Influence of Sucrose Esters on the In Vivo Percutaneous Penetration of Octyl Methoxycinnamate Formulated in Nanocapsules,Nanoemulsion, and Emulsion

ABSTRACT

The influence of sucrose laureate and sucrose oleate on the in vivo percutaneous penetration of octyl methoxycinnamate (OMC) formulated in i) colloidal suspensions (nano-emulsions and nanocapsules), and ii) conventional o/w emulsions was evaluated. The results showed that nano-emulsions formulated with sucrose laureate exhibited the highest penetration in the stratum corneum compared to the other formulations. A two-fold increase in OMC skin deposition was observed with the nano-emulsion containing sucrose laureate when compared to the control. The data obtained suggest that the total amount of OMC detected in the stratum corneum and the penetration depth are strongly dependent upon the formulation's nature, the particle size, and the type of enhancer.     

Genetic Algorithm for Opto-thermal Skin Hydration Depth Profiling Measurements

Stratum corneum is the outermost skin layer, and the water content in stratum corneum plays a key role in skin cosmetic properties as well as skin barrier functions. However, to measure the water content, especially the water concentration depth profile, within stratum corneum is very difficult. Opto-thermal emission radiometry, or OTTER, is a promising technique that can be used for such measurements. In this paper, a study on stratum corneum hydration depth profiling by using a genetic algorithm (GA) is presented. The pros and cons of a GA compared against other inverse algorithms such as neural networks, maximum entropy, conjugate gradient, and singular value decomposition will be discussed first. Then, it will be shown how to use existing knowledge to optimize a GA for analyzing the opto-thermal signals. Finally, these latest GA results on hydration depth profiling of stratum corneum under different conditions, as well as on the penetration profiles of externally applied solvents, will be shown.     

Design and evaluation of a self-adhesive naproxen-loaded film prepared from a nanoparticle dispersion

Naproxen-loaded nanoparticles were used to prepare, in a one-step process, unilaminar films of Eudragit E-100 (EE-100), avoiding the use of organic solvents and assuring the homogeneity and molecular dispersion of the drug. Nanoparticle films (NP-F) and conventional films (CV-F, prepared by casting of methanolic solutions onto a Teflon disc) were assayed by their mechanical properties, skin adhesivity, and calorimetric studies to compare their behavior. Different proportions of plasticizer (triacetin) were included to evaluate the quality of the films. Film characterization included in vitro drug release studies through a cellulose membrane using Franz-type cells, and in vivo stratum corneum penetration experiments by the tape stripping technique. The results showed that NP-F were semi-transparent to transparent, suggesting a good compatibility between naproxen and EE-100. Differential calorimetric studies (DSC) confirmed a molecular dispersion of naproxen in the EE-100 matrix. Taking into account the mechanical properties of the films, a 20% triacetin concentration can be considered as optimal for both types of films. The in vitro release data obtained from both systems (NP-F and CV-F) followed the Higuchi's model for matrix systems, with the Fickian diffusion (t(0.5)) being the main release mechanism. Concerning the in vivo penetration studies, no statistical differences were found for the penetrated amount of naproxen across the stratum corneum and the depth of penetration for the two films and between the three contact times (2, 4, and 6 h). The films formulated from nanoparticle dispersions (NP-F) were shown to be effective for the transdermal administration of naproxen, and can be considered as an interesting alternative for the preparation of films with several technological advantages.     

Enhancing Effects of Fatty Acids on Piroxicam Permeation Through Rat Skins

To increase the skin permeation of piroxicam from the Poloxamer 407 gel, fatty acid was added as a penetration enhancer to the Poloxamer 407 gel containing 1% piroxicam. The enhancing effects of the enhancer on the skin permeation of piroxicam were evaluated using Franz diffusion cells fitted with intact excised rat skins. To elucidate the modes of the action of enhancers, thermal analysis and histological examinations were conducted. Among fatty acids tested, linoleic acid showed the highest enhancing effects, with an enhancement factor (EF) of 1.76. From the thermal analysis results, fatty acids have fluidizing effects on the stratum corneum. The skin pretreated with the Poloxamer 407 gels containing piroxicam including linoleic acid showed a loosely layered stratum corneum and wide intercellular space.     

Enhancing effects of fatty acids on piroxicam permeation through rat skins

To increase the skin permeation of piroxicam from the Poloxamer 407 gel, fatty acid was added as a penetration enhancer to the Poloxamer 407 gel containing 1% piroxicam. The enhancing effects of the enhancer on the skin permeation of piroxicam were evaluated using Franz diffusion cells fitted with intact excised rat skins. To elucidate the modes of the action of enhancers, thermal analysis and histological examinations were conducted. Among fatty acids tested, linoleic acid showed the highest enhancing effects, with an enhancement factor (EF) of 1.76. From the thermal analysis results, fatty acids have fluidizing effects on the stratum corneum. The skin pretreated with the Poloxamer 407 gels containing piroxicam including linoleic acid showed a loosely layered stratum corneum and wide intercellular space.     

Nanovesicular carrier-mediated transdermal delivery of tadalafil: i- formulation and physicsochemical characterization

The limited permeability of stratum corneum, the main skin barrier, towards pharmaceutical active ingredients represents the main obstacle encounter the transdermal drug delivery system. In the current study, penetration enhancer-containing nanoliposomes, that is, penetrosomes were formulated incorporating tadalafil to enhance its transdermal permeability. Hydration-sonication method was used to prepared penetrosomes bearing tadalafil. The prepared nanocarriers were characterized in terms of vesicles shape and surface morphology, size and size distribution, zeta potential, entrapment efficiency, and elasticity. Results pointed to that penetrosomes were spherical in shape with a unilamellar-closed structure in the nanometric narrow size range proved by their law span index. Penetrosomes formulations elaborated deformable vesicles more than the conventional liposomes, with the Penetrosomes-based Labrasol® being the most deformable formulation. Penetrosomes-ultraelastic nanoliposomes represent an attractive vehicle for transdermal delivery of tadalafil to treat erectile dysfunction.     

The effect of skin penetration enhancers on the transdermal delivery of pyridostigmine bromide

In vitro skin penetration studies of pyridostigmine bromide through human cadaver skin were conducted using a diffusion cell with constant hydrodynamic conditions. The results indicate that the drug penetrates poorly through human cadaver skin. However, skin penetration enhancers such as sodium oleate, sodium lauryl sulfate, n-decyl methyl sulfoxide, and N,N-dimethyldodecylamine-N-oxide substantially enhanced the permeability coefficient of the drug through human cadaver skin. The penetration enhancement of pyridostigmine bromide could be due to increased partitioning of the drug in the skin or due to the decreased tortuosity of the porous pathway in the stratum corneum.     

Photoacoustic Analysis of the Penetration Kinetics of Cordia verbenacea DC in Human Skin

Phonophoresis consists of the utilization of ultrasound radiation associated to pharmacological agents in order to enhance transdermal penetration of applied drugs. It is a widely employed resource in physiotherapy practice, normally associated with anti-inflammatory drugs, such as Acheflan. This drug was developed in Brazil from the essential oil of Cordia verbenacea DC, a native plant of the Brazilian southern coast. In previous studies, the photoacoustic (PA) technique proved effective in the study of the penetration kinetics of topically applied products and in the evaluation of drug delivery after phonophoresis application. The present work aimed to evaluate the penetration kinetics of Acheflan in human skin, employing in vivo PA measurements after massage application or phonophoresis application. Ten volunteers (aged between 18 and 30?years) took part in the study. Time evolution of the PA signal was fitted to a Boltzmann curve, S-shaped. After statistical analysis, PA measurements have shown drug penetration for both application forms, but drug delivery was more evident after phonophoresis application, with a characteristic penetration time of less than 15?min for the stratum corneum.     

Percutaneous Absorption Enhancement by Nonionic Surfactants

The influence of nonionic surfactants (polysorbates) on hydrocortisone penetration through hairless mouse skin in vitro has been determined. Permeation was quite slow from purely aqueous media containing surfactants following finite dose application. However, if the vehicle contained high propylene glycol concentrations (40% or more), inclusion of a surfactant increased permeation rate significantly. Similar effects were noted following application of a large donor volume (infinite dose). Synergism was attributed to enhancement of surfactant absorption by the stratum corneum leading to changes in skin barrier resistance. With vehicles containing a surfactant, penetration was higher after finite dose application due to compositional changes within the vehicle.     

Percutaneous Absorption Enhancement by Nonionic Surfactants

The influence of nonionic surfactants (polysorbates) on hydrocortisone penetration through hairless mouse skin in vitro has been determined. Permeation was quite slow from purely aqueous media containing surfactants following finite dose application. However, if the vehicle contained high propylene glycol concentrations (40% or more), inclusion of a surfactant increased permeation rate significantly. Similar effects were noted following application of a large donor volume (infinite dose). Synergism was attributed to enhancement of surfactant absorption by the stratum corneum leading to changes in skin barrier resistance. With vehicles containing a surfactant, penetration was higher after finite dose application due to compositional changes within the vehicle.     

Percutaneous Absorption Enhancement by Nonionic Surfactants

The influence of nonionic surfactants (polysorbates) on hydrocortisone penetration through hairless mouse skin in vitro has been determined. Permeation was quite slow from purely aqueous media containing surfactants following finite dose application. However, if the vehicle contained high propylene glycol concentrations (40% or more), inclusion of a surfactant increased permeation rate significantly. Similar effects were noted following application of a large donor volume (infinite dose). Synergism was attributed to enhancement of surfactant absorption by the stratum corneum leading to changes in skin barrier resistance. With vehicles containing a surfactant, penetration was higher after finite dose application due to compositional changes within the vehicle.     

The effect of skin penetration enhancers on the transdermal delivery of pyridostigmine bromide

Abstract

In vitro skin penetration studies of pyridostigmine bromide through human cadaver skin were conducted using a diffusion cell with constant hydrodynamic conditions. The results indicate that the drug penetrates poorly through human cadaver skin. However, skin penetration enhancers such as sodium oleate, sodium lauryl sulfate, n-decyl methyl sulfoxide, and N,N-dimethyldodecylamine-N-oxide substantially enhanced the permeability coefficient of the drug through human cadaver skin. The penetration enhancement of pyridostigmine bromide could be due to increased partitioning of the drug in the skin or due to the decreased tortuosity of the porous pathway in the stratum corneum.     

Long-Tern Skin Permeation Kinetics of Estradiol: (II) Kinetics of Skin Uptake, Binding, and Metabolism

The in vitro skin permeation system developed in this laboratory was utilized to investigate the kinetics of uptake, binding, and metabolism of estradiol, the female hormone, by the hairless mouse skin. The kinetics of uptake of estradiol and its subsequent metabolism to estrone by the skin were examined by exposing one side of a freshly excised skin to an estradiol solution, while the other side of the skin was protected with an impermeable aluminum foil.

The results concluded that the stratum corneum plays a rate-limiting role in the uptake and binding of estradiol and its metabolism to estrone by the skin. The mechanisms of the uptake and binding of estradiol to whole skin tissue (with stratum corneum) showed a sex dependence, with the rate higher in the female than in the male mouse. On the other hand, no sex-dependent difference was observed in the mechanism and rate of metabolism to estrone.

After stripping off the rate-limiting stratum corneum, the mechanisms of the uptake, binding and metabolism of estradiol all became sex dependent with identical rates observed between male and female mice in the initial 14 hrs of the experiment; Between 14 to 21 hrs, the rates increased substantially with the female skin, but not with the male skin. The increase in the rate of uptake of estradiol by the female skin was related primarily to the increased rate of metabolism of estradiol to estrone.     

Long-Tern Skin Permeation Kinetics of Estradiol: (II) Kinetics of Skin Uptake,Binding, and Metabolism

Abstract

The in vitro skin permeation system developed in this laboratory was utilized to investigate the kinetics of uptake, binding, and metabolism of estradiol, the female hormone, by the hairless mouse skin. The kinetics of uptake of estradiol and its subsequent metabolism to estrone by the skin were examined by exposing one side of a freshly excised skin to an estradiol solution, while the other side of the skin was protected with an impermeable aluminum foil.

The results concluded that the stratum corneum plays a rate-limiting role in the uptake and binding of estradiol and its metabolism to estrone by the skin. The mechanisms of the uptake and binding of estradiol to whole skin tissue (with stratum corneum) showed a sex dependence, with the rate higher in the female than in the male mouse. On the other hand, no sex-dependent difference was observed in the mechanism and rate of metabolism to estrone.

After stripping off the rate-limiting stratum corneum, the mechanisms of the uptake, binding and metabolism of estradiol all became sex dependent with identical rates observed between male and female mice in the initial 14 hrs of the experiment; Between 14 to 21 hrs, the rates increased substantially with the female skin, but not with the male skin. The increase in the rate of uptake of estradiol by the female skin was related primarily to the increased rate of metabolism of estradiol to estrone.     

Design,preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies

The study highlights the significance of co-application of bioactive components into liposomal gel formulations and their comparison to azithromycin for treatment of Acne. A Design of Experiments (DoE) approach was utilized to obtain optimized liposomal formulation encapsulating curcumin, with size and zeta potential of ～100?nm and ～14?mV, respectively, characterized by DLS, HR-TEM, FESEM, and AFM. The curcumin liposomal dispersion depicted excellent stability over the period of 60?days, which was further converted in gel form using Carbopol. Pharmacokinetics of curcumin-loaded liposomal gel showed that T_max for curcumin was achieved within 1?h of post application in both stratum corneum and skin, indicating quick penetration of nano-sized liposomes. Stratum corneum depicted C_max of 688.3?ng/mL and AUC_0-t of 5857.5?h?×?ng/mL, while the skin samples displayed C_max of 203.3?ng/gm and AUC_0-t of 2938.1?h?×?ng/gm. Lauric acid and azithromycin liposomal gel formulations were prepared as per the optimum parameters obtained by DoE. In antibacterial activity using agar diffusion assay, lauric acid gel formulation revealed ～1.5 fold improved antibacterial effect than curcumin gel formulation. Interestingly, their co-application (1:1) exhibited significantly enhanced antibacterial effect against both macrolide-sensitive (1.81 versus 1.25 folds) and resistant strains of P. acnes (2.93 versus 1.22 folds) than their individual counterparts. The in vivo studies in rat ear model displayed a ～2 fold reduction in comedones count and cytokines (TNF-α and IL-1β) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group.     

Stratum Corneum Hydration; Consequences for Skin Permeation Experiments

Abstract

Experimental approaches to the study of drug diffusion in skin in vitro generally fail to take due account of the effects of hydration on the stratum corneum. Attention is therefore drawn to neglect of this aspect of the problem in a recent article which describes an otherwise very sophisticated apparatus for the study of diffusion phenomena.

Chien and Valia¹, have recently described a carefully designed experimental apparatus for long term permeation studies of skin. Most experimental problems are successfully controlled by this technique, which will undoubtedly prove valuable for membrane permeation experiments in general. However, the approach as described neglects an aspect so fundamental to the barrier property of skin in particular, that re-emphasis of the point at issue seems eminently desirable.

The major barrier to diffusion in intact skin is the stratum corneum. As a working hypothesis, the mechanism by which the stratum corneum exerts its barrier effect appears to consist of two components. Firstly, the movement of foreign molecules through the stratum corneum is slow; that is, the activation energy for the diffusion process is generally high. Secondly, for some molecules at least, a fraction of the diffusing material is bound within the stratum corneum, and is effectively immobilised. This seems to be true for steroids, as one example, and was first reported by Vickers². The phenomenon was discussed in terms of the existence of a reservoir for such molecules in the stratum corneum, and has subsequently been demonstrated by in vitro studies³.

The point at issue in the present discussion is that it has long been known that the overall barrier effect of the skin is markedly dependent on the degree of stratum corneum hydration⁴. It has also been shown that both components of the barrier mechanism are separately dependent on the hydration level. The reservoir effect, for example, can be reduced by occlusion of the skin in vivo. This was elegantly demonstrated by Vickers in human volunteers, by re-occluding sites previously treated with a corticosteroid, after the initial corticosteroid induced blanching response had disappeared². Skin blanching was again observed shortly thereafter, which suggests that a fraction of the applied steroid had been retained within the stratum corneum, and that the increase in stratum corneum hydration resulting from the occlusion had released this material from the reservoir, allowing it once again to exhibit its pharmacological effect. Using an in vitro technique, a preliminary attempt has recently been made to assess the change in enthalpy associated with displacement of a representative steroid from stratum corneum reservoir sites by water in this way. A value of -60+11 kJ mole^-1 was obtained⁵ which is consistent with a chemisorption process. Likewise it has been shown that the diffusion constant for the diffusing (non-reservoir bound) fraction is also appreciably increased by stratum corneum hydration⁶.

Any experimental design such as that described by Chien and Valia¹, in which the skin has both faces in contact with aqueous donor and receptor solutions, will inevitably cause the skin sample to become extensively hydrated. Further, the degree of hydration attained will almost certainly be in excess of that achievable in vivo by skin occlusion, and the measurements will therefore relate only to skin under unphysiologically high levels of hydration, where the barrier property is impaired. Such measurements must therefore be of very dubious value. What is clearly required is an experimental situation where the degree of stratum corneum hydration is controllable at least over physiologically realistic limits. Such a situation can, in fact, be established experimentally, and the appropriate mathematical analysis for diffusion under such circumstances has already been described⁷.     

Skin permeation of lidocaine from crystal suspended oily formulations

In vitro permeation of lidocaine (lidocaine base, LID) through excised rat skin was investigated using several LID-suspended oily formulations. The first skin permeation of LID from an LID-suspended oily solution such as liquid paraffin (LP), isopropyl myristate (IPM), polyoxyethylene (2) oleylether (BO-2), and diethyl sebacate (DES) was evaluated and compared with that from polyethylene glycol 400 (PEG400) solution, a hydrophilic base. The obtained permeation rate of LID, Japp, from PEG400, LP, IPM, BO-2, and DES was in the order of DES>BO-2=IPM>LP>PEG400, and increased with LID solubility in the oily solvents, although LID crystals were dispersed in all solvents. Subsequently, oily formulations that consisted of different ratios of the first oily solvent (IPM, BO-2, or DES) (each 0-20%), the second oily solvent (LP) and an oily mixture of microcrystalline wax/white petrolatum/paraffin (1/5/4) were evaluated. BO-2 groups at a concentration of 5% and 10% had the highest Japp among the oily formulations, although a higher BO-2 resulted in lower skin permeation. In addition, pretreatment with BO-2 increased the skin permeation of LID. These results suggest that the penetration enhancing effect by the system may be related to the skin penetration of BO-2 itself. Finally, mathematical analysis was done to evaluate the effect of BO-2, and it was shown that BO-2 improved the LID solubility in stratum corneum lipids to efficiently enhance the LID permeation through skin.     

Percutaneous penetration of uranium in rats after a contamination on intact or wounded skin

The aim of this work is to assess in vivo in a hairless rat model, the percutaneous diffusion of uranium through intact or wounded rat skin. Six types of wounds were simulated by excoriation and burns with 10 N HF, 2, 5 and 14 N HNO3 and 10 N NaOH on anaesthetised hairless rats. Percutaneous penetration through wounded skin towards blood and subsequent urinary excretion of uranium was followed in vivo during 24 h. The influence of the physicochemical form (solution or powder) of uranyl nitrate (UN) on its percutaneous diffusion was also investigated. UN, even as a powder, can diffuse through intact skin. The presence of uranium in blood is more persistent and its urinary elimination is slower after an HF burn than after an HNO3 burn. Excoriation increases dramatically percutaneous absorption of UN. Thus, percutaneous diffusion of UN is largely dependent on skin barrier integrity with a particular importance of stratum corneum.     

An in vivo confocal Raman study of the delivery of trans retinol to the skin

The purpose of this study is to monitor in vivo the delivery of trans-retinol into human skin. Delivery to real systems, such as skin, can be extremely difficult to execute and is problematic to confirm and measure. So far, methods for studying the delivery of compounds through the skin are mostly ex vivo and so inherently influence the skin and may not translate directly to the in vivo situation. Raman spectroscopy is uniquely placed to be able to measure biological processes in vivo, and this paper shows that the trans-retinol penetration into the skin can successfully be measured in vivo using this technique. This study measured the volar forearm of volunteers treated with 0.3% trans-retinol in propylene glycol (PG)/ethanol and 0.3% trans-retinol in caprylic/capric acid triglyceride (MYRITOL318), an oil found in skin creams. Solutions were applied and then confocal Raman depth profiles were obtained of the stratum corneum (SC) and into the viable epidermis (VE) up to 10 hours after treatment. Remarkable differences between a penetrating and a nonpenetrating solution can clearly be observed. Treating with trans-retinol in PG/ethanol results in trans-retinol penetrating through the SC and into the VE. Its penetration was also observed to be highly correlated with the depth of penetration of the PG, which is well known as an efficient penetration enhancer. In contrast, while treating with trans-retinol in MYRITOL318, trans-retinol hardly penetrates at all. For the first time, the penetration of trans-retinol has been monitored directly after application of solutions, in vivo without skin excision. Here, the effect of two different solutions on the delivery of trans-retinol into the skin was measured very effectively in vivo by Raman spectroscopy.     

一种用于药物释控系统的微针阵列及其制作方法的研究

 通过皮肤输送药物最大的障碍是皮肤最外层的角质层．传统的静脉注射用针只有刺透皮肤深入到深层组织内部,才能有效地输送药物,这容易引起感染和疼痛,给患者造成很大的不适．介绍了一种采用硅微加工技术制作的微针,它长度适中,既能穿透皮肤的角质层,又刺激不到深层组织的神经,实现无痛注射的目的．其加工工艺是采用硅的HNA(硝酸+氢氟酸+乙酸)腐蚀系统,是一种硅的各项同性的湿法腐蚀方法．