin penetration of methyl and hexyl nicotinate

The forearm skin penetration of hydrophilic methyl nicotinate (MN) and lipophilic hexyl nicotinate (HN) was assessed around the clock. The sixteen healthy women (median age: 22 years, weight: 57 kg and height: 162 cm) who volunteered for the study were synchronized with a diurnal activity from 07.00h (+/- 1h) to 23.00h (+/- 1h.30min) and a nocturnal rest before and during the 48h sojourn in airconditioned rooms (26 °C +/- 0.5 °C). Both HN (0.5% ethanol solution) and MN (5% ethanol solution) have a vasodilative effect on dermal vessels. The lag time (LT) between the delivery of a fixed volume (10 μl) of the agent at the skin surface and the beginning of the vasodilatation, detected with a laser-Doppler method, was used to quantify the penetration kinetics. Tests were performed every 4h, at fixed clock hours, over a span of a 40h. Two types of tests were done with each of the agents: fixed site (one site only) and shifted sites (10 different places). Both cosinor and ANOVA have been used for statistical analyses. The shortest LT (fastest penetration) was located around 04.00h. The longest LT (slowest penetration) occurred during the day with a single peak around 13.00h in three of the situations, or two peaks (HN with fixed site). A rather large rhythm amplitude (peak-to-trough difference larger than 50% of the 24h mean LT) was validated.

Barrier function parameters in various keratinization disorders: transepidermal water loss and vascular response to hexyl nicotinate

In this study, we characterized the stratum corneum barrier function in 39 patients with various keratinization disorders (autosomal dominant ichthyosis vulgaris [ADI] [n = 7], X-linked recessive ichthyosis [XRI] [n = 6], autosomal recessive congenital ichthyosis [CI] [n = 10], dyskeratosis follicularis [Darier's disease; DD] [n = 8], erythrokeratoderma variabilis [EKV] [n = 8]), and 21 healthy volunteers, using two non-invasive methods: transepidermal water loss (TEWL) measuring outward transport of water through the skin by evaporimetry, and the vascular response to hexyl nicotinate (HN) penetration into the skin as determined by laser-Doppler flowmetry. Significantly increased TEWL values were found on the volar forearm in all three forms of ichthyosis, compared with the healthy control group, with the highest TEWL values in the CI group. The penetration of HN on the volar forearm was accelerated in patients with ADI, XRI and CI, as indicated by a shorter lag time (t0) between HN application and initial vascular response. However, differentiation between CI and the other ichthyoses was not possible by this method. When using both methods in DD and EKV, no differences compared with the healthy controls could be detected on the volar forearm, where the skin was principally unaffected; only the measurements from the affected skin on alternative sites demonstrated significantly increased TEWL values. In ADI and CI, however, normal-appearing skin also showed impaired values. We conclude that both TEWL and the vascular response to penetration of HN are suitable methods to monitor the skin barrier function in keratinization disorders, and are helpful in discriminating between these disorders.

Skin barrier function in healthy volunteers as assessed by transepidermal water loss and vascular response to hexyl nicotinate: intra- and inter-individual variability

This study assesses the variability of two non-invasive methods of measuring stratum corneum barrier function in vivo. Transepidermal water loss (TEWL), and the vascular response to hexyl nicotinate (HN) penetration as determined by laser-Doppler flowmetry, were measured in a group of 21 healthy volunteers. Each time profile of the vascular response to HN penetration was analysed using the following parameters: the baseline cutaneous blood flow, the lag-time between application and initial response (t0), the time between application and maximum response (tmax), the maximum response, and the slope of the curve. TEWL measured on the left volar forearm showed a normal range of 3.9-7.6 g/m2h and a small inter-individual variability [coefficient of variation (CV) 19.4%]. TEWL values at three other forearm sites did not show differences of clinical importance compared with the left volar forearm. The parameters of the vascular response to HN penetration spanned a wider normal range than the TEWL values (CV between 33 and 52%). Repeat measurements after a 1-2 month interval showed highly reproducible individual TEWL values. The mean difference between first and second measurements was only 0.03 g/m2h; the relative difference 0.6%. The intra-individual reproducibility of t0 and tmax. for HN penetration was also high (relative differences of 2.8 and 3.1%, respectively). The other vascular response parameters were less reproducible (relative differences of 6.9-18.6%). We conclude that TEWL and selected parameters of HN penetration, as non-invasive tests of the stratum corneum barrier function, yield reproducible results and are hence useful for investigations assessing the skin barrier function in various disorders.

Mediators of increased blood flow in porcine skin

Nicotinates and benzalkonium chloride (B.Cl) cause inflammatory changes in human skin, thought to be dependent upon prostaglandin formation. This study has examined the effects of hexyl-nicotinate (HN) and B.Cl on blood flow in porcine skin. The role of prostaglandins and interleukin (IL)-1 in the blood flow response has been investigated. Blood flow was increased by both HN and B.Cl, the response to B.Cl being more protracted. Cyclooxygenase inhibitor pretreatment reduced these responses. IL-1-like biological activity was identified in normal porcine epidermis and the amounts recovered from inflamed skin were similar. Thus prostaglandin formation in HN or B.Cl-induced inflammation, if IL-1 dependent, is not associated with the loss of significant amounts of the cytokine from the epidermis.

In vivo evaluation in man by two noninvasive methods of the stratum corneum barrier function after physical and chemical modifications

Synopsis This study investigated the effect of different treatments on skin permeability, in vivo in man, by two noninvasive methods: transepidermal water loss (TEWL) determination measured with an evaporimeter, and Laser Doppler velocimetry (LDV) to measure the lag time before the vasodilatation induced by application of methyl and hexyl nicotinates. Different treatments were performed on forearms of volunteers: 1. removal of the stratum corneum by stripping, 2. occlusion and hydration of the stratum corneum, 3. application of three surfactants in aqueous solution (Tween 60, sodium dodecyl sulphate and cetyl trimethylammonium bromide). Increase in TEWL and decrease in lag time before the vasodilating effects of nicotinates measured with LDV after all treatments confirmed the modifications in skin permeability. The variations observed were more or less significant depending on the treatment, the investigative method, and the molecule used for the penetration study. With methyl (hydrophilic) nicotinate, the more TEWL increased, the more lag time decreased. A significant decrease in lag time after hexyl (lipophilic) nicotinate application was observed when there was a very high increase in TEWL. The lipophilic nature of the stratum corneum barrier was confirmed in vivo. Use of these two complementary methods, TEWL and LDV, allows the evaluation in vivo of the effect of different treatments on skin permeability in man.

In vitro release of nicotinic acid alkyl esters from poloxamer vehicles

Poloxamers are poly(oxyethylene)poly(oxypropylene) block copolymers. Aqueuous solutions of these polyols show reverse thermal gelation, low toxicity and good solubilization capacity. As such, they appear to be useful as components of topical drug delivery systems. The objectives of this study were to systematically investigate the effects of (1) poloxamer lipophilicity, (2) poloxamer concentration and (3) temperature on the in vitro release rate of drug from formulations containing hexyl nicotinate. Studies were conducted in a membrane-less model using isopropylmyristate as the receptor phase; for some studies, a series of n-alkyl nicotinates (methyl, ethyl, butyl and hexyl) were used as model compounds. Results indicated that the diffusion coefficients decreased with increasing poloxamer concentration and increased with increasing temperature. Results with different poloxamers indicated that the release rate increased with increasing poloxamer hydrophilic-lipophilic balance (HLB). The order of release rate for alkyl nicotinates was methyl > ethyl > butyl > hexyl. The markedly lower release rate for hexyl nicotinate was explained by a stronger interaction between drug and poloxamer.

Racial differences in pharmacodynamic response to nicotinates in vivo in human skin: black and white.

This study evaluated the vasodilation induced in young whites and blacks by topical application of two nicotinates, methylnicotinate (MN) and hexylnicotinate (HN) at the same concentration and in the same vehicle. To assess the influence of skin surface lipids and water content of the stratum corneum on the penetration of the substances, the drugs were applied on the back, on untreated skin and pre-occluded and pre-delipidized sites. Skin blood flow was monitored with laser Doppler velocimetry. The initial response recorded at 15 min (IR), the peak response (PR) and the area under the curve (AUC) were used to characterize the pharmacodynamic response. Statistically significant racial differences in the penetration of nicotinates were detected for the area under the response curve in the untreated and occluded sites, for the initial response and peak response in the pre-occluded site. Occlusion increased (even though not significantly) penetration, except for blacks in the methylnicotinate experiment. Delipidization elicited significantly lower responses for the IR and PR in the MN study, rendering the penetration similar in the two groups. No major differences were recorded between the two nicotinates. The effect of delipidization was most noticeable in blacks in the MN study. We suggest that there are racial (blacks vs. whites) differences in percutaneous penetration of nicotinates, with decreased levels in black skin recorded in all sites investigated.

(2) A double-blind placebo-controlled trial of topical hexyl nicotinate lotion in primary Raynaud's phenomenon

(2) A double-blind placebo-controlled trial of topical hexyl nicotinate lotion in primary Raynaud's phenomenon

The effects of topically applied hexyl nicotinate lotion on the cutaneous blood flow in patients with Raynaud's phenomenon.

The effect of the epicutaneous application of 0.1% and 1.0% hexyl nicotinate lotion on upper limb skin blood flow was investigated in 25 patients with Raynaud's phenomenon (RP) and five healthy volunteers. Assessments were made using laser Doppler velocimetry. The 0.1% lotion induced an increase in cutaneous blood flow in both controls and patients when applied at different sites on the upper limb. Increased cutaneous blood flow occurred more often when the lotion was applied to the forearm than to the fingers. A greater increase in blood flow and an increased percentage of positive responses was elicited with the 1.0% hexyl nicotinate lotion. Hexyl nicotinate lotion may be of value in the topical treatment of RP.

Surfactant effects in topical drug availability

The effects of two surfactants, sodium lauryl sulphate (SLS) and Brij 36T on the thermodynamic activity of methyl nicotinate (MN) and hexyl nicotinate (HN) in aqueous gels have been investigated. In vivo, the permeability of the skin has been assessed by measuring the time of onset of the erythema which is induced by these nicotinate esters. Times of onset of erythema caused by gels containing SLS correlate with the in vitro release rates. This suggests that over this time interval (less than 15 min) SLS does not affect the barrier function of the skin. Results obtained for Brij 36T-containing gels, however, imply that this surfactant does increase skin permeability. That SLS is normally considered to be the more powerful penetration enhancer yet has no observable effect indicates that the two surfactants exert their effect in different ways.

Alterations in scalp blood flow after the epicutaneous application of 3% minoxidil and 0.1% hexyl nicotinate in alopecia

Alterations in scalp blood flow after the epicutaneous application of 3% minoxidil and 0.1% hexyl nicotinate in alopecia

Laser velocimetry for the non-invasive assessment of the percutaneous absorption of nicotinates

The use of laser velocimetry for the non-invasive assessment of the effects of topically applied solvents and a model vasodilator, hexyl nicotinate, is reported. The importance of excluding solvent effects on the recorded response is emphasised and the value of the technique for predicting the effects of formulation changes is illustrated.

Pharmacodynamic Measurement of Percutaneous Penetration Enhancement In Vivo

Enhanced skin penetration of hexyl nicotinate was measured in human subjects using laser Doppler velocimetry (LDV). The local pharmacodynamic response (vasodilatation) to hexyl nicotinate permitted the kinetics and extent of penetration to be evaluated following topical application of 10mM drug in a 60:40v/v propylene glycol: isopropyl alcohol vehicle. Prior to hexyl nicotinate administration, the application site was either untreated (control) or subjected to one of four 30-min pretreatments: (a) occlusion with a polypropylene chamber; (b) occlusion (as in a) in the presence of 0.3mL of the vehicle; (c) occlusion (as in a) in the presence of 0.3mL of the vehicle containing 25% 2-pyrrolidone; and (d) occlusion (as in a) in the presence of 0.3mL of the vehicle containing 25% laurocapram (1-dodecylhexahydro-2H-azepin-2-one). The time-course and magnitude of the LDV response were characterized by the onset of action, time to peak, peak height, and area under the curve (AUC). The onset of action and time to peak were significantly shortened, and the peak height and AUC significantly increased with pretreatments a–d. For example, time to peak values were 35 ± 4, 29 ± 3, 22 ± 5, 19 ± 4, and 17 ± 4min for control and pretreatments a-d, respectively (n=8). Pretreatments with vehicle, vehicle plus 2-pyrrolidone, and vehicle plus laurocapram did not cause LDV-detectable alterations in skin blood flow. The data support, therefore, a novel, simple, noninvasive, and objective demonstration of enhanced skin penetration of hexyl nicotinate in humans.

The influence of urea on percutaneous absorption.

The release characteristics of aqueous and oily creams (BP) containing urea up to concentrations of 10% have been studied. The results show that the urea has little influence on the ability of the formulation to release its active ingredient, in this case, hexyl nicotinate. The preparations were then assessed in an in vivo experiment by measuring the time of onset of erythema induced by the hexyl nicotinate. The urea influenced the time of onset of erythema, and a mechanism for its action is proposed.